WO2021170070A1 - Utilisations d'inhibiteur du récepteur du facteur de croissance des fibroblastes - Google Patents

Utilisations d'inhibiteur du récepteur du facteur de croissance des fibroblastes Download PDF

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WO2021170070A1
WO2021170070A1 PCT/CN2021/078053 CN2021078053W WO2021170070A1 WO 2021170070 A1 WO2021170070 A1 WO 2021170070A1 CN 2021078053 W CN2021078053 W CN 2021078053W WO 2021170070 A1 WO2021170070 A1 WO 2021170070A1
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group
alkyl
cholangiocarcinoma
amino
membered
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PCT/CN2021/078053
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盛泽娟
强晓妍
吴永谦
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南京药捷安康生物科技有限公司
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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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to a fibroblast growth factor receptor inhibitor for treating cholangiocarcinoma diseases, and pharmaceutically acceptable salts and isomers thereof, and a pharmaceutical composition containing the same for treating cholangiocarcinoma Disease method, its use for treating cholangiocarcinoma disease, and its use in preparing medicine for treating mammalian cholangiocarcinoma disease.
  • Cholangiocarcinoma is a highly heterogeneous malignant tumor, which occurs from the capillary duct to the common bile duct, and can originate in any part of the biliary system. According to the anatomical location, cholangiocarcinoma can be divided into intrahepatic cholangiocarcinoma (iCCA), hilar cholangiocarcinoma (pCCA) and distal cholangiocarcinoma (dCCA). They have special similarities. , But there are also differences between tumors and within tumors, these differences will affect the pathological mechanism and prognosis of tumors.
  • iCCA intrahepatic cholangiocarcinoma
  • pCCA hilar cholangiocarcinoma
  • dCCA distal cholangiocarcinoma
  • CCA currently has few treatments, poor curative effect, and low survival rate. Since CCA patients have no obvious clinical symptoms in the early stage, they often have metastasized when they are diagnosed. Late diagnosis will affect the patient's choice of effective treatment. Considering that CCA has significant resistance to chemotherapy, the generally effective treatment is surgical resection and/or liver transplantation. Chemotherapy is only used as palliative treatment. At present, for CCA, complete resection of the lesion is the only effective treatment method. Traditionally, because of local tumor infiltration, peritoneal or distant metastasis, lack of biliary reconstruction plan, and insufficient prediction of residual liver after surgery, less than one-third of patients have a chance of resection at the time of diagnosis.
  • liver transplantation has rapid tumor recurrence and low survival rate (10%-25%), liver transplantation has not been recommended for patients with CCA who cannot be surgically removed.
  • systemic chemotherapy is the main palliative treatment.
  • fibroblast growth factor receptor is the driving gene of certain cancers, and maintains the malignant characteristics of tumor cells in a “cell autonomy” manner.
  • Mitogenic and survival signals promote tumor cell invasion and metastasis, promote epithelial-mesenchymal transition, promote angiogenesis, participate in tumor recurrence and drug resistance, as oncogenes, participate in multiple steps in the development of tumors.
  • WO2018040885A1 discloses a class of pan-FGFR inhibitors. Such compounds have good inhibitory activity on pan-FGFR and can be used to treat pan-FGFR-mediated cancers.
  • FGFR mutations are common in cholangiocarcinoma, especially FGFR2 fusion.
  • About 13% to 14% of intrahepatic cholangiocarcinomas can detect FGFR gene fusion, and the fusion gene can cause ligand-independent tyrosine kinase activation and activation downstream signal path.
  • Inhibition of FGFR can inhibit/kill cholangiocarcinoma cells by inhibiting tumor proliferation, epithelial-mesenchymal transition, angiogenesis, etc.
  • the present invention studies the new use of the compound described in the following general formula (I) or its pharmaceutically acceptable salts and isomers in the field of cancer. Studies have found that the compound of general formula (I) or its pharmaceutically acceptable salts and isomers have therapeutic effects on cholangiocarcinoma. Therefore, the object of the present invention is to provide a new use of the compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof in the treatment of cholangiocarcinoma.
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered cycloalkyl groups containing 0 to 3 O, S and/or N atoms, 3 to 8 membered heterocyclic groups, 6 to 14 membered aromatic groups optionally substituted by 1 to 3 R 5 Group or 5- to 10-membered heteroaryl group, wherein the S atom in any ring is optionally oxidized to S(O) or S(O) 2 , and the carbon atom in any ring can be optionally oxidized to C( O);
  • Ring B is selected from 3 to 10 membered saturated or unsaturated heterocyclic groups containing at least 1 N heteroatom or 5 to 6 membered N heteroaryl groups optionally substituted with 1 to 3 R6, and, on ring B The N atom of is directly connected to the Warhead bond, wherein any S atom in ring B can be optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by substituents, halogenated C 1-4 alkyl, 3-8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 8 membered aryl group and 5 to 10 membered heteroaryl group, the substituents are selected from: hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylcarbonyl Amino, C 1-4 alkylsulfonylamino, 3-8 membered heterocyclic group and 6-12 membered spiro heterocyclic group.
