WO2022179608A1 - 多靶点蛋白激酶抑制剂的用途 - Google Patents

多靶点蛋白激酶抑制剂的用途 Download PDF

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WO2022179608A1
WO2022179608A1 PCT/CN2022/077932 CN2022077932W WO2022179608A1 WO 2022179608 A1 WO2022179608 A1 WO 2022179608A1 CN 2022077932 W CN2022077932 W CN 2022077932W WO 2022179608 A1 WO2022179608 A1 WO 2022179608A1
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biliary tract
formula
compound
tract cancer
pharmaceutically acceptable
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PCT/CN2022/077932
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English (en)
French (fr)
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徐雯
谢颖
魏苗苗
马玉秀
史慧静
孙静
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石药集团中奇制药技术（石家庄）有限公司
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Publication of WO2022179608A1 publication Critical patent/WO2022179608A1/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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the application belongs to the field of medicine, and specifically relates to the preparation of multi-targeted protein kinase inhibitors for the treatment or prevention of diseases caused by one or more than one of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, and SRC kinases.
  • PTKs Protein tyrosine kinases
  • PTKs transfer the ⁇ -phosphate group on adenosine triphosphate to the protein tyrosine residue of the substrate, and phosphorylate the phenolic hydroxyl group.
  • PTKs are out of control during the regulation process, it will affect the correct activation of its downstream signaling pathways, which will lead to the disorder of cell proliferation regulation and cause many diseases. Excessive transformation, proliferation, anti-apoptosis, promotion of cell survival and the formation of malignant tumors.
  • EGFR Epidermal Growth Factor Receptor
  • FGFRs Fibroblast Growth Factor Receptor
  • PDGFR Platelet-derived Growth Factor Receptor
  • RET Rearranged during The RET protein encoded by the proto-oncogene of Transfection
  • EGFR includes EGFR (ErbB-1), human epidermal growth factor receptor type 2 HER-2 (ErbB-2), human epidermal growth factor receptor type 3 HER3 (ErbB-3) and human epidermal growth factor receptor type 4 HER4 (ErbB-4), among which, EGFR and HER-2 are the most closely related tumor targets among the EGFR family members. Studies have shown that EGFR exhibits overexpression, gene mutation or gene fusion in various tumors such as lung cancer, gastric cancer, epidermoid cancer, renal cancer, ovarian cancer, etc.
  • FGFR mainly includes four subtypes of FGFR1/2/3/4, which are overexpressed or overactivated by gene amplification, mutation, fusion or ligand induction, and have important effects on tumor cell proliferation, invasion and migration and tumor angiogenesis. important role. Studies have found that FGFRs are mutated, overexpressed or overactivated in a variety of tumors, such as lung cancer, gastric cancer, cholangiocarcinoma, colorectal cancer, and liver cancer.
  • Biliary Tract Carcinoma is an aggressive and genetically heterogeneous malignant tumor, including Gallbladder Carcinoma (GBC), Cholangio Carcinoma (CC) and Ampullary Cancer. Cholangiocarcinoma Including intrahepatic and extrahepatic cholangiocarcinoma.
  • GBC Gallbladder Carcinoma
  • CC Cholangio Carcinoma
  • Ampullary Cancer Cholangiocarcinoma Including intrahepatic and extrahepatic cholangiocarcinoma.
  • the incidence of BTC is low, accounting for about 3% of gastrointestinal tumors, of which primary gallbladder cancer accounts for more than 50% of BTC. Most of BTC has no symptoms in the early stage, and it is difficult to attract attention before jaundice. About 60-70% of BTC patients are in the stage of unresection or metastasis when they are diagnosed, and the prognosis is poor, and the 5-year survival rate is less than 5%.
  • BTC has a high recurrence rate and distant metastasis rate.
  • adjuvant therapy such as chemotherapy and radiotherapy is usually required.
  • chemotherapy is mainly used for advanced BTC, and oxaliplatin combined with 5-fluorouracil (5-FU), oxaliplatin/irinotecan/5-FU, and irinotecan combined with capecitabine can be considered, but the efficacy is insufficient. good.
  • Pemigatinib (pemigatinib, Pemazyre), a selective FGFR inhibitor, was approved by the U.S. Food and Drug Administration on April 17, 2020 for the treatment of adults with previously treated but ineffective advanced FGFR2 genes Fusion cholangiocarcinoma has become the first targeted drug in the history of cholangiocarcinoma treatment, ending the era of only chemotherapy for cholangiocarcinoma.
  • pemigatinib a selective FGFR inhibitor
  • Tumors are often related to the imbalance of multiple signal transduction pathways and multiple targets.
  • the single-target drug treatment of tumors may not achieve the expected therapeutic effect, and its application is also limited by drug side effects and drug resistance.
  • Targeted drugs have become a new direction of drug research.
  • multi-target drugs can act on multiple tumor-related targets, although their activity against a single target may be reduced compared to single-target drugs, but may benefit from multi-target modulation
  • the resulting synergy makes the total effect possibly greater than the sum of the individual effects, resulting in better efficacy and fewer adverse effects.
  • CN106660970B discloses compounds of general formula as shown in formula A, especially compounds of formula 1 (Example 22), these compounds are a class of protein tyrosines that inhibit RET, KDR, EGFR, FGFR1, FLT-1, etc. There is no relevant research report on the multi-target inhibitor of acid kinase activity that can be used for the treatment of human biliary tract cancer.
  • a technical problem to be solved by this application is to provide a multi-targeted protein kinase inhibitor represented by formula A or a pharmaceutically acceptable salt thereof, especially compound 1 or a pharmaceutically acceptable salt thereof in the preparation of Use in a medicament for the treatment or prevention of a related disorder caused by one or more of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases.
  • a multi-targeted protein kinase inhibitor represented by formula A or a pharmaceutically acceptable salt thereof, which is used for the treatment or prevention of RET, KDR , use in a medicament for a related disorder caused by one or more of EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases,
  • R 1 is —O(CH 2 ) n R 3 , where n is 3, 4 or 5, and R 3 is —NR e R f , where Re and R f are each independently at each occurrence selected from methyl , or Re and R f together form -(CH 2 ) 4 -;
  • R 1 is selected from
  • the compound represented by the formula A is compound 1,
  • the associated disorder is associated by one or more than one of RET, KDR, EGFR, FGFR1/2/3, FLT-1, HER-2, LCK, EphA1, SRC kinases disease.
  • the associated disorder is a tumor disease; preferably, the tumor disease is a solid tumor; further preferably, the solid tumor is biliary tract cancer.
  • the biliary tract cancer is caused by one or more than one of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases.
  • the biliary tract cancer is advanced biliary tract cancer.
  • the biliary tract cancer is locally advanced biliary tract cancer.
  • the biliary tract cancer is locally advanced unresectable biliary tract cancer.
  • the biliary tract cancer is metastatic biliary tract cancer.
  • the biliary tract cancer is treatment-failed or intolerable biliary tract cancer.
  • the biliary tract cancer is biliary tract cancer that has failed or is intolerant of first-line therapy.
  • the biliary tract cancer is gallbladder cancer or cholangiocarcinoma.
  • the cholangiocarcinoma is intrahepatic cholangiocarcinoma and/or extrahepatic cholangiocarcinoma; preferably intrahepatic cholangiocarcinoma.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof, especially Compound 1 or a pharmaceutically acceptable salt thereof, is used as the only active ingredient for preparing the medicament.
  • the compound represented by formula A or a pharmaceutically acceptable salt thereof, in particular Compound 1 or a pharmaceutically acceptable salt thereof is used in combination with one or more of other therapeutic agents to prepare the medicament .
  • the other therapeutic agents include but are not limited to targeted drugs or chemotherapeutic drugs, and the other targeted drugs or chemotherapeutic drugs refer to targeted drugs or chemotherapeutic drugs clinically used to treat tumor-related diseases.
  • a multi-targeted protein kinase inhibitor represented by formula A or a pharmaceutically acceptable salt thereof, which is used for the treatment or prevention of RET, KDR, EGFR, FGFR, FLT , related conditions caused by one or more of HER, LCK, EphA, SRC kinases,
  • R 1 is —O(CH 2 ) n R 3 , where n is 3, 4 or 5, and R 3 is —NR e R f , where Re and R f are each independently at each occurrence selected from methyl , or Re and R f together form -(CH 2 ) 4 -;
  • R 1 is selected from
  • the compound represented by the formula A is compound 1,
  • the associated disorder is associated by one or more than one of RET, KDR, EGFR, FGFR1/2/3, FLT-1, HER-2, LCK, EphA1, SRC kinases disease.
  • the associated disorder is a tumor disease; preferably, the tumor disease is a solid tumor; further preferably, the solid tumor is biliary tract cancer.
  • the biliary tract cancer is caused by one or more than one of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases.
  • the biliary tract cancer is advanced biliary tract cancer.
  • the biliary tract cancer is locally advanced biliary tract cancer.
  • the biliary tract cancer is locally advanced unresectable biliary tract cancer.
  • the biliary tract cancer is metastatic biliary tract cancer.
  • the biliary tract cancer is treatment-failed or intolerable biliary tract cancer.
  • the biliary tract cancer is biliary tract cancer that has failed or is intolerant of first-line therapy.
  • the biliary tract cancer is gallbladder cancer or cholangiocarcinoma.
  • the cholangiocarcinoma is intrahepatic cholangiocarcinoma and/or extrahepatic cholangiocarcinoma; preferably intrahepatic cholangiocarcinoma.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof, especially Compound 1 or a pharmaceutically acceptable salt thereof, is used as the only active ingredient for preparing a medicament.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof, especially Compound 1 or a pharmaceutically acceptable salt thereof is used in combination with one or more of other therapeutic agents to prepare a medicament, or For the treatment or prevention of related disorders caused by one or more than one of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases.
  • the other therapeutic agents include but are not limited to targeted drugs or chemotherapeutic drugs, and the other targeted drugs or chemotherapeutic drugs refer to targeted drugs or chemotherapeutic drugs clinically used to treat tumor-related diseases.
  • a multi-targeted protein kinase inhibitor represented by formula A or the use of a pharmaceutically acceptable salt thereof as a medicine
  • R 1 is —O(CH 2 ) n R 3 , where n is 3, 4 or 5, and R 3 is —NR e R f , where Re and R f are each independently at each occurrence selected from methyl , or Re and R f together form -(CH 2 ) 4 -;
  • R 1 is selected from
  • the compound represented by the formula A is compound 1,
  • the medicament is for the treatment of a related disorder caused by one or more of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases.
  • the associated disorder is associated by one or more than one of RET, KDR, EGFR, FGFR1/2/3, FLT-1, HER-2, LCK, EphA1, SRC kinases disease.
  • the associated disorder is a tumor disease; preferably, the tumor disease is a solid tumor; further preferably, the solid tumor is biliary tract cancer.
  • the biliary tract cancer is caused by one or more than one of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases.
  • the biliary tract cancer is advanced biliary tract cancer.
  • the biliary tract cancer is locally advanced biliary tract cancer.
  • the biliary tract cancer is locally advanced unresectable biliary tract cancer.
  • the biliary tract cancer is metastatic biliary tract cancer.
  • the biliary tract cancer is treatment-failed or intolerable biliary tract cancer.
  • the biliary tract cancer is biliary tract cancer that has failed or is intolerant of first-line therapy.
  • the biliary tract cancer is gallbladder cancer or cholangiocarcinoma.
  • the cholangiocarcinoma is intrahepatic cholangiocarcinoma and/or extrahepatic cholangiocarcinoma; preferably intrahepatic cholangiocarcinoma.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof, especially Compound 1 or a pharmaceutically acceptable salt thereof, is used as the only active ingredient for preparing the medicament.
  • the compound represented by formula A or a pharmaceutically acceptable salt thereof, in particular Compound 1 or a pharmaceutically acceptable salt thereof is used in combination with one or more of other therapeutic agents to prepare the medicament .
  • the other therapeutic agents include but are not limited to targeted drugs or chemotherapeutic drugs, and the other targeted drugs or chemotherapeutic drugs refer to targeted drugs or chemotherapeutic drugs clinically used to treat tumor-related diseases.
  • a method of treating or preventing related disorders caused by one or more than one of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases comprises administering to a subject or patient a multi-targeted protein kinase inhibitor of formula A or a pharmaceutically acceptable salt thereof containing a therapeutically effective amount,
  • R 1 is —O(CH 2 ) n R 3 , where n is 3, 4 or 5, and R 3 is —NR e R f , where Re and R f are each independently at each occurrence selected from methyl , or Re and R f together form -(CH 2 ) 4 -;
  • R 1 is selected from
  • the compound represented by the formula A is compound 1,
  • the associated disorder is associated by one or more than one of RET, KDR, EGFR, FGFR1/2/3, FLT-1, HER-2, LCK, EphA1, SRC kinases disease.
  • the associated disorder is a tumor disease; preferably, the tumor disease is a solid tumor; further preferably, the solid tumor is biliary tract cancer.
  • the biliary tract cancer is caused by one or more than one of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases.
  • the biliary tract cancer is advanced biliary tract cancer.
  • the biliary tract cancer is locally advanced biliary tract cancer.
  • the biliary tract cancer is locally advanced unresectable biliary tract cancer.
  • the biliary tract cancer is metastatic biliary tract cancer.
  • the biliary tract cancer is treatment-failed or intolerable biliary tract cancer.
  • the biliary tract cancer is biliary tract cancer that has failed or is intolerant of first-line therapy.
  • the biliary tract cancer is gallbladder cancer or cholangiocarcinoma.
  • the cholangiocarcinoma is intrahepatic cholangiocarcinoma and/or extrahepatic cholangiocarcinoma; preferably intrahepatic cholangiocarcinoma.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof, especially Compound 1 or a pharmaceutically acceptable salt thereof, is used as the only active ingredient for preparing a medicament.
  • the compound represented by formula A or a pharmaceutically acceptable salt thereof, especially Compound 1 or a pharmaceutically acceptable salt thereof is used in combination with one or more of other therapeutic agents to prepare a medicament, or For the treatment or prevention of related disorders caused by one or more than one of RET, KDR, EGFR, FGFR, FLT, HER, LCK, EphA, SRC kinases.
  • the other therapeutic agents include but are not limited to targeted drugs or chemotherapeutic drugs, and the other targeted drugs or chemotherapeutic drugs refer to targeted drugs or chemotherapeutic drugs clinically used to treat tumor-related diseases.
