WO2021170070A1 - Uses of fibroblast growth factor receptor inhibitor - Google Patents

Uses of fibroblast growth factor receptor inhibitor Download PDF

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Publication number
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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French (fr)
Chinese (zh)
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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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Publication of WO2021170070A1 publication Critical patent/WO2021170070A1/en

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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.

Abstract

The present invention relates to the technical field of medicine, relates to uses of a fibroblast growth factor receptor inhibitor, and specifically relates to a compound as represented by formula (I) for use in treating cholangiocarcinoma, a pharmaceutically acceptable salt and an isomer of the compound, a pharmaceutical composition comprising same, a method for using same in treating cholangiocarcinoma, uses of same in treating cholangiocarcinoma, and uses of same in preparing a medicament for treating mammalian cholangiocarcinoma. Variables in the formula are as defined in the description. Research shows that the compound of formula (I) or the pharmaceutically acceptable salt or the isomer of same provides significant therapeutic effect and provides great potential in clinical applications.

Description

成纤维细胞生长因子受体抑制剂的用途Use of fibroblast growth factor receptor inhibitor 技术领域Technical field
本发明属于医药技术领域，具体涉及用于治疗胆管癌疾病的成纤维细胞生长因子受体抑制剂及其药学上可接受的盐、异构体，包含其的药物组合物，使用其治疗胆管癌疾病的方法，其用于治疗胆管癌疾病的用途，及其在制备治疗哺乳动物胆管癌疾病的药物中的用途。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.
背景技术Background technique
胆管癌(cholangiocarcinoma，CCA)是一种异质性强的恶性肿瘤，其发生位置遍布于毛细胆管到胆总管，可起源于胆道***的任何部位。根据解剖部位，胆管癌可分为肝内胆管癌(intrahepatic cholangiocarcinoma，iCCA)、肝门部胆管癌(perihilar cholangiocarcinoma，pCCA)和远端胆管癌(distal cholangiocarcinoma，dCCA)，它们有特殊的相似之处，但也有肿瘤间和肿瘤内部的差异，这些差异会影响肿瘤的病理机制和预后。Cholangiocarcinoma (CCA) 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.
CCA目前的治疗手段少，疗效较差，存活率低。由于CCA患者早期无明显临床症状，确诊时，其常常已经发生转移。晚期诊断会影响患者选择有效的治疗方式，考虑到CCA对化疗有显著的抵抗性，一般有效的治疗方法是手术切除和/或肝移植，化疗仅作为姑息治疗。目前，对于CCA，手术完整切除病灶是其唯一有效的治疗方法。传统上，因为局部肿瘤的浸润、腹膜或远处转移、缺乏胆道重建方案及预测术后残余肝脏不足等，只有不到1/3的患者在诊断时有可切除的机会。总体来讲，手术切除后5年存活率低，iCCA为22％～44％，pCCA为11％～41％，dCCA为27％～37％。肝移植因为有肿瘤快速复发和较低的存活率(10％～25％)，因此对于不能手术切除的CCA患者，历来不推荐肝移植。对于不能行手术切除或出现转移的CCA患者，***的化疗是主要的姑息疗法。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. In general, the 5-year survival rate after surgical resection is low, iCCA is 22% to 44%, pCCA is 11% to 41%, and dCCA is 27% to 37%. Because 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. For CCA patients who cannot be surgically removed or have metastases, systemic chemotherapy is the main palliative treatment.
吉西他滨和顺铂联合治疗与单独使用吉西他滨相比性价比更高。尽管与单一药物治疗相比，联合治疗可以改善患者的肿瘤无进展生存期和总生存期，但是在已转移的CCA，其中位生存期仍然只是接近1年。The combination of gemcitabine and cisplatin is more cost-effective than gemcitabine alone. Although combined therapy can improve the progression-free survival and overall survival of patients compared with single-drug therapy, the median survival of metastatic CCA is still only close to 1 year.
近年来，越来越多的证据表明成纤维细胞生长因子受体(fibroblast growth factor receptor，FGFR)是某些癌症的驱动基因，并且以“细胞自治”的方式维持肿瘤细胞的恶性特征，通过诱导促有丝***和生存信号、促进肿瘤细胞侵袭转移、促进上皮间质转化、促进血管生成、参与肿瘤复发耐药作用，作为癌基因参与肿瘤发生发展进程的多重步骤。In recent years, more and more evidences have shown that fibroblast growth factor receptor (FGFR) 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公开了一类pan-FGFR抑制剂，此类化合物对pan-FGFR有很好的抑制活性，可用来治疗pan-FGFR介导的癌症。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变异在胆管癌中较常见，特别是FGFR2融合，大约13％～14％的肝内胆管癌可检测到FGFR基因融合，且融合基因可引起非配体依赖的酪氨酸激酶激活并活化下游信号通路。抑制FGFR，可以通过抑制肿瘤的增殖、上皮间质转化、血管生成等，从而抑制/杀死胆管癌细胞。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.
目前，尽管部分FGFR抑制剂在临床前实验和临床试验中证明对FGFR变异的胆管癌有一定效果，但对胆管癌的疗效仍有较大的提升空间，具有巨大的未满足的临床需求。At present, although some FGFR inhibitors have proved to have a certain effect on FGFR-mutated cholangiocarcinoma in preclinical experiments and clinical trials, there is still a large room for improvement in the efficacy of cholangiocarcinoma, and there is a huge unmet clinical need.
发明内容Summary of the invention
1.发明概述1. Summary of the invention
本发明研究了如下通式(I)所述的化合物或其药学上可接受的盐、异构体在癌症领域的新用途。研究发现，通式(I)所述的化合物或其药学上可接受的盐、异构体对于胆管癌具有治疗作用。因此，本发明的目的是，提供通式(I)所述的化合物或其药学上可接受的盐、异构体在治疗胆管癌方面的新用途。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.
因此，在本发明的第一方面中，提供了一种通式(I)所示的化合物或其药学上可接受的盐、异构体在制备治疗哺乳动物胆管癌疾病的药物中的用途，Therefore, in the first aspect of the present invention, there is provided a use of a compound represented by general formula (I) or a pharmaceutically acceptable salt or isomer thereof in the preparation of a medicine for treating cholangiocarcinoma disease in mammals,
Figure PCTCN2021078053-appb-000001
Figure PCTCN2021078053-appb-000001
其中，in,
R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的含0～3个O、S和/或N原子的3～8元环烷基、3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子可任选地被氧化为C(O)； 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);
环B选自任选被1～3个R6取代的含至少1个N杂原子的3～10元饱和或不饱和的杂环基或5～6元含N杂芳基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子可任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
(v)氨基-羰基、氰基-羰基、C 1-6烷基-羰基、C 1-6烷基氨基-羰基、(C 1-6烷基) 2氨基-羰基、C 1-6烷氧基-羰基、3～8元环烷基-羰基和3～8元杂环 基-羰基； (v) Amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy Group-carbonyl, 3-8 membered cycloalkyl-carbonyl and 3-8 membered heterocyclyl-carbonyl;
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000002
Figure PCTCN2021078053-appb-000002
R 11，R 12，R 13独立地选自氢，卤素，氰基，任选被取代基取代的C 1-4烷基、卤代C 1-4烷基、3～8元环烷基、3～8元杂环基、5～8元芳基和5～10元杂芳基，所述取代基选自：羟基、氨基、羧基、氰基、硝基、卤素、C 1～4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、3～8元杂环基和6-12元螺杂环基。 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.
在本发明的第二方面中，提供了一种通式(I)所述的化合物或其药学上可接受的盐、异构体用于治疗胆管癌疾病的用途：In the second aspect of the present invention, there is provided a use of the compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof for the treatment of cholangiocarcinoma diseases:
Figure PCTCN2021078053-appb-000003
Figure PCTCN2021078053-appb-000003
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
在本发明的第三方面中，提供了一种用于治疗胆管癌疾病的通式(I)所述的化合物或其药学上可接受的盐、异构体：In the third aspect of the present invention, there is provided a compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof for the treatment of cholangiocarcinoma diseases:
Figure PCTCN2021078053-appb-000004
Figure PCTCN2021078053-appb-000004
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
在本发明的第四方面中，提供了一种用于治疗胆管癌疾病的方法，该方法包括向有需要的患者或受试者给予治疗有效量的通式(I)所述的化合物或其药学上可接受的盐、异构体：In the fourth aspect of the present invention, there is provided a method for treating cholangiocarcinoma disease, the method 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:
Figure PCTCN2021078053-appb-000005
Figure PCTCN2021078053-appb-000005
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
在本发明的第五方面中，提供了一种用于治疗胆管癌疾病的药物组合物，该药物组合物包含治疗有效量的通式(I)所述的化合物或其药学上可接受的盐、异构体并任选地包含药学上可接受的载体：In the fifth aspect of the present invention, there is provided a pharmaceutical composition for the treatment of cholangiocarcinoma diseases, the pharmaceutical composition 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:
Figure PCTCN2021078053-appb-000006
Figure PCTCN2021078053-appb-000006
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
2.发明详述2. Detailed description of the invention
如上所述，在本发明的第一方面中，提供了一种通式(I)所示的化合物或其药学上可接受的盐、异构体在制备治疗哺乳动物胆管癌疾病的药物中的用途：As mentioned above, in the first aspect of the present invention, there is provided a compound represented by general formula (I) or a pharmaceutically acceptable salt or isomer thereof in the preparation of a medicament for the treatment of cholangiocarcinoma in mammals. use:
Figure PCTCN2021078053-appb-000007
Figure PCTCN2021078053-appb-000007
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
在一个实施方式中，In one embodiment,
R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～10元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～ 6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
(v)氨基-羰基、氰基-羰基、C 1-6烷基-羰基、C 1-6烷基氨基-羰基、(C 1-6烷基) 2氨基-羰基、C 1-6烷氧基-羰基、3～8元环烷基-羰基和3～8元杂环基-羰基； (v) Amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy Group-carbonyl, 3-8 membered cycloalkyl-carbonyl and 3-8 membered heterocyclyl-carbonyl;
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000008
Figure PCTCN2021078053-appb-000008
R 11，R 12，R 13独立地选自氢，卤素，氰基，任选被取代基取代的 C 1-4烷基、卤代C 1-4烷基、3～8元环烷基、3～8元杂环基、5～8元芳基和5～10元杂芳基，所述取代基选自：羟基、氨基、羧基、氰基、硝基、卤素、C 1～4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、3～8元杂环基和6-12元螺杂环基。 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.