  • a method for treating cholangiocarcinoma disease comprising administering to a patient or subject in need a therapeutically effective amount of a compound of general formula (I) or Pharmaceutically acceptable salts and isomers:
  • a pharmaceutical composition for the treatment of cholangiocarcinoma diseases comprising a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof , Isomer and optionally a pharmaceutically acceptable carrier:
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring is optionally Oxidized to S(O) or S(O) 2 , and carbon atoms in any ring are optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 R 3 ⁇ 10 3-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by substituents, halogenated C 1-4 alkyl, 3-8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 8 membered aryl group and 5 to 10 membered heteroaryl group, the substituents are selected from: hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylcarbonyl Amino, C 1-4 alkylsulfonylamino, 3-8 membered heterocyclic group and 6-12 membered spiro heterocyclic group.
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring is optionally Oxidized to S(O) or S(O) 2 , carbon atoms in any ring can be optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 3 R 3 ⁇ 6-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • the compound of general formula (I) has a structure represented by general formula (II),
  • the ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
  • the Warhead is selected from:
  • the ring A is phenyl.
  • the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
  • the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
  • the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutant cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
  • the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
  • the drug for treating cholangiocarcinoma disease may contain the compound of general formula (I) or its pharmaceutically acceptable salt or isomer, and may also contain a pharmaceutically acceptable carrier.
  • the medicament may contain one or more pharmaceutically acceptable carriers, and may be administered to patients or subjects in need of such treatment by oral, parenteral, rectal or pulmonary administration, etc. .
  • the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, and syrups. ⁇ etc.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • parenteral administration the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the injection When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field.
  • the additive When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug.
  • the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be made into an inhalant or spray.
  • the drug for the treatment of cholangiocarcinoma disease in addition to containing the compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof, also contains one or more second treatments Active agent.
  • the second therapeutically active agent is antimetabolites, growth factor inhibitors, mitotic inhibitors, antitumor hormones, alkylating agents, metal platinums, topoisomerase inhibitors, hormones Drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoint inhibitors or antibodies related to tumor immunotherapy, small molecule drugs related to tumor immunotherapy.
  • the compound of the general formula (I) or a pharmaceutically acceptable salt, isomer thereof, and a second therapeutically active agent are administered in a combined manner to a patient or subject in need of treatment. Examiner.
  • the compound of the general formula (I), or a pharmaceutically acceptable salt, isomer, and the second therapeutically active agent are applied to the needs sequentially, simultaneously, or as a compound preparation.
  • the patient or subject refers to a mammal.
  • the mammal refers to human mammals and/or animal mammals.
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring is optionally Oxidized to S(O) or S(O) 2 , and carbon atoms in any ring are optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 R 3 ⁇ 10 3-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by substituents, halogenated C 1-4 alkyl, 3-8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 8 membered aryl group and 5 to 10 membered heteroaryl group, the substituents are selected from: hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylcarbonyl Amino, C 1-4 alkylsulfonylamino, 3-8 membered heterocyclic group and 6-12 membered spiro heterocyclic group.
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring is optionally Oxidized to S(O) or S(O) 2 , and carbon atoms in any ring are optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 3 R 3 ⁇ 6-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • the compound of general formula (I) has a structure represented by general formula (II),
  • the ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
  • the Warhead is selected from:
  • the ring A is phenyl.
  • the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
  • the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
  • the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutated cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
  • the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
  • the use includes administering a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof to a patient or subject in need.
  • a therapeutically effective amount of the compound of the general formula (I) or a pharmaceutically acceptable salt or isomer thereof can also be combined with one or more pharmaceutically acceptable carriers to prepare a pharmacologically Any acceptable pharmaceutical formulation.
  • the pharmaceutical preparation may contain one or more pharmaceutically acceptable carriers, and may be administered to patients or subjects in need of such treatment in oral, parenteral, rectal or pulmonary administration, etc.
  • the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, and syrups. ⁇ etc.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • parenteral administration the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the injection When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field.
  • the additive When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug.
  • the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be made into an inhalant or spray.
  • the use further includes administering to a patient or subject in need a therapeutically effective amount of the compound of general formula (I) or a pharmaceutically acceptable salt, isomer and one or Multiple second therapeutically active agents.
  • the second therapeutically active agent is antimetabolites, growth factor inhibitors, mitotic inhibitors, antitumor hormones, alkylating agents, metal platinums, topoisomerase inhibitors, hormones Drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoint inhibitors or antibodies related to tumor immunotherapy, small molecule drugs related to tumor immunotherapy.
  • the compound of the general formula (I) or a pharmaceutically acceptable salt, isomer thereof, and a second therapeutically active agent are administered in a combined manner to a patient or subject in need of treatment. Examiner.
  • the compound of the general formula (I), or a pharmaceutically acceptable salt, isomer, and the second therapeutically active agent are applied to the needs sequentially, simultaneously, or as a compound preparation.
  • the patient or subject refers to a mammal.
  • the mammal refers to human mammals and/or animal mammals.