  • a kit comprising the compound represented by formula A of the aforementioned (first aspect, second aspect, third aspect, fourth aspect) or a pharmaceutically acceptable salt thereof, Especially Compound 1 or a pharmaceutically acceptable salt thereof.
  • the kit includes one or more containers containing a compound of Formula A or a pharmaceutically acceptable salt thereof, particularly Compound 1 or a pharmaceutically acceptable salt thereof.
  • the kit comprises the aforementioned (first aspect, second aspect, third aspect, fourth aspect) medicament.
  • the compounds represented by formula A are not particularly
  • the pharmaceutically acceptable salts of the compound shown in the formula A include but are not limited to hydrochloride, sulfate, oxalate, maleate or malate; preferably hydrochloride, sulfuric acid salt or maleate; more preferably hydrochloride; still more preferably dihydrochloride; even more preferably the anhydrous form of dihydrochloride or a hydrate thereof.
  • the pharmaceutically acceptable salt of the compound represented by formula A as described above is the disalt of compound 1 acid salts (compounds of formula 2),
  • the compound of Formula 2 is in a crystalline form.
  • the crystalline form of the compound of Formula 2 (Form I), using Cu-K ⁇ radiation, has a powder X-ray diffraction pattern expressed as a 2 ⁇ angle (°) with characteristic diffraction peaks at ( ⁇ 0.2 °): 12.4, 18.8, 20.3, 24.6.
  • the powder X-ray diffraction pattern in 2 ⁇ angles (°) has characteristic diffraction peaks ( ⁇ 0.2°) at: 9.8, 12.4, 18.8, 20.3, 24.6.
  • the powder X-ray diffraction pattern in 2 ⁇ angles (°) has characteristic diffraction peaks ( ⁇ 0.2°) at the following positions: 8.1, 9.8, 12.4, 18.8, 20.3, 24.6, 29.9.
  • the powder X-ray diffraction pattern in 2 ⁇ angles (°) has characteristic diffraction peaks ( ⁇ 0.2°) at the following positions: 8.1, 9.8, 12.4, 18.8, 19.3, 20.3, 24.6, 28.6 , 29.9.
  • the powder X-ray diffraction pattern in 2 ⁇ angles (°) has characteristic diffraction peaks ( ⁇ 0.2°) at: 8.1, 9.8, 12.4, 16.1, 18.8, 19.3, 20.3, 24.6 , 28.6, 29.9, 30.9.
  • Cu-K ⁇ radiation is used, having an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 2 .
  • the crystalline form of the compound of Formula 2 (Form I) has a DSC curve with endothermic peaks at 231.0 ⁇ 5°C and 284.2 ⁇ 5°C, respectively.
  • the crystalline form of the compound of Formula 2 (Form I) has a TGA curve that begins to decompose at 205.6 ⁇ 5°C.
  • the aforementioned are prepared into clinically acceptable formulations, including but not limited to oral formulations, injection formulations, topical formulations Administration preparations or external preparations; oral preparations are preferred; tablets and capsules are further preferred.
  • the aforementioned medicament contains a therapeutically effective amount of a compound of formula A or a pharmaceutically acceptable salt thereof to be administered at a daily dose ranging from about 0.001 mg/kg to about 1000 mg/kg, preferably about 0.01mg/kg-800mg/kg, or 0.1mg/kg-600mg/kg, or 1mg/kg-500mg/kg, or 2mg/kg-400mg/kg, or 3mg/kg-300mg/kg, or 4mg/kg -200mg/kg, or 5mg/kg-100mg/kg, or 10mg/kg-50mg/kg.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof.
  • each preparation unit of the aforementioned medicine contains 0.1-5000 mg, preferably 1-1000 mg, or 10-800 mg, or 20-700 mg, or 22-650 mg of the compound represented by formula A or a pharmaceutically acceptable salt thereof. , or 25-650mg, or 50-600mg, or 85-500mg, or 86-500mg, or 90-500mg, or 100-500mg, or 100-450mg, or 100-400mg, or 150-350mg, or 170-350mg , or 173-350mg, or 175-350mg, or 200-300mg, or 150-200mg.
  • the dosage is based on the compound of formula A.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof.
  • each preparation unit of the aforementioned medicine contains 0.1-5000 mg, preferably 1-1000 mg, or 10-800 mg, or 25-700 mg, or 50-600 mg, or 80 mg of the dihydrochloride salt of the compound represented by formula A.
  • the dosages are based on the dihydrochloride salt of the compound of formula A in anhydrous form.
  • the dihydrochloride of the compound represented by formula A is the dihydrochloride of compound 1. More preferably, it is the crystalline form of the compound represented by the formula 2; even more preferably, it is the crystal form I of the compound represented by the formula 2.
  • the aforementioned medicament contains a therapeutically effective amount of the compound represented by Formula A or a pharmaceutically acceptable salt thereof, and its dosage is: 20mg-1500mg per administration; preferably, 50mg per administration -1200mg; preferably, 100mg-1000mg per administration; preferably, 200mg-800mg per administration; further preferably, 250mg-700mg per administration; further preferably, 300mg-600mg per administration; further Preferably, each administration is 300mg-550mg; more preferably, each administration is 300mg-500mg; further preferably, each administration is 300mg-450mg; exemplary administration doses include, each administration 20mg, 22mg , 25mg, 40mg, 43mg, 45mg, 50mg, 80mg, 85mg, 86mg, 90mg, 100mg, 150mg, 170mg, 173mg, 175mg, 180mg, 200mg, 250mg, 259mg
  • the aforementioned medicament contains a therapeutically effective amount of the dihydrochloride of the compound represented by formula A, and its dosage is: 25mg-900mg per administration; preferably, 200mg-800mg per administration; Further preferably, each administration is 300mg-700mg; further preferably, each administration is 300mg-600mg; further preferably, each administration is 400mg-600mg; further preferably, each administration is 450mg-600mg; exemplary Dosages include 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, or 900 mg per administration.
  • the dosages are based on the dihydrochloride salt of Compound A in anhydrous form.
  • the dihydrochloride of the compound represented by formula A is the dihydrochloride of compound 1. More preferably, it is the crystalline form of the compound represented by the formula 2; even more preferably, it is the crystal form I of the compound represented by the formula 2.
  • the daily dosing frequency of the aforementioned agents is once daily, twice daily, three times daily, or four times daily; preferably once daily.
  • the aforementioned medicament contains a therapeutically effective amount of the compound represented by formula A or a pharmaceutically acceptable salt thereof, and its daily dosage is 20mg-1500mg; preferably 50mg-1200mg; more preferably 100mg- 1000mg; more preferably 200mg-800mg; more preferably 250mg-700mg; more preferably 300mg-600mg; more preferably 300mg-550mg; Dosages include daily administration of 20mg, 22mg, 25mg, 40mg, 43mg, 45mg, 50mg, 80mg, 85mg, 86mg, 90mg, 100mg, 150mg, 170mg, 173mg, 175mg, 180mg, 200mg, 250mg, 259mg, 260mg, 300mg, 302mg, 310mg, 340mg, 346mg, 350mg, 400mg, 380mg, 385mg, 389mg, 3
  • the aforementioned medicine contains a therapeutically effective amount of the dihydrochloride of the compound represented by formula A, and its daily dosage is 25mg-900mg; preferably 200mg-800mg; more preferably 300mg-700mg; further Preferably it is 300mg-600mg; more preferably 400mg-600mg; further preferably 450mg-600mg; 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg or 900mg.
  • the dosages are based on the dihydrochloride salt of Compound A in anhydrous form.
  • the dihydrochloride of the compound represented by formula A is the dihydrochloride of compound 1. More preferably, it is the crystalline form of the compound represented by the formula 2; even more preferably, it is the crystal form I of the compound represented by the formula 2.
  • the daily administration frequency is one, two, three or more times.
  • the aforementioned medicine contains a therapeutically effective amount of the compound represented by Formula A or a pharmaceutically acceptable salt thereof, and its dosage and dosage frequency are: once a day, 20mg-1500mg per administration; Preferably, once a day, 50mg-1200mg each time; preferably, once a day, 100mg-1000mg each time; preferably, once a day, each time 200mg-800mg; more preferably Preferably, once a day, 250mg-700mg each time; more preferably, once a day, 300mg-600mg each time; further preferably, once a day, each time 300mg-550mg; example
  • the recommended dosage and frequency of administration include, once daily, 20 mg, 22 mg, 25 mg, 40 mg, 43 mg, 45 mg, 50 mg, 80 mg, 85 mg, 86 mg, 90 mg, 100 mg, 150 mg, 170 mg, 173 mg, 175 mg, 180mg, 200mg, 250mg, 259mg, 260m
  • the aforementioned medicine contains a therapeutically effective amount of the dihydrochloride of the compound represented by formula A, and its dosage and dosage frequency are: once a day, 25mg-900mg each time; preferably, Administer once a day, 200mg-800mg each time; more preferably, once a day, 300mg-700mg each time; further preferably, once a day, 300mg-600mg each time; further preferably , administered once a day, 400mg-600mg each time; further preferably, once a day, 450mg-600mg each time; Exemplary doses and frequencies include, once a day, each time 25mg, 50mg, 100mg, 200mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg or 900mg.
  • the dosages are based on the dihydrochloride salt of Compound A in anhydrous form.
  • the dihydrochloride of the compound represented by formula A is the dihydrochloride of compound 1. More preferably, it is the crystalline form of the compound represented by the formula 2; even more preferably, it is the crystal form I of the compound represented by the formula 2.
  • the aforementioned medicament contains a therapeutically effective amount of the compound represented by formula A or a pharmaceutically acceptable salt thereof, and its administration dosage frequency is: once a day, administered for 21 days, and discontinued for 7 days, Every 28 days is a cycle.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof.
  • the aforementioned medicaments are administered orally, by injection, topically, or in vitro.
  • the medicament is administered orally or by injection; preferably, it is administered orally.
  • the compound represented by Formula A or a pharmaceutically acceptable salt thereof as described above is Compound 1 The dihydrochloride salt; preferably the crystalline form of the compound represented by the formula 2; more preferably the crystal form I of the compound represented by the formula 2.
  • the aforementioned (first aspect, second aspect, third aspect, fourth aspect, fifth aspect) compound represented by formula A or a pharmaceutically acceptable salt thereof, particularly compound 1 or a pharmaceutically acceptable salt thereof Acceptable salts may be administered in a single dose or in divided doses; preferably, in a single dose.
  • the therapeutically effective dose and dose frequency of the compound represented by formula A or a pharmaceutically acceptable salt thereof, particularly Compound 1 or a pharmaceutically acceptable salt thereof can be determined by methods such as modeling, dose escalation studies or clinical trials. method and by taking into account factors such as the nature and severity of the disease to be treated, the age, general condition and weight of the patient, as well as the particular compound being administered, its pharmacokinetic properties, and the route of administration.
  • chemotherapeutic drugs refer to chemical drugs for the treatment of tumors, including but not limited to cytotoxic drugs, antimetabolites, antibiotics, alkaloids, hormones and other drugs.
  • targeted drug refers to a drug or its preparation for targeted therapy, which prevents the growth or proliferation of cancer cells by interfering with specific molecules required for carcinogenesis or tumor proliferation, including but not limited to small molecule targeted drugs and macromolecule targeted drugs, wherein, small molecule targeted drugs include but are not limited to protein kinase inhibitors, such as protein tyrosine kinase inhibitors, macromolecule targeted drugs include but are not limited to monoclonal antibodies, antibody conjugated drugs and Immunotherapy drugs.
  • the dosage of the compound represented by the formula A or its pharmaceutically acceptable salt, especially the compound 1 or its pharmaceutically acceptable salt described in this application, can be calculated in the form of free base unless otherwise specified, or it can be actually used in the specific dosage form.
  • a hydrate if a hydrate is contained, it can be calculated in the form of a unit other than water, and can also be calculated in the form of the hydrate.
  • the hydrochloride of compound 1 if the hydrochloride of compound 1 is used, it is calculated as the hydrochloride of compound 1; if the hydrate of compound 1 hydrochloride is used, it can be calculated as the hydrochloride of compound 1, or as the hydrochloride of compound 1. Hydrate meter.
  • the dosage of the compound represented by formula A or a pharmaceutically acceptable salt thereof, especially Compound 1 or a pharmaceutically acceptable salt thereof described in this application, can be fluctuated within a clinically acceptable range, for example, 100 mg per administration,
  • the administered dose can fluctuate within 10% of the dose range, that is, 90 mg to 110 mg.
  • first-line treatment is not limited to the approved first-line chemotherapy regimen for the treatment of biliary tract cancer, but also includes the first non-first-line chemotherapy regimen for the treatment of biliary tract cancer after diagnosis, immunotherapy, targeted therapy and other systemic drug treatments, "Failure after first-line therapy” also includes disease progression within 6 months of adjuvant chemotherapy.
  • the single administration described in this application means that it does not need to be used in combination with other drugs with anti-tumor effects, but it does not exclude the use of some adjuvant drugs that do not have anti-tumor effects.
  • the “2 ⁇ ”, “2 ⁇ angle” or “2 ⁇ angle” mentioned in this application refers to the diffraction angle, the unit is ° or degree, and the error range of 2 ⁇ can be ⁇ 0.5°, ⁇ 0.4°, ⁇ 0.3 °, ⁇ 0.2°, or ⁇ 0.1°; in some embodiments of the present application, the margin of error for 2 ⁇ is ⁇ 0.2°.
  • substantially as shown means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96% of the X-ray powder diffraction pattern. %, or at least 97%, or at least 98%, or at least 99% of the peaks are shown in their graph. Further, when the content of a certain crystal form in the product is gradually reduced, some diffraction peaks in the powder X-ray diffraction pattern that belong to the crystal form may be reduced due to the detection sensitivity of the instrument.
  • characteristic diffraction peak refers to a diffraction peak in an X-ray powder diffraction pattern that can be used to represent the crystal form, which is related to the peak position, peak shape and relative peak intensity of the diffraction peak, for example, small angle peaks, peaks
  • the shape is sharp, and the relative peak intensity is at least 3% or more, or at least 5% or more, or at least 10% or more, or at least 20% or more, or at least 30% or more, or at least 40% or more, or at least 50% or more, or at least 60% or more, or at least 70% or more, or at least 75% or more of the diffraction peaks.
