WO2024046407A1 - 杂芳基氧基萘类化合物的用途 - Google Patents

杂芳基氧基萘类化合物的用途 Download PDF

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WO2024046407A1
WO2024046407A1 PCT/CN2023/116023 CN2023116023W WO2024046407A1 WO 2024046407 A1 WO2024046407 A1 WO 2024046407A1 CN 2023116023 W CN2023116023 W CN 2023116023W WO 2024046407 A1 WO2024046407 A1 WO 2024046407A1
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tumor
drugs
cell carcinoma
squamous cell
compound
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PCT/CN2023/116023
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English (en)
French (fr)
Inventor
刘晓雯
徐雯
王娟
张翱
耿美玉
宋子兰
艾菁
杨汉煜
张阳
郝红茹
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上海润石医药科技有限公司
中国科学院上海药物研究所
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Priority to CN202380010390.8A priority Critical patent/CN117956999A/zh
Publication of WO2024046407A1 publication Critical patent/WO2024046407A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicine, and specifically relates to the use of multi-target protein kinase inhibitors in the preparation of drugs for the treatment and/or prevention of tumors, especially in the preparation of drugs for the treatment of squamous cell carcinoma, esophageal cancer and/or gastroesophageal junction. Use in cancer drugs.
  • Squamous cell carcinoma also known as epidermoid carcinoma, includes different types of cancer caused by squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the lining of the respiratory and digestive tracts, including, for example, the skin, head and neck, digestive tract (e.g., esophagus), and respiratory tract (e.g., lungs), depending on the location of the body. of squamous cell carcinoma.
  • Esophageal cancer (or esophageal cancer) is one of the most common malignant tumors worldwide, ranking 8th and 6th in terms of cancer incidence and death respectively. Moreover, compared with the general population, the risk of multiple primary malignant tumors in the esophageal cancer population is increased, with the incidence rate being as high as 9.5% to 21.9%. Histologically, there are two main types of esophageal cancer, namely squamous cell carcinoma (esophageal squamous cell carcinoma) and adenocarcinoma (esophageal adenocarcinoma).
  • squamous cell carcinoma esophageal squamous cell carcinoma
  • adenocarcinoma esophageal adenocarcinoma
  • the first-line treatment for advanced esophageal cancer is chemotherapy combined with immunotherapy and combined chemotherapy.
  • levels I recommendations are mainly single-agent chemotherapy and single-agent immunotherapy.
  • Targeted drugs are approved for marketing.
  • Radiotherapy and chemotherapy which are common in the treatment of esophageal cancer, while improving the survival rate of patients, may increase the number of related primary malignant tumors. risk of occurrence.
  • CN108699030A discloses compound A (corresponding to compound S10), which is a compound with fibroblast growth factor receptor (FGFR) and vascular endothelial cell growth factor receptor (KDR or VEGFR2) inhibitory activity.
  • FGFR fibroblast growth factor receptor
  • KDR vascular endothelial cell growth factor receptor
  • the technical problem to be solved by this application is to provide the use of Compound A or a pharmaceutically acceptable salt thereof for preparing drugs for treating tumors, especially squamous cell carcinoma, digestive tract squamous carcinoma, esophageal cancer or gastroesophageal junction cancer.
  • the application provides the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors, wherein the tumor is esophageal cancer or gastroesophageal junction cancer,
  • the gastroesophageal junction cancer is gastroesophageal junction squamous cell carcinoma or gastroesophageal junction adenocarcinoma; preferably, it is gastroesophageal junction squamous cell carcinoma.
  • the esophageal cancer is esophageal squamous cell carcinoma or esophageal adenocarcinoma; preferably, it is esophageal squamous cell carcinoma.
  • the tumor is a tumor associated with gene abnormalities and/or protein expression abnormalities of FGFR and/or VEGFR.
  • the tumor is accompanied by gene abnormalities and/or protein expression abnormalities of one, two or three of FGFR, VEGFR, colony-stimulating factor 1 receptor (CSF1R) of tumors.
  • the tumor is a tumor with one, two or three gene mutations among FGFR, VEGFR and CSF1R.
  • the tumor is a locally advanced tumor or a metastatic tumor; preferably, it is an unresectable locally advanced tumor or an unresectable metastatic tumor.
  • the tumor is a tumor that has failed prior treatment.
  • the tumor is a tumor that has failed systemic drug treatment.
  • the tumor is a tumor that has failed first-line treatment.
  • the tumor is a tumor that has failed second-line treatment.
  • the tumor is a tumor that has failed subsequent line therapy.
  • the tumor is immunotherapy drugs, chemotherapy drugs, radiotherapy, biological therapy, traditional Chinese medicine Tumors that have failed one, two, three or more treatments with small molecule targeted drugs.
  • 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 the application, the tumor is a tumor that has failed treatment with radiotherapy and immunotherapeutic drugs. In some embodiments of the first aspect of the application, the tumor is a tumor that has failed treatment with radiotherapy and chemotherapeutic drugs. In some embodiments of the first aspect of the application, the tumor is a tumor that has failed treatment with chemotherapy drugs and immunotherapy drugs. In some embodiments of the first aspect of the application, the tumor is a tumor that has failed treatment with chemotherapy drugs, immunotherapy drugs and radiotherapy.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma accompanied by abnormal gene or protein expression of FGFR and/or VEGFR.
  • the esophageal squamous cell carcinoma is associated with one, two or three gene abnormalities and/or proteins of FGFR, VEGFR, and colony-stimulating factor 1 receptor (CSF1R). Esophageal squamous cell carcinoma with abnormal expression.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma with one, two or three gene mutations among FGFR, VEGFR and CSF1R.
  • the esophageal squamous cell carcinoma is locally advanced esophageal squamous cell carcinoma or metastatic (eg, stage IV) esophageal squamous cell carcinoma; preferably unresectable locally advanced esophageal squamous cell carcinoma or unresectable metastasis Esophageal squamous cell carcinoma.
  • the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed previous treatment.
  • the esophageal squamous cell carcinoma is esophageal squamous cell carcinoma that has failed systemic drug treatment.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed first-line treatment.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed second-line treatment.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed subsequent line treatment.
  • the esophageal squamous cell carcinoma is one, two, three or more of immunotherapy drugs, chemotherapy drugs, radiotherapy, biological therapy, traditional Chinese medicine treatment, and small molecule targeted drugs. Esophageal squamous cell carcinoma that has failed multiple treatments.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed treatment with radiotherapy, immunotherapy drugs or chemotherapy drugs.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed treatment with radiotherapy and immunotherapy drugs.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed treatment with radiotherapy and chemotherapy drugs.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed treatment with chemotherapy drugs and immunotherapy drugs.
  • the esophageal squamous cell carcinoma is an esophageal squamous cell carcinoma that has failed treatment with chemotherapy drugs, immunotherapy and radiotherapy.
  • the aforementioned chemotherapeutic drugs are selected from the group consisting of cytotoxic drugs, antimetabolite drugs, antibiotic drugs, alkaloid drugs, DNA topoisomerase inhibitor chemotherapeutic drugs, and anti-microtubule drugs.
  • Chemotherapy drugs, platinum chemotherapy drugs and hormone drugs preferably, the aforementioned chemotherapy drugs are selected from the group consisting of antimetabolite drugs, alkaloid drugs, DNA topoisomerase inhibitor chemotherapy drugs, anti-microtubule chemotherapy drugs and platinum drugs. Chemotherapy-like drugs.
  • the aforementioned chemotherapy drugs are selected from taxane drugs, platinum drugs, fluorouracil drugs or DNA topoisomerase inhibitor chemotherapy drugs.
  • the taxane drug is selected from paclitaxel, docetaxel or cabazitaxel; preferably paclitaxel.
  • the DNA topoisomerase inhibitor chemotherapy drug is selected from hydroxycamptothecin, irinotecan, topotecan, etoposide or teniposide.
  • the platinum drug is selected from cisplatin, carboplatin, epithioplatin, loplatin, oxaliplatin or nedaplatin; preferably cisplatin, oxaliplatin or nedaplatin.
  • the aforementioned chemotherapeutic drug is selected from paclitaxel, cisplatin or nedaplatin.
  • the aforementioned immunotherapy drug is selected from the group consisting of anti-programmed death receptor 1 antibody (anti-PD-1 antibody), anti-programmed death receptor-ligand 1 antibody (anti-PD-L1 Antibodies) and antibody drug conjugates.
  • anti-PD-1 antibody anti-programmed death receptor 1 antibody
  • anti-PD-L1 Antibodies anti-programmed death receptor-ligand 1 antibody
  • antibody drug conjugates Preferably, the antibody-drug conjugate is an anti-HER2 antibody-drug conjugate.
  • the anti-PD-1 antibody is selected from the group consisting of pembrolizumab, camrelizumab, tislelizumab, nivolumab, cetamip Rizumab, sintilimab or toripalimab; preferably, the anti-PD-1 antibody is selected from the group consisting of toripalimab, sintilimab or tislelizumab.
  • the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, avelumab and durvalumab.
  • the anti-HER2 antibody drug conjugate is selected from trastuzumab or disituzumab.
  • the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs; preferably, the tumor that has failed to be treated is a taxane+platinum-based chemotherapy drug+anti-PD- 1.
  • Tumors that have failed antibody treatment are toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, paclitaxel + loplatin + camrelizumab Tumors that have failed one, two, or three treatments of anti-, paclitaxel + nedaplatin, or sintilimab.
  • the tumor that failed treatment is one or two of toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, paclitaxel + loplatin + camrelizumab.
  • Tumors that have failed one or three treatments is esophageal squamous cell carcinoma; preferably, the tumor is gastroesophageal junction squamous cell carcinoma.
  • the tumor is a tumor that has failed to be treated with chemotherapy drugs; preferably, the tumor is a tumor that has failed to be treated with taxane + platinum chemotherapy drugs; preferably, the treatment Tumors that failed were tumors that failed paclitaxel + cisplatin or paclitaxel + nedaplatin.
  • the tumor is esophageal squamous cell carcinoma.
  • the tumor is a tumor that has failed chemotherapy drugs, immunotherapy and radiotherapy; preferably, the tumor is a taxane+platinum chemotherapy drug+radiotherapy+anti-PD- 1.
  • Tumors that have failed antibody treatment preferably, the tumors that have failed treatment are tumors that have failed treatment with tislelizumab + radiotherapy + paclitaxel + cisplatin.
  • the tumor is esophageal squamous cell carcinoma.
  • the pharmaceutically acceptable salt is selected from the group consisting of 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; further preferred are hydrochloride, maleate, phosphate, tartrate and fumarate. Acid salt; more preferably hydrochloride salt; even more preferably dihydrochloride salt.
  • the pharmaceutically acceptable salt of compound A is compound B,
  • the compound B is in solid form; preferably, it is in crystalline form.
  • the crystalline form of Compound B is Form I.
  • the X-ray powder diffraction pattern expressed at the 2 ⁇ angle includes characteristic peaks at the following positions: 5.0 ⁇ 0.2 °, 13.5 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.4 ⁇ 0.2° and 25.2 ⁇ 0.2°.
  • the crystalline form I uses Cu-K ⁇ radiation
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle includes characteristic peaks at the following positions: 5.0 ⁇ 0.2°, 13.5 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.4 ⁇ 0.2° and 25.2 ⁇ 0.2°.
  • the crystalline form I uses Cu-K ⁇ radiation
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle includes characteristic peaks at the following positions: 5.0 ⁇ 0.2°, 13.5 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.4 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.3 ⁇ 0.2° and 25.2 ⁇ 0.2°.
  • the crystalline form I uses Cu-K ⁇ radiation
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle includes characteristic peaks at the following positions: 5.0 ⁇ 0.2°, 10.4 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.5 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.4 ⁇ 0.2°, 22.0 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.4 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.3 ⁇ 0.2°, 25.2 ⁇ 0.2° and 26.6 ⁇ 0.2°.
  • the crystalline form I uses Cu-K ⁇ radiation
  • the X-ray powder diffraction pattern expressed at a 2 ⁇ angle includes characteristic peaks at the following positions: 5.0 ⁇ 0.2°, 10.0 ⁇ 0.2°, 10.4 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.5 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.4 ⁇ 0.2°, 18.0 ⁇ 0.2°, 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°.
  • Compound A is administered by a pharmaceutical route, including, but not limited to, a route selected from the group consisting of: oral, parenteral, or topical. In a specific embodiment, administration is by oral route.
  • the drug is formulated into clinically acceptable formulations, including but not limited to oral formulations, parenteral formulations, local administration formulations or topical formulations; oral formulations are preferred; tablets are further preferred and capsules.
  • each preparation unit of the medicine contains 0.1-200 mg of the compound A or a pharmaceutically acceptable salt thereof, preferably 1-150 mg, or 1-100 mg, or 1-80 mg, Or 1-60mg, or 1-50mg, or 1-40mg, or 1-30mg, or 1-20mg, or 1-10mg, or 1-6mg, for example, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 8mg , 10mg, 15mg, 20mg, 25mg.
  • each preparation unit of the drug contains 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg of the compound A or a pharmaceutically acceptable salt thereof , 15mg, 20mg, 25mg.
  • each preparation unit of the medicine contains 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, or 9 mg of the compound A or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is based on the mass containing compound B.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a single dose or in divided doses; preferably, in a single dose; preferably, the pharmaceutically acceptable salt of the compound A
  • the salt is Compound B; further preferably, it is administered as Compound B.
  • the dosage of Compound A or a pharmaceutically acceptable salt thereof is determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient .
  • the dosage of Compound A or a pharmaceutically acceptable salt thereof is 1-50 mg per day.
  • the dosage is 1-30 mg per day.
  • the dosage is 1-25 mg per day.
  • the dosage is 1-20 mg per day.
  • the dose administered is 2-18 mg per day.
  • the dose administered is 4-16 mg per day.
  • the dosage is 5-15 mg per day.
  • the dosage is 4-10 mg per day.
  • the dosage is 4-9 mg per day.
  • the dosage is 2-9 mg per day.
  • the dosage is 2-6 times daily mg.
  • the dosage is 5-9 mg per day.
  • the dose administered is 6-9 mg per day.
  • the dose administered is 6-8 mg per day.
  • the dose administered is 6-12 mg per day.
  • the dosage is 6-10 mg per day.
  • the dosage is 2, 3, 4, 5, 6, 7, 8, 9, 10 mg per day.
  • the dosage is 2, 4, 5, 6, 7, 8, 9, 10 mg per day.
  • the dosage is 6, 7, 8, 9 mg per day.
  • the dose administered is 4 mg per day.
  • the dose administered is 5 mg per day.
  • the dose administered is 6 mg per day.
  • the dose administered is 7 mg per day.
  • the dose administered is 8 mg per day.
  • the dose administered is 9 mg per day.
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is administered in the form of an oral solid preparation containing Compound B. Further preferably, the daily dose is based on the mass containing Compound B.
  • the administration frequency of Compound A or a pharmaceutically acceptable salt thereof is once, twice, three or more times per day. In some embodiments of the first aspect of the application, Compound A or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments of the first aspect of the application, Compound A or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments of the first aspect of the application, Compound A or a pharmaceutically acceptable salt thereof is administered three times daily.
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is administered in the form of an oral solid preparation containing Compound B.
  • the administration method is comprehensively determined based on the activity, toxicity, and patient tolerance of the drug.
  • the compound A or a pharmaceutically acceptable salt thereof is administered in a continuous or interval administration manner.
  • the interval administration includes a administration period and a drug withdrawal period; preferably, during the administration period, the compound A or a pharmaceutically acceptable salt thereof is administered once, twice, three or more times a day.