在一个实施方式中，R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； In one embodiment, 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子可任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～6元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、 C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000009
Figure PCTCN2021078053-appb-000009
在一个实施方式中，所述的通式(I)化合物具有通式(II)所示结构，In one embodiment, the compound of general formula (I) has a structure represented by general formula (II),
Figure PCTCN2021078053-appb-000010
Figure PCTCN2021078053-appb-000010
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环B为3-6元饱和杂环基，优选为以下基团：The ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
Figure PCTCN2021078053-appb-000011
Figure PCTCN2021078053-appb-000011
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述Warhead选自The Warhead is selected from
Figure PCTCN2021078053-appb-000012
Figure PCTCN2021078053-appb-000012
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环A为苯基。The ring A is phenyl.
在一个实施方式中，所述化合物为表1所示的化合物或其药学上可接受的盐、异构体。In one embodiment, the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
表1本发明的化合物Table 1 Compounds of the present invention
Figure PCTCN2021078053-appb-000013
Figure PCTCN2021078053-appb-000013
Figure PCTCN2021078053-appb-000014
Figure PCTCN2021078053-appb-000014
在进一步的实施方式中，所述化合物为In a further embodiment, the compound is
Figure PCTCN2021078053-appb-000015
化合物9或其药学上可接受的盐、异构体。
Figure PCTCN2021078053-appb-000015
Compound 9 or a pharmaceutically acceptable salt or isomer thereof.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌、肝门部胆管癌和远端胆管癌中的任何一种或其任何组合。In one embodiment, the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌。In one embodiment, the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR介导的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR变异的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌为FGFR2变异的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
在一个实施方式中，所述FGFR2变异的胆管癌为FGFR2变异的肝内胆管癌。In one embodiment, the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌、FGFR突变的胆管癌、和FGFR过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌、FGFR2突变的胆管癌、和FGFR2过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutant cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR2融合的胆管癌为FGFR2融合的肝内胆管癌。In one embodiment, the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
在一个实施方式中，所述的治疗胆管癌疾病的药物，除了含有通式(I)所述的化合物或其药学上可接受的盐、异构体，还可以含有药 学上可接受的载体。In one embodiment, 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.
在一个实施方式中，所述药物可以包含一种或多种药学上可接受的载体，可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，药物组合物可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，药物组合物可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，药物组合物可制成栓剂等。用于经肺给药时，药物组合物可制成吸入剂或喷雾剂等。In one embodiment, 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. . When used for oral administration, 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.剂 etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field. When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug. 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.
在一个实施方式中，所述的治疗胆管癌疾病的药物，除了含有通式(I)所述的化合物或其药学上可接受的盐、异构体，还含有一种或多种第二治疗活性剂。In one embodiment, 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.
在一个实施方式中，所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝***抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点抑制剂或肿瘤免疫治疗相关的抗体、肿瘤免疫治疗相关的小分子药物。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用联合给药的方式施用于需要治疗的患者或受试者。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用先后、同时或制成复方制剂的方式施用于需要治疗的患者或受试者。In one embodiment, 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 being treated.
在一个实施方式中，所述的患者或受试者是指哺乳动物。In one embodiment, the patient or subject refers to a mammal.
在一个实施方式中，所述的哺乳动物是指人类哺乳动物和/或动物类哺乳动物。In one embodiment, the mammal refers to human mammals and/or animal mammals.
在本发明的第二方面中，提供了一种通式(I)所述的化合物或其药学上可接受的盐、异构体用于治疗胆管癌疾病的用途，In the second aspect of the present invention, there is provided a use of the compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof for the treatment of cholangiocarcinoma diseases,
Figure PCTCN2021078053-appb-000016
Figure PCTCN2021078053-appb-000016
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
在一个实施方式中，In one embodiment,
R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～10元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基 的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
(v)氨基-羰基、氰基-羰基、C 1-6烷基-羰基、C 1-6烷基氨基-羰基、(C 1-6烷基) 2氨基-羰基、C 1-6烷氧基-羰基、3～8元环烷基-羰基和3～8元杂环基-羰基； (v) Amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy Group-carbonyl, 3-8 membered cycloalkyl-carbonyl and 3-8 membered heterocyclyl-carbonyl;
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000017
Figure PCTCN2021078053-appb-000017
R 11，R 12，R 13独立地选自氢，卤素，氰基，任选被取代基取代的C 1-4烷基、卤代C 1-4烷基、3～8元环烷基、3～8元杂环基、5～8元芳基和5～10元杂芳基，所述取代基选自：羟基、氨基、羧基、氰基、硝基、卤素、C 1～4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、3～8元杂环基和6-12元螺杂环基。 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.
在一个实施方式中，R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； In one embodiment, 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～6元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000018
Figure PCTCN2021078053-appb-000018
在一个实施方式中，所述的通式(I)化合物具有通式(II)所示结构，In one embodiment, the compound of general formula (I) has a structure represented by general formula (II),
Figure PCTCN2021078053-appb-000019
Figure PCTCN2021078053-appb-000019
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环B为3-6元饱和杂环基，优选为以下基团：The ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
Figure PCTCN2021078053-appb-000020
Figure PCTCN2021078053-appb-000020
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述Warhead选自The Warhead is selected from
Figure PCTCN2021078053-appb-000021
Figure PCTCN2021078053-appb-000021
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环A为苯基。The ring A is phenyl.
在一个实施方式中，所述化合物为表1所示的化合物或其药学上可接受的盐、异构体。In one embodiment, the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
在进一步的实施方式中，所述化合物为In a further embodiment, the compound is
Figure PCTCN2021078053-appb-000022
化合物9或其药学上可接受的盐、异构体。
Figure PCTCN2021078053-appb-000022
Compound 9 or a pharmaceutically acceptable salt or isomer thereof.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌、肝门部胆管癌和远端胆管癌中的任何一种或其任何组合。In one embodiment, the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌。In one embodiment, the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR介导的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR变异的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌为FGFR2变异的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
在一个实施方式中，所述FGFR2变异的胆管癌为FGFR2变异的肝内胆管癌。In one embodiment, the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌、FGFR突变的胆管癌、和FGFR过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的 胆管癌、FGFR2突变的胆管癌、和FGFR2过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR variant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutated cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR2融合的胆管癌为FGFR2融合的肝内胆管癌。In one embodiment, the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
在一个实施方式中，所述用途包括向有需要的患者或受试者给予治疗有效量的通式(I)化合物或其药学上可接受的盐、异构体。In one embodiment, 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.
在一个实施方式中，治疗有效量的通式(I)所述的化合物或其药学上可接受的盐、异构体，还可以与一种或多种药学上可接受的载体制成药学上可接受的任意药物制剂。In one embodiment, 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.
在一个实施方式中，所述药物制剂可以包含一种或多种药学上可接受的载体，可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，药物组合物可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，药物组合物可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。In one embodiment, 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. By. When used for oral administration, 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.剂 etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field. When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug. 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.
在一个实施方式中，所述用途还包括向有需要的患者或受试者给予治疗有效量的通式(I)所述的化合物或其药学上可接受的盐、异构体和一种或多种第二治疗活性剂。In one embodiment, 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.
在一个实施方式中，所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝***抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点抑制剂或肿瘤免疫治疗相关的抗体、肿瘤免疫治疗相关的小分子药物。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用联合给药的方式施用于需要 治疗的患者或受试者。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用先后、同时或制成复方制剂的方式施用于需要治疗的患者或受试者。In one embodiment, 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 being treated.
在一个实施方式中，所述的患者或受试者是指哺乳动物。In one embodiment, the patient or subject refers to a mammal.
在一个实施方式中，所述的哺乳动物是指人类哺乳动物和/或动物类哺乳动物。In one embodiment, the mammal refers to human mammals and/or animal mammals.
在本发明的第三方面中，提供了一种用于治疗胆管癌疾病的通式(I)所述的化合物或其药学上可接受的盐、异构体，In the third aspect of the present invention, there is provided a compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof for the treatment of cholangiocarcinoma diseases,
Figure PCTCN2021078053-appb-000023
Figure PCTCN2021078053-appb-000023
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
在一个实施方式中，In one embodiment,
R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～10元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
(v)氨基-羰基、氰基-羰基、C 1-6烷基-羰基、C 1-6烷基氨基-羰基、(C 1-6烷基) 2氨基-羰基、C 1-6烷氧基-羰基、3～8元环烷基-羰基和3～8元杂环基-羰基； (v) Amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy Group-carbonyl, 3-8 membered cycloalkyl-carbonyl and 3-8 membered heterocyclyl-carbonyl;
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000024
Figure PCTCN2021078053-appb-000024
R 11，R 12，R 13独立地选自氢，卤素，氰基，任选被取代基取代的C 1-4烷基、卤代C 1-4烷基、3～8元环烷基、3～8元杂环基、5～8元芳基和5～10元杂芳基，所述取代基选自：羟基、氨基、羧基、氰基、硝基、卤素、C 1～4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、3～8元杂环基和6-12元螺杂环基。 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.