  • the present application achieves one or more of the following beneficial technical effects: (1) the compound 1 or a pharmaceutically acceptable salt thereof has good inhibitory activity (less than 100 nM) on various protein kinases; (2) the compound 1 or a pharmaceutically acceptable salt thereof has good inhibitory activity on human cholangiocarcinoma cells and human intrahepatic cholangiocarcinoma cells; (3) the compound 1 or a pharmaceutically acceptable salt thereof (for example, the disalt of compound 1) (4) the compound 1 or its compound 1 or its acid salt) showed good tolerance in the clinical phase I trial, with few types of adverse reactions, and a low incidence of side reactions above grade 3, suggesting that its clinical safety is good; (4) the compound 1 or its A pharmaceutically acceptable salt (for example, the dihydrochloride of Compound 1) can control disease progression to a certain extent in patients with advanced or metastatic biliary tract malignancies who have failed or are intolerant of first-line therapy in Phase II clinical trials, Its effect is better than that of commonly used clinical chemotherapy drugs. It has clinical potential for the treatment of
  • Figure 2 XRPD spectrum of the crystal form I of the dihydrochloride salt of Compound 1 obtained in Preparation Example 2 in Test Example 3 after long-term stability test.
  • Test conditions wavelength 252nm; column temperature 45°C.
  • Detection medium purified water, pH2.0 phosphoric acid-disodium hydrogen phosphate buffer
  • Preparation of reference solution take an appropriate amount of the reference substance of the compound of formula 1, accurately weigh it, add solvent to make it completely dissolved, and dilute to make a solution of 100 ⁇ g/mL, accurately measure 10uL, and use HPLC to determine the content of compound 1 in the reference solution. .
  • Light tube type Cu target, ceramic X-ray tube
  • Test method Weigh the sample (about 3mg) and place it in an aluminum oxide crucible for testing. Under the condition of 20mL/min dry nitrogen (protective gas), at a heating rate of 10K/min, heat the sample from 20°C to 340°C.
  • Detection instrument Dionex ICS-900 ion chromatograph
  • test solution take an appropriate amount of the test product, accurately weigh it, dissolve it with the eluent (12.5mmol/L sodium hydroxide solution) and quantitatively dilute it into a solution containing about 0.5mg of the test product per 1mL, shake well , as the test solution.
  • Preparation of reference solution take an appropriate amount of sodium chloride (equivalent to 18 mg of chloride ion), accurately weigh it, put it in a 250 mL volumetric flask, dissolve it with eluent and make up to volume, shake well, and use it as a reference solution.
  • sodium chloride equivalent to 18 mg of chloride ion
  • Determination method Precisely measure 10 ⁇ L of the reference solution and the test solution, respectively, inject them into the ion chromatograph, record the chromatogram, and calculate the chloride ion content by the peak area according to the external standard method.
  • Test method Add the sample to be tested into a biological solvent medium, and prepare a solution or suspension with a target concentration of 10 mg/mL. The resulting solution or suspension was shaken continuously at 200 rpm at 37°C. The suspension was filtered at 0.5 hours and the compound concentration in the filtrate was determined using HPLC.
  • the chloride ion content was determined by ion chromatography, and the stoichiometric ratio of the hydrochloride was calculated (see Table 2 below), and it was inferred that the base/acid ratio of the hydrochloride was 1:2.
  • the obtained hydrochloride sample was taken for X-ray powder diffraction, which showed good crystallinity and was named as the crystal form I of the dihydrochloride. Its XRPD characterization spectrum is shown in Figure 1, and the main diffraction peak data are shown in Table 3.
  • endothermic peak 1 there is an endothermic peak starting point at 219.1 °C, and the peak is reached around 231.0 °C
  • endothermic peak 2 there is an endothermic peak starting at 235.1 °C
  • the starting point reaches a peak around 284.2°C, and decomposition occurs at about 205°C.
  • the PLM image shows that the crystalline particles are regular morphology.
  • solid oral dosage forms require the solubility of the drug in water to be greater than 0.1 g/L, and solution preparations such as injections or oral liquids require the solubility of the drug to be above 10 g/L.
  • the solubility should meet the clinically required dose concentration.
  • the dihydrochloride of Preparation Example 2 can be considered for the preparation of solid oral dosage forms, and can be further considered for the preparation of solution preparations such as injections or oral liquids.
  • Figure 2 shows the XRPD spectrum of the crystal form I of the dihydrochloride salt of Compound 1 obtained in Preparation Example 2 after the long-term stability test.
  • the dihydrochloride salt of compound 1 obtained in Preparation Example 2 can maintain chemical stability and crystal form stability under the condition of 40°C/75%RH (opening) for 7 days. Therefore, the sample obtained in Preparation Example 2 has better performance. Thermal stability, in line with the regulations for storage as an API.
  • Test method Using ELISA method, the enzyme reaction substrate 20 ⁇ g/mL Poly(Glu, Tyr) 4:1 was coated on the ELISA plate, and the enzyme, sample, ATP (5 ⁇ M) and other reactions were added, and the reaction was carried out with anti-phosphotyrosine. Monoclonal antibody (4G10) was used to detect the phosphorylation of the substrate, and goat anti-mouse IgG labeled with horseradish peroxidase (HRP) was added, and tetramethylbenzidine (TMB) was used to detect the phosphorylation of the substrate.
  • HRP horseradish peroxidase
  • TMB tetramethylbenzidine
  • Inhibition rate (OD value of negative control group-OD value of compound well)/(OD value of negative control group-OD value of non-enzyme control well) ⁇ 100%
  • Test method using the Caliper method, add 2 ⁇ L of 25 ⁇ compound solution to each well, and add 2 ⁇ L of reaction solution containing 25% DMSO to the non-enzyme control wells and negative control wells; add 10 ⁇ L of 5 ⁇ kinase solution to each well, and add to the non-enzyme control wells 10 ⁇ L of reaction solution; centrifuge the detection plate at 1000 rpm to mix well; mix equal volumes of 2.6 ⁇ ATP solution and 2.6 ⁇ substrate solution to obtain 1.3 ⁇ ATP-substrate solution, and add 38 ⁇ L of ATP-substrate solution to each well; Centrifuge the detection plate at 1000 rpm to mix well; place the detection plate at 30°C for 1 hour; add 20 ⁇ L of 35 mM EDTA to each well to stop the reaction. Caliper read conversion rate.
  • Inhibition rate (conversion rate of negative control wells - conversion rate of compound wells)/(conversion rate of negative control wells - conversion rate of non-enzyme control wells) ⁇ 100%
  • Test method Using the ADP Glo method, add 1 ⁇ L of 10 ⁇ compound solution to each well, and add 1 ⁇ L of reaction solution containing 10% DMSO to the non-enzyme control wells and negative control wells; add 4 ⁇ L of 2.5 ⁇ kinase solution to each well, and to the non-enzyme control wells Add 4 ⁇ L of reaction solution; centrifuge the detection plate at 1000rpm to mix well; mix 4 ⁇ ATP solution and 4 ⁇ substrate solution in equal volume to obtain 2 ⁇ ATP-substrate solution, add 5 ⁇ L of 2 ⁇ ATP-substrate solution to each well Centrifuge the detection plate at 1000 rpm to mix well; place the detection plate at 30°C for 1 hour; add 10 ⁇ L of ADP-Glo reaction reagent to each well, and place at 27°C for 40 minutes; add 20 ⁇ L of Detection reagent to each well and place at 27°C for 30 minutes minutes; Envision reads the luminescent signal.
  • Inhibition rate (reading value of negative control well-reading value of compound well)/(reading value of negative control well-reading value of no enzyme control well) ⁇ 100%
  • Compound 1 and its dihydrochloride salt (Preparation Example 2) have good inhibitory activity against targets such as RET, KDR, EGFR, FGFR1/2/3, FLT-1, LCK, HER-2 and EphA1.
  • targets such as RET, KDR, EGFR, FGFR1/2/3, FLT-1, LCK, HER-2 and EphA1.
  • other pharmaceutically acceptable salts of compound 1 also have similar effects as above.
  • Human cholangiocarcinoma cell HuCCT1 purchased from Shangcheng Beina Chuanglian Biotechnology Co., Ltd.
  • human hepatocholangiocarcinoma cell RBE purchased from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • the medium was RPMI Medium 1640 medium containing 10% FBS, and the culture environment was 37°C, 5% CO 2 .
  • the MTT method was used to determine the inhibitory effect of compound 1 dihydrochloride (Preparation Example 2) on the proliferation of human cholangiocarcinoma cells HuCCT1 and human intrahepatic cholangiocarcinoma cells RBE.
  • Test procedure cells in logarithmic growth phase were inoculated in a certain number of 96-well plates (100 ⁇ L/well), and 100 ⁇ L of compound 1 containing different concentration gradients were added to each well after 24 hours of adherence. Set corresponding blank wells (only medium) and normal wells (drug concentration is 0). After 72 hours of drug action, add MTT working solution (5mg/mL), 20 ⁇ L per well; act at 37°C for 4 hours, shake the plate to remove the supernatant, add 150 ⁇ L of DMSO; shake and mix well, and the microplate reader detects light at 550 nm. Density value (OD).
  • the inhibition rate of cell growth was calculated using the following formula:
  • Inhibition rate (%) (well with normal OD value - well with administration of OD value) / (well with normal OD value - blank well with OD value) ⁇ 100%
  • the median inhibitory concentration IC 50 of the drug was calculated by SPSS19.0.
  • the dihydrochloride salt of compound 1 (preparation example 2) has a good inhibitory effect on the proliferation of HuCCT1 and RBE cells. Similarly, other pharmaceutically acceptable salts of compound 1 also have similar effects as above.
  • the age is 18-75 years old (including the boundary value), and the gender is not limited;
  • the interval between last chemotherapy, radiotherapy, targeted therapy and surgery should be at least 4 weeks before enrollment;
  • the expected survival period is at least 3 months
  • Hemoglobin (Hb) ⁇ 90g/L no blood transfusion within 14 days before screening examination
  • ALT and AST Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ⁇ 2.5 times the upper limit of normal (if there are patients with liver metastases, ⁇ 5.0 times the upper limit of normal);
  • Urine routine indicates urine protein ⁇ ++ and 24-hour urine protein>1.0g
  • Abnormal coagulation function (INR>1.5 or prothrombin time (PT)>ULN+4 seconds or APTT>1.5ULN): bleeding tendency (such as active peptic ulcer) or receiving thrombolytic or anticoagulation therapy By;
  • HCV antibody test result is positive, additional HCV RNA test (the test result is higher than the upper limit of the normal range of the research center).
  • HIV positive Human immunodeficiency virus infection
  • the subject has a pregnancy event during the study
  • Safety indicators including vital signs and physical examination, electrocardiogram and echocardiography, laboratory tests, adverse events, etc.
  • MTD Maximum tolerated dose assessment: the previous dose at which dose escalation was discontinued due to a DLT event.
  • the maximum tolerated dose (or 800 mg) group obtained in the dose escalation phase will conduct a multi-center, open-label extension study to evaluate the efficacy, safety and pharmacokinetics of Compound 1 dihydrochloride in patients with advanced solid tumors. Eligible subjects directly enter the first-week dosing period, continuous dosing for 21 days, rest for 7 days, and 28 days as a dosing cycle until disease progression or unacceptable toxicity.
  • screening began within 28 days (D-28 to D-1) before taking the investigational drug.
  • the process requires the completion of relevant safety checks and efficacy evaluations, and PK blood sample collection throughout the study period. If the comprehensive data analysis during the study shows that the subject cannot tolerate the dose, a dose group will be reduced as the recommended starting dose after discussion between the sponsor and the investigator.
  • HB Hemoglobin
  • the coagulation function test conforms to: International Normalized Ratio (INR) ⁇ 1.5 or Partially Activated Prothrombin Time (APTT) ⁇ 1.5 ⁇ ULN;
  • Total bilirubin ⁇ 1.5 ⁇ ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ⁇ 2.5 ⁇ ULN; for subjects with tumor involvement in the liver, TBIL is acceptable ⁇ 3 ⁇ ULN, AST ⁇ 5 ⁇ ULN, ALT ⁇ 5 ⁇ ULN;
  • ⁇ QT interval (QTc) value ⁇ 450ms; or congenital long QT syndrome, family history of long QT syndrome;
  • cardiovascular/cerebrovascular diseases such as: stroke ( ⁇ 6 months prior to administration), myocardial infarction ( ⁇ 6 months prior to administration), unstable angina, congestive heart failure ( ⁇ NYHA Class II) or severe arrhythmia;
  • gastrointestinal diseases such as gastrointestinal perforation and abdominal fistula, such as active peptic ulcers, inflammatory bowel disease (including ulcerative colitis and Crohn's disease) within 28 days before administration ), abdominal fistula, gastrointestinal perforation, intestinal obstruction, intra-abdominal abscess, etc.;
  • HBsAg positive and HBV DNA >2000IU/mL (or >1 ⁇ 104 copies/mL);
  • HIV Human immunodeficiency virus
  • CR Complete remission
  • Partial remission At least 30% reduction in the sum of target lesion diameters from baseline.
  • PD Disease progression
  • Stable disease The degree of reduction of target lesions does not reach the PR level, and the degree of increase does not reach the level of PD. Between the two, the minimum sum of diameters can be used as a reference in the study.
  • CR Complete remission
  • Incomplete response/non-progression presence of one or more non-target lesions and/or persistent tumor marker levels above normal.
  • Disease progression Definite progression of an existing non-target lesion. NOTE: The appearance of one or more new lesions is also considered disease progression.
  • FDG-PET evaluation of lesions generally requires additional testing for supplementary confirmation, and it is reasonable to combine FDG-PET and supplemental CT findings to evaluate progress (especially for new suspicious diseases). New lesions can be identified by FDG-PET, which is performed according to the following procedure: baseline FDG-PET is negative and subsequent follow-up FDG-PET is positive, indicating disease progression.
  • Efficacy indicators include: objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR);
  • ORR objective response rate
  • PFS progression-free survival
  • OS overall survival
  • DCR disease control rate
  • DOR duration of response
  • ORR From the day of the first administration, including the percentage of subjects with complete remission (CR) and partial remission (PR) among all enrolled subjects;
  • PFS The time from the date of the first dose to the date of tumor progression (assessed by imaging diagnosis of PD) or the date of all-cause death (whichever occurs first);
  • OS The time from the day of the first administration until death due to any cause (the time of the last follow-up for subjects who were lost to follow-up; the end of follow-up for subjects who were still alive at the end of the study;
  • DCR defined as the percentage of subjects with CR, PR or stable disease (SD) in all enrolled subjects from the day of the first dose;
  • DOR The time from the first tumor assessment as CR or PR to the first assessment as PD or death from any cause.