  • the compound A or a pharmaceutically acceptable salt thereof is administered once a day, and then the administration is stopped for a period of time during the drug withdrawal period, followed by the administration period, and then the drug withdrawal period, and this is repeated multiple times. .
  • the ratio in days between the dosing period and the drug withdrawal period is 3:1 to 5, preferably 3:1 to 3, more preferably 3:1 to 2, more preferably 3:1 or 3:1.5 (That is 2:1).
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is administered in the form of an oral solid preparation containing Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is: continuous administration, once a day. In some embodiments of the first aspect of the present application, the administration method of Compound A or a pharmaceutically acceptable salt thereof is: continuous administration, twice a day. In some embodiments of the first aspect of the present application, the administration method of Compound A or a pharmaceutically acceptable salt thereof is: continuous administration, 3 times a day.
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is administered in the form of an oral solid preparation containing Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is: continuous administration for 3 weeks, followed by 1 week of discontinuation.
  • the administration is once a day for 21 days, then 7 days off; then the administration is once a day, 21 days on, then 7 days off, and so on.
  • the interval administration method of 3 weeks of continuous administration and 1 week of discontinuation can be repeated multiple times.
  • dosing is administered twice daily for 21 days followed by 7 days off; then administered twice daily for 21 days followed by 7 days off, and so on.
  • the interval administration method of 3 weeks of continuous administration and 1 week of discontinuation can be repeated multiple times.
  • dosing is administered 3 times a day for 21 days, followed by 7 days off; followed by dosing 3 times a day for 21 days, followed by 7 days off, and so on.
  • the interval administration method of 3 weeks of continuous administration and 1 week of discontinuation can be repeated multiple times.
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is administered in the form of an oral solid preparation containing Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is: continuous administration for 2 weeks, followed by 1 week of discontinuation.
  • dosing is once daily for 14 days followed by 7 days off; followed by dosing once daily for 14 days followed by 7 days off for 2 weeks.
  • the drug administration method can be repeated multiple times at intervals of one week.
  • the drug is administered twice a day for 14 days, and then stopped for 7 days; then the drug is administered twice a day, continued for 14 days, and then stopped for 7 days, and so on for 2 weeks and then 1 week off.
  • the interval dosing method can be repeated multiple times.
  • dosing is administered three times a day for 14 days followed by 7 days off; followed by dosing three times a day for 14 days followed by 7 days off for 2 weeks.
  • the drug administration method can be repeated multiple times at intervals of one week.
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is administered in the form of an oral solid preparation containing Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is continuous administration for 3 weeks and discontinuation of administration for 2 weeks.
  • the administration is m times per day for 21 days, followed by 14 days off; then m times per day, continued administration for 21 days, followed by 14 days off, and so on.
  • the interval dosing method of 3 weeks of continuous administration and 2 weeks of drug withdrawal can be repeated multiple times.
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is administered in the form of an oral solid preparation containing Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is continuous administration for 5 days and drug withdrawal for 2 days.
  • the administration is m times per day for 5 days, then 2 days off; then m times per day, 5 days off, and then 2 days off, and so on for 5 days off.
  • the 2-day interval dosing method can be repeated multiple times.
  • the pharmaceutically acceptable salt of compound A is compound B. Further preferably, it is administered in the form of an oral solid preparation containing Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is oral administration at a dose of n mg m times per day, and continuous administration.
  • the pharmaceutically acceptable salt of compound A is compound B.
  • it is administered in the form of an oral solid preparation containing Compound B.
  • the dosage is based on the mass of Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is oral administration at a dose of n mg m times a day, for 3 consecutive weeks, and 1 week off.
  • the dosage method is every 4 weeks.
  • the pharmaceutically acceptable salt of compound A is compound B.
  • it is administered in the form of an oral solid preparation containing Compound B.
  • the dosage is based on the mass of Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is oral administration at a dose of n mg m times per day, for 2 weeks of continuous administration, and 1 week of discontinuation.
  • the dosage is given every 3 weeks as a cycle.
  • the pharmaceutically acceptable salt of compound A is compound B.
  • it is administered in the form of an oral solid preparation containing Compound B.
  • the dosage is based on the mass of Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is oral administration at a dose of 6 mg once a day for continuous administration.
  • the pharmaceutically acceptable salt of compound A is compound B.
  • it is administered in the form of an oral solid preparation containing Compound B.
  • the dosage is based on the mass of Compound B.
  • the administration method of Compound A or a pharmaceutically acceptable salt thereof is oral administration at a dose of 6 mg once a day for 3 consecutive weeks and 1 week off. administration method.
  • the pharmaceutically acceptable salt of compound A is compound B.
  • it is administered in the form of an oral solid preparation containing Compound B.
  • the dosage is based on the mass of Compound B.
  • m is selected from 1, 2 or 3. In some embodiments of the first aspect of the application, m is 1. In some embodiments of the first aspect of the application, m is 2. In some embodiments of the first aspect of the application, m is 3.
  • n is 1, 2, 3, 4, 5, 6, 7, 8 or 9. In some embodiments of the first aspect of the application, n is 1. In some embodiments of the first aspect of the application, n is 2. In some embodiments of the first aspect of the application, n is 3. In some embodiments of the first aspect of the application, n is 4. In some embodiments of the first aspect of the application, n is 5. In some embodiments of the first aspect of the application, n is 6. In some embodiments of the first aspect of the application, n is 7. In some embodiments of the first aspect of the application, n is 8. In some embodiments of the first aspect of the application, n is 9.
  • the compound A or a pharmaceutically acceptable salt thereof is combined with one, two, three or more of the drugs commonly used in clinical treatment of esophageal cancer or gastroesophageal junction cancer.
  • the drugs commonly used in clinical treatment of esophageal cancer or gastroesophageal junction cancer are commonly used in clinical treatment of esophageal cancer or gastroesophageal junction cancer.
  • Various combinations are used in the preparation of said medicaments.
  • the drug is further used in combination with one, two, three or more of the drugs commonly used in clinical treatment of esophageal cancer or gastroesophageal junction cancer.
  • the application provides a method of treating a tumor in an individual, comprising administering to the individual a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof according to the first aspect, wherein the tumor is esophageal cancer. or gastroesophageal junction cancer.
  • the method further includes a therapeutically effective amount of other drugs, and the other drugs are selected from one of the drugs commonly used in clinical treatment of esophageal cancer or gastroesophageal junction cancer. , two, three or more.
  • the present application provides Compound A or a pharmaceutically acceptable salt thereof for treating tumors, wherein the tumor is esophageal cancer or gastroesophageal junction cancer.
  • other drugs are further included, and the other drugs are selected from one, two, three or more drugs commonly used in clinical treatment of esophageal cancer or gastroesophageal junction cancer.
  • the other drugs are selected from one, two, three or more drugs commonly used in clinical treatment of esophageal cancer or gastroesophageal junction cancer.
  • the present application provides a pharmaceutical composition for treating tumors, which includes Compound A or a pharmaceutically acceptable salt thereof as described in the first aspect, and optionally includes a pharmaceutically acceptable carrier, wherein,
  • the tumor is esophageal cancer or gastroesophageal junction cancer.
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound A, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises the hydrochloride salt of Compound A, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises Compound B, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a solid form of Compound B, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a crystalline form of Compound B, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises Form I of Compound B, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition includes Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and further includes a therapeutically effective amount of other drugs, and the other drugs are selected from Drugs commonly used clinically to treat esophageal cancer or gastroesophageal junction cancer.
  • the pharmaceutical composition includes compound B and a pharmaceutically acceptable carrier, and further includes a therapeutically effective amount of other drugs, and the other drugs are selected from commonly used clinical drugs for treating esophagus.
  • the other drugs are selected from commonly used clinical drugs for treating esophagus.
  • the present application provides a pharmaceutical kit comprising (a) a pharmaceutical composition of at least one unit dose of Compound A or a pharmaceutically acceptable salt thereof and (b) instructions for treating tumors, wherein, The tumor is esophageal cancer or gastroesophageal junction cancer.
  • a kit comprising (a) at least one unit dose of an oral preparation of Compound A or a pharmaceutically acceptable salt thereof and (b) instructions for treating a tumor, wherein the tumor is esophageal cancer or Gastroesophageal junction cancer.
  • the "unit dose” refers to a pharmaceutical composition or oral preparation packaged in a single package for the convenience of taking. For example, per pharmaceutical composition, per tablet, or per capsule.
  • this application provides the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors, wherein the tumor is alimentary tract squamous cell carcinoma,
  • the tumor is an upper gastrointestinal squamous cell carcinoma; preferably, the upper gastrointestinal squamous cell carcinoma is selected from esophageal squamous cell carcinoma or gastroesophageal junction squamous cell carcinoma.
  • the tumor is a tumor associated with one, two or three gene abnormalities or protein expression abnormalities in FGFR, VEGFR, colony-stimulating factor 1 receptor (CSF1R) .
  • the tumor is a tumor with one, two or three gene mutations among FGFR, VEGFR and CSF1R.
  • the tumor is a locally advanced tumor or a metastatic tumor; preferably, it is an unresectable locally advanced tumor or an unresectable metastatic tumor.
  • the tumor is a tumor that has failed prior treatment.
  • the tumor is a tumor that has failed systemic drug treatment.
  • the tumor is a tumor that has failed first-line treatment.
  • the tumor is a tumor that has failed second-line treatment.
  • the tumor is a tumor that has failed subsequent line treatments.
  • the tumor is one, two, three or more of immunotherapy drugs, chemotherapy drugs, radiotherapy, biological therapy, traditional Chinese medicine treatment, and small molecule targeted drugs. Tumors that fail treatment.
  • the tumor is a tumor that has failed to be treated with radiotherapy, immunotherapy drugs or chemotherapy drugs.
  • the tumor is a tumor that has failed treatment with radiotherapy and immunotherapy drugs.
  • the tumor is a tumor that has failed treatment with radiotherapy and chemotherapy drugs.
  • the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs.
  • the tumor is a tumor that has failed treatment with chemotherapy drugs, immunotherapy drugs and radiotherapy.
  • the aforementioned chemotherapeutic drugs are selected from the group consisting of cytotoxic drugs, antimetabolite drugs, antibiotic drugs, alkaloid drugs, DNA topoisomerase inhibitor chemotherapeutic drugs, and anti-microtubule drugs.
  • Chemotherapy drugs, platinum chemotherapy drugs and hormone drugs preferably, the aforementioned chemotherapy drugs are selected from the group consisting of antimetabolite drugs, alkaloid drugs, DNA topoisomerase inhibitor chemotherapy drugs, anti-microtubule chemotherapy drugs and platinum drugs. Chemotherapy-like medicine.
  • the aforementioned chemotherapy drugs are selected from taxane drugs, platinum drugs, fluorouracil drugs or DNA topoisomerase inhibitor chemotherapy drugs.
  • the taxane drug is selected from paclitaxel, docetaxel or cabazitaxel; preferably paclitaxel.
  • the DNA topoisomerase inhibitor chemotherapy drug is selected from hydroxycamptothecin, irinotecan, topotecan, etoposide or teniposide.
  • the platinum drug is selected from cisplatin, carboplatin, epithioplatin, loplatin, oxaliplatin or nedaplatin; preferably cisplatin, oxaliplatin or nedaplatin.
  • the aforementioned chemotherapeutic drug is selected from paclitaxel, cisplatin or nedaplatin.
  • the aforementioned immunotherapy drug is selected from the group consisting of anti-programmed death receptor 1 antibody (anti-PD-1 antibody), anti-programmed death receptor-ligand 1 antibody (anti-PD-L1 Antibodies) and antibody drug conjugates.
  • anti-PD-1 antibody anti-programmed death receptor 1 antibody
  • anti-PD-L1 Antibodies anti-programmed death receptor-ligand 1 antibody
  • antibody drug conjugates Preferably, the antibody-drug conjugate is an anti-HER2 antibody-drug conjugate.
  • the anti-PD-1 antibody is selected from the group consisting of pembrolizumab, camrelizumab, tislelizumab, nivolumab, cetamip Rizumab, sintilimab or toripalimab; preferably, the anti-PD-1 antibody is selected from the group consisting of toripalimab, sintilimab or tislelizumab.
  • the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, avelumab and durvalumab.
  • the anti-HER2 antibody drug conjugate is selected from trastuzumab or disituzumab.
  • the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs; preferably, the tumor that has failed to be treated is a taxane+platinum-based chemotherapy drug+anti-PD- 1.
  • Tumors that have failed antibody treatment are toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, paclitaxel + loplatin + camrelizumab
  • the tumor is esophageal squamous cell carcinoma.
  • the tumor is a tumor that has failed to be treated with chemotherapy drugs; preferably, the tumor is a tumor that has failed to be treated with taxane + platinum chemotherapy drugs; preferably, the tumor
  • the above-mentioned tumors that failed treatment were tumors that failed to be treated with paclitaxel + cisplatin or paclitaxel + nedaplatin.
  • the tumor is esophageal squamous cell carcinoma.
  • the tumor is a tumor that has failed chemotherapy drugs, immunotherapy and radiotherapy; preferably, the tumor is taxane+platinum chemotherapy drug+radiotherapy+anti-PD- 1.
  • Tumors that have failed antibody treatment preferably, the tumors that have failed treatment are tumors that have failed treatment with tislelizumab + radiotherapy + chemotherapy.
  • the tumor is esophageal squamous cell carcinoma.
  • the present application provides the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors,
  • the tumor is squamous cell carcinoma.
  • the tumor is selected from head and neck squamous cell carcinoma, gastrointestinal squamous cell carcinoma or respiratory tract squamous cell carcinoma; preferably, The tumor is selected from the group consisting of head and neck squamous cell carcinoma, upper gastrointestinal tract squamous cell carcinoma or respiratory tract squamous cell carcinoma; further preferably, the tumor is selected from the group consisting of esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, head and neck squamous cell carcinoma and lung squamous cell carcinoma.
  • the tumor is selected from the group consisting of esophageal squamous cell carcinoma, gastroesophageal junction squamous cell carcinoma, nasopharyngeal squamous cell carcinoma and lung squamous cell carcinoma; further preferably, the tumor is selected from the group consisting of nasopharyngeal squamous cell carcinoma, esophageal squamous cell carcinoma and lung squamous cell carcinoma. Cancer; further preferably, the tumor is esophageal squamous cell carcinoma.
  • the tumor is a tumor associated with one, two or three gene abnormalities or protein expression abnormalities of FGFR, VEGFR, and CSF1R.
  • the tumor is a tumor associated with one, two or three genetic abnormalities of FGFR, VEGFR, and CSF1R.
  • the tumor is a locally advanced tumor or a metastatic tumor; preferably, it is an unresectable locally advanced tumor or an unresectable metastatic tumor.
  • the tumor is a tumor that has failed or relapsed from prior treatment.
  • the tumor is a tumor that has failed systemic drug treatment.
  • the tumor is a tumor that has failed first-line treatment.
  • the tumor is a tumor that failed second-line treatment, or failed subsequent-line treatment.
  • the tumor is one, two, three or more of immunotherapy drugs, chemotherapy drugs, radiotherapy, biological therapy, traditional Chinese medicine treatment, and small molecule targeted drugs. Tumors that fail treatment.
  • the tumor is a tumor that has failed to be treated with radiotherapy, immunotherapy drugs or chemotherapy drugs.
  • the tumor is a tumor that has failed treatment with radiotherapy and immunotherapy drugs.
  • the tumor is a tumor that has failed treatment with radiotherapy and chemotherapy drugs.