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring is optionally Oxidized to S(O) or S(O) 2 , and carbon atoms in any ring are optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 R 3 ⁇ 10 3-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by substituents, halogenated C 1-4 alkyl, 3-8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 8 membered aryl group and 5 to 10 membered heteroaryl group, the substituents are selected from: hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylcarbonyl Amino, C 1-4 alkylsulfonylamino, 3-8 membered heterocyclic group and 6-12 membered spiro heterocyclic group.
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring is optionally Oxidized to S(O) or S(O) 2 , and carbon atoms in any ring are optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 3 R 3 ⁇ 6-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • the compound of general formula (I) has a structure represented by general formula (II),
  • the ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
  • the Warhead is selected from:
  • the ring A is phenyl.
  • the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
  • the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
  • the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutant cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
  • the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
  • the compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof is administered to a patient or subject in need in a therapeutically effective amount.
  • a therapeutically effective amount of the compound of the general formula (I) or a pharmaceutically acceptable salt or isomer thereof can also be combined with one or more pharmaceutically acceptable carriers to prepare a pharmacologically Any acceptable pharmaceutical formulation.
  • the pharmaceutical preparation may contain one or more pharmaceutically acceptable carriers, and may be administered to patients or subjects in need of such treatment in oral, parenteral, rectal or pulmonary administration, etc.
  • the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, and syrups. ⁇ etc.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • parenteral administration the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the injection When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field.
  • the additive When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug.
  • the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be made into an inhalant or spray.
  • the compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof can also be combined with one or more second therapeutically active agents to be administered to patients in need or Subject.
  • the second therapeutically active agent is antimetabolites, growth factor inhibitors, mitotic inhibitors, antitumor hormones, alkylating agents, metal platinums, topoisomerase inhibitors, hormones Drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoint inhibitors or antibodies related to tumor immunotherapy, small molecule drugs related to tumor immunotherapy.
  • the compound of the general formula (I) or a pharmaceutically acceptable salt, isomer thereof, and a second therapeutically active agent are administered in a combined manner to a patient or subject in need of treatment. Examiner.
  • the compound of the general formula (I), or a pharmaceutically acceptable salt, isomer, and the second therapeutically active agent are applied to the needs sequentially, simultaneously, or as a compound preparation.
  • the patient or subject refers to a mammal.
  • the mammal refers to human mammals and/or animal mammals.
  • a method for treating cholangiocarcinoma disease comprising administering to a patient or subject in need a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable Salt, isomer of
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring is optionally Oxidized to S(O) or S(O) 2 , and carbon atoms in any ring are optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 R 3 ⁇ 10 3-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by substituents, halogenated C 1-4 alkyl, 3-8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 8 membered aryl group and 5 to 10 membered heteroaryl group, the substituents are selected from: hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylcarbonyl Amino, C 1-4 alkylsulfonylamino, 3-8 membered heterocyclic group and 6-12 membered spiro heterocyclic group.
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups, or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring may optionally Is oxidized to S(O) or S(O) 2 , the carbon atoms in any ring can be optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 3 R 3 ⁇ 6-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B can be optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B can be optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • (iii) optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ⁇ 6 alkyl group, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy Group, C 1-6 alkylamino group, (C 1-6 alkyl) 2 amino group, C 1-6 alkylcarbonylamino group, C 1-6 alkylsulfonylamino group and 3-8 membered heterocyclic group substituted C 1 ⁇ 6 alkyl group, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, halo C 1-6 alkyl, halo C 1- 6 Alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, the 3-8 membered heterocyclic group may be optional It is selected from hydroxy, amino, carboxyl, cyano, nitro, halogen
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • the compound of general formula (I) has a structure represented by general formula (II),
  • the ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
  • the Warhead is selected from:
  • the ring A is phenyl.
  • the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
  • the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
  • the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutant cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
  • the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
  • a therapeutically effective amount of the compound of the general formula (I) or a pharmaceutically acceptable salt or isomer thereof can also be combined with one or more pharmaceutically acceptable carriers to prepare a pharmacologically Any acceptable pharmaceutical formulation.
  • the pharmaceutical preparation may contain one or more pharmaceutically acceptable carriers, and may be administered to patients or subjects in need of such treatment in oral, parenteral, rectal or pulmonary administration, etc.
  • the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, and syrups. ⁇ etc.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • parenteral administration the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the injection When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field.
  • the additive When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug.
  • the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be made into an inhalant or spray.
  • the method further comprises administering to a patient or subject in need a therapeutically effective amount of the compound of general formula (I) or a pharmaceutically acceptable salt, isomer, and one or Multiple second therapeutically active agents.
  • the second therapeutically active agent is antimetabolites, growth factor inhibitors, mitotic inhibitors, antitumor hormones, alkylating agents, metal platinums, topoisomerase inhibitors, hormones Drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoint inhibitors or antibodies related to tumor immunotherapy, small molecule drugs related to tumor immunotherapy.