  • Safety assessment includes evaluation of vital signs and physical examination, electrocardiogram, laboratory tests, adverse events, etc.
  • PK blood samples were collected at any time point on the 28th ( ⁇ 3) day visit of each cycle for the detection of the drug concentration of compound 1. Descriptive statistical analysis was performed on drug concentrations, and corresponding curves were drawn.
  • PFS Primary endpoint: PFS was estimated by Kaplan-Meier method with median time and 95% CI, and the corresponding survival curve was drawn.
  • OS and DOR were estimated by the Kaplan-Meier method with the median time and 95% CI, and the corresponding survival curves were drawn. ORR, DCR, etc., percentages are given and 95% CIs were calculated using the Clopper-Pearson method.
  • ORR Objective Response Rate
  • DCR Disease Control Rate
  • the data in the above table shows that the dihydrochloride of compound 1 of the present application can control the disease progression of patients with advanced or metastatic biliary tract malignant tumors who have failed or are intolerant of first-line treatment to a certain extent, especially the intrahepatic bile duct.
  • Disease progression in cancer patients The results of disease progression-free survival (PFS) and duration of response (DOR) were good, and there are still patients under further follow-up, and the results of PFS and DOR will continue to be prolonged.
  • PFS disease progression-free survival
  • DOR duration of response
  • the postoperative pathology showed intrahepatic cholangiocarcinoma (adenocarcinoma), T2NxM1 stage IV, chronic cholecystitis.
  • single-agent capecitabine adjuvant chemotherapy was given, and the imaging examination on May 28, 2021 indicated that the disease progressed and was discontinued. In June 2021, it was changed to gemcitabine + cisplatin chemotherapy, and the first course of treatment was discontinued due to intolerance of toxic reactions.
  • CT plain scan + enhanced examination showed that the right hemi-liver was missing after surgery, and there were several low-density nodules in the remaining liver, the largest one was about 14mm in diameter, and metastasis was considered.
  • the stage was T2NxM1 (liver metastasis) IV, and the ECOG was 1 point.
  • this product was given (once a day, 600 mg each time, orally, for 21 consecutive days and then stopped for 7 days, that is, 28 days as a cycle), and the first imaging efficacy evaluation was SD after 8 weeks of treatment. PR was assessed at 13, 16, and 24 weeks afterward.
  • Tip In the case that the commonly used clinical anticancer drugs (capecitabine, gemcitabine + cisplatin chemotherapy) do not show good curative effect, the dihydrochloride salt of compound 1 of the present application shows partial remission of the disease.
  • compound 1 and its pharmaceutically acceptable salts are multi-targeted protein kinase inhibitors, which have potent effects on a variety of protein kinases.
  • Good inhibitory activity further, it has inhibitory activity below 100nM for several protein kinases related to biliary tract cancer, and will show good therapeutic effect on biliary tract cancer caused by different gene mutations.
  • Compound 1 and its pharmaceutically acceptable salts eg, dihydrochloride
  • the pharmaceutically acceptable salt of the compound 1 represented by the dihydrochloride salt of the compound 1 has good safety.
  • the pharmaceutically acceptable salt of compound 1 represented by the dihydrochloride salt of compound 1 can control the incidence of advanced or metastatic biliary tract malignant tumors that have failed or are intolerant of first-line treatment to a certain extent.
  • Compound 1 of the present application or a pharmaceutically acceptable salt thereof has the potential for clinical application in the treatment of biliary tract cancer.

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Abstract

涉及多靶点蛋白激酶抑制剂或其药学上可接受的盐在制备用于治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一个或多于一个导致的相关病症的药物中的用途，尤其是胆道癌，及其治疗上述疾病的方法。涉及式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐对多种激酶具有良好抑制活性，在体外对人胆管癌细胞和肝内胆管癌细胞亦具有良好的抑制活性，且在临床I期试验中表现出良好的安全性，在临床II期试验中能够一定程度上控制一线治疗失败或不耐受的晚期或转移性胆道恶性肿瘤的患者的疾病进展，具有治疗胆道癌的临床潜力。

Description

多靶点蛋白激酶抑制剂的用途
相关申请的引用
本申请要求2021年2月25日在中国提交的、名称为“多靶点蛋白激酶抑制剂的用途”、申请号为202110209218.8的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。
技术领域
本申请属于医药领域，具体涉及多靶点蛋白激酶抑制剂在制备用于治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一个或多于一个导致的相关病症的药物中的用途，特别是在制备治疗胆道癌的药物中的用途及其治疗上述疾病的方法。
背景技术
蛋白酪氨酸激酶(Protein tyrosine kinases，PTKs)作为蛋白激酶家族中非常重要的一员，PTKs将三磷酸腺苷上的γ-磷酸基转移到底物的蛋白酪氨酸残基上，通过将酚羟基磷酸化来完成细胞间的信息传递，在细胞发育、调节和肿瘤细胞的分化、迁移、凋亡等过程中起着至关重要的作用。若PTKs在调节过程中失控将会影响其下游信号通路的正确激活，进而引起细胞增殖调节功能紊乱而引发许多疾病，如酪氨酸激酶活性过高使受体磷酸化进而激活下游信号，导致细胞过度转化、增殖、对抗细胞凋亡、促进细胞生存进而形成恶性肿瘤。
表皮生长因子受体(Epidermal Growth Factor Receptor，EGFR)、成纤维生长因子受体(Fibroblast Growth Factor Receptors，FGFRs)、血小板源生长因子受体(Platelet-derived Growth Factor Receptor，PDGFR)、RET(Rearranged during Transfection)原癌基因编码的RET蛋白等就是PTKs的重要成员，是肿瘤治疗的重要靶标。
EGFR包括EGFR(ErbB-1)、2型人表皮生长因子受体HER-2(ErbB-2)、3型人表皮生长因子受体HER3(ErbB-3)及4型人表皮生长因子受体HER4(ErbB-4)，其中，EGFR和HER-2是EGFR家族成员中与肿瘤关系最为密切的靶点。研究表明，EGFR在多种肿瘤如肺癌、胃癌、表皮样癌、肾癌、卵巢癌等中表现出过度表达、基因突变或基因融合。
FGFR主要包括FGFR1/2/3/4四种亚型，它们通过基因扩增、突变、融合或配体诱导等方式过度表达或过度激活，对肿瘤细胞增殖、侵袭和迁移及肿瘤血管的生成具有重要作用。研究发现，FGFRs在多种肿瘤如肺癌、胃癌、胆管癌、结直肠癌、肝癌等中均表现出突变、过度表达或过度激活。
胆道癌(Biliary Tract Carcinoma，BTC)是一种具有侵袭性、遗传异质性的恶性肿瘤，包括胆囊癌(Gallbladder Carcinoma，GBC)，胆管癌(Cholangio Carcinoma，CC)和壶腹癌等，胆管癌包括肝内和肝外胆管癌。BTC发病率较低，约占消化道肿瘤的3％，其中原发性胆囊癌约占BTC的50％以上。BTC早期多没有自觉症状，在出现黄疸以前难以引起注意，约60-70％BTC患者被诊断时已处于不能切除或转移的阶段，预后欠佳，5年存活率＜5％。BTC具有较高的复发率和远处转移率，为尽可能延长患者生存期或改善症状，通常需要进行辅助治疗如化疗、放疗等。目前对于晚期BTC主要采用化疗，可考虑采用奥沙利铂联合5-氟尿嘧啶(5-FU)、奥沙利铂/伊利替康/5-FU、伊利替康联合卡培他滨，但疗效欠佳。
培米加替尼(pemigatinib、Pemazyre)是一种选择性FGFR抑制剂，2020年4月17日被美国食品药品监督管理局批准上市，用于成人治疗先前经过治疗但效果不佳的晚期FGFR2基因融合型胆管癌，成为首款胆管癌治疗史上的靶向药物，终结了胆管癌唯化疗方法的时代。但在临床试验中，也观察到了培米加替尼在治疗过程中存在的毒副作用，最常见的有高磷血症、斑秃、腹泻、指甲毒性、味觉异常、恶心、便秘、口腔炎症、眼睛发干、呕吐、关节痛等，另一个潜在毒性是眼睛毒性。
肿瘤常与多条信号转导通路、多个靶点调节失衡相关，单靶点药物治疗肿瘤不一定能达到预期治疗效果，且其应用也受限于药物毒副作用和耐药性，因此，多靶点药物成为新的药物研究方向。相比单靶点药物，多靶点药物可以作用于肿瘤相关的多个靶点，即使其针对单一靶点的活性相比于单靶点 药物可能有所降低，但可能受益于多靶点调节所产生的协同作用，使总效应可能大于单个效应的总和，从而获得更好的疗效和产生更小的不良反应。
CN106660970B公开了如式A所示的通式化合物，特别是具有式1所示的化合物(实施例22)，这些化合物是一类具有抑制RET、KDR、EGFR、FGFR1、FLT-1等蛋白酪氨酸激酶活性的多靶点抑制剂，目前尚无其可用于人胆道癌治疗的相关研究报道。
Figure PCTCN2022077932-appb-000001
发明内容
本申请所要解决的一个技术问题是提供一种如式A所示的多靶点蛋白激酶抑制剂或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐在制备用于治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的相关病症的药物中的用途。
具体而言，在本申请的第一方面中，提供了一种如式A所示的多靶点蛋白激酶抑制剂或其药学上可接受的盐，在制备用于治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的相关病症的药物中的用途，
Figure PCTCN2022077932-appb-000002
其中，
R 1为-O(CH 2) nR 3，其中n为3、4或5，R 3为-NR eR f，其中R e和R f各自在每次出现时彼此独立地选自甲基，或者R e和R f一起形成-(CH 2) 4-；
其中R 2为
Figure PCTCN2022077932-appb-000003
在一个实施方案中，所述的式A所示化合物中，R 1选自
Figure PCTCN2022077932-appb-000004
Figure PCTCN2022077932-appb-000005
在一个实施方案中，所述式A所示化合物为化合物1，
Figure PCTCN2022077932-appb-000006