  • the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs.
  • the tumor is a tumor that has failed treatment with chemotherapy drugs, immunotherapy drugs and radiotherapy.
  • the aforementioned chemotherapeutic drugs are selected from the group consisting of cytotoxic drugs, antimetabolite drugs, antibiotic drugs, alkaloid drugs, DNA topoisomerase inhibitor chemotherapeutic drugs, and anti-microtubule drugs.
  • Chemotherapy drugs, platinum chemotherapy drugs and hormone drugs preferably, the aforementioned chemotherapy drugs are selected from the group consisting of antimetabolite drugs, alkaloid drugs, DNA topoisomerase inhibitor chemotherapy drugs, anti-microtubule chemotherapy drugs and platinum drugs. Chemotherapy-like drugs.
  • the aforementioned chemotherapy drugs are selected from taxane drugs, platinum drugs, fluorouracil drugs or DNA topoisomerase inhibitor chemotherapy drugs.
  • the taxane is selected from paclitaxel, docetaxel, or cabazitaxel; preferably paclitaxel.
  • the DNA topoisomerase inhibitor chemotherapeutic agent is selected from hydroxycamptothecin, irinotecan, topotecan, etoposide, or teniposide.
  • the platinum drug is selected from cisplatin, carboplatin, epithioplatin, loplatin, oxaliplatin or nedaplatin; preferably cisplatin, oxaliplatin or nedaplatin.
  • the aforementioned chemotherapeutic agent is selected from paclitaxel, cisplatin, or nedaplatin.
  • the aforementioned immunotherapy drug is selected from the group consisting of anti-programmed death receptor 1 antibody (anti-PD-1 antibody), anti-programmed death receptor-ligand 1 antibody (anti-PD-L1 Antibodies) and antibody drug conjugates.
  • anti-PD-1 antibody anti-programmed death receptor 1 antibody
  • anti-PD-L1 Antibodies anti-programmed death receptor-ligand 1 antibody
  • antibody drug conjugates Preferably, the antibody-drug conjugate is an anti-HER2 antibody-drug conjugate.
  • the anti-PD-1 antibody is selected from the group consisting of pembrolizumab, camrelizumab, tislelizumab, nivolumab, cimepilimab, cinda Rizumab or toripalimab; preferably, the anti-PD-1 antibody is selected from toripalimab, sintilimab or tislelizumab.
  • the anti-PD-L1 antibody is selected from the group consisting of atezolizumab, Velumab and durvalumab.
  • the anti-HER2 antibody drug conjugate is selected from trastuzumab or disituzumab.
  • the tumor is a tumor that has failed to be treated with chemotherapy drugs and immunotherapy drugs; preferably, the tumor is treated with taxanes + platinum chemotherapy drugs + anti-PD-1 antibodies Failed tumor; preferably, the tumor is toripalimab + paclitaxel + cisplatin, sintilimab + paclitaxel + cisplatin, paclitaxel + loplatin + camrelizumab, paclitaxel + neda Tumors that have failed one, two, three or more treatments including platinum and sintilimab.
  • the tumor is a tumor that has failed to be treated with chemotherapy drugs; preferably, the tumor is a tumor that has failed to be treated with taxane + platinum chemotherapy drugs; preferably, the tumor For tumors that have failed treatment with paclitaxel + cisplatin, paclitaxel + carboplatin, or paclitaxel + nedaplatin.
  • the tumor is a tumor that has failed chemotherapy drugs, immunotherapy and radiotherapy; preferably, the tumor is a taxane+platinum chemotherapy drug+radiotherapy+anti-PD- 1.
  • Tumors that have failed antibody treatment preferably, the tumors are tumors that have failed treatment with tislelizumab + radiotherapy + chemotherapy.
  • the present application provides a method for treating tumors in an individual, comprising administering to the individual a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof according to the first aspect, wherein the tumor is squamous. Cell carcinoma.
  • the method further includes a therapeutically effective amount of other drugs, and the other drugs are selected from one or two drugs commonly used in clinical treatment of squamous cell carcinoma. Three or more species.
  • the present application provides Compound A or a pharmaceutically acceptable salt thereof for treating tumors, wherein the tumors are squamous cell carcinomas.
  • other drugs are further included, and the other drugs are selected from one, two, three or more drugs commonly used in clinical treatment of squamous cell carcinoma.
  • the present application provides a pharmaceutical composition for treating tumors, which includes Compound A or a pharmaceutically acceptable salt thereof, and optionally includes a pharmaceutically acceptable carrier, wherein the tumor is squamous cell cancer.
  • the pharmaceutical composition comprises a pharmaceutically acceptable salt of Compound A, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises the hydrochloride salt of Compound A, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises Compound B, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a solid form of Compound B, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a crystalline form of Compound B, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises Form I of Compound B, and optionally a pharmaceutically acceptable carrier.
  • the pharmaceutical composition includes Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and further includes a therapeutically effective amount of other drugs, and the other drugs are selected from Drugs commonly used clinically to treat squamous cell carcinoma.
  • the pharmaceutical composition includes compound B and a pharmaceutically acceptable carrier, and further includes a therapeutically effective amount of other drugs, and the other drugs are selected from commonly used clinical treatments for squamous cell carcinoma.
  • first aspect uses (first aspect), methods (second aspect), compounds or pharmaceutically acceptable salts thereof (aspect 2.1), pharmaceutical compositions (third aspect), kits (aspect 2.1), Fourth aspect), use (fifth aspect), method (seventh aspect), compound or its pharmaceutically acceptable salt (eighth aspect) or pharmaceutical composition (ninth aspect) further contains other drugs, compound A or its pharmaceutically acceptable salt Medicinal salts and other drugs are administered simultaneously or sequentially to a tumor patient, wherein the tumor is the esophageal cancer or gastroesophageal junction cancer described in the first aspect, the digestive tract squamous cell carcinoma described in the fifth aspect, or the sixth aspect Squamous cell carcinoma.
  • the other drugs include but are not limited to chemotherapy drugs, immunotherapy drugs, and small molecule targeted drugs.
  • the "prior treatment” mentioned in this application includes, but is not limited to, one, two, three or more of radiotherapy, chemotherapy, and targeted therapy (including immunotherapy and small molecule targeted drug therapy).
  • Immunotherapy as described in this application includes immune checkpoint inhibitors, tumor vaccines, cellular immune cell therapy, non-specific immunomodulators and immunomodulatory antibody-drug conjugates (or antibody-drug conjugates, Antibody-drug). Conjugate).
  • First-line treatment as described in this application is not limited to first-line drug treatment regimens approved for the treatment of specific tumor conditions (e.g., esophageal cancer, gastroesophageal junction cancer, nasopharyngeal squamous cell carcinoma, lung squamous cell carcinoma, etc.), but also includes diagnostics It is the first non-first-line chemotherapy regimen, immunotherapy, targeted therapy and other systemic drug treatments used to treat specific tumor diseases. "Failure of first-line treatment” also includes disease progression within 6 months of adjuvant chemotherapy.
  • the compound A or its pharmaceutically acceptable salt for example, compound B
  • squamous cell carcinoma for example, nasopharyngeal carcinoma
  • lung squamous cell carcinoma for example, esophageal squamous cell carcinoma
  • the compound A or a pharmaceutically acceptable salt thereof showed good tolerability in clinical phase I trials and had few adverse reactions, indicating that it has good clinical safety.
  • solid form refers to a compound in a solid form, including the crystalline form and amorphous form of Compound B.
  • the "crystalline form” mentioned in this application refers to a compound in a crystalline form, including the anhydrous and solvent-free form (or anhydrous form), hydrate form, solvate form and co-crystal form of Compound B.
  • the crystalline form is preferably an anhydrous and solvent-free form or a hydrate form; further preferably it is an anhydrous and solvent-free form.
  • Treatment means alleviating, alleviating or ameliorating the symptoms of a disease or condition, ameliorating underlying metabolic symptoms, inhibiting a disease or symptom, such as preventing the development of a disease or condition, ameliorating a disease or condition, causing a disease or Remission of symptoms, remission of disease or condition caused by condition, or prevent the symptoms of a disease or condition.
  • treatment failure refers to disease progression during treatment, recurrence after treatment, or intolerable side effects.
  • systemic drug therapy includes neoadjuvant therapy and adjuvant therapy, as well as chemotherapy, small molecule targeted therapy and immunotherapy for advanced patients.
  • the "gene abnormality” mentioned in this application refers to one or more events such as fusion, amplification, rearrangement or mutation of the genes of FGFR, VEGFR or CSF1R.
  • the "abnormal protein expression” mentioned in this application refers to one or more events of protein overexpression, misfolding, or kinase domain duplication.
  • references in this application to "optionally” or “optionally/where” refer to inclusion or exclusion, meaning that the subsequently described event or circumstance may but need not occur, and the description includes whether the event or circumstance occurs or does not occur. occasion.
  • Machine kinds” or “more times” mentioned in this application in some cases, means 4 or more times, such as “one, two, three or more” situations; in In some cases, it means 2, 3 or more, such as "one or more”.
  • Head and neck squamous cell carcinoma in this application is also called “head and neck squamous cell carcinoma”.
  • "Digestive tract squamous cell carcinoma” in this application is also called “digestive tract squamous cell carcinoma”.
  • "Respiratory squamous cell carcinoma” in this application is also called “respiratory squamous cell carcinoma”.
  • "Upper gastrointestinal squamous cell carcinoma” in this application is also called “upper respiratory tract squamous cell carcinoma”.
  • Esophageal squamous cell carcinoma in this application is also called “esophageal squamous cell carcinoma” or “esophageal squamous cell carcinoma” or “esophageal squamous cell carcinoma”.
  • Gastroesophageal junction squamous cell carcinoma in this application is also called “gastroesophageal junction squamous cell carcinoma”.
  • Lung squamous cell carcinoma in this application is also called “lung squamous cell carcinoma”.
  • Nasopharyngeal squamous cell carcinoma in this application is also called “nasopharyngeal squamous cell carcinoma” or “nasopharyngeal squamous cell carcinoma”.
  • composition of the present application can be prepared by methods known in the art.
  • composition refers to a mixture of one or more compounds of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the purpose of pharmaceutical compositions is to facilitate the administration to an organism of pharmaceutically acceptable salts, stereoisomers or prodrugs of the compounds of the present application.
  • the pharmaceutical composition of the present application can be prepared by conventional methods in the art.
  • the term “pharmaceutically acceptable carrier” may also be referred to as “excipient” or “pharmaceutically acceptable excipient” or “pharmaceutically acceptable excipient” and refers to a substance that has no obvious effect on the organism. Those excipients that have a stimulating effect and do not impair the biological activity and performance of the active compound.
  • pharmaceutically acceptable carrier includes, but is not limited to: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, fillers, etc.
  • Those skilled in the art can select specific pharmaceutically acceptable excipients according to actual needs and prepare them into the required dosage form, for example, tablets. Knowledge about excipients is well known to those skilled in the art. For example, you can refer to "Pharmacology” (edited by Trafford, 5th edition, People's Medical Publishing House, 2003).
  • ORR calculated from the day of first administration, including the percentage of subjects with complete remission (CR) and partial remission (PR) among all enrolled subjects.
  • PFS The length of time from the first dose until the date of tumor progression (PD assessed by imaging diagnosis) or the date of death from any cause (whichever occurs first).
  • OS The time calculated from the day of first administration until death due to any cause (subjects who were lost to follow-up are the last follow-up time; subjects who are still alive at the end of the study are the end of follow-up date.
  • DCR defined as the percentage of subjects with CR, PR or stable disease (SD) among all enrolled subjects calculated from the day of first administration.
  • DOR the time from when the tumor was first evaluated as CR or PR to when the tumor was first evaluated as PD or death from any cause.
  • CR refers to complete remission, that is, all target lesions disappear, and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to ⁇ 10 mm.
  • PR Refers to partial response, in which the sum of target lesion diameters is reduced by at least 30% compared with baseline levels.
  • PD refers to disease progression, taking the minimum value of the sum of the diameters of all target lesions measured during the entire study as a reference, with a relative increase of at least 20% in diameter (if the baseline measurement value is the smallest, the baseline value is used as the reference); and must If the relative value of the sum of diameters increases by at least 5 mm, the appearance of one or more new lesions is also considered disease progression.
  • SD means that the disease is stable, and the reduction of target lesions does not reach the PR level, and the increase does not reach the PD level, and is somewhere in between.
  • the compounds of the present application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods known to those skilled in the art. Equivalent alternatives and preferred implementations include but are not limited to the embodiments of this application.
  • the tube pressure is 40kV
  • the tube flow is 40mA
  • the 2 ⁇ scanning range is 3-40°
  • the scanning step is 0.02° (2 ⁇ )
  • the scanning speed is 10s/step
  • the sample plate is a zero-background sample plate.
  • Detection instrument Dionex ICS-900 ion chromatograph
  • Determination method Precisely measure 10 ⁇ L each of the reference solution and the test solution, inject them into the ion chromatograph respectively, record the chromatogram, and calculate the chloride ion content based on the peak area according to the external standard method.
  • Method Place the sample into the tared sample basket, weigh the sample automatically, and analyze the sample according to the parameters in the table below.
  • the temperature range is room temperature to 350°C, the heating rate is 10°C/min, the purge gas is nitrogen, the flow rate of the equilibrium chamber: 40mL/min, the flow rate of the sample chamber: 25mL/min.
  • Example 2 The results show that the sample obtained in Example 2 and the samples of different salts obtained in Example 3 have good solubility in water, and the solubility is significantly better than that of the free base, which meets the general requirements for the solubility of raw materials in oral dosage forms, especially the sample obtained in Example 2. It complies with the general requirements for the solubility of raw materials in various pharmaceutical dosage forms (such as solid oral dosage forms, injections, oral liquids, etc.).
  • the sample obtained in Example 2 also has better solubility than Compound A in the buffer solution.
  • Example 3 is slightly hygroscopic (maleate) or has hygroscopicity, but the weight gain due to moisture absorption is not high; the sample obtained in Example 2 is slightly hygroscopic, but the weight gain due to moisture attraction is lower.
  • Example 2 The sample obtained in Example 2 was mechanically ground using a mortar for 2 minutes and 5 minutes respectively.
  • the X-ray powder diffraction test showed that no crystalline transformation occurred after grinding the crystalline form I.
  • Example 2 Further, the samples obtained in Example 2 were dropped into an appropriate amount of organic solvents (methanol, ethanol, acetone, acetonitrile, ethyl acetate, etc.) and then mechanically ground. After X-ray powder diffraction testing, the results showed that the crystalline Form I after grinding was No crystalline transformation occurred.
  • organic solvents methanol, ethanol, acetone, acetonitrile, ethyl acetate, etc.
  • the salts of Compound A of the present application have good medicinal potential.
  • Compound B of the present application and its crystal form I have better medicinal potential than other crystal forms or other salt forms.
  • Drug Compound B, tablet.
  • 1.1 Inclusion criteria Mainly include: (1) Aged 18 to 70 years old (including 18 and 70 years old) when signing informed consent; (2) Unresectable locally advanced or metastatic entities confirmed by histopathology or cytology Cancer patients who have failed or are intolerant to standard treatments, or have no alternative standard treatment options; (3) There is at least one measurable lesion that meets the definition of RECIST v1.1; (4) ECOG performance status (PS) score: 0 ⁇ 1 points; etc.
  • PS ECOG performance status
  • Dose ramping phase Starting dose: 1mg, 2mg, 4mg, 6mg, 9mg, 12mg, 16mg, 20mg, 25mg, once a day, orally.