  • the compound of the general formula (I) or a pharmaceutically acceptable salt, isomer thereof, and a second therapeutically active agent are administered in a combined manner to a patient or subject in need of treatment. Examiner.
  • the compound of the general formula (I), or a pharmaceutically acceptable salt, isomer, and the second therapeutically active agent are applied to the needs sequentially, simultaneously, or as a compound preparation.
  • the patient or subject refers to a mammal.
  • the mammal refers to human mammals and/or animal mammals.
  • a pharmaceutical composition for the treatment of cholangiocarcinoma diseases comprising a therapeutically effective amount of a compound of general formula (I) or a pharmaceutically acceptable salt thereof , Isomers and optionally a pharmaceutically acceptable carrier,
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring is optionally Oxidized to S(O) or S(O) 2 , and carbon atoms in any ring are optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 R 3 ⁇ 10 3-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • R 11 , R 12 , and R 13 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by substituents, halogenated C 1-4 alkyl, 3-8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 8 membered aryl group and 5 to 10 membered heteroaryl group, the substituents are selected from: hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-4 alkyl , C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, (C 1-4 alkyl) 2 amino, C 1-4 alkylcarbonyl Amino, C 1-4 alkylsulfonylamino, 3-8 membered heterocyclic group and 6-12 membered spiro heterocyclic group.
  • R 1 and R 2 are each independently selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, carboxyl, C 1-6 alkyl, and C 1-6 alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, hydroxyl, C 1-6 alkyl and (C 1-6 alkyl) 2 amino C 1-6 alkyl;
  • Ar is selected from 6 to 14 membered aryl groups or 5 to 10 membered heteroaryl groups optionally containing 0 to 3 O, S and/or N atoms;
  • Ring A is selected from 3 to 8 membered heterocyclic groups, 6 to 14 membered aryl groups, or 5 to 10 membered heteroaryl groups optionally substituted with 1 to 3 R 5, wherein the S atom in any ring may optionally Is oxidized to S(O) or S(O) 2 , the carbon atoms in any ring can be optionally oxidized to C(O);
  • Ring B is selected from optionally substituted with 1 to 6 3 R 3 ⁇ 6-membered saturated or unsaturated heterocyclic group containing at least one N heteroatoms, and, with the N atom on ring B Warhead bond directly connected, wherein, any S atom in ring B is optionally oxidized to S(O) or S(O) 2 , and any carbon atom in ring B is optionally oxidized to C(O);
  • X is selected from CR 7 and N;
  • R 5 , R 6 , and R 7 are each independently selected from
  • n 1 and m 2 represent 1, 2 or 3, and the sum of m 1 and m 2 is less than or equal to 5;
  • the compound of general formula (I) has a structure represented by general formula (II),
  • the ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
  • the Warhead is selected from:
  • the ring A is phenyl.
  • the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
  • the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
  • the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
  • the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
  • the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutant cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
  • the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
  • the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
  • the compound of the general formula (I) or a pharmaceutically acceptable salt or isomer thereof can also be combined with one or more pharmaceutically acceptable carriers to make a pharmaceutically acceptable Of any pharmaceutical preparations.
  • the pharmaceutical preparation may contain one or more pharmaceutically acceptable carriers, and may be administered to patients or subjects in need of such treatment in oral, parenteral, rectal or pulmonary administration, etc.
  • the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions and oral suspensions. , Syrup, etc.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • parenteral administration the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections.
  • the injection When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field.
  • the additive When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug.
  • the pharmaceutical composition When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for pulmonary administration, the pharmaceutical composition can be made into an inhalant or spray.
  • the pharmaceutical composition further comprises one or more second therapeutically active agents.
  • the second therapeutically active agent is antimetabolites, growth factor inhibitors, mitotic inhibitors, antitumor hormones, alkylating agents, metal platinums, topoisomerase inhibitors, hormones Drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoint inhibitors or antibodies related to tumor immunotherapy, small molecule drugs related to tumor immunotherapy.
  • the compound of the general formula (I) or a pharmaceutically acceptable salt, isomer thereof, and a second therapeutically active agent are administered in a combined manner to a patient or subject in need of treatment. Examiner.
  • the compound of the general formula (I), or a pharmaceutically acceptable salt, isomer, and the second therapeutically active agent are applied to the needs sequentially, simultaneously, or as a compound preparation.
  • the patient or subject refers to a mammal.
  • the mammal refers to human mammals and/or animal mammals.
  • halogen in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.
  • any C in the substituent structure can be replaced by "-C(O)-"; if it contains a heteroatom, the heteroatom can form an oxide, such as Can be Alternatively, for example, S can be oxidized to S(O) or S(O) 2 .
  • the "cyano group” in the present invention refers to a -CN group.
  • amino group in the present invention refers to the -NH 2 group.
  • hydroxyl group in the present invention refers to the -OH group.
  • the "thio group” in the present invention refers to the -S- group.
  • nitro group in the present invention refers to the -NO 2 group.
  • halo in the present invention means that any hydrogen atom in the substituent can be replaced by one or more identical or different halogen atoms.