在一个实施方案中，所述相关病症为由RET、KDR、EGFR、FGFR1/2/3、FLT-1、HER-2、LCK、EphA1、SRC激酶中的一种或多于一种导致的相关病症。
在一个实施方案中，所述相关病症为肿瘤疾病；优选地，所述肿瘤疾病为实体瘤；进一步优选地，所述实体瘤为胆道癌。
在一个实施方案中，所述胆道癌是由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的。
在一个实施方案中，所述胆道癌为晚期胆道癌。
在一个实施方案中，所述胆道癌为局部晚期胆道癌。
在一个实施方案中，所述胆道癌为不能手术切除的局部晚期胆道癌。
在一个实施方案中，所述胆道癌为转移性胆道癌。
在一个实施方案中，所述胆道癌为治疗失败或不耐受的胆道癌。
在一个实施方案中，所述胆道癌为经一线治疗失败或不耐受的胆道癌。
在一个实施方案中，所述胆道癌为胆囊癌或胆管癌。
在一个实施方案中，所述胆管癌为肝内胆管癌和/或肝外胆管癌；优选为肝内胆管癌。
在一个实施方案中，所述式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐作为唯一的活性成分，用于制备所述药物。
在一个实施方案中，式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐与其他治疗剂中的一种或多种联合用于制备所述药物。所述的其他治疗剂包括但不限于靶向药物或化疗药物，所述的其他靶向药物或化疗药物是指临床用于治疗肿瘤相关疾病的靶向药物或化疗药物。
本申请的第二方面中，提供了一种如式A所示的多靶点蛋白激酶抑制剂或其药学上可接受的盐，其用于治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的相关病症，
Figure PCTCN2022077932-appb-000007
其中，
R 1为-O(CH 2) nR 3，其中n为3、4或5，R 3为-NR eR f，其中R e和R f各自在每次出现时彼此独立地选自甲基，或者R e和R f一起形成-(CH 2) 4-；
其中R 2为
Figure PCTCN2022077932-appb-000008
在一个实施方案中，所述的式A所示化合物中，R 1选自
Figure PCTCN2022077932-appb-000009
Figure PCTCN2022077932-appb-000010
在一个实施方案中，所述式A所示化合物为化合物1，
Figure PCTCN2022077932-appb-000011
在一个实施方案中，所述相关病症为由RET、KDR、EGFR、FGFR1/2/3、FLT-1、HER-2、LCK、EphA1、SRC激酶中的一种或多于一种导致的相关病症。
在一个实施方案中，所述相关病症为肿瘤疾病；优选地，所述肿瘤疾病为实体瘤；进一步优选地，所述实体瘤为胆道癌。
在一个实施方案中，所述胆道癌是由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的。
在一个实施方案中，所述胆道癌为晚期胆道癌。
在一个实施方案中，所述胆道癌为局部晚期胆道癌。
在一个实施方案中，所述胆道癌为不能手术切除的局部晚期胆道癌。
在一个实施方案中，所述胆道癌为转移性胆道癌。
在一个实施方案中，所述胆道癌为治疗失败或不耐受的胆道癌。
在一个实施方案中，所述胆道癌为经一线治疗失败或不耐受的胆道癌。
在一个实施方案中，所述胆道癌为胆囊癌或胆管癌。
在一个实施方案中，所述胆管癌为肝内胆管癌和/或肝外胆管癌；优选为肝内胆管癌。
在一个实施方案中，所述式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐作为唯一的活性成分，用于制备药物。
在一个实施方案中，式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐与其他治疗剂中的一种或多种联合用于制备药物，或用于治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的相关病症。所述的其他治疗剂包括但不限于靶向药物或化疗药物，所述的其他靶向药物或化疗药物是指临床用于治疗肿瘤相关疾病的靶向药物或化疗药物。
本申请的第三方面中，提供了一种如式A所示的多靶点蛋白激酶抑制剂或其药学上可接受的盐作为药物的用途，
Figure PCTCN2022077932-appb-000012
其中，
R 1为-O(CH 2) nR 3，其中n为3、4或5，R 3为-NR eR f，其中R e和R f各自在每次出现时彼此独立地选自甲基，或者R e和R f一起形成-(CH 2) 4-；
其中R 2为
Figure PCTCN2022077932-appb-000013
在一个实施方案中，所述的式A所示化合物中，R 1选自
Figure PCTCN2022077932-appb-000014
Figure PCTCN2022077932-appb-000015
在一个实施方案中，所述式A所示化合物为化合物1，
Figure PCTCN2022077932-appb-000016
在一个实施方案中，所述药物用于治疗由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的相关病症。
在一个实施方案中，所述相关病症为由RET、KDR、EGFR、FGFR1/2/3、FLT-1、HER-2、LCK、EphA1、SRC激酶中的一种或多于一种导致的相关病症。
在一个实施方案中，所述相关病症为肿瘤疾病；优选地，所述肿瘤疾病为实体瘤；进一步优选地，所述实体瘤为胆道癌。
在一个实施方案中，所述胆道癌是由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的。
在一个实施方案中，所述胆道癌为晚期胆道癌。
在一个实施方案中，所述胆道癌为局部晚期胆道癌。
在一个实施方案中，所述胆道癌为不能手术切除的局部晚期胆道癌。
在一个实施方案中，所述胆道癌为转移性胆道癌。
在一个实施方案中，所述胆道癌为治疗失败或不耐受的胆道癌。
在一个实施方案中，所述胆道癌为经一线治疗失败或不耐受的胆道癌。
在一个实施方案中，所述胆道癌为胆囊癌或胆管癌。
在一个实施方案中，所述胆管癌为肝内胆管癌和/或肝外胆管癌；优选为肝内胆管癌。
在一个实施方案中，所述式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐作为唯一的活性成分，用于制备所述药物。
在一个实施方案中，式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐与其他治疗剂中的一种或多种联合用于制备所述药物。所述的其他治疗剂包括但不限于靶向药物或化疗药物，所述的其他靶向药物或化疗药物是指临床用于治疗肿瘤相关疾病的靶向药物或化疗药物。
在本申请的第四方面中，提供了一种治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的相关病症的方法，所述方法包括给予受试者或患者含有治疗有效量的式A所示的多靶点蛋白激酶抑制剂或其药学上可接受的盐，
Figure PCTCN2022077932-appb-000017
其中，
R 1为-O(CH 2) nR 3，其中n为3、4或5，R 3为-NR eR f，其中R e和R f各自在每次出现时彼此独立地选自甲基，或者R e和R f一起形成-(CH 2) 4-；
其中R 2为
Figure PCTCN2022077932-appb-000018
在一个实施方案中，所述的式A所示化合物中，R 1选自
Figure PCTCN2022077932-appb-000019
Figure PCTCN2022077932-appb-000020
在一个实施方案中，所述式A所示化合物为化合物1，
Figure PCTCN2022077932-appb-000021
在一个实施方案中，所述相关病症为由RET、KDR、EGFR、FGFR1/2/3、FLT-1、HER-2、LCK、EphA1、SRC激酶中的一种或多于一种导致的相关病症。
在一个实施方案中，所述相关病症为肿瘤疾病；优选地，所述肿瘤疾病为实体瘤；进一步优选地，所述实体瘤为胆道癌。
在一个实施方案中，所述胆道癌是由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的。
在一个实施方案中，所述胆道癌为晚期胆道癌。
在一个实施方案中，所述胆道癌为局部晚期胆道癌。
在一个实施方案中，所述胆道癌为不能手术切除的局部晚期胆道癌。
在一个实施方案中，所述胆道癌为转移性胆道癌。
在一个实施方案中，所述胆道癌为治疗失败或不耐受的胆道癌。
在一个实施方案中，所述胆道癌为经一线治疗失败或不耐受的胆道癌。
在一个实施方案中，所述胆道癌为胆囊癌或胆管癌。
在一个实施方案中，所述胆管癌为肝内胆管癌和/或肝外胆管癌；优选为肝内胆管癌。
在一个实施方案中，所述式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐作为唯一的活性成分，用于制备药物。
在一个实施方案中，式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐与其他治疗剂中的一种或多种联合用于制备药物，或者用于治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的相关病症。所述的其他治疗剂包括但不限于靶向药物或化疗药物，所述的其他靶向药物或化疗药物是指临床用于治疗肿瘤相关疾病的靶向药物或化疗药物。
本申请的第五个方面中，提供了一种试剂盒，包含前述(第一方面、第二方面、第三方面、第四方面)的式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐。
在一个实施方案中，所述试剂盒包括一种或多种容器，所述容器中包含式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐。
在一个实施方案中，所述试剂盒，包含前述(第一方面、第二方面、第三方面、第四方面)药物。
在本申请中，如前(第一方面、第二方面、第三方面、第四方面、第五方面)所述的式A所示化合物，特别是化合物1的药学上可接受的盐没有特别的限制，例如，所述式A所示化合物的药学上可接受的盐包括但不限于盐酸盐、硫酸盐、草酸盐、马来酸盐或苹果酸盐；优选为盐酸盐、硫酸盐或马来酸盐；进一步优选为盐酸盐；更进一步优选为二盐酸盐；更进一步优选为二盐酸盐的无水形式或其水合物。
在一些实施方案中，如前(第一方面、第二方面、第三方面、第四方面、第五方面)所述的式A所示化合物的药学上可接受的盐为化合物1的二盐酸盐(式2所示的化合物)，
Figure PCTCN2022077932-appb-000022
在一些实施方案中，所述式2所示的化合物为结晶形式。
在一些实施方案中，式2所示化合物的结晶形式(晶型I)，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：12.4、18.8、20.3、24.6。
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：9.8、12.4、18.8、20.3、24.6。
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：8.1、9.8、12.4、18.8、20.3、24.6、29.9。
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：8.1、9.8、12.4、18.8、19.3、20.3、24.6、28.6、29.9。
或者，使用Cu-Kα辐射，以2θ角度(°)表示的粉末X-射线衍射图谱在以下位置有特征衍射峰(±0.2°)：8.1、9.8、12.4、16.1、18.8、19.3、20.3、24.6、28.6、29.9、30.9。
或者，使用Cu-Kα辐射，具有基本上如图1或图2所示的X-射线粉末衍射图谱。
在一些实施方案中，式2所示化合物的结晶形式(晶型I)，其DSC曲线在231.0±5℃和284.2±5℃处分别有吸热峰。
在一些实施方案中，式2所示化合物的结晶形式(晶型I)，其TGA曲线在205.6±5℃处开始发生分解。
在一些实施方案中，前述(第一方面、第二方面、第三方面、第四方面、第五方面，下同)药物制成临床接受的制剂，包括但不限于口服制剂、注射制剂、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。在一些实施方案中，前述药物中含有治疗有效量的式A所示化合物或其药学上可接受的盐以从约0.001mg/kg至约1000mg/kg的每日给药剂量范围给予，优选约0.01mg/kg-800mg/kg，或0.1mg/kg-600mg/kg，或1mg/kg-500mg/kg，或2mg/kg-400mg/kg，或3mg/kg-300mg/kg，或4mg/kg-200mg/kg，或5mg/kg-100mg/kg，或10mg/kg-50mg/kg。优选地，所述式A所示化合物或其药学上可接受的盐为化合物1或其药学上可接受的盐。
在一些实施方案中，前述药物每个制剂单位中含有式A所示化合物或其药学上可接受的盐 0.1-5000mg，优选1-1000mg，或10-800mg，或20-700mg，或22-650mg，或25-650mg，或50-600mg，或85-500mg，或86-500mg，或90-500mg，或100-500mg，或100-450mg，或100-400mg，或150-350mg，或170-350mg，或173-350mg，或175-350mg，或200-300mg，或150-200mg。所述剂量以式A所示化合物计。优选地，所述式A所示化合物或其药学上可接受的盐为化合物1或其药学上可接受的盐。
在一个实施方案中，前述药物每个制剂单位中含有式A所示化合物的二盐酸盐0.1-5000mg，优选1-1000mg，或10-800mg，或25-700mg，或50-600mg，或80-500mg，或90-500mg，或100-500mg，或100-450mg，或100-400mg，或150-350mg，或200-300mg，或150-200mg；示例性的例子包括，25mg、50mg、100mg、150mg或200mg。所述剂量以无水形式的式A所示化合物的二盐酸盐计。优选地，所述式A所示化合物的二盐酸盐为化合物1的二盐酸盐。进一步优选为所述式2所示化合物的结晶形式；更进一步优选为所述式2所示化合物的晶型I。
在一个实施方案中，前述药物中含有治疗有效量的式A所示化合物或其药学上可接受的盐，其给药剂量为：每次给药20mg-1500mg；优选地，每次给药50mg-1200mg；优选地，每次给药100mg-1000mg；优选地，每次给药200mg-800mg；进一步优选地，每次给药250mg-700mg；进一步优选地，每次给药300mg-600mg；进一步优选地，每次给药300mg-550mg；进一步优选地，每次给药300mg-500mg；进一步优选地，每次给药300mg-450mg；示例性的给药剂量包括，每次给药20mg、22mg、25mg、40mg、43mg、45mg、50mg、80mg、85mg、86mg、90mg、100mg、150mg、170mg、173mg、175mg、180mg、200mg、250mg、259mg、260mg、300mg、302mg、310mg、340mg、346mg、350mg、400mg、380mg、385mg、389mg、390mg、400mg、430mg、432mg、440mg、450mg、475mg、500mg、518mg、520mg、550mg、560mg、562mg、600mg、605mg、610mg、648mg、650mg、690mg、691mg、700mg、750mg、778mg、800mg或900mg。所述剂量以化合物A计。优选地，所述式A所示化合物或其药学上可接受的盐为化合物1或其药学上可接受的盐。
