New Uses of Multikinase Inhibitors

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to a novel use of a multikinase inhibitor. Specifically, it relates to a compound represented by formula (I) for treating biliary tract cancer, or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof, and a drug composition containing the same. It also relates to a method for treating biliary tract cancer using the same, a use for treating biliary tract cancer, and a use in manufacturing a drug for treating biliary tract cancer. The definitions of each variable in the above formula are as defined in the specification. Research results reveal that a multikinase inhibitor compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof has a therapeutic role against biliary tract cancer, and is considered to have very great potential for clinical application, particularly as it has a significant therapeutic role against cholangiocarcinoma.

Description

Technology Field

[0001] The present invention belongs to the field of pharmaceutical technology and, specifically, relates to a multi-kinase inhibitor compound for treating biliary tract cancer or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof, and relates to a method of treating biliary tract cancer using the pharmaceutical composition, a use for treating biliary tract cancer, and a use in manufacturing a drug for treating biliary tract cancer. Background Technology

[0002] Biliary tract cancer (BTC) is a malignant tumor originating from the epithelial cells of the biliary tract. Although it occurs relatively rarely in clinical practice and has a relatively low incidence rate, it has recently shown a gradually increasing trend. Early clinical symptoms are not specific, so in many cases, the disease is already in the terminal stage by the time of diagnosis. Depending on the anatomical location, it can be classified into cholangiocarcinoma (CCA) and gallbladder carcinoma (GBC).

[0003] Cholangiocarcinoma is a highly dysplastic malignant tumor formed within the bile ducts, accounting for 3% of all tumors of the digestive system. Cholangiocarcinoma can be classified into three types based on the anatomical location of the lesion: intrahepatic cholangiocarcinoma (iCC), perihilar cholangiocarcinoma (pCC), and distal cholangiocarcinoma (dCC). Here, intrahepatic cholangiocarcinoma is located within the liver parenchyma and accounts for approximately 10% to 20%, while hilar and distal cholangiocarcinomas both belong to extrahepatic cholangiocarcinoma and account for about 80% of cholangiocarcinomas (Rizvi, S., & Gores, GJ (2013). Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma. Gastroenterology, 145(6), 1215-1229). Cholangiocarcinoma has a very poor prognosis; patients initially have no specific clinical symptoms, and metastasis has typically already occurred by the time of diagnosis. Because cholangiocarcinoma exhibits significant resistance to chemotherapy, chemotherapy is typically used for palliative care, and generally, effective treatments are surgical resection and / or liver transplantation. Surgery is the primary treatment method for resecting cholangiocarcinoma, and postoperative survival is determined primarily by negative tumor margins, the absence of vascular invasion and lymphatic metastasis, and sufficient residual liver function. Since the majority of patients are already in the terminal stage of the disease at the time of diagnosis, recurrence is frequent, and the probability of recurrence within 2 to 3 years after surgical resection is approximately 49% to 64%. The survival rate 5 years after surgical resection is also very low, with 22% to 44% for intrahepatic cholangiocarcinoma, 11% to 41% for hilar cholangiocarcinoma, and 27% to 37% for distal cholangiocarcinoma.Due to causes such as local tumor invasion, peritoneal or distant metastasis, a lack of biliary reconstruction options, and an insufficient prediction of the residual liver after surgery, fewer than one-third of patients are given the opportunity to undergo resection surgery. For patients who are ineligible for resection, liver transplantation is an alternative treatment option. However, liver transplantation has very strict patient selection criteria and limited availability; even for eligible patients, the prognosis remains very poor and the recurrence rate is high, resulting in a survival rate of only 10–25%. Currently, the preferred treatment options for patients with unresectable or metastatic tumors include 1) clinical trials; 2) fluorouracil-based or gemcitabine-based chemotherapy; or 3) optimal supportive care.

[0004] The incidence and mortality rates of cholangiocarcinoma are on the rise every year. According to current research, the occurrence and treatment of cholangiocarcinoma may be associated with various targets.

[0005] The Fibroblast Growth Factor Receptor (FGFR) can regulate cell survival and proliferation, and many studies have already suggested that FGFR mutations are potential therapeutic targets for various tumors. FGFR2 fusions are one of the key causative factors for cholangiocarcinoma; the gene is commonly found in intrahepatic cholangiocarcinoma, accounting for approximately 15% of cases. In addition to FGFR fusion variants, a series of FGFR variants, such as FGFR2 N549H, FGFR2 V564F, FGFR3 K650E, and FGFR3 R248C, have also been found to be resistant to cholangiocarcinoma (Shiao MS, Chiablaem K, Charoensawan V et al. Emergence of Intrahepatic Cholangiocarcinoma: How High-Throughput Technologies Expedite the Solutions for a Rare Cancer Type. Frontiers in Genetics. 2018;9:309.).