在一个实施方式中，R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； In one embodiment, 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元 杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～6元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000025
Figure PCTCN2021078053-appb-000025
在一个实施方式中，所述的通式(I)化合物具有通式(II)所示结构，In one embodiment, the compound of general formula (I) has a structure represented by general formula (II),
Figure PCTCN2021078053-appb-000026
Figure PCTCN2021078053-appb-000026
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环B为3-6元饱和杂环基，优选为以下基团：The ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
Figure PCTCN2021078053-appb-000027
Figure PCTCN2021078053-appb-000027
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述Warhead选自The Warhead is selected from
Figure PCTCN2021078053-appb-000028
Figure PCTCN2021078053-appb-000028
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环A为苯基。The ring A is phenyl.
在一个实施方式中，所述化合物为表1所示的化合物或其药学上可接受的盐、异构体。In one embodiment, the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
在进一步的实施方式中，所述化合物为In a further embodiment, the compound is
Figure PCTCN2021078053-appb-000029
化合物9或其药学上可接受的盐、异构体。
Figure PCTCN2021078053-appb-000029
Compound 9 or a pharmaceutically acceptable salt or isomer thereof.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌、肝门部胆管癌和远端胆管癌中的任何一种或其任何组合。In one embodiment, the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌。In one embodiment, the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR介导的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR变异的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌为FGFR2变异的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
在一个实施方式中，所述FGFR2变异的胆管癌为FGFR2变异的肝内胆管癌。In one embodiment, the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌、FGFR突变的胆管癌、和FGFR过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌、FGFR2突变的胆管癌、和FGFR2过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutant cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR2融合的胆管癌为FGFR2融合的肝内胆管癌。In one embodiment, the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
在一个实施方式中，所述通式(I)化合物或其药学上可接受的盐、异构体以治疗有效量施用于有需要的患者或受试者。In one embodiment, 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.
在一个实施方式中，治疗有效量的通式(I)所述的化合物或其药学上可接受的盐、异构体，还可以与一种或多种药学上可接受的载体制成药学上可接受的任意药物制剂。In one embodiment, 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.
在一个实施方式中，所述药物制剂可以包含一种或多种药学上可接受的载体，可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，药物组合物可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，药物组合物可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。In one embodiment, 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. By. When used for oral administration, 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.剂 etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field. When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug. 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.
在一个实施方式中，所述通式(I)所述的化合物或其药学上可接受的盐、异构体还可以和一种或多种第二治疗活性剂组合施用于有需 要的患者或受试者。In one embodiment, 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.
在一个实施方式中，所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝***抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点抑制剂或肿瘤免疫治疗相关的抗体、肿瘤免疫治疗相关的小分子药物。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用联合给药的方式施用于需要治疗的患者或受试者。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用先后、同时或制成复方制剂的方式施用于需要治疗的患者或受试者。In one embodiment, 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 being treated.
在一个实施方式中，所述的患者或受试者是指哺乳动物。In one embodiment, the patient or subject refers to a mammal.
在一个实施方式中，所述的哺乳动物是指人类哺乳动物和/或动物类哺乳动物。In one embodiment, the mammal refers to human mammals and/or animal mammals.
在本发明的第四方面中，提供了一种用于治疗胆管癌疾病的方法，该方法包括向有需要的患者或受试者给予治疗有效量的式(I)化合物或其药学上可接受的盐、异构体，In the fourth aspect of the present invention, there is provided a method for treating cholangiocarcinoma disease, the method 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
Figure PCTCN2021078053-appb-000030
Figure PCTCN2021078053-appb-000030
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
在一个实施方式中，In one embodiment,
R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或 5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～10元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
(v)氨基-羰基、氰基-羰基、C 1-6烷基-羰基、C 1-6烷基氨基-羰基、(C 1-6烷基) 2氨基-羰基、C 1-6烷氧基-羰基、3～8元环烷基-羰基和3～8元杂环基-羰基； (v) Amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy Group-carbonyl, 3-8 membered cycloalkyl-carbonyl and 3-8 membered heterocyclyl-carbonyl;
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000031
Figure PCTCN2021078053-appb-000031
R 11，R 12，R 13独立地选自氢，卤素，氰基，任选被取代基取代的C 1-4烷基、卤代C 1-4烷基、3～8元环烷基、3～8元杂环基、5～8元芳基 和5～10元杂芳基，所述取代基选自：羟基、氨基、羧基、氰基、硝基、卤素、C 1～4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、3～8元杂环基和6-12元螺杂环基。 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.
在一个实施方式中，R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； In one embodiment, 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子可任选地被氧化为S(O)或S(O) 2，任意环中的碳原子可任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～6元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子可任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子可任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基，所述的3～8元杂环基可任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituents of,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环 烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000032
Figure PCTCN2021078053-appb-000032
在一个实施方式中，所述的通式(I)化合物具有通式(II)所示结构，In one embodiment, the compound of general formula (I) has a structure represented by general formula (II),
Figure PCTCN2021078053-appb-000033
Figure PCTCN2021078053-appb-000033
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环B为3-6元饱和杂环基，优选为以下基团：The ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
Figure PCTCN2021078053-appb-000034
Figure PCTCN2021078053-appb-000034
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述Warhead选自The Warhead is selected from
Figure PCTCN2021078053-appb-000035
Figure PCTCN2021078053-appb-000035
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环A为苯基。The ring A is phenyl.
在一个实施方式中，所述化合物为表1所示的化合物或其药学上可接受的盐、异构体。In one embodiment, the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
在进一步的实施方式中，所述化合物为In a further embodiment, the compound is
Figure PCTCN2021078053-appb-000036
化合物9或其药学上可接受的盐、异构体。
Figure PCTCN2021078053-appb-000036
Compound 9 or a pharmaceutically acceptable salt or isomer thereof.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌、肝门部胆管癌和远端胆管癌中的任何一种或其任何组合。In one embodiment, the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌。In one embodiment, the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR介导的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR变异的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌为FGFR2变异的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
在一个实施方式中，所述FGFR2变异的胆管癌为FGFR2变异的肝内胆管癌。In one embodiment, the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌、FGFR突变的胆管癌、和FGFR过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌、FGFR2突变的胆管癌、和FGFR2过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutant cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR2融合的胆管癌为FGFR2融合的肝内胆管癌。In one embodiment, the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
在一个实施方式中，治疗有效量的通式(I)所述的化合物或其药学上可接受的盐、异构体，还可以与一种或多种药学上可接受的载体制成药学上可接受的任意药物制剂。In one embodiment, 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.
在一个实施方式中，所述药物制剂可以包含一种或多种药学上可接受的载体，可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，药物组合物可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液 体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，药物组合物可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，药物组合物可制成栓剂等。用于经肺给药时，药物组合物可制成吸入剂或喷雾剂等。In one embodiment, 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. By. When used for oral administration, 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.剂 etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field. When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug. 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.
在一个实施方式中，所述方法还包括向有需要的患者或受试者给予治疗有效量的通式(I)所述的化合物或其药学上可接受的盐、异构体和一种或多种第二治疗活性剂。In one embodiment, 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.
在一个实施方式中，所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝***抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点抑制剂或肿瘤免疫治疗相关的抗体、肿瘤免疫治疗相关的小分子药物。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用联合给药的方式施用于需要治疗的患者或受试者。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用先后、同时或制成复方制剂的方式施用于需要治疗的患者或受试者。In one embodiment, 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 being treated.
在一个实施方式中，所述的患者或受试者是指哺乳动物。In one embodiment, the patient or subject refers to a mammal.
在一个实施方式中，所述的哺乳动物是指人类哺乳动物和/或动物类哺乳动物。In one embodiment, the mammal refers to human mammals and/or animal mammals.
在本发明的第五方面中，提供了一种用于治疗胆管癌疾病的药物组合物，该药物组合物包含治疗有效量的通式(I)所述的化合物或其药学上可接受的盐、异构体并任选地包含药学上可接受的载体，In the fifth aspect of the present invention, there is provided a pharmaceutical composition for the treatment of cholangiocarcinoma diseases, the pharmaceutical composition 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,
Figure PCTCN2021078053-appb-000037
Figure PCTCN2021078053-appb-000037
其中上述通式(I)中的各个变量如上文中所定义。Wherein each variable in the above general formula (I) is as defined above.
在一个实施方式中，In one embodiment,
R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～10元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
(v)氨基-羰基、氰基-羰基、C 1-6烷基-羰基、C 1-6烷基氨基-羰基、(C 1-6 烷基) 2氨基-羰基、C 1-6烷氧基-羰基、3～8元环烷基-羰基和3～8元杂环基-羰基； (v) Amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy Group-carbonyl, 3-8 membered cycloalkyl-carbonyl and 3-8 membered heterocyclyl-carbonyl;
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000038
Figure PCTCN2021078053-appb-000038
R 11，R 12，R 13独立地选自氢，卤素，氰基，任选被取代基取代的C 1-4烷基、卤代C 1-4烷基、3～8元环烷基、3～8元杂环基、5～8元芳基和5～10元杂芳基，所述取代基选自：羟基、氨基、羧基、氰基、硝基、卤素、C 1～4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、3～8元杂环基和6-12元螺杂环基。 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.