  • the multiple dosing period will begin 7 days after a single dose (continuous dosing, every 28 days as a cycle, until disease progression or intolerable toxic reactions occur).
  • Subjects who have completed the first cycle of single-dose and multiple-dose treatment and observation, and who have benefited from and tolerated the study drug treatment, may enter the extended treatment period according to the subject's wishes, and the extended treatment period One cycle every 4 weeks.
  • Dose expansion phase 4mg, 6mg, once a day, orally.
  • every 4 weeks is a cycle; for the 3 weeks on and 1 week off group, every 4 weeks is a cycle; for the 2 weeks on and 1 week off group, every 3 weeks is a cycle.
  • Effectiveness indicators include objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR); (2) Safety assessment: including life expectancy Assessment of signs and physical examination, electrocardiogram, ECOG PS score, laboratory tests, adverse events, etc.
  • Compound B has shown good efficacy in patients with solid tumors.
  • Compound B shows clinical benefit against esophageal cancer and squamous cell carcinoma (eg, esophageal squamous cell carcinoma, lung squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, etc.), especially esophageal squamous cell carcinoma.
  • esophageal cancer and squamous cell carcinoma eg, esophageal squamous cell carcinoma, lung squamous cell carcinoma, nasopharyngeal squamous cell carcinoma, etc.
  • Subject S03002 male, 57 years old, was diagnosed with esophageal squamous cell carcinoma on August 23, 2020.
  • the subject participated in the clinical trial "Toripalimab/placebo + paclitaxel injection + cisplatin injection” in September 2020, and applied “Tripalimab” from September 24, 2020 to January 2021 / placebo + paclitaxel injection + cisplatin injection” treatment, "toripalimab / placebo” was applied from February 2021 to April 2021, the best efficacy was SD, and the efficacy evaluation on April 20, 2021 was PD leaves the group.
  • the final efficacy evaluations of the subjects in the first, second, and third weeks were all PR, and the best efficacy was PR.
  • Subject S03008 is a male, 68 years old, who was diagnosed with esophageal squamous cell carcinoma on August 30, 2019. The subject participated in the clinical trial "sintilimab/placebo + paclitaxel + cisplatin" from October 17, 2019 to December 2021. The best efficacy was PR, and the menstrual efficacy evaluation in December 2021 was PD.
  • the subject's efficacy evaluation at the end of the first week was SD
  • the efficacy evaluation at the end of the second, third, and fifth weeks were all PR
  • the best efficacy was PR. Still taking medication.
  • Subject S03009 male, 49 years old, was diagnosed with stage III esophageal squamous cell carcinoma in January 2021. Starting from February 2021, "albumin-paclitaxel combined with nedaplatin” will be used for 3 cycles of treatment, but the best efficacy is unknown. Starting from April 2021, he will participate in the clinical trial “tislelizumab/placebo + concurrent chemoradiotherapy (chemotherapy drug: paclitaxel + cisplatin for injection)". The efficacy evaluation in December 2021 was PD.
  • the final efficacy evaluations of the subjects in the first, second, and third weeks were all PR, and the best efficacy was PR.
  • Subject S03018 male, 64 years old, was diagnosed with esophageal squamous cell carcinoma on February 10, 2022. From February 19, 2022 to April 26, 2022, "nab-paclitaxel + loplatin + camrelizumab" was used for 2 cycles of treatment. The best efficacy was SD, and the treatment was stopped due to intolerance. The efficacy was evaluated as PD on July 5, 2022.
  • Subject S03025 male, 66 years old, was diagnosed with esophageal squamous cell carcinoma on August 1, 2017. From August 8, 2019 to November 20, 2019, "toripalimab injection/placebo + paclitaxel + cisplatin” was used for 6 cycles of treatment, with the best efficacy SD. From December 11, 2019 to August 10, 2021, “Toripalimab injection/placebo” maintenance treatment was continued for 25 cycles, with the best efficacy SD. "Paclitaxel polymer micelles” were used for 6 cycles of treatment from December 8, 2021 to March 22, 2022, and the best efficacy was SD. On January 11, 2023, the efficacy was evaluated as PD.
  • Subject S01001 male, 40 years old, was diagnosed with nasopharyngeal squamous cell carcinoma on June 1, 2017. From June 23, 2017 to July 17, 2017, "paclitaxel + cisplatin” was used for 2 cycles of treatment, and the best efficacy was SD. From August 4, 2017 to August 9, 2017, “gemcitabine + ifosfamide” was used for 1 cycle, and the best efficacy was SD. Radiotherapy was given to the "neck and cervical lymph nodes" from September 18, 2017 to November 18, 2017, and the best curative effect was PR; 2 cycles of "cisplatin” were simultaneously applied from September 18, 2017 to October 30, 2017. , best efficacy SD.
  • Radiotherapy was given to the "thoracic spine" from April 27, 2018 to May 4, 2018; from November 7, 2019 to January 16, 2020, "jenosumab injection (PD-1 monoclonal antibody)" was used to treat 6 cycle, best efficacy SD.
  • the menstrual efficacy evaluation in June 2020 was PD.
  • Subject S09009 male, 57 years old, was diagnosed with lung squamous cell carcinoma on February 7, 2020. From May 11, 2020 to June 25, 2020, radiotherapy was given to "right hilar + hilar lymph node metastasis". Simultaneous application of "cisplatin + etoposide” treatment from May 11, 2020, the best efficacy SD; 32 cycles of "sintilimab” treatment from July 23, 2020 to November 25, 2022, the best Efficacy SD. Menstrual therapy in February 2023 The efficacy assessment is PD.
  • Compound B monotherapy is generally safe and controllable.
  • Common ( ⁇ 10%) adverse reactions include proteinuria, hypertension, hypoalbuminemia, decreased platelet count, decreased white blood cell count, increased alanine aminotransferase, Elevated aspartate aminotransferase, hyperuricemia, rash, anemia, and fatigue.
  • Most of the cases were grade 2 or below in severity, most were not treated, and the outcome was mostly improvement/recovery; indicating that the adverse reactions of Compound B were relatively mild.
  • the type of adverse reactions of Compound B is comparable to other protein kinase inhibitors of the same type, the severity of adverse reactions is relatively mild, and the incidence of adverse reactions of grade 3 and above is relatively low.

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Abstract

杂芳基氧基萘类化合物的用途，具体是化合物A或其可药用盐在制备用于***疾病的药物中的用途，该化合物A或其可药用盐表现出良好的肿瘤治疗效果和较好的耐受性，具有***的临床潜力。

Description

杂芳基氧基萘类化合物的用途
本申请要求2022年8月31日向中国国家知识产权局提交的，专利申请号为202211062094.6，发明名称为“杂芳基氧基萘类化合物的用途”的在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药领域，具体涉及多靶点蛋白激酶抑制剂在制备用于治疗和/或预防肿瘤的药物中的用途，特别是在制备治疗鳞状细胞癌、食管癌和/或胃食管交界部癌的药物中的用途。
背景技术
鳞状细胞癌(squamous cell carcinoma，SCC)，也称为表皮样癌，包括由鳞状细胞引起的不同类型的癌症。这些细胞形成于皮肤表面、身体中空器官的内壁以及呼吸道和消化道的内壁上，例如，根据身***置，包括皮肤、头颈部、消化道(例如，食道)和呼吸道(例如，肺部)等的鳞状细胞癌。
食管癌(或食道癌)是全球范围内常见的恶性肿瘤之一，分别位于癌症类型发病和死亡顺位的第8位和第6位。而且，与一般人群比较，食管癌人群的多原发性恶性肿瘤发生风险增加，发病率高达9.5％～21.9％。从组织学上划分，食管癌主要有两种类型，即鳞状细胞癌(食管鳞癌)和腺癌(食管腺癌)。