  • Halogen is as defined above.
  • C 1-6 alkyl group in the present invention refers to a linear or branched alkyl group derived from a hydrocarbon moiety containing 1 to 6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl Group, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-
  • C 2-8 alkenyl group in the present invention refers to a linear or branched alkenyl group derived from an alkene group of 2-8 carbon atoms containing a carbon-carbon double bond by removing one hydrogen atom, such as vinyl, 1- Propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3 -Pentadienyl, 1,4-pentadienyl, 1-hexenyl, 1,4-hexadienyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1,4-ring Hexadienyl, cycloheptenyl, 1,4-cycloheptadienyl, cyclooctenyl, 1,5-cyclooctadienyl, etc., and also include possible polycyclic ring systems, such as
  • C 2-8 alkynyl group in the present invention refers to a linear or branched alkynyl group derived from an alkyne group of 2 to 8 carbon atoms containing a carbon-carbon triple bond by removing one hydrogen atom, such as ethynyl and propane. Alkynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl and the like.
  • C 1-6 alkylamino according to the present invention, "(C 1-6 alkyl) 2 amino", “C 1-6 alkylcarbonylamino”, “C 1-6 alkylsulfonylamino” , “C 1-6 alkylaminocarbonyl”, “(C 1-6 alkyl) 2 amino-carbonyl”, “C 1-6 alkoxy-carbonyl”, “C 1-6 alkylsulfonyl”, “C 1-6 alkylthio", “C 1-6 alkyl-carbonyl", “3-8 membered cycloalkyl-carbonyl", “3-8 membered heterocyclyl-carbonyl”, “(C 1 -6 alkyl) 2 amino C 1-6 alkyl", “C 2-4 alkenylcarbonylamino", “C 1-6 alkoxy C 1-6 alkoxy”, “amino-carbonyl", “Cyano-carbonyl”,”C 1-4 alkylcarbonylamino", “C 1-4 alkyls
  • C 1-6 alkoxy refers to the present invention as hereinbefore defined "C 1-6 alkyl” group linked to the parent molecule through an oxygen atom, i.e., "C 1-6 alkyl -O- "Groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentyloxy and n-hexoxy, etc.
  • the "C 1-4 alkoxy group” refers to the above-mentioned examples containing 1 to 4 carbon atoms, that is, the "C 1-4 alkyl-O-" group.
  • the "fused ring" in the present invention refers to a multi-ring system structure formed by two or more ring structures connected in a union, spiro, or bridge connection.
  • the combined ring refers to a condensed ring structure formed by two or more ring structures sharing two adjacent ring atoms (that is, sharing a bond).
  • the bridged ring refers to a condensed ring structure formed by two or more ring structures sharing two non-adjacent ring atoms.
  • the spiro ring refers to a condensed ring structure formed by two or more ring structures sharing one ring atom with each other.
  • the "3-8 membered cycloalkyl group” in the present invention refers to a monovalent group derived from a 3-8 membered cycloalkane or (as required) a divalent group, which may be a monocyclic cycloalkyl group , Bicyclic cycloalkyl system or polycyclic cycloalkyl system (also called fused ring system).
  • a monocyclic ring system is a cyclic hydrocarbon group containing 3 to 8 carbon atoms.
  • 3- to 8-membered cycloalkyl groups include, but are not limited to: cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl and the like.
  • the fused-ring cycloalkyl group includes a bicyclic cycloalkyl group, a bridged cycloalkyl group, and a spirocycloalkyl group.
  • the bicyclic cycloalkyl group can be a 6-12 membered bicyclic cycloalkyl group, a 7-10 membered bicyclic cycloalkyl group, and representative examples thereof include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1 ]Heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • the spiro ring group can be 6-12 membered spiro ring group, 7-11 membered spiro ring group, examples of which include but are not limited to:
  • the bridging ring group can be a 6-12-membered bridging ring group or a 7-11-membered bridging ring group, examples of which include but are not limited to:
  • the "3- to 10-membered heterocyclic group” in the present invention refers to a 3- to 10-membered non-aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1 to 3 heteroatoms, and ring-forming atoms including carbon atoms, nitrogen atoms and sulfur atoms can be oxo.
  • the "3- to 8-membered heterocyclic group” in the present invention refers to the above-mentioned 3-8 membered cyclic group, and the "3 to 6-membered heterocyclic group” refers to the above-mentioned 3-6 membered cyclic group.
  • heterocyclic group in the present invention refers to a monocyclic heterocyclic group, a bicyclic heterocyclic group system or a polycyclic heterocyclic group system (also called a fused ring system), including saturated and partially saturated heterocyclic groups, But does not include aromatic rings.
  • the single heterocyclic group may be 3-8 membered heterocyclic group, 3-8 membered saturated heterocyclic group, 3-6 membered heterocyclic group, 4-7 membered heterocyclic group, 5-7 membered heterocyclic group, 5 ⁇ 6-membered heterocyclic group, 5- to 6-membered oxygen-containing heterocyclic group, 5 to 6-membered nitrogen-containing heterocyclic group, 5 to 6-membered saturated heterocyclic group, etc.