在一个实施方式中，R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； In one embodiment, 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子可任选地被氧化为S(O)或S(O) 2，任意环中的碳原子可任选地被氧化为C(O)； 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);
环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～6元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
(i)氢，(i) Hydrogen,
(ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
(iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、 C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基、C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
(iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
Warhead选自Warhead selected
Figure PCTCN2021078053-appb-000039
Figure PCTCN2021078053-appb-000039
在一个实施方式中，所述的通式(I)化合物具有通式(II)所示结构，In one embodiment, the compound of general formula (I) has a structure represented by general formula (II),
Figure PCTCN2021078053-appb-000040
Figure PCTCN2021078053-appb-000040
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环B为3-6元饱和杂环基，优选为以下基团：The ring B is a 3-6 membered saturated heterocyclic group, preferably the following group:
Figure PCTCN2021078053-appb-000041
Figure PCTCN2021078053-appb-000041
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述Warhead选自The Warhead is selected from
Figure PCTCN2021078053-appb-000042
Figure PCTCN2021078053-appb-000042
在进一步的实施方式中，在通式(II)所述的结构中，In a further embodiment, in the structure described by the general formula (II),
所述环A为苯基。The ring A is phenyl.
在一个实施方式中，所述化合物为表1所示的化合物或其药学上可接受的盐、异构体。In one embodiment, the compound is a compound shown in Table 1 or a pharmaceutically acceptable salt or isomer thereof.
在进一步的实施方式中，所述化合物为In a further embodiment, the compound is
Figure PCTCN2021078053-appb-000043
化合物9或其药学上可接受的盐、异构体。
Figure PCTCN2021078053-appb-000043
Compound 9 or a pharmaceutically acceptable salt or isomer thereof.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌、肝门部胆管癌和远端胆管癌中的任何一种或其任何组合。In one embodiment, the cholangiocarcinoma disease is any one or any combination of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma.
在一个实施方式中，所述胆管癌疾病为肝内胆管癌。In one embodiment, the cholangiocarcinoma disease is intrahepatic cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR介导的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
在一个实施方式中，所述胆管癌为FGFR变异的胆管癌。In one embodiment, the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌为FGFR2变异的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
在一个实施方式中，所述FGFR2变异的胆管癌为FGFR2变异的肝内胆管癌。In one embodiment, the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌、FGFR突变的胆管癌、和FGFR过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌、FGFR2突变的胆管癌、和FGFR2过表达的胆管癌中的任何一种或其任何组合。In one embodiment, the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutant cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
在一个实施方式中，所述FGFR变异的胆管癌是指FGFR2融合的胆管癌。In one embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 fusion cholangiocarcinoma.
在一个实施方式中，所述FGFR2融合的胆管癌为FGFR2融合的 肝内胆管癌。In one embodiment, the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
在一个实施方式中，所述通式(I)所述的化合物或其药学上可接受的盐、异构体，还可以与一种或多种药学上可接受的载体制成药学上可接受的任意药物制剂。In one embodiment, 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.
在一个实施方式中，所述药物制剂可以包含一种或多种药学上可接受的载体，可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，所述药物组合物可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，所述药物组合物可制成注射剂、包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。In one embodiment, 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. By. When used for oral administration, 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. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the pharmaceutical composition can be made into injections, including injections, sterile powders for injections, and concentrated solutions for injections. When preparing the injection, it can be produced by the conventional method in the existing pharmaceutical field. When preparing the injection, the additive may not be added, or an appropriate additive may be added according to the nature of the drug. 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.
在一个实施方式中，所述药物组合物还包含一种或多种第二治疗活性剂。In one embodiment, the pharmaceutical composition further comprises one or more second therapeutically active agents.
在一个实施方式中，所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝***抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点抑制剂或肿瘤免疫治疗相关的抗体、肿瘤免疫治疗相关的小分子药物。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用联合给药的方式施用于需要治疗的患者或受试者。In one embodiment, 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.
在一个实施方式中，所述的通式(I)所述的化合物或其药学上可接受的盐、异构体与第二治疗活性剂采用先后、同时或制成复方制剂的方式施用于需要治疗的患者或受试者。In one embodiment, 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 being treated.
在一个实施方式中，所述的患者或受试者是指哺乳动物。In one embodiment, the patient or subject refers to a mammal.
在一个实施方式中，所述的哺乳动物是指人类哺乳动物和/或动物类哺乳动物。In one embodiment, the mammal refers to human mammals and/or animal mammals.
3.定义3. Definition
本发明所述的“卤素”是指氟、氯、溴、碘等，优选氟，氯。The "halogen" in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.
本发明所述的“氧代”是指取代基结构中的任一C可被“-C(O)-”替换；若含有杂原子，其杂原子可形成氧化物，如
Figure PCTCN2021078053-appb-000044
可被
Figure PCTCN2021078053-appb-000045
替换，如S可被氧化为S(O)或S(O) 2。 The "oxo" in the present invention means that 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
Figure PCTCN2021078053-appb-000044
Can be
Figure PCTCN2021078053-appb-000045
Alternatively, for example, S can be oxidized to S(O) or S(O) 2 .
本发明所述的“氰基”是指-CN基团。The "cyano group" in the present invention refers to a -CN group.
本发明所述的“氨基”是指-NH 2基团。 The "amino group" in the present invention refers to the -NH 2 group.
本发明所述的“羟基”是指-OH基团。The "hydroxyl group" in the present invention refers to the -OH group.
本发明所述的“羰基”是指-C(＝O)-基团。The "carbonyl group" in the present invention refers to a -C(=O)- group.
本发明所述的“硫基”是指-S-基团。The "thio group" in the present invention refers to the -S- group.
本发明所述的“磺酰基”是指-S(＝O) 2-基团。 The "sulfonyl group" in the present invention refers to the -S(=O) 2 -group.
本发明所述的“羧基”是指-C(＝O)-OH基团。The "carboxyl group" in the present invention refers to the -C(=O)-OH group.
本发明所述的“硝基”是指-NO 2基团。 The "nitro group" in the present invention refers to the -NO 2 group.
本发明所述的“卤代”是指取代基中的任一氢原子可被一个或多个相同或不同的卤素原子替代。“卤素”如前文所定义。The "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.
本发明所述的“C 1-6烷基”指含有1～6个碳原子的烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、1，2-二甲基丁基、1，3-二甲基丁基、2，3-二甲基丁基、2-乙基丁基和1-甲基-2-甲基丙基等。所述“C 1-4烷基”指含有1～4个碳原子的上述烷基。 The "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-methyl Group-2-methylpropyl and so on. The "C 1-4 alkyl group" refers to the above-mentioned alkyl group containing 1 to 4 carbon atoms.
本发明所述的“C 2-8烯基”指含有碳碳双键的2～8个碳原子的烯烃部分去除一个氢原子衍生的直链或支链的烯烃基，如乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1，3-丁二烯基、1-戊烯基、2-戊烯基、3-戊烯基、1，3-戊二烯基、1，4-戊二烯基、1-己烯基、1，4-己二烯基、环丁烯基、环戊烯基、环己烯基、1，4-环己二烯基、环庚烯基、1，4-环庚二烯基、环辛烯基、1，5-环辛二烯基等，还包括可能形成的多环***，例如螺环烯、并环烯、桥环烯等。所述“C 2-4烯基”指含有2～4个碳原子的上述烯基。 The "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 spirocycloalkenes, And cycloalkenes, bridged cycloalkenes, etc. The "C 2-4 alkenyl group" refers to the above-mentioned alkenyl group containing 2 to 4 carbon atoms.
本发明所述的“C 2-8炔基”指含有碳碳叁键的2～8个碳原子的炔烃部分去除一个氢原子衍生的直链或支链的炔烃基，如乙炔基、丙炔基、 2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基等。 The "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.
本发明所述的“C 1-6烷基氨基”、“(C 1-6烷基) 2氨基”、“C 1-6烷基羰基氨基”、“C 1-6烷基磺酰氨基”、“C 1-6烷基氨基羰基”、“(C 1-6烷基) 2氨基-羰基”、“C 1-6烷氧基-羰基”、“C 1-6烷基磺酰基”、“C 1-6烷基硫基”、“C 1-6烷基-羰基”、“3～8元环烷基-羰基”、“3～8元杂环基-羰基”、“(C 1-6烷基) 2氨基C 1-6烷基”、“C 2-4烯基羰基氨基”、“C 1-6烷氧基C 1-6烷氧基”、“氨基-羰基”、“氰基-羰基”、“C 1-4烷基羰基氨基”、“C 1-4烷基磺酰氨基”、“C 1-4烷氧基C 1-4烷氧基”、“C 1-4烷基氨基”、“(C 1-4烷基) 2氨基”分别指C 1-6烷基-NH-、(C 1-6烷基)(C 1-6烷基)N-、C 1-6烷基-C(O)-NH-、C 1-6烷基-S(O) 2-NH-、C 1-6烷基-NH-C(O)-、(C 1-6烷基)(C 1-6烷基)N-C(O)-、C 1-6烷基-O-C(O)-、C 1-6烷基-S(O) 2-、C 1-6烷基-S-、C 1-6烷基-C(O)-、3～8元环烷基-C(O)-、3～8元杂环基-C(O)-、(C 1-6烷基)(C 1-6烷基)N-C 1-6烷基-、C 2-4烯基-C(O)-NH-、C 1-6烷基-O-C 1-6烷基-O-、NH 2-C(O)-、CN-C(O)-、C 1-4烷基-C(O)-NH-、C 1-4烷基-S(O) 2-NH-、C 1-4烷基-O-C 1-4烷基-O-、C 1-4烷基-NH-、(C 1-4烷基)(C 1-4烷基)N-；所述“C 1-6烷基”如前文所定义，优选为“C 1-4烷基”。 "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 alkylsulfonylamino", "C 1-4 alkoxy C 1-4 alkoxy", "C 1- 4 alkylamino" and "(C 1-4 alkyl) 2 amino" respectively refer to C 1-6 alkyl-NH-, (C 1-6 alkyl)(C 1-6 alkyl)N-, C 1-6 alkyl-C(O)-NH-, C 1-6 alkyl-S(O) 2 -NH-, C 1-6 alkyl-NH-C(O)-, (C 1-6 Alkyl) (C 1-6 alkyl) NC(O)-, C 1-6 alkyl-OC(O)-, C 1-6 alkyl-S(O) 2 -, C 1-6 alkyl -S-, C 1-6 alkyl-C(O)-, 3-8 membered cycloalkyl-C(O)-, 3-8 membered heterocyclic group-C(O)-, (C 1-6 Alkyl) (C 1-6 alkyl) NC 1-6 alkyl-, C 2-4 alkenyl-C(O)-NH-, C 1-6 alkyl-OC 1-6 alkyl-O- , NH 2 -C(O)-, CN-C(O)-, C 1-4 alkyl-C(O)-NH-, C 1-4 alkyl-S(O) 2 -NH-, C 1-4 alkyl-OC 1-4 alkyl-O-, C 1-4 alkyl-NH-, (C 1-4 alkyl)(C 1-4 alkyl)N-; said "C 1 -6 alkyl" is as defined above, and is preferably "C 1-4 alkyl".