早期食管癌的临床症状不明显，难于发现，大多数食管癌患者在确诊时已为局部晚期或存在远处转移，虽然已有外科手术治疗、内镜治疗、放疗、化疗、免疫治疗等方法在临床使用，但仍面临患者预后差的问题，5年总体生存率仅为10～20％。
根据中国临床肿瘤学会(CSCO)食管癌诊疗指南(2022年版)，晚期食管癌的一线治疗以化疗联合免疫治疗、联合化疗为主，对于分层为鳞癌和HER-2阴性腺癌(PS＝0-2)，推荐的二线及以上治疗中，对于分层为PS＝0-2的情况，I级推荐以单药化疗和单药免疫治疗为主，目前也尚未有治疗食管癌的小分子靶向药物获批上市。而且，获指南推荐用于晚期食管癌治疗的化疗药物中，常使用含铂和氟尿嘧啶类的药物，但其常伴随细胞毒性副作用，同时，也有多项研究表明，食管癌相关多原发性恶性肿瘤的发病与基因因素、医源性因素(例如放疗或化疗等)等作用明显相关，食管癌治疗过程中常见的放疗和化疗在提高患者生存率的同时，可能增加相关多原发性恶性肿瘤的发生风险。因此，对于现有治疗失败的食管癌患者，后线治疗中尚无标准的治疗方案，相同或类似作用机制的治疗方式的疗效难以保证，患者既往接受前线治疗进展后急需有效的治疗药物，以解决临床上未被满足的需求。
CN108699030A公开了化合物A(对应于化合物S10)，其是一种具有成纤维生长因子受体(FGFR)、血管内皮细胞生长因子受体(KDR或VEGFR2)抑制活性的化合物，目前尚无其可用于鳞状细胞癌、消化道鳞癌、食管癌、胃食管交界部癌等的治疗的相关研究报道。
发明内容
本申请要解决的技术问题是提供化合物A或其可药用盐用于制备***，特别是鳞状细胞癌、消化道鳞癌、食管癌或胃食管交界部癌的药物中的用途。
具体而言，第一方面，本申请提供了化合物A或其可药用盐在制备用于***的药物中的用途，其中，所述肿瘤为食管癌或胃食管交界部癌，
在本申请第一方面的一些实施方案中，所述胃食管交界部癌为胃食管交界部鳞癌或胃食管交界部腺癌；优选为胃食管交界部鳞癌。
在本申请第一方面的一些实施方案中，所述食管癌为食管鳞癌或食管腺癌；优选为食管鳞癌。
在本申请第一方面的一些实施方案中，所述肿瘤为伴有FGFR和/或VEGFR的基因异常和/或蛋白表达异常的肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为伴有FGFR、VEGFR、集落刺激因子1受体(CSF1R)中的一种、两种或三种的基因异常和/或蛋白表达异常的肿瘤。优选地，所述肿瘤为伴有FGFR、VEGFR、CSF1R中的一种、两种或三种基因突变的肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为局部晚期肿瘤或转移性肿瘤；优选为不可手术切除的局部晚期肿瘤或不可手术切除的转移性肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为在先治疗失败的肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为***性药物治疗失败的肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为一线治疗失败的肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为二线治疗失败的肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为后线治疗失败的肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为免疫治疗药物、化疗药物、放疗、生物治疗、中药 治疗、小分子靶向药物中的一种、两种、三种或更多种治疗失败的肿瘤。
在本申请第一方面的一些实施方案中，所述肿瘤为放疗、免疫治疗药物或化疗药物治疗失败的肿瘤。在本申请第一方面的一些实施方案中，所述肿瘤为放疗和免疫治疗药物治疗失败的肿瘤。在本申请第一方面的一些实施方案中，所述肿瘤为放疗和化疗药物治疗失败的肿瘤。在本申请第一方面的一些实施方案中，所述肿瘤为化疗药物和免疫治疗药物治疗失败的肿瘤。在本申请第一方面的一些实施方案中，所述肿瘤为化疗药物、免疫治疗药物和放疗治疗失败的肿瘤。
在本申请第一方面的一些实施方案中，所述食管鳞癌为伴有FGFR和/或VEGFR的基因异常或蛋白表达异常的食管鳞癌。
在本申请第一方面的一些实施方案中，所述食管鳞癌为伴有FGFR、VEGFR、集落刺激因子1受体(CSF1R)中的一种、两种或三种的基因异常和/或蛋白表达异常的食管鳞癌。优选地，所述食管鳞癌为伴有FGFR、VEGFR、CSF1R中的一种、两种或三种基因突变的食管鳞癌。
在本申请第一方面的一些实施方案中，所述食管鳞癌为局部晚期食管鳞癌或转移性(例如IV期)食管鳞癌；优选为不可切除的局部晚期食管鳞癌或不可切除的转移性食管鳞癌。
在本申请第一方面的一些实施方案中，所述食管鳞癌为在先治疗失败的食管鳞癌。
在本申请第一方面的一些实施方案中，所述食管鳞癌为***性药物治疗失败的食管鳞癌。
在本申请第一方面的一些实施方案中，所述食管鳞癌为一线治疗失败的食管鳞癌。
在本申请第一方面的一些实施方案中，所述食管鳞癌为二线治疗失败的食管鳞癌。
在本申请第一方面的一些实施方案中，所述食管鳞癌为后线治疗失败的食管鳞癌。
在本申请第一方面的一些实施方案中，所述食管鳞癌为免疫治疗药物、化疗药物、放疗、生物治疗、中药治疗、小分子靶向药物中的一种、两种、三种或更多种治疗失败的食管鳞癌。在本申请第一方面的一些实施方案中，所述食管鳞癌为放疗、免疫治疗药物或化疗药物治疗失败的食管鳞癌。在本申请第一方面的一些实施方案中，所述食管鳞癌为放疗和免疫治疗药物治疗失败的食管鳞癌。在本申请第一方面的一些实施方案中，所述食管鳞癌为放疗和化疗药物治疗失败的食管鳞癌。在本申请第一方面的一些实施方案中，所述食管鳞癌为化疗药物和免疫治疗药物治疗失败的食管鳞癌。在本申请第一方面的一些实施方案中，所述食管鳞癌为化疗药物、免疫治疗和放疗治疗失败的食管鳞癌。
在本申请第一方面的一些实施方案中，前述化疗药物选自细胞毒类药、抗代谢类药、抗生素类药、生物碱类药、DNA拓扑异构酶抑制剂类化疗药、抗微管类化疗药、铂类化疗药和激素类药；优选地，前述化疗药物选自抗代谢类药、生物碱类药、DNA拓扑异构酶抑制剂类化疗药、抗微管类化疗药和铂类化疗药。
在本申请第一方面的一些实施方案中，前述化疗药物选自紫杉烷类药物、铂类药物、氟尿嘧啶类药物或DNA拓扑异构酶抑制剂类化疗药。在本申请第一方面的一些实施方案中，所述紫杉烷类药物选自紫杉醇、多西他赛或卡巴它赛；优选为紫杉醇。在本申请第一方面的一些实施方案中，所述DNA拓扑异构酶抑制剂类化疗药选自羟喜树碱、伊立替康、拓扑替康、依托泊苷或替尼泊苷。在本申请第一方面的一些实施方案中，所述铂类药物选自顺铂、卡铂、环硫铂、洛铂、奥沙利铂或奈达铂；优选为顺铂、奥沙利铂或奈达铂。在本申请第一方面的一些实施方案中，前述化疗药物选自紫杉醇、顺铂或奈达铂。
在本申请第一方面的一些实施方案中，前述免疫治疗药物选自抗程序性死亡受体1抗体(抗PD-1抗体)、抗程序性死亡受体-配体1抗体(抗PD-L1抗体)和抗体偶联药物。优选地，所述抗体偶联药物为抗HER2抗体偶联药物。在本申请第一方面的一些实施方案中，所述抗PD-1抗体选自帕博利珠单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、西米普利单抗、信迪利单抗或特瑞普利单抗；优选地，所述抗PD-1抗体选自特瑞普利单抗、信迪利单抗或替雷利珠单抗。在本申请第一方面的一些实施方案中，所述抗PD-L1抗体选自阿特珠单抗、阿维鲁单抗和度伐鲁单抗。在本申请第一方面的一些实施方案中，所述抗HER2抗体偶联药物选自曲妥珠单抗或迪西妥单抗。
在本申请第一方面的一些实施方案中，所述肿瘤为化疗药物和免疫治疗药物治疗失败的肿瘤；优选地，所述治疗失败的肿瘤为紫杉烷类+铂类化疗药+抗PD-1抗体治疗失败的肿瘤；优选地，所述治疗失败的肿瘤为特瑞普利单抗+紫杉醇+顺铂、信迪利单抗+紫杉醇+顺铂、紫杉醇+洛铂+卡瑞利珠单抗、紫杉醇+奈达铂、信迪利单抗中的一种、两种或三种治疗失败的肿瘤。优选地，所述治疗失败的肿瘤为特瑞普利单抗+紫杉醇+顺铂、信迪利单抗+紫杉醇+顺铂、紫杉醇+洛铂+卡瑞利珠单抗中的一种、两种或三种治疗失败的肿瘤。优选地，所述肿瘤为食管鳞癌；优选地，所述肿瘤为胃食管交界部鳞癌。
在本申请第一方面的一些实施方案中，所述肿瘤为化疗药物治疗失败的肿瘤；优选地，所述肿瘤为紫杉烷类+铂类化疗药治疗失败的肿瘤；优选地，所述治疗失败的肿瘤为紫杉醇+顺铂、或紫杉醇+奈达铂治疗失败的肿瘤。优选地，所述肿瘤为食管鳞癌。
在本申请第一方面的一些实施方案中，所述肿瘤为化疗药物、免疫治疗和放疗治疗失败的肿瘤；优选地，所述肿瘤为紫杉烷类+铂类化疗药+放疗+抗PD-1抗体治疗失败的肿瘤；优选地，所述治疗失败的肿瘤为替雷利珠单抗+放疗+紫杉醇+顺铂治疗失败的肿瘤。优选地，所述肿瘤为食管鳞癌。
在本申请第一方面的一些实施方案中，所述可药用盐选自盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐和对甲苯磺酸盐；优选地为盐酸盐、氢溴酸盐、马来酸盐、磷酸盐、酒石酸盐、富马酸盐和琥珀酸盐；进一步优选地为盐酸盐、马来酸盐、磷酸盐、酒石酸盐和富马酸盐；进一步优选为盐酸盐；更进一步优选为二盐酸盐。
在本申请第一方面的一些实施方案中，所述化合物A的可药用盐为化合物B，
在本申请第一方面的一些实施方案中，所述化合物B为固体形式；优选地，其为结晶形式。
在本申请第一方面的一些实施方案中，所述化合物B的结晶形式为晶型I，使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图谱包含以下位置的特征峰：5.0±0.2°、13.5±0.2°、19.3±0.2°、20.5±0.2°、21.4±0.2° 和25.2±0.2°。
在本申请第一方面的一些实施方案中，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图谱包含以下位置的特征峰：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°和25.2±0.2°。
在本申请第一方面的一些实施方案中，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图谱包含以下位置的特征峰：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°和25.2±0.2°。
在本申请第一方面的一些实施方案中，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图谱包含以下位置的特征峰：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°和26.6±0.2°。
在本申请第一方面的一些实施方案中，所述晶型I使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图谱包含以下位置的特征峰：5.0±0.2°、10.0±0.2°、10.4±0.2°、11.2±0.2°、13.5±0.2°、14.1±0.2°、15.7±0.2°、17.4±0.2°、18.0±0.2°、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°和30.1±0.2°。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐通过药用途径给药，所述途径包括但不限于选自以下的途径：口服、非肠道或局部。在一个特定的实施方案中，通过口服给药。
在本申请第一方面的一些实施方案中，所述药物制成临床接受的制剂，包括但不限于口服制剂、非肠道制剂、局部给药制剂或外用制剂；优选口服制剂；进一步优选片剂和胶囊剂。
在本申请第一方面的一些实施方案中，所述药物每个制剂单位中含有所述化合物A或其可药用盐0.1-200mg，优选1-150mg，或1-100mg，或1-80mg，或1-60mg，或1-50mg，或1-40mg，或1-30mg，或1-20mg，或1-10mg，或1-6mg，例如，1mg、2mg、3mg、4mg、5mg、6mg、8mg、10mg、15mg、20mg、25mg。在本申请第一方面的一些实施方案中，所述药物每个制剂单位中含有所述化合物A或其可药用盐1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、15mg、20mg、25mg。在本申请第一方面的一些实施方案中，所述药物每个制剂单位中含有所述化合物A或其可药用盐1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的质量计。
在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐以单剂量施用或分剂量施用；优选地，以单剂量施用；优选地，所述化合物A的可药用盐为化合物B；进一步优选地，以化合物B的形式施用。
在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐的给药剂量根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐的给药剂量为每日1-50毫克。优选地，给药剂量为每日1-30毫克。优选地，给药剂量为每日1-25毫克。优选地，给药剂量为每日1-20毫克。优选地，给药剂量为每日2-18毫克。优选地，给药剂量为每日4-16毫克。优选地，给药剂量为每日5-15毫克。优选地，给药剂量为每日4-10毫克。优选地，给药剂量为每日4-9毫克。优选地，给药剂量为每日2-9毫克。优选地，给药剂量为每日2-6 毫克。优选地，给药剂量为每日5-9毫克。优选地，给药剂量为每日6-9毫克。优选地，给药剂量为每日6-8毫克。优选地，给药剂量为每日6-12毫克。优选地，给药剂量为每日6-10毫克。优选地，给药剂量为每日2、3、4、5、6、7、8、9、10毫克。优选地，给药剂量为每日2、4、5、6、7、8、9、10毫克。优选地，给药剂量为每日6、7、8、9毫克。优选地，给药剂量为每日4毫克。优选地，给药剂量为每日5毫克。优选地，给药剂量为每日6毫克。优选地，给药剂量为每日7毫克。优选地，给药剂量为每日8毫克。优选地，给药剂量为每日9毫克。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。进一步优选地，所述日剂量以含化合物B的质量计。
在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐的给药频率为每日给药一次、两次、三次或更多次。在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐每日给药一次。在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐每日给药两次。在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐每日给药三次。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。