在一个实施方案中，前述药物中含有治疗有效量的式A所示化合物的二盐酸盐，其给药剂量为：每次给药25mg-900mg；优选地，每次给药200mg-800mg；进一步优选地，每次给药300mg-700mg；进一步优选地，每次给药300mg-600mg；进一步优选地，每次给药400mg-600mg；进一步优选地，每次给药450mg-600mg；示例性的给药剂量包括，每次给药25mg、50mg、100mg、200mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg或900mg。所述剂量以无水形式的化合物A的二盐酸盐计。优选地，所述式A所示化合物的二盐酸盐为化合物1的二盐酸盐。进一步优选为所述式2所示化合物的结晶形式；更进一步优选为所述式2所示化合物的晶型I。
在一个实施方案中，前述药物的每日给药剂量频率为每天给药一次、每天给药两次、每天给药三次或每天给药四次；优选为每天给药一次。
在一个实施方案中，前述药物中含有治疗有效量的式A所示化合物或其药学上可接受的盐，其每日给药剂量为20mg-1500mg；优选为50mg-1200mg；进一步优选为100mg-1000mg；进一步优选为200mg-800mg；进一步优选为250mg-700mg；进一步优选为300mg-600mg；进一步优选为300mg-550mg；进一步优选为300mg-500mg；进一步优选为300mg-450mg；示例性的每日给药剂量包括，每日给药20mg、22mg、25mg、40mg、43mg、45mg、50mg、80mg、85mg、86mg、90mg、100mg、150mg、170mg、173mg、175mg、180mg、200mg、250mg、259mg、260mg、300mg、302mg、310mg、340mg、346mg、350mg、400mg、380mg、385mg、389mg、390mg、400mg、430mg、432mg、440mg、450mg、475mg、500mg、518mg、520mg、550mg、560mg、562mg、600mg、605mg、610mg、648mg、650mg、690mg、691mg、700mg、750mg、778mg、800mg或900mg。所述剂量以化合物A计。优选地，所述式A所示化合物或其药学上可接受的盐为化合物1或其药学上可接受的盐。其中，每日给药频率为一次、二次、三次或多次。
在一个实施方案中，前述药物中含有治疗有效量的式A所示化合物的二盐酸盐，其每日给药剂量为25mg-900mg；优选为200mg-800mg；进一步优选为300mg-700mg；进一步优选为300mg-600mg；进一步优选为400mg-600mg；进一步优选为450mg-600mg；示例性的每日给药剂量包括，每日给药25mg、50mg、100mg、200mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg或900mg。所述剂量以无水形式的化合物A的二盐酸盐计。优选地，所述式 A所示化合物的二盐酸盐为化合物1的二盐酸盐。进一步优选为所述式2所示化合物的结晶形式；更进一步优选为所述式2所示化合物的晶型I。其中，每日给药频率为一次、二次、三次或多次。
在一个实施方案中，前述药物中含有治疗有效量的式A所示化合物或其药学上可接受的盐，其给药剂量和剂量频率为：每天给药一次，每次给药20mg-1500mg；优选地，每天给药一次，每次给药50mg-1200mg；优选地，每天给药一次，每次给药100mg-1000mg；优选地，每天给药一次，每次给药200mg-800mg；进一步优选地，每天给药一次，每次给药250mg-700mg；进一步优选地，每天给药一次，每次给药300mg-600mg；进一步优选地，每天给药一次，每次给药300mg-550mg；示例性的给药剂量和频率包括，每天给药一次，每次给药20mg、22mg、25mg、40mg、43mg、45mg、50mg、80mg、85mg、86mg、90mg、100mg、150mg、170mg、173mg、175mg、180mg、200mg、250mg、259mg、260mg、300mg、302mg、310mg、340mg、346mg、350mg、400mg、380mg、385mg、389mg、390mg、400mg、430mg、432mg、440mg、450mg、475mg、500mg、518mg、520mg、550mg、560mg、562mg、600mg、605mg、610mg、648mg、650mg、690mg、691mg、700mg、750mg、778mg、800mg或900mg。所述剂量以化合物A计。优选地，所述式A所示化合物或其药学上可接受的盐为化合物1或其药学上可接受的盐。
在一个实施方案中，前述药物中含有治疗有效量的式A所示化合物的二盐酸盐，其给药剂量和剂量频率为：每天给药一次，每次给药25mg-900mg；优选地，每天给药一次，每次给药200mg-800mg；进一步优选地，每天给药一次，每次给药300mg-700mg；进一步优选地，每天给药一次，每次给药300mg-600mg；进一步优选地，每天给药一次，每次给药400mg-600mg；进一步优选地，每天给药一次，每次给药450mg-600mg；示例性的给药剂量和频率包括，每天给药一次，每次给药25mg、50mg、100mg、200mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg或900mg。所述剂量以无水形式的化合物A的二盐酸盐计。优选地，所述式A所示化合物的二盐酸盐为化合物1的二盐酸盐。进一步优选为所述式2所示化合物的结晶形式；更进一步优选为所述式2所示化合物的晶型I。
在一个实施方案中，前述药物中含有治疗有效量的式A所示化合物或其药学上可接受的盐，其给药剂量频率为：每天给药一次，给药21天，停药7天，每28天为一周期。优选地，所述式A所示化合物或其药学上可接受的盐为化合物1或其药学上可接受的盐。
在一个实施方案中，前述药物通过口服给予、注射给予、局部给予或体外给予。在一个优选的实施方案中，所述药物通过口服给予或注射给予；优选地，通过口服给予。
在一些实施方案中，如前(第一方面、第二方面、第三方面、第四方面、第五方面)所述的式A所示化合物或其药学上可接受的盐，其为化合物1的二盐酸盐；优选为所述式2所示化合物的结晶形式；进一步优选为所述式2所示化合物的晶型I。
在一个实施方案中，前述(第一方面、第二方面、第三方面、第四方面、第五方面)式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐可以单剂量施用或分剂量施用；优选地，以单剂量施用。
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。当本文出现商品名时，旨在指代其对应的商品或其活性成分。
在本申请中，式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐的治疗有效剂量和剂量频率可以通过诸如建模、剂量递增研究或临床试验的方法和通过考虑诸如待治疗疾病的特性和严重程度、患者的年龄、一般情况和体重，以及所施用的具体化合物，它的药物代谢动力学特性，以及施用途径等因素进行确定。
本申请所述的“化疗药物”是指治疗肿瘤的化学药物，包括但不限于细胞毒类、抗代谢类、抗生素类、生物碱类、激素类及其它类药物。
本申请所述的“靶向药物”是指用于靶向治疗的药物或其制剂，通过干扰癌变或肿瘤增生所需的特定分子阻止癌细胞增长或增殖，包括但不限于小分子靶向药物和大分子靶向药物，其中，小分子靶向药物包括但不限于蛋白激酶抑制剂，例如蛋白酪氨酸激酶抑制剂，大分子靶向药物包括但不限于单 克隆抗体、抗体偶联药物和免疫治疗药物。
本申请所述的式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐的剂量，除非特别说明，可以游离碱形式计，也可以实际使用的具体形式计，若含有水合物，可以除水之外的单元形式计，也可以该水合物形式计。例如，若使用化合物1的盐酸盐，则以化合物1的盐酸盐计；若使用化合物1盐酸盐的水合物，则可以化合物1的盐酸盐计，也可以化合物1盐酸盐的水合物计。
本申请所述的式A所示化合物或其药学上可接受的盐，特别是化合物1或其药学上可接受的盐的剂量，可在临床接受的范围内浮动，例如每次给药100mg，给药剂量可在10％剂量范围内上下浮动，即90mg～110mg。
本申请所述的“一线治疗”不限于经批准用于治疗胆道癌一线化疗方案，还包括诊断后首个用于治疗胆道癌的非一线化疗方案、免疫治疗、靶向治疗等系统性药物治疗，“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。
如无特别说明，本申请所述的“2θ”、“2θ角”或“2θ角度”是指衍射角，单位为°或度，2θ的误差范围可以为±0.5°、±0.4°、±0.3°、±0.2°或±0.1°；在本申请的一些实施方案中，2θ的误差范围为±0.2°。
术语“基本上如图所示”是指X-射线粉末衍射图谱中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少96％，或至少97％，或至少98％，或至少99％的峰显示在其图中。进一步地，当产品中某种晶型的含量逐渐降低时，其粉末X-射线衍射图谱中的一些归属于该晶型的衍射峰可能会由于仪器的检测灵敏度的因素而变少。
术语“特征衍射峰”是指在X-射线粉末衍射图谱中，可用于代表该晶型的衍射峰，其与衍射峰的峰位置、峰形和相对峰强度有关，例如，小角度峰，峰形尖锐，且相对峰强度至少3％以上，或至少5％以上，或至少10％以上，或至少20％以上，或至少30％以上，或至少40％以上，或至少50％以上，或至少60％以上，或至少70％以上，或至少75％以上的衍射峰。
本申请取得以下一种或多种有益的技术效果：(1)所述化合物1或其药学上可接受的盐对多种蛋白激酶具有良好的抑制活性(小于100nM)；(2)所述化合物1或其药学上可接受的盐对人胆管癌细胞和人肝内胆管癌细胞具有良好的抑制活性；(3)所述化合物1或其药学上可接受的盐(例如，化合物1的二盐酸盐)在临床I期试验中表现出较好的耐受性，不良反应种类少，3级以上副反应发生率很低，提示其临床安全性较好；(4)所述化合物1或其药学上可接受的盐(例如，化合物1的二盐酸盐)在临床II期试验中，能够一定程度上控制一线治疗失败或不耐受的晚期或转移性胆道恶性肿瘤的患者的疾病进展，其效果优于临床常用的化疗药。具有治疗胆道癌的临床潜力。
附图说明
图1：制备例2所得化合物1的二盐酸盐的晶型I的XRPD谱图；
图2：测试例3中制备例2所得化合物1的二盐酸盐的晶型I在长期稳定性测试后的XRPD谱图。
具体实施方式
下文将结合具体制备例和实施例对本申请的技术方案做更进一步的详细说明。下列制备例和实施例仅为示例性地说明和解释本申请，而不应被解释为对本申请保护范围的限制。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，仍属于本申请的保护范围。除非另有说明，以下制备例和实施例中使用的原料、试剂(例如，有机溶剂、无极溶剂、激酶、底物、抗体、缓冲液、反应液等)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。
以下制备例中，分析检测条件如下：
1、含量
检测仪器：Agilent 1260(LC1260-3-DAD)高效液相色谱仪
柱子：C18 4.6×250mm，5μm
测试条件：波长252nm；柱温45℃。
2、溶解度(水及pH2.0缓冲液)
检测仪器：Agilent 1260高效液相色谱仪
检测介质：纯化水、pH2.0磷酸-磷酸氢二钠缓冲液
对照品溶液制备：取式1化合物对照品适量，精密称定，加溶剂使其完全溶解，并稀释制成100μg/mL的溶液，精密量取10uL，使用HPLC测定对照品溶液中化合物1的含量。
3、X-射线粉末衍射(X-Ray Powder Diffraction，XRPD)
检测仪器：Bruker D2 PHASER型粉末X-射线衍射仪
测试条件：
光管类型：Cu靶，陶瓷X光管；
X-射线波长：CuKα，
Figure PCTCN2022077932-appb-000023
1.5406；
电压电流：30kV，10mA；
扫描范围：3～40°2θ；
扫描总时间：40min；
扫描速度：0.5秒/步；
样品用量：3mg
采集软件：Diffrac Plus XRD Commander
分析软件：MDI Jade 6.0。
4、差示扫描量热-热重分析(Differential Scanning Calorimetry-Thermogravimetric Analysis，DSC-TGA)
检测仪器：NETZSCH STA449F3同步热分析仪
测试方法：称取样品(约3mg)，置于三氧化二铝坩埚内进行测试，在20mL/min干燥氮气(保护气体)的条件下，以10K/min的升温速率，加热样品从20℃至340℃。
仪器控制软件：NETZSCH-proteus
分析软件：Proteus Analysis。
5、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)
实验操作：
供试品溶液制备：取供试品适量，精密称定，用淋洗液(12.5mmol/L氢氧化钠溶液)溶解并定量稀释成每1mL中约含供试品0.5mg的溶液，摇匀，作为供试品溶液。
对照品溶液制备：取氯化钠适量(相当于氯离子18mg)，精密称定，置250mL量瓶中，用淋洗液溶解并定容，摇匀，作为对照品溶液。
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。
6、核磁氢谱
仪器型号：Bruker Advance 600型核磁共振谱仪
测定条件：以DMSO-d 6为溶剂，在室温下(～25℃)进行测试。
7、生物溶媒中溶解度测定
用于溶解度测定的生物溶媒介质(SGF，FeSSIF和FaSSIF)的配制过程见下表1：
表1
Figure PCTCN2022077932-appb-000024
Figure PCTCN2022077932-appb-000025
测试方法：将待测样品加入到生物溶媒介质中，配制成目标浓度为10mg/mL的溶液或混悬液。所得溶液或混悬液在37℃条件下以200rpm的转速持续振摇。在0.5小时将混悬液过滤，使用HPLC测定滤液中的化合物浓度。
制备例1：化合物1的制备
Figure PCTCN2022077932-appb-000026
使用CN106660970B中的方法(实施例22)，制备得到化合物1为15g。
制备例2：化合物1的二盐酸盐的制备
Figure PCTCN2022077932-appb-000027
称取制备例1所得的化合物1(10g，21.58mmol)于茄型瓶中，加入甲醇溶剂(110mL)，升温至55±5℃，搅拌至溶清，滴加盐酸(3.7mL，44.4mmol)，搅拌20分钟，缓慢加入200mL乙酸乙酯，降温至5±5℃，搅拌2±1h，抽滤，滤饼用乙酸乙酯(20mL)洗涤，得白色的化合物1的二盐酸盐(11g)，收率94.8％。
1H-NMR(600MHz，DMSO-d 6)δ：15.41(s，1H)，11.78(s，1H)，10.44(s，1H)，8.80(s，1H)，8.42(s，1H)，7.78(dd，J＝9.6Hz，J＝2.4Hz，1H)，7.58-7.52(m，2H)，7.47(s，1H)，4.24(t，J＝6Hz，2H)，4.03(s，3H)，3.15-3.14(m，2H)，2.76-2.75(m，6H)，1.90-1.88(m，4H).
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2)，可以推断得到该盐酸盐的碱/酸比为1∶2。
表2
Figure PCTCN2022077932-appb-000028
取所得盐酸盐样品进行X-射线粉末衍射，其呈现良好的结晶性，命名为二盐酸盐的晶型I，其XRPD表征谱图如图1所示，主要衍射峰数据如表3。取样品进行DSC-TGA测试，有两个吸热峰，吸热峰1：在219.1℃有一吸热峰起始点，在231.0℃附近达到峰值；吸热峰2：在235.1℃有一吸热峰起始点，在284.2℃附近达到峰值，在205℃左右发生分解。PLM图显示其结晶颗粒为规则形态。