本发明所述的“C 1-6烷氧基”是指前文所定义的“C 1-6烷基”通过氧原子与母体分子连接的基团，即“C 1-6烷基-O-”基团，如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、正戊氧基、新戊氧基和正己氧基等。所述的“C 1-4烷氧基”指含有1～4个碳原子的上述实例，即“C 1-4烷基-O-”基团。 "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.
本发明所述的“稠环”是指由两个或两个以上环状结构以并、螺、桥的连接方式所形成的多环系结构。所述的并环是指由两个或两个以上环状结构彼此共用两个相邻的环原子(即共用一个键)所形成的稠环结构。所述的桥环是指有两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的稠环结构。所述的螺环是指由两个或两个以上环状结构彼此共用一个环原子所形成的稠环结构。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.
本发明所述的“3～8元环烷基”，是指从3-8元环烷烃衍生得到的一价基团或(根据需要的)二价基团，其可以是单环环烷基、双环环烷基***或者是多环环烷基***(也称为稠环***)。单环***是含3至8个碳原子的环烃基基团。3～8元环烷基的实例包括但不限于：环丙烷基、环 丁烷基、环戊烷基、环己烷基、环庚烷基、环辛烷基等。稠环环烷基包括并环环烷基、桥环烷基、螺环烷基。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. Examples of 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.
并环环烷基可以为6-12元并环环烷基、7-10元并环环烷基，其的代表性例子包括但不限于双环[3.1.1]庚烷、双环[2.2.1]庚烷、双环[2.2.2]辛烷、双环[3.2.2]壬烷、双环[3.3.1]壬烷和双环[4.2.1]壬烷。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.
所述的螺环基可以为6-12元螺环基、7-11元螺环基，其实例包括但不限于：
Figure PCTCN2021078053-appb-000046
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:
Figure PCTCN2021078053-appb-000046
所述的桥环基可以为6-12元桥环基、7-11元桥环基，其实例包括但不限于：
Figure PCTCN2021078053-appb-000047
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:
Figure PCTCN2021078053-appb-000047
本发明所述的“3～10元杂环基”是指3-10元的非芳香性的环状基团，其中至少一个环碳原子被选自O、S、N的杂原子替代，优选1～3个杂原子，同时包括碳原子、氮原子和硫原子在内的成环原子可以被氧代。本发明所述的“3～8元杂环基”是指3-8元的上述环状基团，“3～6元杂环基”是指3-6元的上述环状基团。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.
本发明所述的“杂环基”，是指单环杂环基、双环杂环基***或多环杂环基***(也称为稠环***)，包括饱和、部分饱和的杂环基，但不包括芳环。单杂环基可以为3～8元杂环基、3～8元饱和杂环基、3～6元杂环基、4～7元元杂环基、5～7元杂环基、5～6元杂环基、5～6元含氧杂环基、5～6元含氮杂环基、5～6元饱和杂环基等。“3-8”元饱和杂环基，其实例包括但不限于氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、四氢吡咯基、四氢噻吩基、咪唑烷基、吡唑烷基、1，2-噁唑烷基、1，3-噁唑烷基、1，2-噻唑烷基、1，3-噻唑烷基、四氢-2H-吡喃基、四氢-2H-噻喃基、哌啶基、哌嗪基、吗啉基、1，4-二氧杂环己烷基、1，4-氧硫杂环己烷基；“3-8”元部分饱和杂环基，其实例包括但不限于4，5-二氢异噁唑基、4，5-二氢噁唑基、2，5-二氢噁唑基、2，3-二氢噁唑基、3，4-二氢-2H-吡咯基、2，3-二氢-1H-吡咯基、2，5-二氢-1H-咪唑基、4，5-二氢-1H-咪唑基、4，5-二氢-1H-吡唑基、4，5-二氢-3H-吡唑基、4，5-二氢噻唑基、2，5-二氢噻唑基、2H-吡喃基、4H-吡喃基、2H-噻喃基、4H-噻喃基、2，3，4，5-四氢吡啶基、1，2-异噁嗪基、1，4-异噁嗪基或6H-1，3-噁嗪基等。稠杂环包括并 杂环基、螺杂环基、桥杂环基，可以是饱和的、部分饱和的或不饱和的，但不是芳香性的。稠杂环基是稠合到苯环、5-6元的单环环烷基、5-6元单环环烯基、5-6元单环杂环基或5-6元单环杂芳基的5-6元单环杂环基环。所述的并杂环基可以为6-12元并环基、7-10元并环基、6-10元并环基、6-12元饱和并环基，代表性实例包括但不限于：3-氮杂双环[3.1.0]己烷基、3，6-二氮杂双环[3.2.0]庚烷基、3，8-二氮杂双环[4.2.0]辛烷基、3，7-二氮杂双环[4.2.0]辛烷基、八氢吡咯并[3，4-c]吡咯基、八氢吡咯并[3，4-b]吡咯基、八氢吡咯并[3，4-b][1，4]噁嗪基、八氢-1H-吡咯并[3，4-c]吡啶基、2，3-二氢苯并呋喃-2-基、2，3-二氢苯并呋喃-3-基、二氢吲哚-1-基、二氢吲哚-2-基、二氢吲哚3-基、2，3-二氢苯并噻吩-2基、八氢-1H-吲哚基、八氢苯并呋喃基。The "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-dihydroisoxazolyl, 4,5-di Hydroxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2 ,5-Dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4 ,5-Dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetra Hydropyridyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl, etc. 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 Benzofuran-3-yl, indoline-1-yl, indoline-2-yl, indoline 3-yl, 2,3-dihydrobenzothiophene-2, octahydro- 1H-indolyl, octahydrobenzofuranyl.
所述的螺杂环基可以为6-12元螺杂环基、7-11元螺杂环基、6-12元饱和螺环基，其实例包括但不限于：
Figure PCTCN2021078053-appb-000048
Figure PCTCN2021078053-appb-000049
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:
Figure PCTCN2021078053-appb-000048
Figure PCTCN2021078053-appb-000049
所述的桥杂环基可以为6-12元桥杂环基、7-11元桥杂环基、6-12元饱和桥杂环基，其实例包括但不限于：
Figure PCTCN2021078053-appb-000050
Figure PCTCN2021078053-appb-000051
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:
Figure PCTCN2021078053-appb-000050
Figure PCTCN2021078053-appb-000051
本发明所述“6～14元芳基”，是指含有6～14个碳原子的环状芳香性基团，包括“6-8元单环芳基”，例如苯基；包括“8～14元稠环芳基”，例如戊搭烯、萘、菲等。本发明所述“5～8元芳基”，是指含有5～8个碳原子的上述环状芳香性基团，其实例包括但不限于苯基。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.
本发明所述“5～10元杂芳基”是指至少一个环碳原子被选自O、S、N的杂原子替代的芳香性的5-10元环状基团，优选1～3个杂原子，同时包括碳原子、硫原子被氧代的情况，例如碳原子被C(O)替代，硫原 子被S(O)、S(O) 2替代。本发明所述的杂芳基包括单杂芳基和稠杂芳基。单杂芳基可以为5～7元杂芳基、5～6元杂芳基，其实例包括但不仅限于呋喃基、咪唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、噻二唑基、噻吩基、***基和三嗪基。在某些实施中，稠杂芳基是稠合到苯基环、5元或6元单环环烷基、5元或6元单环环烯基、5元或6元单环杂环基、或5元或6元单环杂芳基的5元或6元单环杂芳环，其中稠合的环烷基、环烯基和杂环基被作为独立氧代基或硫代基的一个或两个基团选择性取代。稠杂芳基可以为8-12元并杂芳基、9～10元并杂芳基，例子包括但不限于苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁二唑基、苯并噻二唑基(benzthiadiazolyl)、苯并噻唑基、噌啉基、5，6-二氢喹啉-2-基、5，6-二氢异喹啉-1-基、呋喃并吡啶基(furopyridinyl)、吲唑基、吲哚基、异喹啉基、萘啶基、嘌呤基、喹啉基、5，6，7，8-四氢喹啉-2-基、5，6，7，8-四氢喹啉基、5，6，7，8-四氢喹啉-4-基、5，6，7，8-四氢异喹啉-1-基、噻吩并吡啶基(thienopyridinyl)、4，5，6，7-四氢并[c][1，2，5]噁二唑基和6，7-二氢并[c][1，2，5]噁二唑-4(5H)酮基。 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. In certain implementations, 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-1-yl, thienopyridyl ( thienopyridinyl), 4,5,6,7-tetrahydro[c][1,2,5]oxadiazole and 6,7-dihydro[c][1,2,5]oxadiazole- 4(5H) Ketone.