在本申请第一方面的一些实施方案中，给药方法根据药物的活性、毒性以及患者的耐受性等来综合确定。在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐以连续给药或间隔给药的方式给予。优选地，所述间隔给药包括给药期和停药期；优选地，在给药期内，所述化合物A或其可药用盐每日给药一次、两次、三次或更多次。例如，在给药期内，所述化合物A或其可药用盐每日给药一次，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此反复进行多次。其中，给药期和停药期的以天数计的比值为3∶1～5，优选为3∶1～3，较优选为3∶1～2，更优选为3∶1或3∶1.5(即2∶1)。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为：连续给药，每天给药1次。在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为：连续给药，每天给药2次。在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为：连续给药，每天给药3次。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为：连续给药3周，然后停药1周。在本申请第一方面的一些实施方案中，每天给药1次，持续给药21天，然后停药7天；接着每天给药1次，持续给药21天，然后停药7天，如此连续给药3周停药1周的间隔给药方式可以反复进行多次。在本申请第一方面的一些实施方案中，每天给药2次，持续给药21天，然后停药7天；接着每天给药2次，持续给药21天，然后停药7天，如此连续给药3周停药1周的间隔给药方式可以反复进行多次。在本申请第一方面的一些实施方案中，每天给药3次，持续给药21天，然后停药7天；接着每天给药3次，持续给药21天，然后停药7天，如此连续给药3周停药1周的间隔给药方式可以反复进行多次。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为：连续给药2周，然后停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。在一些实施 方案中，每天给药2次，持续给药14天，然后停药7天；接着每天给药2次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。在一些实施方案中，每天给药3次，持续给药14天，然后停药7天；接着每天给药3次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为连续给药3周停药2周。在本申请第一方面的一些实施方案中，每天给药m次，持续给药21天，然后停药14天；接着每天给药m次，持续给药21天，然后停药14天，如此连续给药3周停药2周的间隔给药方式可以反复进行多次。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为连续给药5天停药2天。在一些实施方案中，每天给药m次，持续给药5天，然后停药2天；接着每天给药m次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为以每日m次，每次n毫克的剂量口服给药，连续用药。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。进一步优选地，所述剂量以化合物B的质量计。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为以每日m次，每次n毫克的剂量口服给药，连续用药3周，停药1周的给药方式给药，每4周为一个周期。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。进一步优选地，所述剂量以化合物B的质量计。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为以每日m次，每次n毫克的剂量口服给药，连续用药2周，停药1周的给药方式给药，每3周为1个周期。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。进一步优选地，所述剂量以化合物B的质量计。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为以每日1次，每次6毫克的剂量口服给药，连续用药。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。进一步优选地，所述剂量以化合物B的质量计。
在本申请第一方面的一些实施方案中，化合物A或其可药用盐的给药方法为以每日1次，每次6毫克的剂量口服给药，连续用药3周，停药1周的给药方式给药。优选地，所述化合物A的可药用盐为化合物B。进一步优选地，以含有化合物B的口服固体制剂形式给予。进一步优选地，所述剂量以化合物B的质量计。
在本申请第一方面的一些实施方案中，m选自1、2或3。在本申请第一方面的一些实施方案中，m为1。在本申请第一方面的一些实施方案中，m为2。在本申请第一方面的一些实施方案中，m为3。
在本申请第一方面的一些实施方案中，n为1、2、3、4、5、6、7、8或9。在本申请第一方面的一些实施方案中，n为1。在本申请第一方面的一些实施方案中，n为2。在本申请第一方面的一些实施方案中， n为3。在本申请第一方面的一些实施方案中，n为4。在本申请第一方面的一些实施方案中，n为5。在本申请第一方面的一些实施方案中，n为6。在本申请第一方面的一些实施方案中，n为7。在本申请第一方面的一些实施方案中，n为8。在本申请第一方面的一些实施方案中，n为9。
在本申请第一方面的一些实施方案中，所述化合物A或其可药用盐与临床上常用的治疗食管癌或胃食管交界部癌的药物中的一种、两种、三种或更多种联合用于制备所述药物。
在本申请第一方面的一些实施方案中，所述药物进一步与临床上常用的治疗食管癌或胃食管交界部癌的药物中的一种、两种、三种或更多种联合使用。
第二方面，本申请提供了一种治疗个体中的肿瘤的方法，包括向所述个体给予治疗有效量的第一方面所述化合物A或其可药用盐，其中，所述肿瘤为食管癌或胃食管交界部癌。
在本申请第二方面的一些实施方案中，所述方法，进一步包括治疗有效量的其它药物，所述其它药物选自临床上常用的治疗食管癌或胃食管交界部癌的药物中的一种、两种、三种或更多种。
在不存在矛盾和冲突的情况下，第一方面所述的技术方案或技术特征适用于第二方面。
第2.1方面，本申请提供了化合物A或其可药用盐，其用于***，其中，所述肿瘤为食管癌或胃食管交界部癌。
在本申请第2.1方面的一些实施方案中，进一步包括其它药物，所述其它药物选自临床上常用的治疗食管癌或胃食管交界部癌的药物中的一种、两种、三种或更多种。
在不存在矛盾和冲突的情况下，第一方面所述的技术方案或技术特征适用于第2.1方面。
第三方面，本申请提供了一种用于***的药物组合物，其包含第一方面所述的化合物A或其可药用盐，并任选地包含药学上可接受的载体，其中，所述肿瘤为食管癌或胃食管交界部癌。
在本申请第三方面的一些实施方案中，所述药物组合物包含化合物A的可药用盐，并任选地包含药学上可接受的载体。在本申请第三方面的一些实施方案中，所述药物组合物包含化合物A的盐酸盐，并任选地包含药学上可接受的载体。在本申请第三方面的一些实施方案中，所述药物组合物包含化合物B，并任选地包含药学上可接受的载体。在本申请第三方面的一些实施方案中，所述药物组合物包含化合物B的固体形式，并任选地包含药学上可接受的载体。在本申请第三方面的一些实施方案中，所述药物组合物包含化合物B的结晶形式，并任选地包含药学上可接受的载体。在本申请第三方面的一些实施方案中，所述药物组合物包含化合物B的晶型I，并任选地包含药学上可接受的载体。
在本申请第三方面的一些实施方案中，所述药物组合物，包含化合物A或其可药用盐及药学上可接受的载体，进一步包括治疗有效量的其它药物，所述其它药物选自临床上常用的治疗食管癌或胃食管交界部癌的药物。
在本申请第三方面的一些实施方案中，所述药物组合物，包含化合物B及药学上可接受的载体，进一步包括治疗有效量的其它药物，所述其它药物选自临床上常用的治疗食管癌或胃食管交界部癌的药物中的一种、两种、三种或更多种。
在不存在矛盾和冲突的情况下，第一方面所述的技术方案或技术特征适用于第三方面。
第四方面，本申请提供了一种药物试剂盒，其包含(a)至少一个单位剂量的化合物A或其可药用盐的药物组合物和(b)用于***的说明书，其中，所述肿瘤为食管癌或胃食管交界部癌。在一些方案 中，提供了一种试剂盒，其包含(a)至少一个单位剂量的化合物A或其可药用盐的口服制剂和(b)用于***的说明书，其中，所述肿瘤为食管癌或胃食管交界部癌。所述的“单位剂量”是指为了服用的方便，包装在单个包装中的药物组合物或口服制剂。例如，每份药物组合物、每片片剂或每粒胶囊。
在不存在矛盾和冲突的情况下，第一方面所述的技术方案或技术特征适用于第四方面。
第五方面，本申请提供了化合物A或其可药用盐在制备用于***的药物中的用途，其中，所述肿瘤为消化道鳞癌，
在本申请第五方面的一些实施方案中，所述肿瘤为上消化道鳞癌；优选地，所述上消化道鳞癌选自食管鳞癌或胃食管交界部鳞癌。
在本申请第五方面的一些实施方案中，所述肿瘤为伴有FGFR、VEGFR、集落刺激因子1受体(CSF1R)中的一种、两种或三种的基因异常或蛋白表达异常的肿瘤。优选地，所述肿瘤为伴有FGFR、VEGFR、CSF1R中的一种、两种或三种基因突变的肿瘤。
在本申请第五方面的一些实施方案中，所述肿瘤为局部晚期肿瘤或转移性肿瘤；优选为不可手术切除的局部晚期肿瘤或不可手术切除的转移性肿瘤。
在本申请第五方面的一些实施方案中，所述肿瘤为在先治疗失败的肿瘤。
在本申请第五方面的一些实施方案中，所述肿瘤为***性药物治疗失败的肿瘤。
在本申请第五方面的一些实施方案中，所述肿瘤为一线治疗失败的肿瘤。
在本申请第五方面的一些实施方案中，所述肿瘤为二线治疗失败的肿瘤。
在本申请第五方面的一些实施方案中，所述肿瘤为后线治疗失败的肿瘤。
在本申请第五方面的一些实施方案中，所述肿瘤为免疫治疗药物、化疗药物、放疗、生物治疗、中药治疗、小分子靶向药物中的一种、两种、三种或更多种治疗失败的肿瘤。在本申请第五方面的一些实施方案中，所述肿瘤为放疗、免疫治疗药物或化疗药物治疗失败的肿瘤。在本申请第五方面的一些实施方案中，所述肿瘤为放疗和免疫治疗药物治疗失败的肿瘤。在本申请第五方面的一些实施方案中，所述肿瘤为放疗和化疗药物治疗失败的肿瘤。在本申请第五方面的一些实施方案中，所述肿瘤为化疗药物和免疫治疗药物治疗失败的肿瘤。在本申请第五方面的一些实施方案中，所述肿瘤为化疗药物、免疫治疗药物和放疗治疗失败的肿瘤。
在本申请第五方面的一些实施方案中，前述化疗药物选自细胞毒类药、抗代谢类药、抗生素类药、生物碱类药、DNA拓扑异构酶抑制剂类化疗药、抗微管类化疗药、铂类化疗药和激素类药；优选地，前述化疗药物选自抗代谢类药、生物碱类药、DNA拓扑异构酶抑制剂类化疗药、抗微管类化疗药和铂类化疗 药。
在本申请第五方面的一些实施方案中，前述化疗药物选自紫杉烷类药物、铂类药物、氟尿嘧啶类药物或DNA拓扑异构酶抑制剂类化疗药。在本申请第五方面的一些实施方案中，所述紫杉烷类药物选自紫杉醇、多西他赛或卡巴它赛；优选为紫杉醇。在本申请第五方面的一些实施方案中，所述DNA拓扑异构酶抑制剂类化疗药选自羟喜树碱、伊立替康、拓扑替康、依托泊苷或替尼泊苷。在本申请第五方面的一些实施方案中，所述铂类药物选自顺铂、卡铂、环硫铂、洛铂、奥沙利铂或奈达铂；优选为顺铂、奥沙利铂或奈达铂。在本申请第五方面的一些实施方案中，前述化疗药物选自紫杉醇、顺铂或奈达铂。
在本申请第五方面的一些实施方案中，前述免疫治疗药物选自抗程序性死亡受体1抗体(抗PD-1抗体)、抗程序性死亡受体-配体1抗体(抗PD-L1抗体)和抗体偶联药物。优选地，所述抗体偶联药物为抗HER2抗体偶联药物。在本申请第五方面的一些实施方案中，所述抗PD-1抗体选自帕博利珠单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、西米普利单抗、信迪利单抗或特瑞普利单抗；优选地，所述抗PD-1抗体选自特瑞普利单抗、信迪利单抗或替雷利珠单抗。在本申请第五方面的一些实施方案中，所述抗PD-L1抗体选自阿特珠单抗、阿维鲁单抗和度伐鲁单抗。在本申请第五方面的一些实施方案中，所述抗HER2抗体偶联药物选自曲妥珠单抗或迪西妥单抗。
在本申请第五方面的一些实施方案中，所述肿瘤为化疗药物和免疫治疗药物治疗失败的肿瘤；优选地，所述治疗失败的肿瘤为紫杉烷类+铂类化疗药+抗PD-1抗体治疗失败的肿瘤；优选地，所述治疗失败的肿瘤为特瑞普利单抗+紫杉醇+顺铂、信迪利单抗+紫杉醇+顺铂、紫杉醇+洛铂+卡瑞利珠单抗、紫杉醇+奈达铂、信迪利单抗中的一种两种、三种或更多种治疗失败的肿瘤。优选地，所述肿瘤为食管鳞癌。
在本申请第五方面的一些实施方案中，所述肿瘤为化疗药物治疗失败的肿瘤；优选地，所述肿瘤为紫杉烷类+铂类化疗药治疗失败的所述肿瘤；优选地，所述治疗失败的肿瘤为紫杉醇+顺铂或紫杉醇+奈达铂治疗失败的肿瘤。优选地，所述肿瘤为食管鳞癌。
在本申请第五方面的一些实施方案中，所述肿瘤为化疗药物、免疫治疗和放疗治疗失败的肿瘤；优选地，所述肿瘤为紫杉烷类+铂类化疗药+放疗+抗PD-1抗体治疗失败的肿瘤；优选地，所述治疗失败的肿瘤为替雷利珠单抗+放疗+化疗治疗失败的肿瘤。优选地，所述肿瘤为食管鳞癌。
在不存在矛盾和冲突的情况下，第一方面所述的技术方案或技术特征适用于第五方面。
第六方面，本申请提供了化合物A或其可药用盐在制备用于***的药物中的用途，
其中，所述肿瘤为鳞状细胞癌。
在本申请第六方面的一些实施方案中，所述肿瘤选自头颈部鳞癌、消化道鳞癌或呼吸道鳞；优选地， 所述肿瘤选自头颈部鳞癌、上消化道鳞癌或呼吸道鳞癌；进一步优选地，所述肿瘤选自食管鳞癌、胃食管交界部鳞癌、头颈部鳞癌和肺鳞癌；进一步优选地，所述肿瘤选自食管鳞癌、胃食管交界部鳞癌、鼻咽鳞癌和肺鳞癌；进一步优选地，所述肿瘤选自鼻咽鳞癌、食管鳞癌和肺鳞癌；进一步优选地，所述肿瘤为食管鳞癌。
在本申请第六方面的一些实施方案中，所述肿瘤为伴有FGFR、VEGFR、CSF1R中的一种、两种或三种的基因异常或蛋白表达异常的肿瘤。优选地，所述肿瘤为伴有FGFR、VEGFR、CSF1R中的一种、两种或三种的基因异常的肿瘤。
在本申请第六方面的一些实施方案中，所述肿瘤为局部晚期肿瘤或转移性肿瘤；优选为不可手术切除的局部晚期肿瘤或不可手术切除的转移性肿瘤。
在本申请第六方面的一些实施方案中，所述肿瘤为在先治疗失败或复发的肿瘤。
在本申请第六方面的一些实施方案中，所述肿瘤为***性药物治疗失败的肿瘤。
在本申请第六方面的一些实施方案中，所述肿瘤为一线治疗失败的肿瘤。
在本申请第六方面的一些实施方案中，所述肿瘤为二线治疗失败的、或后线治疗失败的肿瘤。
在本申请第六方面的一些实施方案中，所述肿瘤为免疫治疗药物、化疗药物、放疗、生物治疗、中药治疗、小分子靶向药物中的一种、两种、三种或更多种治疗失败的肿瘤。在本申请第六方面的一些实施方案中，所述肿瘤为放疗、免疫治疗药物或化疗药物治疗失败的肿瘤。在本申请第六方面的一些实施方案中，所述肿瘤为放疗和免疫治疗药物治疗失败的肿瘤。在本申请第六方面的一些实施方案中，所述肿瘤为放疗和化疗药物治疗失败的肿瘤。在本申请第六方面的一些实施方案中，所述肿瘤为化疗药物和免疫治疗药物治疗失败的肿瘤。在本申请第六方面的一些实施方案中，所述肿瘤为化疗药物、免疫治疗药物和放疗治疗失败的肿瘤。
在本申请第六方面的一些实施方案中，前述化疗药物选自细胞毒类药、抗代谢类药、抗生素类药、生物碱类药、DNA拓扑异构酶抑制剂类化疗药、抗微管类化疗药、铂类化疗药和激素类药；优选地，前述化疗药物选自抗代谢类药、生物碱类药、DNA拓扑异构酶抑制剂类化疗药、抗微管类化疗药和铂类化疗药。
在本申请第六方面的一些实施方案中，前述化疗药物选自紫杉烷类药物、铂类药物、氟尿嘧啶类药物或DNA拓扑异构酶抑制剂类化疗药。在一些实施方案中，所述紫杉烷类药物选自紫杉醇、多西他赛或卡巴它赛；优选为紫杉醇。在一些实施方案中，所述DNA拓扑异构酶抑制剂类化疗药选自羟喜树碱、伊立替康、拓扑替康、依托泊苷或替尼泊苷。在一些实施方案中，所述铂类药物选自顺铂、卡铂、环硫铂、洛铂、奥沙利铂或奈达铂；优选为顺铂、奥沙利铂或奈达铂。在一些实施方案中，前述化疗药物选自紫杉醇、顺铂或奈达铂。
在本申请第六方面的一些实施方案中，前述免疫治疗药物选自抗程序性死亡受体1抗体(抗PD-1抗体)、抗程序性死亡受体-配体1抗体(抗PD-L1抗体)和抗体偶联药物。优选地，所述抗体偶联药物为抗HER2抗体偶联药物。在一些实施方案中，所述抗PD-1抗体选自帕博利珠单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、西米普利单抗、信迪利单抗或特瑞普利单抗；优选地，所述抗PD-1抗体选自特瑞普利单抗、信迪利单抗或替雷利珠单抗。在一些实施方案中，所述抗PD-L1抗体选自阿特珠单抗、阿 维鲁单抗和度伐鲁单抗。在一些实施方案中，所述抗HER2抗体偶联药物选自曲妥珠单抗或迪西妥单抗。
在本申请第六方面的一些实施方案中，所述肿瘤为化疗药物和免疫治疗药物治疗失败的肿瘤；优选地，所述肿瘤为紫杉烷类+铂类化疗药+抗PD-1抗体治疗失败的肿瘤；优选地，所述肿瘤为特瑞普利单抗+紫杉醇+顺铂、信迪利单抗+紫杉醇+顺铂、紫杉醇+洛铂+卡瑞利珠单抗、紫杉醇+奈达铂、信迪利单抗中的一种、两种、三种或更多种治疗失败的肿瘤。
在本申请第六方面的一些实施方案中，所述肿瘤为化疗药物治疗失败的肿瘤；优选地，所述肿瘤为紫杉烷类+铂类化疗药治疗失败的肿瘤；优选地，所述肿瘤为紫杉醇+顺铂、紫杉醇+卡铂或紫杉醇+奈达铂治疗失败的肿瘤。
在本申请第六方面的一些实施方案中，所述肿瘤为化疗药物、免疫治疗和放疗治疗失败的肿瘤；优选地，所述肿瘤为紫杉烷类+铂类化疗药+放疗+抗PD-1抗体治疗失败的肿瘤；优选地，所述肿瘤为替雷利珠单抗+放疗+化疗治疗失败的肿瘤。
在不存在矛盾和冲突的情况下，第一方面所述的技术方案或技术特征适用于第六方面。