[0006] The Janus kinase / signal transducer and transcriptional activator (JAK / STAT) pathway can participate in cancer cell proliferation and regulate the tumor microenvironment via IL6 (Labib PL, Goodchild G, Pereira SP. Molecular Pathogenesis of Cholangiocarcinoma. BMC Cancer. 2019;19(1):185). It has already been reported that constitutive phosphorylation of STAT3 was observed in human cholangiocarcinoma cell lines with seven different genetic characteristics, confirming that the negative feedback loop of the IL-6 / JAK / STAT3 pathway is epigenetically silencing in cholangiocarcinoma cells, leading to sustained signaling (Isomoto H, Mott JL, Kobayashi S, et al. Sustained IL-6 / STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology. 2007;132(1):384-396).

[0007] The expression of Aurora kinase A (Aurora A) can also be upregulated in cholangiocarcinoma and is associated with relatively low progression-free survival and overall survival (Ding X, Huang T, Ahn KS et al. Su1459 - Aurora Kinase A Sustains Cholangiocarcinoma Proliferation and Represents a New Therapeutic Target. Gastroenterology. 2018;154(6):S-1153). WO2018108079A1 discloses a multi-kinase inhibitor compound that can produce an anti-tumor effect by inhibiting, regulating, and / or controlling the activity of one or more protein kinases, such as Aurora kinase and VEGFR kinase.

[0008] In conclusion, the optimal adjuvant therapy strategy following surgery for cholangiocarcinoma remains uncertain, and clinical results supporting standard adjuvant therapy are very limited. Although clinical studies on targeted inhibitors for cholangiocarcinoma are currently underway, there are still many patients without FGFR variants, and effective targeted therapy is in urgent need. Consequently, there is a significant unmet clinical need for FGFR variant, non-FGFR variant, and wild-type FGFR cholangiocarcinoma, making the development of effective targeted agents for cholangiocarcinoma an urgent clinical requirement.

[0009] 1. Brief Description of the Invention

[0010] The present invention investigated new uses in the field of cancer for a multikinase inhibitor compound represented by the following formula (I) or its pharmaceutically acceptable salts, stereoisomers, and crystalline forms. As a result of the research, it was discovered that the multikinase inhibitor compound represented by formula (I) or its pharmaceutically acceptable salts, stereoisomers, and crystalline forms have a therapeutic role against biliary tract cancer, and in particular, exhibit a very significant therapeutic effect against cholangiocarcinoma.

[0011] Accordingly, the object of the present invention is to provide a new use for treating biliary tract cancer of a multikinase inhibitor compound represented by formula (I) or its pharmaceutically acceptable salts, stereoisomers, and crystalline forms.

[0012] Accordingly, in the first aspect of the present invention, a use is provided for preparing a drug for treating biliary tract cancer in the form of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof.

[0013]

[0014] Here, Ar is a phenyl group optionally substituted by 1 to 3 R6s, and each R6 is independently hydrogen, amino, cyano, halogen, C1-4 Selected from alkyl groups and trifluoromethyl;

[0015] Y is CR3 and;

[0016] P is CR4 and;

[0017] W is N and;

[0018] R3 is hydrogen and C 1-4 Selected from alkyl groups;

[0019] R4 is -(CH2) n -(5-11) It is a heterocyclic ring, wherein n=0~6, the ring-forming S atoms of the heterocyclic ring are optionally oxidized to S(O) or S(O)2, the ring-forming C atoms are optionally oxidized to C(O), and the heterocyclic ring is optionally one to a number of C atoms 1-3 Alkyl group and C 3-6 It is substituted by a substituent independently selected from the cycloalkyl group.

[0020] In a second aspect of the present invention, a compound represented by formula (I) or its pharmaceutically acceptable salts, stereoisomers, and crystalline forms are provided for use in treating biliary tract cancer.

[0021]

[0022] Here, the definition of each variable in the above equation (I) is as defined above.

[0023] In a third aspect of the present invention, a compound represented by formula (I) for treating biliary tract cancer, or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof is provided,

[0024]

[0025] Here, the definition of each variable in the above equation (I) is as defined above.

[0026] In a fourth aspect of the present invention, a method for treating biliary tract cancer is provided, wherein the method comprises administering a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof to a patient in need.

[0027]

[0028] Here, the definition of each variable in the above equation (I) is as defined above.

[0029] In a fifth aspect of the present invention, a pharmaceutical composition for treating biliary tract cancer is provided, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof, and optionally comprises a pharmaceutically acceptable vector (carrier).

[0030]

[0031] Here, the definition of each variable in the above equation (I) is as defined above. Specific details for implementing the invention

[0032] 2. Detailed Description of the Invention

[0033] As described above, the first aspect of the present invention provides a use in manufacturing a drug for treating biliary tract cancer in the form of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof.

[0034]

[0035] Here, the definition of each variable in the above equation (I) is as defined above.