本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐或其溶剂化物。这样的可药用盐包括诸如以下的酸的盐：盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸(诸如乙酸、HOOC-(CH 2)n-COOH(其中n是0～4))等。碱的盐：钠盐、钾盐、钙盐、铵盐等。本领域技术人员知晓多种无毒的可药用加成盐。 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.
本发明所述的“Warhead”指的是能够与亲核试剂形成共价键的部分。“亲核试剂”是指向亲电体供给电子对以在反应中形成化学键的物质。在一些实施方案中，亲试核剂可为氧亲核试剂，例如，水或羟基；氮亲核试剂，例如，胺；或硫亲核试剂，例如，巯基，诸如，胱氨酸残基侧链中的巯基。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. In some embodiments, 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.
本发明所述的“warhead”是指抑制剂中可逆地或不可逆地参与供体(例如，蛋白质)与底物的反应的部分。warhead可(例如)与蛋白质形成共价键，或可生成稳定过渡态，或是可逆不可逆烷基化剂。例如，warhead可为抑制剂上可参与键形成反应的官能基，其中在warhead的一部分与供体(例如蛋白质的氨基酸残基)之间形成新的共价键。warhead是亲电 体且“供体”是亲核试剂，诸如半胱氨酸残基侧链。适宜做warhead部分的包括但不限于以下结构：The "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. For example, 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:
Figure PCTCN2021078053-appb-000052
Figure PCTCN2021078053-appb-000052
其中，in,
Z指离去基团(诸如卤素)或活化羟基部分(例如三氟甲磺酸酯)；Z refers to a leaving group (such as halogen) or an activated hydroxyl moiety (such as triflate);
R 11，R 12，R 13独立地选自氢，卤素，氰基，任选被取代基取代的C 1-4烷基、卤 R 11 , R 12 , R 13 are independently selected from hydrogen, halogen, cyano, C 1-4 alkyl optionally substituted by substituents, halogen
代C 1-4烷基、3～8元环烷基、3～8元杂环基、5～8元芳基和5～10元杂芳基，所述取代基选自：羟基、氨基、羧基、氰基、硝基、卤素、C 1～4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基和3～8元杂环基；R 11，R 12，R 13优选为氢或C 1-4烷基。 Substituted C 1-4 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 8 membered aryl and 5 to 10 membered heteroaryl, and the substituents are selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 4 alkyl group, 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 alkylcarbonylamino, C 1-4 alkylsulfonylamino and 3-8 membered heterocyclic group; R 11 , R 12 , and R 13 are preferably hydrogen or C 1 -4 alkyl.
本发明所述的所有数值范围，均表示包括该范围的两个端点、该范围之内的所有整数以及由这些整数形成的子范围。例如“3-8元”包括3、4、5、6、7、8元，“6-14元”包括6、7、8、9、10、11、12、13、14元，“5-10元”包括5、6、7、8、9、10元，“3-10元”包括3、4、5、6、7、8、9、10元，“5-8元”包括5、6、7、8元，“3-6元”包括3、4、5、6元等等。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. For example, "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, and "5- 10 yuan” includes 5, 6, 7, 8, 9, 10 yuan, “3-10 yuan” includes 3, 4, 5, 6, 7, 8, 9, 10 yuan, and “5-8 yuan” includes 5, 6, 7, 8 yuan, "3-6 yuan" includes 3, 4, 5, 6 yuan and so on.
本发明所述的“治疗有效量”是指当给药到患者时至少能够减轻患者病症的症状的前述化合物或其药学上可接受的盐、异构体和/或药物制剂的量。包含“治疗有效量”的实际量会根据多种情况而变化，多种情况包括但不限于所治疗的特定病症、病症的严重程度、患者的体格和健康状况以及给药途径。熟练的医疗从业者可容易地使用医疗领域中 已知的方法确定合适的量。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.
本发明所述的“药学上可接受的载体”包括但不限于固体载体和液体载体。合适的固体载体包括但不限于纤维素、葡萄糖、乳糖、甘露醇、硬脂酸镁、碳酸镁、碳酸钠、糖精钠、蔗糖、糊精、滑石、淀粉、果胶、明胶、黄芪胶、***胶、藻酸钠、对羟基苯甲酸酯、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。合适的液体载体包括但不限于水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油、甘油酯及其混合物。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.
本发明所述的异构体是指立体异构体和互变异构体。The isomers in the present invention refer to stereoisomers and tautomers.
本发明所述的式(I)化合物的“立体异构体”是指当式(I)化合物存在不对称碳原子时，会产生对映异构体；当化合物存在碳碳双键或环状结构时，会产生顺反异构体。本发明所述的式(I)化合物的“互变异构体”，是指当式(I)化合物存在酮或肟时，会产生互变异构体。所有式(I)化合物的对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物，均包括在本发明范围中。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.
本发明所述的“哺乳动物”是指脊椎动物亚门下哺乳纲的一类动物类群，其通过乳腺分泌乳汁来给幼体哺乳。其可分为人类和动物类。动物类的哺乳动物的实例包括但不限制于虎、豹、狼、鹿、长颈鹿、貂、猴、猩猩、貘、狐、树懒、熊、无尾熊、北极熊、象、麝牛、犀牛、海牛、狮子、小熊猫、熊猫、疣猪、羚羊、考拉、猞猁、穿山甲、食蚁兽、水獭、海豚、海象、海豹、鲸鱼、鸭嘴兽、刺猬、袋鼠、河马、鼬、獾、狸、马、牛、羊、骡、驴、狗、鼠、猫、兔。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. Examples of 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.
本发明所述的通式(I)化合物的制备可参见WO2018040885具体实施方式部分。For the preparation of the compound of general formula (I) of the present invention, please refer to WO2018040885 specific embodiment section.
本发明的有益效果The beneficial effects of the present invention
本发明通式(I)所示的化合物或其药学上可接受的盐、异构体、能够有效地治疗胆管癌。研究表明，其对于FGFR变异型胆管癌有非常好的治疗效果。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.
激酶谱实验结果表明，本发明化合物对FGFR1-4均有较好的抑制作用。相对FGFR4，可以有效并且选择性地抑制FGFR1-3。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.
裸鼠癌细胞系异种移植(cell-derived xenograft，CDX)模型PK/PD研究表明，本发明化合物的抑瘤率与其***暴露量呈线性正相关。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.
根据SD大鼠和比格犬体内PK实验，本发明化合物无明显性别差异，绝对生物利用度较高，连续给药无明显的药物蓄积。根据SD大鼠正常饲喂和禁食下的PK参数比较实验，显示食物对本发明化合物在SD大鼠体内的吸收没有明显影响。According to in vivo PK experiments in SD rats and beagle dogs, the compound of the present invention has no obvious gender difference, high absolute bioavailability, and no significant drug accumulation in continuous administration. According to 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.
根据SD大鼠灌胃给予本发明化合物后的组织分布实验，本发明化合物主要分布在小肠、胃、大肠及肝脏中，脑中分布浓度较低，显示透过血脑屏障的风险比较低，且在血细胞中没有明显分布倾向。According to the tissue distribution experiment of SD rats after intragastric administration of the compound of the present invention, 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.
在Caco-2单层细胞模型中，本发明化合物表现出中等渗透性，且没有明显外排特性。In the Caco-2 monolayer cell model, the compound of the present invention exhibits moderate permeability and has no obvious efflux characteristics.
安全药理学研究表明，本发明化合物对SD大鼠的中枢神经***没有影响，对清醒比格犬的心血管和呼吸***没有影响。Safety pharmacology studies have shown that the compound of the present invention has no effect on the central nervous system of SD rats, and has no effect on the cardiovascular and respiratory systems of awake beagle dogs.
为使本发明的目的、技术方案、及优点更加清楚明白，以下对本发明进一步详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。In order to make the objectives, technical solutions, and advantages of the present invention clearer and clearer, the following further describes the present invention in detail. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.
实验例1本发明化合物对
Figure PCTCN2021078053-appb-000053
人源胆管癌CC6204皮下异种移植肿瘤模型的体内药效测试 Experimental Example 1 The compound of the present invention
Figure PCTCN2021078053-appb-000053
In vivo efficacy test of human cholangiocarcinoma CC6204 subcutaneous xenograft tumor model
缩略词表：List of acronyms:
Qd      每日一次Qd Once a day
Qw      每周一次Qw Once a week
CMC-Na  羧甲基纤维素钠CMC-Na Sodium Carboxymethyl Cellulose
测试物：本发明中的化合物，其结构如表1所示，制备可参见WO2018040885具体实施方式部分。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.
盐酸吉西他滨，购自上海泰坦科技股份有限公司。Gemcitabine hydrochloride was purchased from Shanghai Titan Technology Co., Ltd.
瘤块来源：CC6204是源于一名女性患者胆管癌瘤建立的
Figure PCTCN2021078053-appb-000054
异种移植模型。病理诊断为肝内胆管癌，FGFR2-BICC1融合变异。 Tumor source: CC6204 was established from a female patient with cholangiocarcinoma
Figure PCTCN2021078053-appb-000054
Xenograft model. Pathologically diagnosed as intrahepatic cholangiocarcinoma, FGFR2-BICC1 fusion mutation.