  • "3-8" membered saturated heterocyclic group examples of which include, but are not limited to, aziridinyl, oxetanyl, thiiridine, azetidinyl, oxetanyl, sulfur Etanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2- Thiazolidine, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxyl Hexyl, 1,4-oxathiolanyl; "3-8" membered partially saturated heterocyclic group, examples of which include but are not limited to 4,5-dihydroisox
  • the fused heterocyclic ring includes a heterocyclic group, a spiro heterocyclic group, and a bridged heterocyclic group, and may be saturated, partially saturated or unsaturated, but not aromatic.
  • a fused heterocyclic group is fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl, a 5-6 membered monocyclic cycloalkenyl, a 5-6 membered monocyclic heterocyclic group, or a 5-6 membered monocyclic heteroaromatic group 5-6 membered monocyclic heterocyclyl ring.
  • the heterocyclic group may be a 6-12 membered cyclic group, a 7-10 membered cyclic group, a 6-10 membered cyclic group, a 6-12 membered saturated cyclic group, and representative examples include but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3, 7-Diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3, 4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydro Benzo
  • the spiro heterocyclic group may be 6-12 membered spiro heterocyclic group, 7-11 membered spiro heterocyclic group, 6-12 membered saturated spiro heterocyclic group, examples of which include but are not limited to:
  • the bridged heterocyclic group may be 6-12 membered bridged heterocyclic group, 7-11 membered bridged heterocyclic group, 6-12 membered saturated bridged heterocyclic group, examples of which include but are not limited to:
  • the "6- to 14-membered aryl group” in the present invention refers to a cyclic aromatic group containing 6 to 14 carbon atoms, including a "6- to 8-membered monocyclic aryl group", such as phenyl; including “8 to 14-membered fused ring aryl", such as pentene, naphthalene, phenanthrene, etc.
  • the "5- to 8-membered aryl group” in the present invention refers to the above-mentioned cyclic aromatic group containing 5 to 8 carbon atoms, and examples thereof include, but are not limited to, phenyl.
  • the "5- to 10-membered heteroaryl group” in the present invention refers to an aromatic 5- to 10-membered cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1 to 3 Heteroatoms also include cases where carbon atoms and sulfur atoms are replaced by oxo. For example, carbon atoms are replaced by C(O) and sulfur atoms are replaced by S(O) and S(O) 2 .
  • the heteroaryl groups described in the present invention include single heteroaryl groups and condensed heteroaryl groups.
  • Mono-heteroaryl groups can be 5-7 membered heteroaryl groups, 5-6 membered heteroaryl groups, examples of which include but are not limited to furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl , Oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and triazinyl.
  • the fused heteroaryl group is fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclic group , Or 5-membered or 6-membered monocyclic heteroaryl ring of 5-membered or 6-membered monocyclic heteroaryl ring, in which the fused cycloalkyl, cycloalkenyl and heterocyclic groups are regarded as independent oxo groups or thio groups One or two groups are optionally substituted.
  • Condensed heteroaryl groups can be 8-12 membered heteroaryl groups, 9-10 membered heteroaryl groups, examples include but are not limited to benzimidazolyl, benzofuranyl, benzothienyl, and benzoxadiazolyl , Benzothiadiazolyl (benzthiadiazolyl), benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridine Group (furopyridinyl), indazolyl, indolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6, 7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin
  • the "pharmaceutically acceptable salt” in the present invention refers to pharmaceutically acceptable acid and base addition salts or solvates thereof.
  • Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid , Hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH 2 )n-COOH (where n is 0-4)), etc.
  • Salts of bases sodium salt, potassium salt, calcium salt, ammonium salt, etc. Those skilled in the art know a variety of non-toxic pharmaceutically acceptable addition salts.
  • the "Warhead” in the present invention refers to a part capable of forming a covalent bond with a nucleophile.
  • Nucleophile refers to a substance that supplies an electron pair to an electrophile to form a chemical bond in a reaction.
  • the test nucleophile may be an oxygen nucleophile, for example, water or hydroxyl; a nitrogen nucleophile, for example, an amine; or a sulfur nucleophile, for example, a sulfhydryl group, such as a cystine residue side The sulfhydryl group in the chain.
  • warhead in the present invention refers to the part of the inhibitor that reversibly or irreversibly participates in the reaction between the donor (for example, protein) and the substrate.
  • Warhead can, for example, form a covalent bond with a protein, or can generate a stable transition state, or be a reversible and irreversible alkylating agent.
  • the warhead may be a functional group on the inhibitor that can participate in the bond formation reaction, in which a new covalent bond is formed between a part of the warhead and the donor (for example, an amino acid residue of a protein).
  • Warhead is an electrophile and the "donor" is a nucleophile, such as a cysteine residue side chain. Suitable parts of warhead include but are not limited to the following structures:
  • Z refers to a leaving group (such as halogen) or an activated hydroxyl moiety (such as triflate);
  • R 11 , R 12 , R 13 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by substituents, halogen
  • R 11 , R 12 , and R 13 are preferably hydrogen or C 1 -4 alkyl.