表3制备例2所得二盐酸盐的晶型I的XRPD衍射峰数据表
Figure PCTCN2022077932-appb-000029
测试例1：溶解度测试
取制备例2样品，在水中及pH2.0缓冲液中进行溶解度测试，测试结果如下表4所示：
表4溶解度结果
Figure PCTCN2022077932-appb-000030
结果：制备例2的样品在水及pH2.0缓冲液中均具有高溶解度，虽然在酸性条件下，制备例2的溶解度相比其在水中的溶解度有所降低，但依然具有＞10mg/mL的溶解度，符合制剂要求。
根据药物剂型对原料药溶解度的一般要求，固体口服剂型要求药物的水中溶解度大于0.1g/L，注射剂或口服液等溶液制剂则要求药物的溶解度在10g/L以上，更重要的是，药物的溶解度应满足临床所需的剂量浓度。基于表4的溶解度结果，制备例2的二盐酸盐可考虑用于制备固体口服剂型，还可以进一步考虑用于制备注射剂或口服液等溶液制剂。
测试例2：生物溶媒中的溶解度测试
称取制备例2的样品(20mg)，加入不同的生物溶媒(2mL)，进行溶解度测试，结果见表5。
表5样品在不同生物溶媒中的溶解度
实施例 盐 时间 FaSSIF(pH6.5) FeSSIF(pH5.0) SGF(pH1.2)
制备例2 二盐酸盐 0.5h 溶清，＞10 5.07 溶清，＞10
结果：制备例2所得样品在不同的生物溶媒中，均能保持良好的溶解度，且溶解速度快。
测试例3：长期稳定性测试
取制备例2所得盐样品适量，在40±2℃、75％±5％RH条件下，聚乙烯膜封口放置5个月，进行长期试验，结果如下：
表6样品的稳定性结果及晶型检测结果
Figure PCTCN2022077932-appb-000031
表7制备例2的晶体样品在长期稳定性测试后的XRPD数据表
Figure PCTCN2022077932-appb-000032
制备例2所得化合物1的二盐酸盐的晶型I在长期稳定性测试后的XRPD谱图如图2所示。
结果：制备例2所得的化合物1的二盐酸盐能维持化学稳定和晶型稳定，符合作为原料药储存的规定。
测试例4：固体稳定性测试
取制备例2的二盐酸盐，分别放置于40℃/75％RH(开口)条件下7天，进行稳定性测试，结果见表8。
表8稳定性结果及晶型检测结果
Figure PCTCN2022077932-appb-000033
结果：在40℃/75％RH(开口)条件下放置7天，制备例2所得的化合物1的二盐酸盐能维持化学稳定和晶型稳定，因此，制备例2所得样品具有较好的热稳定性，符合作为原料药储存的规定。
测试例5：机械稳定性测试
取制备例2的二盐酸盐适量，进行机械研磨5分钟后进行X-射线粉末衍射，结果显示，晶型未发生变化。
实施例1 体外酶学试验
1.1化合物对RET、KDR、EGFR、FGFR1、FLT-1等激酶的抑制试验
试验方法：使用ELISA方法，将酶反应底物20μg/mL Poly(Glu，Tyr) 4∶1包被酶标板，加入酶、样品、ATP(5μM)等反应，用抗磷酸化酪氨酸的单抗(4G10)检测底物磷酸化，再加辣根过氧化物酶(HRP)标记的羊抗鼠Ig G，四甲基联苯胺(TMB)显色检测底物磷酸化程度；同时设无酪氨酸激酶的对照和相应DMSO浓度的对照孔；加入0.18M H 2SO 450μL/孔中止反应，用微孔板酶标仪读数，比色反应，观察光密度(OD) 450nm值。
抑制率＝(阴性对照组OD值-化合物孔OD值)/(阴性对照组OD值-无酶对照孔OD值)×100％
测定化合物对酪氨酸激酶蛋白的相对抑制率。
根据各浓度抑制率，采用LOGIT法计算半数抑制浓度IC 50。以上每个实验重复3次，求出3次实验的平均IC 50值作为抑制能力的最终指标。试验结果见表9。
表9化合物1的体外酶学试验结果(IC 50，nM)
化合物 RET KDR EGFR FGFR1 FLT-1
化合物1 ＜20 ＜20 ＜100 ＜20 ＜50
1.2化合物对FGFR2/3、LCK、EphA1等激酶的抑制试验
试验方法：使用Caliper方法，每孔加入2μL 25×化合物溶液，其中，无酶对照孔和阴性对照孔加入2μL含有25％DMSO的反应液；每孔加入10μL 5×激酶溶液，无酶对照孔加入10μL反应液；将检测板1000rpm离心以混匀；将2.6×的ATP溶液与2.6×底物溶液等体积混合，得到1.3×的ATP-底物溶液，每孔加入38μL的ATP-底物溶液；将检测板1000rpm离心以混匀；将检测板置于30℃反应1小时；每孔加入20μL的35mM EDTA终止反应。Caliper读取转化率。
抑制率＝(阴性对照孔转化率-化合物孔转化率)/(阴性对照孔转化率-无酶对照孔转化率)×100％
Prism 5.0进行IC 50值拟合，结果见表10。
表10制备例2样品的体外酶学试验结果(IC 50，nM)
化合物 FGFR2 FGFR3 LCK EphA1
制备例2样品 ＜50 ＜50 ＜20 ＜100
1.3化合物对HER-2激酶的抑制试验
试验方法：使用ADP Glo方法，每孔加入1μL 10×化合物溶液，其中，无酶对照孔和阴性对照孔加入1μL含有10％DMSO的反应液；每孔加入4μL 2.5×激酶溶液，无酶对照孔加入4μL反应液；将检测板1000rpm离心以混匀；将4×的ATP溶液与4×底物溶液等体积混合，得到2×的ATP-底物溶液，每孔加入5μL的2×ATP-底物溶液；将检测板1000rpm离心以混匀；将检测板置于30℃反应1小时；每孔加入10μL ADP-Glo反应试剂，27℃放置40分钟；每孔加入20μL Detection试剂，27℃放置30分钟；Envision读取冷光信号。
抑制率＝(阴性对照孔读值-化合物孔读值)/(阴性对照孔读值-无酶对照孔读值)×100％
Prism 5.0进行IC 50值拟合，结果见表11。
表11制备例2样品的体外酶学试验结果(IC 50，nM)
化合物 HER-2
制备例2样品 ＜50
结论：化合物1及其二盐酸盐(制备例2)对RET、KDR、EGFR、FGFR1/2/3、FLT-1、LCK、HER-2和EphA1等靶点具有良好的抑制活性。同理，化合物1的药学上可接受的其它盐也具有以上相似的作用。
实施例2 体外细胞学试验
细胞来源：人胆管癌细胞HuCCT1：购自商城北纳创联生物科技有限公司；人肝胆管癌细胞RBE：购自中国科学院上海生命科学研究院。
细胞培养条件：培养基均为含10％FBS的RPMI Medium 1640培养基，培养环境均为37℃、5％CO 2。
采用MTT法，测定化合物1的二盐酸盐(制备例2)对人胆管癌细胞HuCCT1和人肝内胆管癌细胞RBE增殖的抑制作用。
试验步骤：将处于对数生长期的细胞以一定数量接种于96孔板(100μL/孔)，贴壁24h后每孔加入100μL含不同浓度梯度化合物1，每个浓度设3个复孔，并设相应的空白孔(只有培养基)及正 常孔(药物浓度为0)。药物作用72小时后，加入MTT工作液(5mg/mL)，每孔20μL；37℃作用4小时，甩板去除上清液，加入DMSO 150μL；微孔震荡混匀，酶标仪550nm处检测光密度值(OD)。
采用下列公式计算细胞生长的抑制率：
抑制率(％)＝(OD值 正常孔-OD值 给药孔)/(OD值 正常孔-OD值 空白孔)×100％
根据各浓度抑制率，用SPSS19.0计算药物半数抑制浓度IC 50。
表12：对HuCCT1、RBE细胞增殖的抑制作用(IC 50，μM)
细胞种类 HuCCT1 RBE
抑制活性 ＜2 ＜10
结论：化合物1的二盐酸盐(制备例2)对HuCCT1和RBE细胞增殖均有良好的抑制作用。同理，化合物1的药学上可接受的其它盐也具有以上相似的作用。
实施例3 I期临床研究
1.1主要研究目的
考察化合物1的二盐酸盐(制备例2)在晚期实体瘤患者中的安全性和耐受性，确定最大耐受剂量，为后续研究阶段推荐安全剂量。
1.2研究方法
1.2.1病例纳入标准
本研究使用的病例纳入标准如下：
(1)入选标准：
1)自愿参与临床试验并签署知情同意书；
2)年龄18-75周岁(含边界值)，性别不限；
3)经组织病理学或细胞学证实的复发、不可切除的局部晚期或转移的晚期实体瘤患者，标准治疗失败或不耐受，由研究者判断适合接受小分子酪氨酸激酶抑制剂治疗；
4)入组前距离上次化疗、放疗、靶向治疗及手术治疗间隔至少4周；
5)ECOG评分：0～1分；
6)预期生存期至少3个月；
7)实验室检查满足如下标准：
中性粒细胞计数(ANC)≥1.5×10^9/L
血小板计数(PLT)≥100×10^9/L
血红蛋白(Hb)≥90g/L(筛选检查前14天内未输血)；
谷丙转氨酶(ALT)和天冬氨酸转氨酶(AST)≤2.5倍正常值上限(如有肝转移患者，≤5.0倍正常值上限)；
总胆红素≤1.5倍正常值上限；
血清肌酐≤1.5倍正常值上限；
8)男性及女性育龄受试者同意在治疗期间及治疗完成后6个月采取有效的避孕措施；女性受试者在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期受试者。
(2)排除标准
1)入组前4周内参加过其他药物临床试验，且入组接受治疗；
2)无法吞咽、慢性腹泻和肠梗阻，存在影响药物服用和吸收的多种因素；
3)符合以下任意一条标准者排除：
-QTc)值女性≥470ms，男性≥450ms；或者先天性长QT综合症，正在服用已知可延长QT间期的药物，长QT综合症的家族史
-静息心电图显示节律、传导或形态有任何重要意义的临床异常，需要临床干预。
4)尿常规提示尿蛋白≥++且24小时尿蛋白＞1.0g者；
5)根据研究者的判断，有严重的危害患者安全、或影响患者完成研究的伴随疾病(如控制不良的高血压(收缩压≥140mmHg或者舒张压≥90mmHg，尽管进行了最佳的药物治疗)、糖尿病等)；
6)进入研究前4周内有症状性转移性脑或脑膜肿瘤；
7)入组时有上次治疗有未恢复为1级的不良事件(脱发和色素沉着除外)；
8)入组前4周内进行过外科大手术或尚未从之前的任何有创性操作中完全恢复；
9)凝血功能异常(INR＞1.5或凝血酶原时间(PT)＞ULN+4秒或APTT＞1.5ULN)：有出血性倾向(如活动性消化性溃疡)或正在接受溶栓或抗凝治疗者；
10)经研究者判断具有肺部感染或肺炎或间质性肺炎，不适合参加研究者；
11)有活动性乙型肝炎病毒或丙型肝炎病毒感染者
·如HBsAg阳性，加测HBV DNA(测定结果高于所在研究中心正常值范围上限)；
·如HCV抗体检测结果阳性，加测HCV RNA(测定结果高于所在研究中心正常值范围上限)。
12)人类免疫缺陷病毒感染者(HIV阳性)或患有其他获得性、先天性免疫缺陷疾病或有器官移植史者；
13)需要合并其他抗肿瘤治疗(包括各种放疗、化疗、免疫治疗、靶向治疗、中药治疗等)；
14)既往有明确的神经或精神障碍史，包括癫痫或痴呆；
15)研究者认为不适合参加研究者。
16)超声心动图左室射血分数小于50％。
(3)脱落/剔除标准：
1)受试者撤回知情同意，要求退出；
2)经研究者判断疾病进展；
3)经剂量调整，受试者仍然无法耐受毒性者；
4)受试者在研究中发生妊娠事件；
5)研究者认为有必要退出研究的情况。
1.2.2安全性评价标准
安全性指标：包括生命体征和体格检查、心电图和超声心动图检查、实验室检查、不良事件等。
最大耐受剂量(MTD)评估：因DLT事件而导致剂量递增终止的前一剂量。
1.2.3治疗方法
该研究纳入了年龄18-75周岁的晚期实体瘤受试者。剂量递增阶段，从25mg剂量开始进行剂量爬坡，分为8组，分组情况详见表13。每个受试者进行单次及多次给药的耐受性和药代动力学研究。单次给药后7天，进入多次给药期。多次给药每28天为一周期，给药21天停药7天，直至疾病进展或出现不可耐受的毒性反应。每个受试者都只接受一个相应的剂量，试验从低剂量开始，某一剂量组中全部受试者耐受性观察结束后，再开始下一剂量组。
表13剂量递增方案
Figure PCTCN2022077932-appb-000034
剂量递增阶段获得的最大耐受剂量(或800mg)组进行多中心、开放的扩展研究，评估化合物1二盐酸盐在晚期实体瘤患者中的疗效、安全性及药代动力学特征。符合入组条件的受试者直接进入第一周给药期，连续给药21天，休息7天，28天为一个给药周期，直至疾病进展或出现不可耐受的毒性反应。
1.3研究结果
截至2020-12-6，共纳入32例晚期实体瘤受试者。
1.3.1安全性
600mg及以下剂量组的不良反应大多数为1-2级，最常见的不良反应为皮疹、腹泻、恶心、呕吐、心电图QT间期延长等。仅在800mg出现2例剂量限制性毒性(DLT)事件，1例为3级的食欲下降，1例为3级的心电图QT间期延长。
1.4与同类产品比较
参考现有技术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14)，比较本申请所述化合物1的二盐酸盐与现有蛋白激酶抑制剂的安全性差异，可以发现，在较宽的给药剂量范围，化合物1的二盐酸盐的3级及以上毒性反应较少，具有较好的安全性。
表14相关蛋白激酶抑制剂的安全性评价
Figure PCTCN2022077932-appb-000035
实施例4 II期临床研究
1.1研究目的
评价化合物1的二盐酸盐(制备例2)在晚期胆道恶性肿瘤受试者中的临床疗效、安全性及药代动力学特征。
1.2研究方法
1.2.1整体研究设计
研究者从受试者本人处获取知情同意书后，在服用试验用药品前28天内(D-28～D-1)开始进行筛选。
起始给药剂量600mg，口服，每天一次，第一天给药后，连续给药21天，休息7天，28天一个给药周期，直至疾病进展或出现不可耐受的毒性反应；并按照流程要求在整个研究期间完成相关的安全性检查和疗效评价、PK血样采集。如果在研究进行期间综合数据分析发现受试者不耐受该剂量，经申办方以及研究者讨论后下调一个剂量组作为推荐起始剂量。
若治疗期间出现毒性反应，按推荐的给药剂量调整原则处理或由研究者根据自身临床经验和试验过程中更新的研究数据，从受试者风险获益以及受试者当下状况综合评估以判断如何处理。对药物可能做出的调整包括下调剂量水平(450mg(剂量水平1)和300mg(剂量水平2)、暂停用药及中止治疗。调整剂量水平后给药频率仍为连续给药21天，休息7天，28天为一个周期。在该研究中，每2个周期(即8周)进行一次疗效评价(针对靶病灶、非靶病灶以及新病灶的综合评估)，进行数据分析。
1.2.2试验人群的选择
本研究使用的病例纳入标准如下：
(1)入选标准：
1)自愿参与临床试验并签署知情同意书；
2)经组织学或细胞学确诊的不能手术切除的局部晚期或转移性胆道恶性肿瘤受试者(包括肝 内、肝外胆管癌以及胆囊癌)，经一线治疗失败(包括辅助化疗6个月内出现疾病进展)或不耐受的受试者；且至少存在一个可测量病灶(根据RECIST 1.1)；
3)年龄18-75周岁(含边界值)；
4)ECOG评分：0～1分；
5)血常规检查符合(14天内未输血状态下)：
·血红蛋白(HB)≥90g/L；
·中性粒细胞绝对值(ANC)≥1.5×10 9/L；
·血小板计数≥75×10 9/L；
6)凝血功能检查符合：国际标准化比值(INR)＜1.5或部分活化凝血酶原时间(APTT)＜1.5×ULN；
7)生化检查符合：
·总胆红素(TBIL)≤1.5×ULN；丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤2.5×ULN；对于肿瘤累及肝脏的受试者，可接受TBIL≤3×ULN，AST≤5×ULN，ALT≤5×ULN；
·血清肌酐(Cr)≤1.5×ULN；
·血清白蛋白≥28g/L；
8)男性及女性育龄受试者同意在治疗期间及治疗完成后6个月采取有效的避孕措施；育龄期女性受试者在研究入组前的7天内血清或尿妊娠试验阴性，且必须为非哺乳期受试者。
(2)排除标准
1)壶腹癌；
2)给药前4周内参加过其他药物临床试验，且入组接受治疗；
3)末次抗肿瘤治疗结束时间距首次给药时间需满足如下时间间隔，否则排除：
·接受任何抗肿瘤治疗(包括但不限于化疗、放疗和靶向治疗等)者≥4周(接受以缓解疼痛为目的的姑息性局部放疗者≥2周)；