动物：Balb/c裸小鼠，5-6周(接种时小鼠周龄)雌性，购自江苏 集萃药康生物科技有限公司。Animals: Balb/c nude mice, 5-6 weeks old (mouse age at the time of inoculation) female, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
试验方法：experiment method:
(1)荷瘤小鼠构建与分组(1) Construction and grouping of tumor-bearing mice
从
Figure PCTCN2021078053-appb-000055
胆管癌异种移植模型CC6204荷瘤小鼠收取肿瘤组织，切成直径为2-3mm的瘤块皮下接种于Balb/c裸小鼠右前肩胛处，待肿瘤平均体积达到133mm 3时开始分组给药。分组方法：给药前称重动物，测量瘤体积。根据瘤体积采用区组设计分组，每组6只小鼠。 From
Figure PCTCN2021078053-appb-000055
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.
(2)给药方案(2) Dosing schedule
按照如下表格进行给药。Dosing according to the following table.
Figure PCTCN2021078053-appb-000056
Figure PCTCN2021078053-appb-000056
a：盐酸吉西他滨每周给药一次，共给药三次a: Gemcitabine hydrochloride is administered once a week for a total of three administrations
注：溶媒对照组的溶媒：含有0.5％(v/v)吐温80的0.5％(w/v)CMC-NaNote: The solvent of the solvent control group: 0.5% (w/v) CMC-Na containing 0.5% (v/v) Tween 80
化合物9组的溶媒：含有0.5％(v/v)吐温80的0.5％(w/v)CMC-NaThe solvent of compound 9 group: 0.5% (w/v) CMC-Na containing 0.5% (v/v) Tween 80
盐酸吉西他滨组的溶媒：生理盐水。The vehicle of gemcitabine hydrochloride group: physiological saline.
(3)实验观察指标(3) Experimental observation indicators
每天监测动物的健康状况及死亡情况，每周测量两次体重以及瘤体积，末次给药后收集样本。肿瘤体积大小的疗效用TGI％评价，相对肿瘤抑制率TGI(％)：TGI＝1-T/C(％)。T/C％为相对肿瘤增值率，即在某一时间点，治疗组和对照组相对肿瘤体积的百分比值。T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)。计算公式为：T/C％＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：溶媒对照组平均RTV；RTV＝V t/V 0，V 0为分组时该动物的瘤体积，V t为治疗后该动物的瘤体积。根据美国国立卫生研究院(NIH)指导原则TGI≥58％，认为此药有效。 The health status and death of the animals were monitored daily, body weight and tumor volume were measured twice a week, and samples were collected after the last administration. The curative effect of tumor size is evaluated by TGI%, and the relative tumor inhibition rate TGI (%): TGI=1-T/C (%). T/C% 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. The calculation formula is: 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. According to the guidelines of the National Institutes of Health (NIH) TGI ≥ 58%, the drug is considered effective.
结果如表2所示：The results are shown in Table 2:
表2本发明的化合物对
Figure PCTCN2021078053-appb-000057
人胆管癌CC6204 Table 2 Pairs of compounds of the present invention
Figure PCTCN2021078053-appb-000057
Human cholangiocarcinoma CC6204
皮下异种移植肿瘤模型肿瘤生长的影响Effect of tumor growth in subcutaneous xenograft tumor model
Figure PCTCN2021078053-appb-000058
Figure PCTCN2021078053-appb-000058
注：Note:
a：TGI：相对肿瘤抑制率。末次给药后测量肿瘤大小，用于计算TGI， a: TGI: relative tumor inhibition rate. Measure the tumor size after the last dose to calculate TGI,
P＜0.05为有统计学差异，P＜0.01为有显著统计学差异，P＜0.001为有极其显著的统计学差异。P<0.05 indicates statistical difference, P<0.01 indicates significant statistical difference, P<0.001 indicates extremely significant statistical difference.
由表2实验结果可见，化合物9对
Figure PCTCN2021078053-appb-000059
人胆管癌CC6204皮下异种移植肿瘤模型具有显著的抑制作用，明显优于临床标准治疗盐酸吉西他滨，说明本发明化合物用于FGFR2融合变异的胆管癌肿瘤治疗，具有较好的临床应用潜力。 From the experimental results in Table 2, it can be seen that the compound 9 pairs
Figure PCTCN2021078053-appb-000059
The human cholangiocarcinoma CC6204 subcutaneous xenograft tumor model has a significant inhibitory effect, which is significantly better than the clinical standard treatment gemcitabine hydrochloride, indicating that the compound of the present invention is used in the treatment of FGFR2 fusion variant cholangiocarcinoma tumors and has good clinical application potential.
实验例2本发明化合物对
Figure PCTCN2021078053-appb-000060
人源胆管癌CC6702皮下异种移植肿瘤模型的体内药效学研究 Experimental Example 2 The compound of the present invention
Figure PCTCN2021078053-appb-000060
In vivo pharmacodynamics study of human cholangiocarcinoma CC6702 subcutaneous xenograft tumor model
缩略词表Abbreviation list
Qd      每日一次Qd Once a day
Qw      每周一次Qw Once a week
CMC-Na  羧甲基纤维素钠CMC-Na Sodium Carboxymethyl Cellulose
测试物：本发明中的化合物，其结构如表1所示，制备可参见WO2018040885具体实施方式部分。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.
动物、瘤块来源、患者信息等材料：Animals, tumor source, patient information and other materials:
CC6702是源于一名亚洲女性患者胆管癌瘤建立的
Figure PCTCN2021078053-appb-000061
异种移植模型。病理诊断为肝内胆管癌，FGFR2-TTC28融合变异。 CC6702 was established from an Asian female patient with cholangiocarcinoma
Figure PCTCN2021078053-appb-000061
Xenograft model. Pathologically diagnosed as intrahepatic cholangiocarcinoma, FGFR2-TTC28 fusion mutation.
Balb/c裸小鼠，6-7周(接种时小鼠周龄)雌性，来源于江苏集萃药康生物科技有限公司Balb/c nude mice, 6-7 weeks old (mouse age at the time of inoculation) female, sourced from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
试验方法：experiment method:
1，荷瘤小鼠构建与分组1. Construction and grouping of tumor-bearing mice
从
Figure PCTCN2021078053-appb-000062
胆管癌异种移植模型CC6702荷瘤小鼠收取肿瘤组织，切成直径为2-3mm的瘤块皮下接种于Balb/c裸小鼠右前肩胛处，待肿瘤平均体积约140mm 3时开始分组给药。分组方法：给药前称重动物，测量瘤体积。根据瘤体积采用区组设计分组，每组7只小鼠。 From
Figure PCTCN2021078053-appb-000062
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.
2，给药方案2. Dosing schedule
按照如下表格进行给药。Dosing according to the following table.
组别Group 剂量(mg/kg)Dose (mg/kg) 给药途径Route of administration 给药频率Dosing frequency 给药周期Dosing cycle
溶媒对照Vehicle control 00 口服灌胃Oral gavage QdQd 45天45 days
化合物9Compound 9 150150 口服灌胃Oral gavage QdQd 45天45 days
化合物9Compound 9 135135 口服灌胃Oral gavage QdQd 45天45 days
注：溶媒对照(化合物9)组的溶媒：含有0.5％(v/v)吐温80的0.5％(w/v)CMC-NaNote: The solvent of the vehicle control (compound 9) group: 0.5% (w/v) CMC-Na containing 0.5% (v/v) Tween 80
3，实验观察指标3. Experimental observation indicators
每天监测动物的健康状况及死亡情况，每周测量两次体重以及瘤体积，末次给药后收集样本。肿瘤体积大小的疗效用TGI％评价，相对肿瘤抑制率TGI(％)：TGI＝1-T/C(％)。T/C％为相对肿瘤增值率，即在某一时间点，治疗组和对照组相对肿瘤体积的百分比值。T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)。计算公式为：T/C％＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：溶媒对照组平均RTV；RTV＝V t/V 0，V 0为分组时该动物的瘤体积，V t为治疗后该动物的瘤体积。根据美国国立卫生研究院(NIH)指导原则TGI≥58％，认为此药有效。 The health status and death of the animals were monitored daily, body weight and tumor volume were measured twice a week, and samples were collected after the last administration. The curative effect of tumor size is evaluated by TGI%, and the relative tumor inhibition rate TGI (%): TGI=1-T/C (%). T/C% 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. The calculation formula is: 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. According to the guidelines of the National Institutes of Health (NIH) TGI ≥ 58%, the drug is considered effective.
结果如下表所示：The results are shown in the following table:
表3本发明的化合物对
Figure PCTCN2021078053-appb-000063
人胆管癌CC6702皮下异种移植肿瘤模型肿瘤生长的影响 Table 3 Compound pairs of the present invention
Figure PCTCN2021078053-appb-000063
Effect of tumor growth in human cholangiocarcinoma CC6702 subcutaneous xenograft tumor model
Figure PCTCN2021078053-appb-000064
Figure PCTCN2021078053-appb-000064
注：Note:
a：TGI：相对肿瘤抑制率。溶媒对照组-85#结束实验前因体重下降超20％被提前安乐，溶媒对照组-3#和37#结束实验前因体重下降超15％超过72小时，被提前安乐不计入分析数据中。末次给药后测量肿瘤大小，用于计算TGI。 a: 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.
由上表实验结果可见，化合物9对
Figure PCTCN2021078053-appb-000065
人胆管癌CC6702皮下异种移植肿瘤模型具有显著的抑制作用，说明本发明化合物用于临床FGFR2变异的肝内胆管癌肿瘤治疗，具有较好的临床应用潜力。 It can be seen from the experimental results of the above table that the compound 9 pairs
Figure PCTCN2021078053-appb-000065
The human cholangiocarcinoma CC6702 subcutaneous xenograft tumor model has a significant inhibitory effect, indicating that the compound of the present invention is used in the treatment of clinical FGFR2 variant intrahepatic cholangiocarcinoma tumors and has good clinical application potential.
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the present invention. Within the scope of protection.