第七方面，本申请提供了一种治疗个体中的肿瘤的方法，包括向所述个体给予治疗有效量的第一方面所述化合物A或其可药用盐，其中，所述肿瘤为鳞状细胞癌。
在本申请第七方面的一些实施方案中，所述方法，进一步包括治疗有效量的其它药物，所述其它药物选自临床上常用的治疗鳞状细胞癌的药物中的一种、两种、三种或更多种。
在不存在矛盾和冲突的情况下，第一方面或第六方面所述的技术方案或技术特征适用于第七方面。
第八方面，本申请提供了化合物A或其可药用盐，其用于***，其中，所述肿瘤为鳞状细胞癌。
在本申请第八方面的一些实施方案中，进一步包括其它药物，所述其它药物选自临床上常用的治疗鳞状细胞癌的药物中的一种、两种、三种或更多种。
在不存在矛盾和冲突的情况下，第一方面或第六方面所述的技术方案或技术特征适用于第八方面。
第九方面，本申请提供了一种用于***的药物组合物，其包含化合物A或其可药用盐，并任选地包含药学上可接受的载体，其中所述肿瘤为鳞状细胞癌。
在本申请第九方面的一些实施方案中，所述药物组合物包含化合物A的可药用盐，并任选地包含药学上可接受的载体。在本申请第九方面的一些实施方案中，所述药物组合物包含化合物A的盐酸盐，并任选地包含药学上可接受的载体。在本申请第九方面的一些实施方案中，所述药物组合物包含化合物B，并任选地包含药学上可接受的载体。在本申请第九方面的一些实施方案中，所述药物组合物包含化合物B的固体形式，并任选地包含药学上可接受的载体。在本申请第九方面的一些实施方案中，所述药物组合物包含化合物B的结晶形式，并任选地包含药学上可接受的载体。在本申请第九方面的一些实施方案中，所述药物组合物包含化合物B的晶型I，并任选地包含药学上可接受的载体。
在本申请第九方面的一些实施方案中，所述药物组合物，包含化合物A或其可药用盐及药学上可接受的载体，进一步包括治疗有效量的其它药物，所述其它药物选自临床上常用的治疗鳞状细胞癌的药物。
在本申请第九方面的一些实施方案中，所述药物组合物，包含化合物B及药学上可接受的载体，进一步包括治疗有效量的其它药物，所述其它药物选自临床上常用的治疗鳞状细胞癌的药物中的一种、两种、三种或更多种。
在不存在矛盾和冲突的情况下，第一方面或第六方面所述的技术方案或技术特征适用于第九方面。
在一些实施方案中，所提供的用途(第一方面)、方法(第二方面)、化合物或其可药用盐(第2.1方面)、药物组合物(第三方面)、试剂盒(第四方面)、用途(第五方面)、用途(第六方面)、方法(第七方面)、化合物或其可药用盐(第八方面)或药物组合物(第九方面)中，化合物A或其可药用盐作为唯一的活性成分单独给予患者。在一些实施方案中，在所提供的用途(第一方面)、方法(第二方面)、化合物或其可药用盐(第2.1方面)、药物组合物(第三方面)、试剂盒(第四方面)、用途(第五方面)、方法(第七方面)、化合物或其可药用盐(第八方面)或药物组合物(第九方面)中进一步含有其它药物，化合物A或其可药用盐与其他它药物同时或依照次序给予肿瘤患者，其中，所述肿瘤为第一方面所述的食管癌或胃食管交界部癌、第五方面所述的消化道鳞癌或第六方面所述的鳞状细胞癌。优选地，所述的其它药物包括但不限于化疗药物、免疫治疗药物、小分子靶向药物。
本申请所述的“在先治疗”包括但不限于放疗、化疗、靶向治疗(包含免疫治疗和小分子靶向药物治疗)中的一种，两种，三种或更多种。
本申请所述的“免疫治疗”包括免疫检查点抑制剂、肿瘤疫苗、细胞免疫细胞治疗、非特异性免疫调节剂及免疫调节抗体-药物偶联物(或称抗体药物偶联物，Antibody-drug Conjugate)。
本申请所述的“一线治疗”不限于经批准用于治疗具体肿瘤病症(例如，食管癌、胃食管交界部癌、鼻咽鳞癌、肺鳞癌等)的一线药物治疗方案，还包括诊断后首个用于治疗食具体肿瘤病症的非一线化疗方案、免疫治疗、靶向治疗等***性药物治疗，“经一线治疗失败”还包括辅助化疗6个月内出现疾病进展。
本申请所述的单独施用，是指无需与其它具有抗肿瘤作用的药物联合使用，但是不排除使用一些不具有抗肿瘤作用的辅助用药。
本申请取得了以下有益的技术效果：(1)所述化合物A或其可药用盐(例如，化合物B)对食管癌、胃食管交界部癌和/或鳞状细胞癌(例如，鼻咽鳞癌、肺鳞癌、食管鳞癌)表现出临床获益，具有治疗食管癌、胃食管交界部癌和鳞状细胞癌的临床潜力；(2)所述化合物A或其可药用盐(例如，化合物B)在临床I期试验中表现出较好的耐受性，不良反应种类少，提示其临床安全性较好。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在含有下列含义。一个特定的短语或术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。
本申请提及的“药学上可接受的”是指其用于制备药物组合物，该药物组合物通常是安全、无毒的并且既不在生物学上或其他方面不合乎需要，并且包括其对于人类药物使用是可接受的。
本申请提及的“固体形式”是指呈固体形态的化合物，包括化合物B的结晶形式和无定型。
本申请提及的“结晶形式”是指呈结晶形态的化合物，包括化合物B的无水且无溶剂形式(或称为无水形式)、水合物形式、溶剂合物形式和共晶形式。所述结晶形式优选为无水且无溶剂形式或水合物形式；进一步优选为无水且无溶剂形式。
本申请提及的“治疗”是指减轻、缓解或改善疾病或病症的症状，改善潜在的代谢引起的症状，抑制疾病或症状，例如阻止疾病或病症的发展、缓解疾病或病症、引起疾病或病症的消退、缓解疾病或病症引起 的病况、或阻止疾病或病症的症状。
本申请提及的“治疗失败”是指治疗过程中疾病进展、治疗结束后复发或毒副作用不可耐受。
本申请提及的“***性药物治疗”包括新辅助治疗和辅助治疗，以及针对晚期患者的化疗、小分子靶向治疗和免疫治疗。
本申请提及的“基因异常”是指FGFR、VEGFR或CSF1R的基因发生融合、扩增、重排或突变中的一种或多种事件。本申请提及的“蛋白表达异常”是指蛋白的过表达、错误折叠或激酶结构域重复中的一种或多种事件。
本申请提及的“任选”或“任选的/地”是指含有或者不含有，意味着随后所描述的事件或情况可以但不必发生，该说明包括该事件或情况发生或不发生的场合。
本申请中提及的“更多种”或“更多次”，在一些情况下，表示4种或4次以上，例如“一种、两种、三种或更多种”的情况；在一些情况下，表示2种、3种或3种以上，例如“一种或多种”的情况。
本申请中“胃食管交界部癌”中“交界部”也称为“结合部”，即其含义同“胃食管结合部癌”。
本申请中的“头颈部鳞癌”也称为“头颈部鳞状细胞癌”。本申请中的“消化道鳞癌”也称为“消化道鳞状细胞癌”。本申请中的“呼吸道鳞癌”也称为“呼吸道鳞状细胞癌”。本申请中的“上消化道鳞癌”也称为“上呼吸道鳞状细胞癌”。本申请中的“食管鳞癌”也称为“食管鳞状细胞癌”或“食道鳞癌”或“食道鳞状细胞癌”。本申请中的“胃食管交界部鳞癌”也称为“胃食管交界部鳞状细胞癌”。本申请中的“肺鳞癌”也称为“肺鳞状细胞癌”。本申请中的“鼻咽鳞癌”也称为“鼻咽鳞状细胞癌”或“鼻咽部鳞状细胞癌”。
本申请的药物组合物可以采用本领域的已知方法制备得到。
术语“药物组合物”是指一种或多种本申请的化合物或其可药用盐与药学上可接受的载体组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物可药用盐、其立体异构体或前药。本申请的药物组合物可以采用本领域的常规方法制备得到。
在本申请的上下文中，术语“药学上可接受的载体”也可称为“赋形剂”或“药学上可接受的辅料”或“药用可接受的辅料”，是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。术语“药学上可接受的载体”包括但不限于：溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、填充剂等。本领域技术人员可根据实际需要选择具体的药用可接受的辅料，制备成需要的剂型，例如，片剂。有关辅料的知识是本领域技术人员众所周知的，例如可以参考《药剂学》(崔福德主编，第5版，人民卫生出版社，2003)。
ORR：从首次给药当日算起，包括完全缓解(CR)和部分缓解(PR)受试者占所有入组受试者的百分率。
PFS：从首次给药当日算起直至肿瘤进展(经影像学诊断评定PD)的日期或全因死亡日期之间的时长(以先发生者优先)。
OS：从首次给药当日算起直至因任何原因引起死亡的时间(失访受试者为最后一次随访时间；研究结束时仍然存活受试者，为随访结束日。
DCR：定义为从首次给药当日算起，包括CR、PR或疾病稳定(SD)的受试者占所有入组受试者的百分比。
DOR：肿瘤第一次评估为CR或PR开始到第一次评估为PD或任何原因死亡的时间。
CR：是指完全缓解，即所有靶病灶消失，全部病理***(包括靶结节和非靶结节)短直径必须减少至＜10mm。
PR：是指部分缓解，靶病灶直径之和比基线水平减少至少30％。
PD：是指疾病进展，以整个研究过程中所有测得的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；且必须满足直径和的相对值增加至少5mm，若出现一个或多个新病灶也视为疾病进展。
SD：是指疾病稳定，靶病灶减小的程度没达到PR水平，增加的程度也没达到PD水平，介于两者之间。
词语“包括”或“包含”应理解为开放的、非排他性的意义，即“包括但不限于”。
在本申请的范围中，任一特征的各种选项可以与其它特征的各种选项相互组合，从而构成许多不同的实施方案。本申请意欲包括由所有技术特征的各种选项所组成的所有可能的实施方案。应理解，在本发明的范围内，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征中间都是可以互相组合的，从而构成新的或优选的技术方案，限于篇幅不再一一赘述。
本申请的化合物可以通过本领域技术人员所知晓的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所知晓的等同替换方式，优选的实施方式包括但不限于本申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
下面会通过实施例具体描述本申请，这些实施例并不意味着对本申请的任何限制。
本申请所使用的所有试剂、溶剂是市售的，无需进一步纯化即可使用。
具体实施方式
下文将结合具体实施例、测试例和试验例对本申请的技术方案做更进一步的详细说明。下列实施例、测试例和试验例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。除非另有说明，以下实施例、测试例中使用的原料、试剂(例如，有机溶剂、无机溶剂等)均为市售商品，或者可以通过已知方法或试剂说明书制备或配制。
以下实施例中，分析检测条件如下：
1、X射线粉末衍射(X-ray powder diffractometer，XRPD)
仪器：德国BRUKER D8 Advance X射线粉末衍射仪。
条件：Cu-Kα辐射管压40kV，管流40mA，2θ扫描范围3-40°，扫描步长为0.02°(2θ)，扫描速度10s/步，样品盘为零背景样品盘。
方法：将样品铺在零背景单晶硅样品盘上，用药匙轻压铺平进行测量。
2、氯化物
检测仪器：戴安ICS-900离子色谱仪
柱子：Dionex Ion Pac AS11-HC阴离子色谱柱(规格：4×250mm)
测定法：精密量取对照品溶液和供试品溶液各10μL，分别注入离子色谱仪，记录色谱图，按外标法以峰面积计算氯离子含量。
3、动态水分吸脱附分析(DVS)
仪器：DVS Intrinsic plus(SMS，UK)。
方法：将样品置于已去皮的样品篮中，样品重量自动称量，按照下表中的参数对样品进行分析。
4、热重分析(TGA)检测条件
仪器：Discovery TGA 55。
条件：温度范围为室温至350℃，加热速率10℃/min，吹扫气体为氮气，平衡室流速：40mL/min，样品室流速：25mL/min。
样品：1-5mg。
实施例1：化合物B的制备
将化合物A(0.52g，参照WO2017140269A1制备实施例10制备得到)和甲醇(25mL)加入反应瓶中，搅拌，待体系分散均匀，在搅拌下滴加盐酸甲醇溶液(1.2mL，2mol/L)，滴毕后继续搅拌5h。过滤，经 真空干燥(30℃下真空干燥12h烘至恒重，再45℃真空烘料至溶剂残留合格)得固体(0.53g)。经核磁检测，确证已成盐。
通过离子色谱法测定氯离子含量，计算该盐酸盐的化学计量比(见下表)，可以推断得到该盐酸盐的碱/酸比为1∶2。
表1
取所得固体样品进行X-射线粉末衍射，结果显示其呈现良好的结晶性，命名为晶型I，其衍射峰数据见表2。
表2实施例1所得晶型I样品XRPD衍射峰数据表
实施例2：化合物B的晶型I的制备
将化合物A(1.0432g，参照WO2017140269A1制备实施例10制备得到)和纯化水(3mL)加入反应瓶中，搅拌使体系分散均匀，滴加盐酸水溶液(2N)，搅拌至完全溶清，加入实施例1所得晶型I样品(0.01g)作为晶种，搅拌析晶20～24h后，进行抽滤。在30℃下真空干燥12h后，再在45℃下真空烘料至溶剂残留合格，得固体(1.112g)，经检测，确证得到化合物B的晶型I，其结晶性良好。所得样品的XRPD表征数据见表3，取样品进行TGA-DSC测试，结果显示样品不含结晶水和结晶溶剂。
表3实施例2所得晶型I样品XRPD衍射峰数据表
实施例3、化合物A其它盐的制备
向装有0.02mol/mL酸(磷酸、马来酸、酒石酸、富马酸)的四氢呋喃/甲醇(1∶1，体积比，以下相同)溶液(5mL)的瓶中，分别依次加入0.01mol/mL化合物A的四氢呋喃/甲醇(1∶1)溶液(10mL)，搅拌混匀，于40℃条件下反应1h。反应液挥干，于50℃下干燥3～4h。均得到固体，经核磁和离子色谱检测，分别得到化合物A的磷酸盐、马来酸盐、酒石酸盐和富马酸盐。
进一步经XRPD检测，所得固体的结晶性均良好。
测试例1：溶解度实验
先将化合物A、实施例2所得样品(化合物B)和实施例3所得样品分别在水中进行溶解度测试。然后将化合物A和实施例2所得样品(化合物B)分别在Na2HPO4-柠檬酸缓冲液(PH4.6)介质中进行溶解度测试，实验结果分别见表4和5。
表4化合物A及其不同盐型的溶解度实验结果(25℃，mg/mL)
表5化合物A及化合物B的溶解度实验结果(25℃，mg/mL)
结果显示实施例2所得样品和实施例3所得的不同盐的样品在水中溶解度良好，且溶解度明显优于游离碱，符合口服剂型对于原料药溶解度的一般要求，特别是实施例2所得的样品，符合多种药物剂型(例如固体口服剂型、注射剂、口服液等)对原料药溶解度的一般要求。实施例2所得样品在缓冲液中亦具有较化合物A更好的溶解度。
测试例2：水的吸附和解吸实验
采用动态水吸附仪(DVS)对实施例2和实施例3所得样品在25℃的温度下，考察其在40～80％相对湿度对水分的吸附和解吸实验，以确定各种不同盐型的引湿性能，实验结果见表6。
表6化合物A不同盐型的引湿性实验结果(DVS，40-80％)
结果显示：实施例3所得样品略有引湿性(马来酸盐)或有引湿性，但引湿增重数值不高；实施例2所得样品略有引湿性，但引湿增重量更低。
测试例3：固体稳定性试验
考察实施例2所得样品在40℃/75％RH(敞口)和60℃(密封)条件下放置7天的物理稳定性和化学稳定性，以及在室温/92.5％RH(敞口)条件下放置10天的物理稳定性，实验结果见下表7。
表7固体稳定性试验结果
注：/表示未检测；晶型结果使用X-射线粉末衍射方法测试。
结果显示在40℃/75％RH和60℃的条件下放置7天，化合物B的纯度未发生明显改变，晶型未发生转变；在92.5％RH的条件下放置10天，其晶型亦未发生转变。说明化合物B具备良好的化学稳定性，其晶型I具备良好的物理稳定性。
测试例4：研磨稳定性实验
取实施例2所得样品，使用研钵分别进行2分钟和5分钟的机械研磨，经X-射线粉末衍射测试，结果表明晶型I研磨后均未发生晶型转变。
进一步地，取实施例2所得样品分别滴加适量有机溶剂(甲醇、乙醇、丙酮、乙腈、乙酸乙酯等)后进行机械研磨，经X-射线粉末衍射测试，结果表明研磨后晶型I均未发生晶型转变。
综上所述，本申请的化合物A的盐具备较好的药用潜力，特别是本申请的化合物B及其晶型I，相对于其它晶型或其它盐型具有更好的药用潜力。
化合物B及其晶型I的制备及测试等相关内容也可参考专利申请CN202210268968.7或PCT/CN2023/082140，其全部内容被引用到本申请中。
试验例1临床I期试验及结果
药物：化合物B，片剂。
1.研究方法
1.1入组标准：主要包括：(1)签署知情同意时年龄18～70周岁(含18周岁及70周岁)；(2)经组织病理学或细胞学证实的不可切除的局部晚期或转移的实体瘤患者，经标准治疗失败或不耐受，或无可选择的标准治疗方案；(3)至少存在一处符合RECIST v1.1定义的可测量病灶；(4)ECOG体力状况(PS)评分：0～1分；等。