  • All numerical ranges described in the present invention include the two endpoints of the range, all integers within the range, and subranges formed by these integers.
  • “3-8 yuan” includes 3, 4, 5, 6, 7, 8 yuan
  • “6-14 yuan” includes 6, 7, 8, 9, 10, 11, 12, 13, 14 yuan
  • “5- 10 yuan” includes 5, 6, 7, 8, 9, 10 yuan
  • “3-10 yuan” includes 3, 4, 5, 6, 7, 8, 9, 10 yuan
  • “5-8 yuan” includes 5, 6, 7, 8 yuan
  • "3-6 yuan” includes 3, 4, 5, 6 yuan and so on.
  • the “therapeutically effective amount” in the present invention refers to the amount of the aforementioned compound or its pharmaceutically acceptable salt, isomer and/or pharmaceutical preparation that can at least alleviate the symptoms of the patient's disease when administered to the patient.
  • the actual amount including the “therapeutically effective amount” will vary according to various conditions, including but not limited to the specific condition being treated, the severity of the condition, the physical and health status of the patient, and the route of administration. A skilled medical practitioner can easily determine the appropriate amount using methods known in the medical field.
  • the "pharmaceutically acceptable carrier” in the present invention includes, but is not limited to, solid carriers and liquid carriers.
  • Suitable solid carriers include, but are not limited to, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, arabic Gum, sodium alginate, parabens, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc.
  • Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, glycerides, and mixtures thereof.
  • the isomers in the present invention refer to stereoisomers and tautomers.
  • the "stereoisomer" of the compound of formula (I) in the present invention means that when the compound of formula (I) has asymmetric carbon atoms, it will produce enantiomers; when the compound has a carbon-carbon double bond or cyclic When structured, cis-trans isomers are produced.
  • the "tautomers” of the compound of formula (I) in the present invention means that when ketones or oximes are present in the compound of formula (I), tautomers are produced. All enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers and their Mixtures are all included in the scope of the present invention.
  • the "mammals” in the present invention refers to a group of animals in the subphylum Mammals of vertebrates, which secrete milk from the mammary glands to feed their larvae. It can be divided into humans and animals.
  • animal mammals include, but are not limited to, tigers, leopards, wolves, deer, giraffes, minks, monkeys, orangutans, tapirs, foxes, sloths, bears, koalas, polar bears, elephants, musk ox, rhinos, Manatee, lion, red panda, panda, warthog, antelope, koala, lynx, pangolin, anteater, otter, dolphin, walrus, seal, whale, platypus, hedgehog, kangaroo, hippo, ferret, badger, raccoon, Horse, cow, sheep, mule, donkey, dog, rat, cat, rabbit.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt or isomer thereof can effectively treat cholangiocarcinoma. Studies have shown that it has a very good therapeutic effect on FGFR variant cholangiocarcinoma.
  • the results of the kinase profile experiment show that the compound of the present invention has a good inhibitory effect on FGFR1-4. Compared with FGFR4, it can effectively and selectively inhibit FGFR1-3.
  • a PK/PD study of a nude mouse cancer cell line xenograft (cell-derived xenograft, CDX) model showed that the tumor inhibition rate of the compound of the present invention is linearly positively correlated with its system exposure.
  • the compound of the present invention has no obvious gender difference, high absolute bioavailability, and no significant drug accumulation in continuous administration.
  • the comparative experiment of PK parameters under normal feeding and fasting of SD rats it is shown that food has no obvious effect on the absorption of the compound of the present invention in SD rats.
  • the compound of the present invention is mainly distributed in the small intestine, stomach, large intestine, and liver.
  • the concentration of the distribution in the brain is low, indicating that the risk of penetrating the blood-brain barrier is relatively low, and There is no obvious tendency to distribute in blood cells.
  • the compound of the present invention exhibits moderate permeability and has no obvious efflux characteristics.
  • Test substance The compound of the present invention, the structure of which is shown in Table 1, and the preparation can be found in the specific embodiment section of WO2018040885.
  • Gemcitabine hydrochloride was purchased from Shanghai Titan Technology Co., Ltd.
  • Tumor source CC6204 was established from a female patient with cholangiocarcinoma Xenograft model. Pathologically diagnosed as intrahepatic cholangiocarcinoma, FGFR2-BICC1 fusion mutation.
  • mice Balb/c nude mice, 5-6 weeks old (mouse age at the time of inoculation) female, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
  • mice From Cholangiocarcinoma xenograft model CC6204 tumor-bearing mice collected tumor tissues, cut into tumor masses with a diameter of 2-3mm, and inoculated subcutaneously into the right anterior scapula of Balb/c nude mice . When the average tumor volume reached 133mm 3 , group administration was started. Grouping method: weigh the animals and measure the tumor volume before administration. According to the tumor volume, the mice were grouped by block design, with 6 mice in each group.
  • the vehicle of gemcitabine hydrochloride group physiological saline.
  • TGI% is the relative tumor growth rate, that is, the percentage value of the relative tumor volume between the treatment group and the control group at a certain point in time.