Claims (15)

  1. 通式(I)所示的化合物或其药学上可接受的盐、异构体在制备治疗哺乳动物胆管癌疾病的药物中的用途，The use of the compound represented by general formula (I) or its pharmaceutically acceptable salt or isomer in the preparation of a medicine for treating cholangiocarcinoma disease in mammals,
    Figure PCTCN2021078053-appb-100001
    Figure PCTCN2021078053-appb-100001
    其中，in,
    R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
    环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
    环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～10元饱和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
    R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
    (i)氢，(i) Hydrogen,
    (ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
    (iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷 基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
    (iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
    (v)氨基-羰基、氰基-羰基、C 1-6烷基-羰基、C 1-6烷基氨基-羰基、(C 1-6烷基) 2氨基-羰基、C 1-6烷氧基-羰基、3～8元环烷基-羰基和3～8元杂环基-羰基； (v) Amino-carbonyl, cyano-carbonyl, C 1-6 alkyl-carbonyl, C 1-6 alkylamino-carbonyl, (C 1-6 alkyl) 2 amino-carbonyl, C 1-6 alkoxy Group-carbonyl, 3-8 membered cycloalkyl-carbonyl and 3-8 membered heterocyclyl-carbonyl;
    m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
    Warhead选自Warhead selected
    Figure PCTCN2021078053-appb-100002
    Figure PCTCN2021078053-appb-100002
    R 11，R 12，R 13独立地选自氢，卤素，氰基，任选被取代基取代的C 1-4烷基、卤代C 1-4烷基、3～8元环烷基、3～8元杂环基、5～8元芳基和5～10元杂芳基，所述取代基选自：羟基、氨基、羧基、氰基、硝基、卤素、C 1～4烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、3～8元杂环基和6-12元螺杂环基。 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.
  2. 如权利要求1所述的用途，The use as claimed in claim 1,
    其中，R 1、R 2分别独立地选自氢、羟基、氨基、氰基、硝基、卤素原子、羧基、C 1-6烷基和C 1-6烷氧基； Wherein, 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、R 4分别独立地选自氢、羟基、C 1-6烷基和(C 1-6烷基) 2氨基C 1-6烷基； 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选自任选含0～3个O、S和/或N原子的6～14元芳基或5～10元杂芳基；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;
    环A选自任选被1～3个R 5取代的3～8元杂环基、6～14元芳基或5～10元杂芳基，其中，任意环中的S原子任选地被氧化为S(O)或S(O) 2，任意环中的碳原子任选地被氧化为C(O)； 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);
    环B选自任选被1～3个R 6取代的含至少1个N杂原子的3～6元饱 和或不饱和的杂环基，并且，环B上的N原子与Warhead键直接相连，其中，任意环B中的S原子任选被氧化为S(O)或S(O) 2，并且任意的环B中的碳原子任选地被氧化为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选自CR 7和N； X is selected from CR 7 and N;
    R 5、R 6、R 7分别独立地选自 R 5 , R 6 , and R 7 are each independently selected from
    (i)氢，(i) Hydrogen,
    (ii)羟基、氨基、羧基、氰基、硝基、卤素原子、C 2-4烯基羰基氨基和＝CH 2， (ii) Hydroxyl group, amino group, carboxyl group, cyano group, nitro group, halogen atom, C 2-4 alkenylcarbonylamino group and =CH 2 ,
    (iii)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基和3～8元杂环基的取代基取代的C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基磺酰基和C 1-6烷基硫基，所述的3～8元杂环基任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1～6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代， (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 and C 1-6 alkylthio, the 3-8 membered heterocyclic group is optionally selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1 ~ 6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 alkyl) 2 amino Substituent substitution,
    (iv)任选被选自羟基、氨基、羧基、氰基、硝基、卤素、C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基和(C 1-6烷基) 2氨基的取代基取代的3～8元环烷基和3～8元杂环基， (iv) optionally selected from hydroxyl, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino and (C 1-6 Alkyl) 3-8 membered cycloalkyl and 3-8 membered heterocyclic group substituted by the substituent of 2 amino group,
    m 1、m 2代表1、2或3，且m 1与m 2相加小于等于5； m 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;
    Warhead选自Warhead selected
    Figure PCTCN2021078053-appb-100003
    Figure PCTCN2021078053-appb-100003
  3. 如权利要求1所述的用途，其中所述通式(I)的化合物为具有以下结构的化合物或其药学上可接受的盐、异构体：The use according to claim 1, wherein the compound of general formula (I) is a compound having the following structure or a pharmaceutically acceptable salt or isomer thereof:
    Figure PCTCN2021078053-appb-100004
    Figure PCTCN2021078053-appb-100004
    Figure PCTCN2021078053-appb-100005
    Figure PCTCN2021078053-appb-100005
  4. 如权利要求3所述的用途，其中所述通式(I)的化合物为
    Figure PCTCN2021078053-appb-100006
    或其药学上可接受的盐、异构体。     The use according to claim 3, wherein the compound of general formula (I) is
    Figure PCTCN2021078053-appb-100006
    Or a pharmaceutically acceptable salt or isomer thereof.
  5. 如权利要求1-4任一项所述的用途，其中所述胆管癌为肝内胆管癌、肝门部胆管癌和远端胆管癌中的任何一种或其任何组合。The use according to any one of claims 1 to 4, wherein the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma, or any combination thereof.
  6. 如权利要求1-4任一项所述的用途，其中所述胆管癌为FGFR介导的胆管癌。The use according to any one of claims 1 to 4, wherein the cholangiocarcinoma is FGFR-mediated cholangiocarcinoma.
  7. 如权利要求1-4任一项所述的用途，其中所述胆管癌为FGFR变异的胆管癌。The use according to any one of claims 1 to 4, wherein the cholangiocarcinoma is FGFR variant cholangiocarcinoma.
  8. 如权利要求7所述的用途，其中所述FGFR变异的胆管癌为FGFR2变异的胆管癌。The use according to claim 7, wherein the FGFR variant cholangiocarcinoma is FGFR2 variant cholangiocarcinoma.
  9. 如权利要求8所述的用途，其中所述FGFR2变异的胆管癌为FGFR2变异的肝内胆管癌。The use according to claim 8, wherein the FGFR2 variant cholangiocarcinoma is FGFR2 variant intrahepatic cholangiocarcinoma.
  10. 如权利要求7所述的用途，其中所述FGFR变异的胆管癌是指FGFR融合的胆管癌、FGFR突变的胆管癌、和FGFR过表达的胆管癌中的任何一种或其任何组合。The use according to claim 7, wherein the FGFR mutant cholangiocarcinoma refers to any one or any combination of FGFR fusion cholangiocarcinoma, FGFR mutant cholangiocarcinoma, and FGFR overexpression cholangiocarcinoma.
  11. 如权利要求7所述的用途，其中所述FGFR变异的胆管癌是指FGFR2融合的胆管癌、FGFR2突变的胆管癌、和FGFR2过表达的胆管癌中的任何一种或其任何组合。The use according to claim 7, wherein the FGFR variant cholangiocarcinoma refers to any one or any combination of FGFR2 fusion cholangiocarcinoma, FGFR2 mutated cholangiocarcinoma, and FGFR2 overexpression cholangiocarcinoma.
  12. 如权利要求11所述的用途，其中所述FGFR2融合的胆管癌为FGFR2融合的肝内胆管癌。The use according to claim 11, wherein the FGFR2 fused cholangiocarcinoma is FGFR2 fused intrahepatic cholangiocarcinoma.
  13. 如权利要求1-4任一项所述的用途，其中所述的治疗胆管癌的药物，除了含有通式(I)所述的化合物或其药学上可接受的盐、异构 体，还含有药学上可接受的载体。The use according to any one of claims 1 to 4, wherein the drug for treating cholangiocarcinoma, in addition to containing the compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof, also contains A pharmaceutically acceptable carrier.
  14. 如权利要求1-4任一项所述的用途，其中所述的治疗胆管癌的药物，除了含有通式(I)所述的化合物或其药学上可接受的盐、异构体，还含有一种或多种第二治疗活性剂，所述的第二治疗活性剂为抗代谢物、生长因子抑制剂、有丝***抑制剂、抗肿瘤激素类、烷化剂类、金属铂类、拓扑异构酶抑制剂、激素药、免疫调节剂、肿瘤抑制基因、癌疫苗、免疫检查点抑制剂、肿瘤免疫治疗相关的抗体、肿瘤免疫治疗相关的小分子药物中的任何一种或其任何组合。The use according to any one of claims 1 to 4, wherein the drug for treating cholangiocarcinoma, in addition to containing the compound of general formula (I) or a pharmaceutically acceptable salt or isomer thereof, also contains One or more second therapeutically active agents, the second therapeutically active agents are antimetabolites, growth factor inhibitors, mitotic inhibitors, antitumor hormones, alkylating agents, metal platinums, topological isomers Any one or any combination of enzyme inhibitors, hormone drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoint inhibitors, tumor immunotherapy-related antibodies, tumor immunotherapy-related small molecule drugs.
  15. 如权利要求1-4任一项所述的用途，其中所述的哺乳动物是人类哺乳动物和/或动物类哺乳动物。The use according to any one of claims 1 to 4, wherein the mammal is a human mammal and/or an animal mammal.
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Publication number Priority date Publication date Assignee Title
CN107286130A (en) * 2016-04-13 2017-10-24 成都融科博海科技有限公司 A kind of Kinase Selectivity inhibitor
CN107793395A (en) * 2016-09-01 2018-03-13 南京药捷安康生物科技有限公司 Fibroblast growth factor acceptor inhibitor and application thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107286130A (en) * 2016-04-13 2017-10-24 成都融科博海科技有限公司 A kind of Kinase Selectivity inhibitor
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