1.2给药方案：
(1)剂量爬坡阶段：起始剂量：1mg、2mg、4mg、6mg、9mg、12mg、16mg、20mg、25mg，每日一次，口服。单次给药后7天进入多次给药期(连续给药，每28天为一个周期，直至疾病进展或出现不可耐受的毒性反应)。完成单次给药及多次给药第一周期治疗与观察的受试者，受试者有获益且可耐受研究药物治疗，依据受试者意愿，可进入延长治疗期，延长治疗期每4周一个周期。
(2)剂量扩展阶段：4mg、6mg，每日一次，口服。对于连续给药组，每4周为1个周期；对于服3周停1周组，每4周为一个周期；对于服2周停1周组，每3周为1个周期。
1.3结果评价：(1)有效性评估：在该研究中，对于剂量爬坡阶段，多次给药第1天后4周、8周、12周及之后的每8周进行一次疗效评价，进行数据分析；对于剂量扩展阶段，服3周停1周组在多次给药第1天后4周、8周、12周及之后的每8周进行一次疗效评价，服2周停1周组在多次给药第1天后每6 周进行一次疗效评价。有效性指标包括客观缓解率(ORR)、无进展生存期(PFS)、总生存期(OS)、疾病控制率(DCR)、缓解持续时间(DOR)；(2)安全性评估：包括对生命体征和体格检查、心电图、ECOG PS评分、实验室检查、不良事件等评估。
2.临床试验结果：
2.1有效性评估结果
在已获得的对不同实体瘤的疗效数据中，化合物B对实体瘤患者表现出了良好的疗效。特别是，化合物B对食管癌和鳞状细胞癌(例如，食管鳞癌、肺鳞癌、鼻咽鳞癌等)表现出临床获益，特别是食管鳞癌。
2.1.1疗效数据：
给药83例实体瘤患者，其中包括48例鳞状细胞癌患者，具体地，包括41例食管鳞癌患者、5例肺鳞癌患者和2例鼻咽鳞癌患者。经评估，在41例食管鳞癌患者中，6例PR，21例SD(其中，11例为靶病灶缩小的SD)；在5例肺鳞癌患者中，4例SD，均为靶病灶缩小的SD；在2例鼻咽鳞癌患者中，1例SD，其为靶病灶缩小的SD。
2.2典型病例
(1)典型病例1
S03002受试者，男，57岁，于2020年8月23日诊断食管鳞癌。该受试者于2020年9月参加临床试验“特瑞普利单抗/安慰剂+注射紫杉醇+注射顺铂”，2020年9月24日至2021年1月应用“特瑞普利单抗/安慰剂+注射紫杉醇+注射顺铂”治疗，2021年2月至2021年4月应用“特瑞普利单抗/安慰剂”，最佳疗效SD，2021年4月20日经疗效评价为PD出组。
该受试者于2021年4月21日签署ICF，筛选分期IV期，于2021年4月30日首次服用试验药物，6mg连续给药，QD。
用药期间，受试者第一、二、三周期末疗效评估均为PR，最佳疗效PR。
(2)典型病例2
S03008受试者男，68岁，于2019年8月30日诊断食管鳞癌。该受试者在2019年10月17日至2021年12月参加临床试验“信迪利单抗/安慰剂+紫杉醇+顺铂”，最佳疗效PR，2021年12月经疗效评价为PD。
该受试者于2022年1月13日签署ICF，筛选分期IV期，于2022年2月9日首次服用试验药物，6mg连续给药，QD。
用药期间，受试者第一周期末疗效评估为SD，第二、三、五周期末疗效评估均为PR，最佳疗效PR。目前仍用药中。
至今疗效评估仍为PR，第18周期用药中。
(3)典型病例3
S03009受试者，男，49岁，于2021年1月诊断食管鳞癌III期。2021年2月起应用“白蛋白紫杉醇联合奈达铂”治疗3周期，最佳疗效未知。2021年4月起参加临床试验“替雷利珠单抗/安慰剂+同步放化疗(化疗药物：紫杉醇+注射用顺铂)”，2021年12月经疗效评价为PD。
该受试者于2022年2月9日签署ICF，筛选分期IV期，于2022年2月21日首次服用试验药物，9mg连续给药，QD。
用药期间，受试者第一、二、三周期末疗效评估均为PR，最佳疗效PR。
(4)典型病例4
S03018受试者，男，64岁，于2022年2月10日诊断食管鳞癌。2022年2月19日至2022年4月26日应用“白蛋白结合型紫杉醇+洛铂+卡瑞利珠单抗”治疗2周期，最佳疗效SD，后因不可耐受停止治疗。2022年7月5日经疗效评价为PD。
该受试者于2022年7月19日签署ICF，筛选分期IV期，于2022年8月1日首次服用试验药物，6mg连续给药，QD。用药期间，受试者第一周期末疗效评估为SD，第二、三周期末疗效评估均为PR，确认最佳疗效PR。
(5)典型病例5
S03025受试者，男，66岁，于2017年8月1日诊断食管鳞癌。2019年8月8日至2019年11月20日应用“特瑞普利单抗注射液/安慰剂+紫杉醇+顺铂”治疗6周期，最佳疗效SD。2019年12月11日至2021年8月10日继续“特瑞普利单抗注射液/安慰剂”维持治疗25周期，最佳疗效SD。2021年12月8日至2022年3月22日应用“紫杉醇聚合物胶束”治疗6周期，最佳疗效SD。2023年1月11日经疗效评价为PD。
该受试者于2023年1月13日签署ICF，筛选分期IV期，于2023年2月7日首次服用试验药物，6mg连续给药，QD。用药期间，受试者第一周期末疗效评估为SD，第二、三、五周期末疗效评估均为PR，确认最佳疗效PR。目前仍继续用药中。
(6)典型病例6
S03033受试者，男，50岁，于2020年8月5日诊断食管鳞癌。2022年10月20日至2023年3月23日应用“紫杉醇+奈达铂”治疗5周期，最佳疗效PR。2023年4月12日至2023年5月10日应用“信迪利单抗”治疗2周期，最佳疗效SD。2023年5月20日经疗效评价为PD。
该受试者于2023年5月25日签署ICF，筛选分期IV期，于2023年6月5日首次服用试验药物，6mg服3周停1周，QD。用药期间，受试者第一周期末疗效评估为PR。目前仍继续用药中。
(7)典型病例7
S01001受试者，男，40岁，于2017年6月1日诊断鼻咽鳞癌。2017年6月23日至2017年7月17日应用“紫杉醇+顺铂”治疗2周期，最佳疗效SD。2017年8月4日至2017年8月9日应用“吉西他滨+异环磷酰胺”治疗1周期，最佳疗效SD。2017年9月18至2017年11月18日予“颈部、颈部***”放疗，最佳疗效PR；2017年9月18日至2017年10月30日同步应用“顺铂”治疗2周期，最佳疗效SD。2018年4月27日至2018年5月4日予“胸椎”放疗；2019年11月7日至2020年1月16日应用“杰诺单抗注射液(PD-1单抗)”治疗6周期，最佳疗效SD。2020年6月经疗效评估为PD。
该受试者于2020年8月19日签署ICF，筛选分期IV期，2020年9月11日首次服用试验药物，2mg(剂量爬坡)，QD。用药期间，最佳疗效SD，靶病灶最大缩小7.9％，SD持续时间为24个月。
(8)典型病例8
S09009受试者，男，57岁，于2020年2月7日诊断肺鳞癌。2020年5月11日至2020年6月25日予“右肺门+肺门***转移灶”放疗。2020年5月11起同步应用“顺铂+依托泊苷”治疗，最佳疗效SD；2020年7月23日至2022年11月25日应用“信迪利单抗”治疗32周期，最佳疗效SD。2023年2月经疗 效评估为PD。
该受试者于2023年2月3日签署ICF，筛选分期IV期，2023年2月10日首次服用试验药物，4mg连续给药，QD。用药期间，最佳疗效SD，靶病灶最大缩小10.7％，SD持续时间为4个月持续中。
2.2安全性评估结果
化合物B单药的治疗整体安全可控，常见(≥10％)的不良反应包括蛋白尿、高血压、低白蛋白血症、血小板计数降低、白细胞计数降低、丙氨酸氨基转移酶升高、天门冬氨酸氨基转移酶升高、高尿酸血症、皮疹、贫血和乏力。严重程度多数为2级及以下，大部分未经治疗，转归多为好转/痊愈；说明化合物B的不良反应相对轻微。化合物B不良反应类型与同类其它蛋白激酶抑制剂相当，不良反应严重程度相对轻微，3级及以上的不良反应发生率相对偏低。
与同类产品比较：参考已公开的几种相关的蛋白激酶抑制剂的临床研究结果(见下表)。
表8相关蛋白激酶抑制剂的安全性评价
注：*：表示该不良反应类型的严重程度有达到3～4级的情况。
本申请说明书中使用的缩略语的全程和中文名如下表9：
表9

以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (33)

  1. 化合物A或其可药用盐在制备用于***的药物中的用途，其中，所述肿瘤为食管癌或胃食管交界部癌，
  2. 根据权利要求1所述的用途，其特征在于，所述肿瘤为食管鳞癌、食管腺癌、胃食管交界部鳞癌或胃食管交界部腺癌；优选地，所述肿瘤为食管鳞癌或胃食管交界部鳞癌。
  3. 根据权利要求1或2所述的用途，其特征在于，所述肿瘤为局部晚期肿瘤或转移性肿瘤；优选为不可手术切除的局部晚期肿瘤或转移性肿瘤。
  4. 根据权利要求1-3中任一项所述的用途，其特征在于，所述肿瘤为在先治疗失败的肿瘤。
  5. 根据权利要求1-4中任一项所述的用途，其特征在于，所述肿瘤为***性药物治疗失败的肿瘤。
  6. 根据权利要求1-5中任一项所述的用途，其特征在于，所述肿瘤为一线治疗失败、二线治疗失败或后线治疗失败的肿瘤。
  7. 根据权利要求1-6中任一项所述的用途，其特征在于，所述肿瘤为免疫治疗药物、化疗药物、放疗、生物治疗、中药治疗、小分子靶向药物中的一种、两种、三种或更多种治疗失败的肿瘤；优选为放疗、免疫治疗药物或化疗药物治疗失败的肿瘤；进一步优选为放疗和免疫治疗药物治疗失败的肿瘤；进一步优选为放疗和化疗药物治疗失败的肿瘤；进一步优选为化疗药物和免疫治疗药物治疗失败的肿瘤；进一步优选为化疗药物、免疫治疗和放疗治疗失败的肿瘤。
  8. 化合物A或其可药用盐在制备用于***的药物中的用途，
    其中，所述肿瘤为鳞状细胞癌。
  9. 根据权利要求8所述的用途，其特征在于，所述肿瘤选自头颈部鳞癌、消化道鳞癌和呼吸道鳞癌； 优选地，所述肿瘤选自头颈部鳞癌、上消化道鳞癌和呼吸道鳞癌；进一步优选地，所述肿瘤选自食管鳞癌、胃食管交界部鳞癌、头颈部鳞癌和肺鳞癌；进一步优选地，所述肿瘤选自食管鳞癌、胃食管交界部鳞癌、鼻咽鳞癌和肺鳞癌；进一步优选地，所述肿瘤选自鼻咽鳞癌、食管鳞癌和肺鳞癌；进一步优选地，所述肿瘤为食管鳞癌。
  10. 根据权利要求8或9所述的用途，其特征在于，所述肿瘤为局部晚期肿瘤或转移性肿瘤；优选为不可手术切除的局部晚期肿瘤或转移性肿瘤。
  11. 根据权利要求8-10中任一项所述的用途，其特征在于，所述肿瘤为在先治疗失败的肿瘤。
  12. 根据权利要求8-11中任一项所述的用途，其特征在于，所述肿瘤为***性药物治疗失败的肿瘤。
  13. 根据权利要求8-12中任一项所述的用途，其特征在于，所述肿瘤为一线治疗失败、二线治疗失败的、或后线治疗失败的肿瘤。
  14. 根据权利要求8-13中任一项所述的用途，其特征在于，所述肿瘤为免疫治疗药物、化疗药物、放疗、生物治疗、中药治疗、小分子靶向药物中的一种、两种、三种或更多种治疗失败的肿瘤。
  15. 根据权利要求7或14所述的用途，其特征在于，所述化疗药物选自细胞毒类药、抗代谢类药、抗生素类药、生物碱类药、DNA拓扑异构酶抑制剂类化疗药、抗微管类化疗药、铂类化疗药和激素类药；优选地，所述化疗药物选自抗代谢类药、生物碱类药、DNA拓扑异构酶抑制剂类化疗药、抗微管类化疗药和铂类化疗药。
  16. 根据权利要求7、14或15所述的用途，其特征在于，所述化疗药物选自紫杉烷类药物、铂类药物、氟尿嘧啶类药物或DNA拓扑异构酶抑制剂类化疗药；优选地，所述紫杉烷类药物选自紫杉醇、多西他赛或卡巴它赛；优选地，所述DNA拓扑异构酶抑制剂类化疗药选自羟喜树碱、伊立替康、拓扑替康、依托泊苷或替尼泊苷；优选地，所述铂类药物选自顺铂、卡铂、环硫铂、洛铂、奥沙利铂或奈达铂；优选为顺铂、奥沙利铂或奈达铂；进一步优选地，所述化疗药物选自紫杉醇、顺铂或奈达铂。
  17. 根据权利要求7或14所述的用途，其特征在于，所述免疫治疗药物选自抗PD-1抗体、抗PD-L1抗体和抗体偶联药物；优选地，所述抗体偶联药物为抗HER2抗体偶联药物；优选地，所述抗PD-1抗体选自帕博利珠单抗、卡瑞利珠单抗、替雷利珠单抗、纳武利尤单抗、西米普利单抗、信迪利单抗或特瑞普利单抗；优选地，所述抗PD-1抗体选自特瑞普利单抗、信迪利单抗或替雷利珠单抗；优选地，所述抗PD-L1抗体选自阿特珠单抗、阿维鲁单抗和度伐鲁单抗；优选地，所述抗HER2抗体偶联药物选自曲妥珠单抗或迪西妥单抗。
  18. 根据权利要求1-17中任一项所述的用途，其特征在于，所述肿瘤为化疗药物和免疫治疗药物治疗失败的肿瘤；优选为紫杉烷类+铂类化疗药+抗PD-1抗体治疗失败的肿瘤；进一步优选为特瑞普利单抗+紫杉醇+顺铂、信迪利单抗+紫杉醇+顺铂、紫杉醇+洛铂+卡瑞利珠单抗、紫杉醇+奈达铂、信迪利单抗中的一种、两种，三种或更多种治疗失败的肿瘤。
  19. 根据权利要求1-16中任一项所述的用途，其特征在于，所述肿瘤为化疗药物治疗失败的肿瘤；优选为紫杉烷类+铂类化疗药治疗失败的肿瘤；进一步优选为紫杉醇+顺铂或紫杉醇+奈达铂治疗失败的肿瘤。
  20. 权利要求1-17中任一项所述的用途，其特征在于，所述肿瘤为化疗药物、免疫治疗和放疗治疗失败的肿瘤；优选为紫杉烷类+铂类化疗药+放疗+抗PD-1抗体治疗失败的肿瘤；进一步优选为替雷利珠单抗 +放疗+紫杉醇+顺铂治疗失败的肿瘤。
  21. 根据权利要求1-20中任一项所述的用途，其特征在于，所述化合物A或其可药用盐的施用剂量为每日1-50毫克；优选为1-30毫克；进一步优选为1-25毫克；进一步优选为1-20毫克；进一步优选为2-18毫克；进一步优选为4-16毫克；进一步优选为5-15毫克；进一步优选为4-10毫克；进一步优选为4-9毫克；进一步优选为2-9毫克；进一步优选为2-6毫克；进一步优选为5-9毫克；进一步优选为6-9毫克；进一步优选为6-8毫克；进一步优选为6-12毫克；进一步优选为6-10毫克；进一步优选为2、3、4、5、6、7、8、9、10毫克。
  22. 根据权利要求1-21中任一项所述的用途，其特征在于，所述化合物A或其可药用盐的给药频率为每日给药一次、两次、三次或更多次。
  23. 根据权利要求1-22中任一项所述的用途，其特征在于，所述化合物A或其可药用盐以连续给药或间隔给药的方式给予；优选地，所述的间隔给药包括给药期和停药期。
  24. 根据权利要求23所述的用途，其特征在于，所述化合物A或其可药用盐的给药方法为：连续给药3周，然后停药1周。
  25. 根据权利要求1-24中任一项所述的用途，其特征在于，所述药物进一步与临床上常用的治疗食管癌、胃食管交界部癌或鳞状细胞癌的药物中的一种、两种、三种或更多种联合使用。
  26. 根据权利要求1-25中任一项所述的用途，其特征在于，所述可药用盐选自盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐和对甲苯磺酸盐；优选地为盐酸盐、氢溴酸盐、马来酸盐、磷酸盐、酒石酸盐、富马酸盐和琥珀酸盐；进一步优选地为盐酸盐、马来酸盐、磷酸盐、酒石酸盐和富马酸盐；进一步优选为盐酸盐。
  27. 根据权利要求1-26中任一项所述的用途，其特征在于，所述化合物A的可药用盐，其为化合物B，
  28. 根据权利要求27所述的用途，其特征在于，所述化合物B为固体形式；优选地，其为结晶形式。
  29. 根据权利要求27或28所述的用途，其特征在于，所述化合物B，其结晶形式为晶型I，使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图谱包含以下位置的特征峰：5.0±0.2°、13.5±0.2°、19.3±0.2°、20.5±0.2°、21.4±0.2°和25.2±0.2°。
  30. 用于***的药物组合物，其包含根据权利要求1-26中任一项所述的化合物A或其可药用盐、或根据权利要求27-29中任一项所述的化合物B，并任选地包含药学上可接受的载体，其中，所述肿瘤为食管癌、胃食管交界部癌或鳞状细胞癌。
  31. 根据权利要求30所述的药物组合物，其特征在于，包含化合物A或其可药用盐及药学上可接受的载体，进一步包括治疗有效量的其它药物，所述其它药物选自临床上常用的治疗食管癌、胃食管交界部癌或鳞状细胞癌的药物中的一种、两种、三种或更多种。
  32. 根据权利要求30或31所述的药物组合物，其特征在于，所述药物组合物，包含化合物B及药学上可接受的载体，进一步包括治疗有效量的其它药物，所述其它药物选自临床上常用的治疗食管癌、胃食管交界部癌或鳞状细胞癌的药物中的一种、两种、三种或更多种。
  33. 一种药物试剂盒，其包含(a)至少一个单位剂量的如权利要求30-32中任一项所述的药物组合物和(b)用于***的说明书，其中，所述肿瘤为食管癌、胃食管交界部癌或鳞状细胞癌。
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