  • T and C are the relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively.
  • T/C% T RTV /C RTV ⁇ 100%
  • T RTV average RTV of the treatment group
  • C RTV average RTV of the vehicle control group
  • RTV V t /V 0
  • V 0 is the animal in the group
  • V t is the tumor volume of the animal after treatment.
  • NGI National Institutes of Health
  • TGI relative tumor inhibition rate. Measure the tumor size after the last dose to calculate TGI
  • P ⁇ 0.05 indicates statistical difference
  • P ⁇ 0.01 indicates significant statistical difference
  • P ⁇ 0.001 indicates extremely significant statistical difference
  • Test substance The compound of the present invention, the structure of which is shown in Table 1, and the preparation can be found in the specific embodiment section of WO2018040885.
  • CC6702 was established from an Asian female patient with cholangiocarcinoma Xenograft model. Pathologically diagnosed as intrahepatic cholangiocarcinoma, FGFR2-TTC28 fusion mutation.
  • Balb/c nude mice 6-7 weeks old (mouse age at the time of inoculation) female, sourced from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
  • mice From Cholangiocarcinoma xenograft model CC6702 tumor-bearing mice collected tumor tissues, cut into tumor masses with a diameter of 2-3mm, and inoculated subcutaneously into the right anterior scapula of Balb/c nude mice . When the average tumor volume was about 140mm 3 , group administration was started. Grouping method: weigh the animals and measure the tumor volume before administration. According to the tumor volume, the mice were grouped by block design, with 7 mice in each group.
  • Dosing frequency Dosing cycle Vehicle control 0 Oral gavage Qd 45 days Compound 9 150 Oral gavage Qd 45 days Compound 9 135 Oral gavage Qd 45 days
  • TGI% is the relative tumor growth rate, that is, the percentage value of the relative tumor volume between the treatment group and the control group at a certain point in time.
  • T and C are the relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively.
  • T/C% T RTV /C RTV ⁇ 100%
  • T RTV average RTV of the treatment group
  • C RTV average RTV of the vehicle control group
  • RTV V t /V 0
  • V 0 is the animal in the group
  • V t is the tumor volume of the animal after treatment.
  • NGI National Institutes of Health
  • Table 3 Compound pairs of the present invention Effect of tumor growth in human cholangiocarcinoma CC6702 subcutaneous xenograft tumor model
  • TGI relative tumor inhibition rate.
  • the vehicle control group -85# was prematurely relieved due to a weight loss of more than 20% before the end of the experiment.
  • the vehicle control group -3# and 37# were prematurely relieved due to a weight loss of over 15% for more than 72 hours before the end of the experiment and were not included in the analysis data. .
  • the tumor size was measured after the last administration and used to calculate the TGI.

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Abstract

La présente invention relève du domaine technique de la médecine, et concerne des utilisations d'un inhibiteur du récepteur du facteur de croissance des fibroblastes, et concerne en particulier un composé tel que représenté par la formule (I) destiné à être utilisé dans le traitement du cholangiocarcinome, un sel pharmaceutiquement acceptable et un isomère du composé, une composition pharmaceutique le comprenant, un procédé d'utilisation associé dans le traitement d'un cholangiocarcinome, leurs utilisations dans le traitement d'un cholangiocarcinome, et leurs utilisations dans la préparation d'un médicament pour le traitement d'un cholangiocarcinome chez un mammifère. Les variables dans la formule sont tels que définis dans la description. La recherche montre que le composé de formule (I) ou le sel pharmaceutiquement acceptable ou l'isomère de celui-ci fournit un effet thérapeutique significatif et fournit un grand potentiel dans des applications cliniques.
PCT/CN2021/078053 2020-02-28 2021-02-26 Utilisations d'inhibiteur du récepteur du facteur de croissance des fibroblastes WO2021170070A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107286130A (zh) * 2016-04-13 2017-10-24 成都融科博海科技有限公司 一种激酶选择性抑制剂
CN107793395A (zh) * 2016-09-01 2018-03-13 南京药捷安康生物科技有限公司 成纤维细胞生长因子受体抑制剂及其用途
CN110022900A (zh) * 2016-09-08 2019-07-16 蓝图药品公司 成纤维细胞生长因子受体4抑制剂与细胞周期蛋白依赖性激酶抑制剂的组合

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* Cited by examiner, † Cited by third party
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CN110386921A (zh) * 2018-04-23 2019-10-29 南京药捷安康生物科技有限公司 成纤维细胞生长因子受体抑制剂化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107286130A (zh) * 2016-04-13 2017-10-24 成都融科博海科技有限公司 一种激酶选择性抑制剂
CN107793395A (zh) * 2016-09-01 2018-03-13 南京药捷安康生物科技有限公司 成纤维细胞生长因子受体抑制剂及其用途
CN110022900A (zh) * 2016-09-08 2019-07-16 蓝图药品公司 成纤维细胞生长因子受体4抑制剂与细胞周期蛋白依赖性激酶抑制剂的组合

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