·接受已批准适应症可用于癌症的中药治疗者≥2周；
4)尿蛋白≥++且24小时尿蛋白定量＞1g；
5)5年内出现过或当前同时患有其他恶性肿瘤，除外已经治愈的子宫颈原位癌、非黑色素瘤的皮肤癌、表浅的膀胱肿瘤和已内窥镜下切除的局限在粘膜层的早期食道、胃肠道恶性肿瘤；
6)接受过任何实体器官、骨髓移植的受试者，但无需免疫抑制的移植(例如角膜移植，毛发移植)除外；
7)入组时存在由于任何既往治疗引起的1级以上的未缓解的毒性反应(脱发和色素沉着除外)且研究者判断影响药物安全性评价；
8)心电图检查符合以下任意一条：
·QT间期(QTc)值≥450ms；或者先天性长QT综合症，长QT综合症的家族史；
·静息心电图显示节律、传导或形态有任何重要意义的临床异常，需要临床干预；
9)超声心动图检查左心室射血分数＜50％；
10)根据研究者的判断，有严重的危害受试者安全、或影响受试者完成研究的伴随疾病，包括但不局限于：
·控制不良的高血压(经治疗后收缩压≥150mmHg或者舒张压≥100mmHg)；
·具有临床意义的心血管/脑血管疾病，如：脑卒中(给药前＜6个月)、心肌梗死(给药前＜6个月)、不稳定型心绞痛、充血性心力衰竭(≥NYHA II级)或严重心律失常；
·需要类固醇治疗的间质性肺炎或需要系统性治疗的严重感染，经研究者判断不适合参加研究；
·心包积液，或在支持治疗4周后仍控制不佳的胸腔积液或腹腔积液；
·存在甲状腺功能异常且经治疗甲状腺功能仍不能维持在正常范围内，或未治疗且有症状者，低T3/T4综合征除外；
11)存在胃肠穿孔、腹瘘等胃肠道疾病的高风险因素，如：给药前28天内出现过活动性消化性渍 疡、炎症性肠病(包括溃疡性结肠炎和克罗恩病)、腹瘘、胃肠穿孔、肠梗阻、腹腔内脓肿等；
12)脊髓转移、脑膜转移和脑转移(给药前无症状或给药前经治疗后症状稳定≥4周的脑转移受试者除外)；
13)已知(或既往未发现)肝病病史，且符合以下任意一条：
·HBsAg阳性且HBV DNA＞2000IU/mL(或＞1×10 4拷贝/mL)；
·HCV抗体阳性且HCV RNA阳性；
·肝硬化；
14)人免疫缺陷病毒(HIV)抗体阳性者；
15)给药前4周内进行过外科手术或尚未从之前的任何有创性操作中恢复，除外胆管支架、胆汁引流等；
16)研究者认为不适合参加。
1.2.3疗效评价标准
参照《实体肿瘤的疗效评价标准1.1版》(New Response Evaluation Criteria in Solid Tumors：Revised RECIST Version 1.1)设立。具体如下：
【缓解标准】
(1)靶病灶评估
完全缓解(CR)：所有靶病灶消失，全部病理淋巴结(包括靶结节和非靶结节)短直径必须减少至＜10mm。
部分缓解(PR)：靶病灶直径之和比基线水平减少至少30％。
疾病进展(PD)：以整个实验研究过程中所有测量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)；除此之外，必须满足直径和的绝对值增加至少5mm(出现一个或多个新病灶也视为疾病进展)。
疾病稳定(SD)：靶病灶减小的程度没达到PR，增加的程度也没达到PD水平，介于两者之间，研究时可以直径之和的最小值作为参考。
(2)非靶病灶评估
完全缓解(CR)：所有非靶病灶消失，且肿瘤标记物恢复至正常水平。所有淋巴结为非病理尺寸(短径＜10mm)。
非完全缓解/非疾病进展：存在一个或多个非靶病灶和/或持续存在肿瘤标记物水平超出正常水平。
疾病进展：已存在的非靶病灶出现明确进展。注：出现一个或多个新病灶也被视为疾病进展。
(3)新病灶
在随访中已检测到的而在基线检查中未发现的病灶将视为新的病灶，并提示疾病进展。例如一个在基线检查中发现有内脏病灶的受试者，当他做CT或MRI的头颅检查时发现有转移灶，该受试者的颅内转移病灶将被视为疾病进展的依据，即使他在基线检查时并未做头颅检查。
如果一个新的病灶是不明确的，比如因其形态小所致，则需要进一步的治疗和随访评价以确认其是否是一个新的病灶。如果重复的检查证实其是一个新的病灶，那么疾病进展的时间应从其最初的发现的时间算起。
病灶进行FDG-PET评估一般需要额外的检测进行补充确认，FDG-PET检查和补充CT检查结果相结合评价进展情况是合理的(尤其是新的可疑疾病)。新的病灶可通过FDG-PET检查予明确的，依据以下程序执行：基线FDG-PET检查结果是阴性的，接下来随访的FDG-PET检查是阳性的，表明疾病的进展。
没有进行基线的FDG-PET检查，后续的FDG-PET检查结果是阳性的：如果随访的FDG-PET阳性检查结果发现的新的病变灶与经CT检查结果相符，证明是疾病进展。
如果随访的FDG-PET的阳性检查结果发现的新的病变灶未能得到CT检查结果的确认，需再行CT检查予以确认(如果得到确认，疾病进展时间从前期FDG-PET检查发现异常算起)。
如果随访的FDG-PET的阳性检查结果与经CT检查已存在的病灶相符，而该病灶在影像学检测上无进展，则疾病无进展。
1.2.4有效性和安全性指标
1.2.4.1有效性指标
疗效指标包括：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)；
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。
1.2.4.2安全性评估
安全性评估包括对生命体征和体格检查、心电图、实验室检查、不良事件等评估。
1.2.5药代动力学评估
针对至少接受过一次药物治疗的受试者，每个周期第28(±3)天访视当天任意一时间点采集PK血样，用于检测化合物1的药物浓度。药物浓度进行描述性统计分析，并绘制相应曲线。
1.2.6统计学处理
1.2.6.1疗效分析
主要终点指标：PFS采用Kaplan-Meier法估计中位时间及95％CI，并绘制相应的生存曲线。
次要疗效指标：OS、DOR采用Kaplan-Meier法估计中位时间及95％CI，并绘制相应的生存曲线。ORR、DCR等，给出百分比并采用Clopper-Pearson方法计算95％CI。
1.2.6.2安全性分析
计算治疗期间的不良事件(Treatment Emergent Adverse Event，TEAE)/与药物相关的TEAE、严重不良事件/反应、导致暂停用药或者中止治疗的TEAE/与药物相关的TEAE的发生率；
1.2.6.3药代动力学分析
药物浓度进行描述性统计分析，并绘制相应曲线。
1.3研究结果
实验对象：研究纳入受试者16例(包括肝内胆管癌12例、肝门胆管癌1例、胆总管癌1例以及胆囊癌2例)。
患者的疗效评估结果如下表15-1和15-2所示：
表15-1
总体最佳疗效 例数 发生率
完全缓解(CR) 0 0.0％
部分缓解(PR) 1 6.25％
疾病稳定(SD) 6 37.5％
疾病进展(PD) 9 56.25％
表15-2
客观缓解率(ORR) 6.25％
疾病控制率(DCR) 43.75％
结果分析：由上表数据显示，本申请的化合物1的二盐酸盐能够一定程度上控制一线治疗失败或不耐受的晚期或转移性胆道恶性肿瘤的患者的疾病进展，特别是肝内胆管癌患者的疾病进展。疾病无进展生存期(PFS)和缓解持续时间(DOR)结果较好，尚有患者在进一步随访，PFS和DOR结果将继续延长。
典型病例：
患者，女性，66岁，2020年11月行右半肝切除+胆囊切除术，术后病理示肝内胆管癌(腺癌)，T2NxM1 IV期，慢性胆囊炎。术后予单药卡培他滨辅助化疗，2021年5月28日影像学检查提示疾病进展而中止。2021年6月更换为吉西他滨+顺铂化疗，第一疗程中因毒性反应不耐受而中止。2021年9月3日CT平扫+增强检查示右半肝术后缺失，余肝内数个低密度结节，大者直径约14mm，考虑转移，分期为T2NxM1(肝转移)IV期，ECOG为1分。
2021年9月8日起给予本品(每日1次，每次600mg，口服，连续用药21天停7天，即28天为一个周期)，治疗8周首次影像学疗效评估为SD，治疗后13周、16周和24周均评估为PR。提示：在临床常用的抗癌药(卡培他滨，吉西他滨+顺铂化疗)均无显示出良好疗效的情况下，本申请的化合物1的二盐酸盐显示出对疾病的部分缓解作用。
综合以上实验结果，根据化合物的临床前体外试验结果，化合物1及其药学上可接受的盐(例如：二盐酸盐)是一种多靶点蛋白激酶抑制剂，对多种蛋白激酶均具有良好的抑制活性，进一步地，对几种与胆道癌相关的蛋白激酶均具有100nM以下水平的抑制活性，对不同基因突变引起的胆道癌将表现出良好的治疗作用，而且，在体外肿瘤细胞的抑制活性评价实验中，化合物1及其药学上可接受的盐(例如：二盐酸盐)表现出良好的抗肿瘤活性。
根据化合物的I期临床研究结果，以化合物1的二盐酸盐为代表的化合物1的药学上可接受的盐具有较好的安全性。
根据化合物的II期临床研究结果，以化合物1的二盐酸盐为代表的化合物1的药学上可接受的盐能够一定程度上控制一线治疗失败或不耐受的晚期或转移性胆道恶性肿瘤的患者的疾病进展，特别是肝内胆管癌患者的疾病进展。其效果优于临床常用的化疗药，具有治疗胆道癌的临床潜力。
因此，综合考虑临床前体外试验、同类药物的临床试验情况以及化合物1或其药学上可接受的盐(例如，二盐酸盐)的I期的安全性和初步疗效结果和II期临床研究结果，本申请的化合物1或其药学上可接受的盐(例如，二盐酸盐)具有治疗胆道癌的临床应用潜力。
本申请说明书中使用的缩略语的全程和中文名如下：
缩写和术语 英文全称 中文释义
ALT Alanine aminotransferase 丙氨酸转氨酶
AST Aspartate aminotransferase 天冬氨酸转氨酶
AE Adverse event 不良事件
HB Haemoglobin 血红蛋白
ULN Upper Limit of Normal 正常值上限
OS Overall survival 总生存期
ORR Objective Response Rate 客观缓解率
PK Pharmacokinetic 药物代谢动力学
DLT Dose-Limiting Toxicit 剂量限制性毒性
MTD Maximum tolerated dose 最大耐受剂量
CR Complete remission 完全缓解
PR Partial remission 部分缓解
PD Progression disease 疾病进展
QD Quaque die 一天一次
SD Stable disease 疾病稳定
DCR Disease Control Rate 疾病控制率
DOR Duration of Response 缓解持续时间
CT computer tomography 计算机断层扫描
TEAE Treatment Emergent Adverse Event 治疗期间的不良事件

Claims (19)

  1. 一种如式A所示的多靶点蛋白激酶抑制剂或其药学上可接受的盐在制备用于治疗或预防由RET、KDR、EGFR、FGFR、FLT、HER、LCK、EphA、SRC激酶中的一种或多于一种导致的相关病症的药物中的用途，
    Figure PCTCN2022077932-appb-100001
    其中，
    R 1为-O(CH 2) nR 3，其中n为3、4或5，R 3为-NR eR f，其中R e和R f各自在每次出现时彼此独立地选自甲基，或者R e和R f一起形成-(CH 2) 4-；
    其中R 2为
    Figure PCTCN2022077932-appb-100002
  2. 根据权利要求1所述的用途，其特征在于，所述的式A所示化合物中，R 1选自
    Figure PCTCN2022077932-appb-100003
  3. 根据权利要求1所述的用途，其特征在于，所述式A所示化合物为化合物1，
    Figure PCTCN2022077932-appb-100004
  4. 根据权利要求1-3任一项所述的用途，其特征在于，所述相关病症为由RET、KDR、EGFR、FGFR1/2/3、FLT-1、HER-2、LCK、EphA1、SRC激酶中的一种或多于一种导致的相关病症。
  5. 根据权利要求1-4任一项所述的用途，其特征在于，所述相关病症为肿瘤疾病；优选地，所述肿瘤疾病为实体瘤；进一步优选地，所述实体瘤为胆道癌；更进一步优选地，所述胆道癌为晚期胆道癌。
  6. 根据权利要求5所述的用途，其特征在于，所述胆道癌为局部晚期胆道癌。
  7. 根据权利要求5或6所述的用途，其特征在于，所述胆道癌为不能手术切除的局部晚期胆道癌。
  8. 根据权利要求5所述的用途，其特征在于，所述胆道癌为转移性胆道癌。
  9. 根据权利要求5-8任一项所述的用途，其特征在于，所述胆道癌为治疗失败或不耐受的胆道癌。
  10. 根据权利要求5-9任一项所述的用途，其特征在于，所述胆道癌为经一线治疗失败或不耐受的胆道癌。
  11. 根据权利要求5-10任一项所述的用途，其特征在于，所述胆道癌为胆囊癌或胆管癌；优选地，所述胆管癌为肝内胆管癌和/或肝外胆管癌；进一步优选地，所述胆管癌为肝内胆管癌。
  12. 根据权利要求1-11任一项所述的用途，其特征在于，所述式A所示化合物的药学上可 接受的盐包括盐酸盐、硫酸盐、草酸盐、马来酸盐或苹果酸盐；优选为盐酸盐、硫酸盐或马来酸盐；进一步优选为盐酸盐；进一步优选为二盐酸盐；更进一步优选为二盐酸盐的无水形式或其水合物。
  13. 根据权利要求1-12任一项所述的用途，其特征在于，所述式A所示化合物或其药学上可接受的盐作为唯一的活性成分，用于制备所述药物。
  14. 根据权利要求1-12任一项所述的用途，其特征在于，式A所示化合物或其药学上可接受的盐与其他治疗剂中的一种或多种联合用于制备所述药物。
  15. 根据权利要求1-14任一项所述的用途，其特征在于，所述药物制成临床接受的制剂，包括但不限于口服制剂、注射制剂、局部给药制剂或外用制剂；优选口服制剂；进一步优选为片剂和胶囊剂。
  16. 根据权利要求1-15任一项所述的用途，其特征在于，所述药物每个制剂单位中含有式A所示化合物或其药学上可接受的盐0.1-5000mg，优选1-1000mg，或10-800mg，或20-700mg，或22-650mg，或25-650mg，或50-600mg，或85-500mg，或86-500mg，或90-500mg，或100-500mg，或100-450mg，或100-400mg，或150-350mg，或170-350mg，或173-350mg，或175-350mg，或200-300mg；所述剂量以式A所示化合物计；以单剂量施用或分剂量施用；优选地，以单剂量施用。
  17. 根据权利要求1-16任一项所述的用途，其特征在于，所述药物中含有治疗有效量的式A所示化合物或其药学上可接受的盐，其给药剂量和剂量频率为：每天给药一次，每次给药20mg-1500mg；优选地，每天给药一次，每次给药20mg、22mg、25mg、40mg、43mg、45mg、50mg、80mg、85mg、86mg、90mg、100mg、150mg、170mg、173mg、175mg、180mg、200mg、250mg、259mg、260mg、300mg、302mg、310mg、340mg、346mg、350mg、400mg、380mg、385mg、389mg、390mg、400mg、430mg、432mg、440mg、450mg、475mg、500mg、518mg、520mg、550mg、560mg、562mg、600mg、605mg、610mg、648mg、650mg、690mg、691mg、700mg、750mg、778mg、800mg或900mg；所述剂量以式A所示化合物计。
  18. 根据权利要求1-17任一项所述的用途，其特征在于，所述药物通过口服给予、注射给予、局部给予或体外给予；优选地，通过口服给予。
  19. 一种试剂盒，包含如权利要求1-18中任一项所述的式A所示化合物或其药学上可接受的盐。
PCT/CN2022/077932 2021-02-25 2022-02-25 多靶点蛋白激酶抑制剂的用途 WO2022179608A1 (zh)

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