[0036] In one embodiment, Ar is a phenyl group optionally substituted by 1 to 3 R6s, each R6 being independently selected from hydrogen and halogen;

[0037] Y is CR3 and;

[0038] P is CR4 and;

[0039] W is N and;

[0040] R3 is hydrogen;

[0041] R4 is -(CH2) n -(5-6) One single heterocycle and -(CH2) n -(7-11) Selected from a condensed heterocyclic ring, where n=0~6, the ring-forming S atom of the heterocyclic ring is optionally oxidized to S(O) or S(O)2, the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic ring is optionally one to a number of C atoms. 1-3 Alkyl group and C 3-6 It is substituted by a substituent independently selected from the cycloalkyl group.

[0042] In a specific embodiment, the (5-6)-membered single heterocyclic group is a (5-6)-membered saturated single heterocyclic group, and the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated heterocyclic group. In a preferred embodiment, the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated ortho-condensed heterocyclic group, a (7-11)-membered saturated spiro-heterocyclic group, or a (7-11)-membered saturated bridge-heterocyclic group.

[0043] In one embodiment, the (5-11) original heterocycle is

[0044]

[0045]

[0046] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups. In a preferred embodiment, the (5-11)-membered heterocyclic group is

[0047] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups.

[0048] In one embodiment, the compound of formula (I) is the compound shown in Table 1 or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0049] Table 1. Compounds of the present invention

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] In a preferred embodiment, the compound of formula (I) is Or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0057] In one embodiment, the biliary system cancer refers to cholangiocarcinoma.

[0058] In a specific embodiment, the cholangiocarcinoma refers to cholangiocarcinoma mediated by FGFR. In a preferred embodiment, the cholangiocarcinoma mediated by FGFR refers to cholangiocarcinoma mediated by any one of FGFR1, FGFR2, FGFR3, or a combination thereof.

[0059] In another specific embodiment, the cholangiocarcinoma refers to non-FGFR variant cholangiocarcinoma. In a preferred embodiment, the non-FGFR variant cholangiocarcinoma refers to non-FGFR2 variant cholangiocarcinoma.

[0060] In another specific embodiment, the cholangiocarcinoma refers to FGFR variant cholangiocarcinoma. In a preferred embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 and / or FGFR3 variant cholangiocarcinoma.

[0061] In a more specific embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR fusion, FGFR mutation, and FGFR overexpression. Here, FGFR mutation includes FGFR point mutations and FGFR insertion / deletion mutations.

[0062] In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 fusion, FGFR2 and / or FGFR3 mutation, and FGFR overexpression. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 and / or FGFR3 mutation. In yet another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 N549H, FGFR2 V564F, and FGFR3 K650E.

[0063] In another specific embodiment, the cholangiocarcinoma refers to a resistant cholangiocarcinoma that is positive for FGFR mutations but does not respond to an FGFR inhibitor, or refers to a resistant cholangiocarcinoma after use of an FGFR inhibitor. In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having resistance to FGFR2 and / or FGFR3 mutations.

[0064] In another specific embodiment, the cholangiocarcinoma refers to any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma, or a combination thereof. In a preferred embodiment, the cholangiocarcinoma refers to hilar cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to distal cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to FGFR2 variant intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to intrahepatic cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to non-FGFR variant intrahepatic cholangiocarcinoma.

[0065] In one embodiment, the cholangiocarcinoma further comprises cholangiocarcinoma mediated by other mechanisms, including cholangiocarcinoma mediated by Orona kinase and cholangiocarcinoma caused by an abnormality in the JAK-STAT signaling pathway mediated by IL-6.

[0066] In one embodiment, the drug for treating the biliary tract cancer may contain, in addition to containing the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form, also contain a pharmaceutically acceptable vector.

[0067] In one embodiment, the drug may comprise one or more pharmaceutically acceptable vectors and may be administered to patients or subjects requiring such therapeutic regimens in a manner such as oral administration, extraoral administration, rectal administration, or transpulmonary administration. When used for oral administration, the pharmaceutical composition may be prepared as a general solid formulation such as tablets, capsules, pellets, granules, etc.; or it may also be prepared as an oral liquid formulation such as an oral liquid, oral suspension, syrup, etc. When prepared as an oral formulation, appropriate amounts of fillers, thickeners, disintegrants, lubricants, etc. may be added. When used for extraoral administration, the pharmaceutical composition may be prepared as an injectable solution, an injectable sterile powder, and an injectable concentrate. When preparing the injectable, conventional methods in the existing pharmaceutical field may be chosen, and when formulating the injectable, additives may not be added, or appropriate additives may be added depending on the properties of the drug. When used for rectal administration, the pharmaceutical composition may be manufactured as a suppository, etc. When used for intrapulmonary administration, the pharmaceutical composition may be manufactured as an inhaler or nebulizer, etc.

[0068] In one embodiment, the drug for treating biliary tract cancer contains, in addition to containing a compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form, one or more second therapeutic agents.

[0069] In a specific embodiment, the second therapeutic active agent is a metabolic antagonist, a growth factor inhibitor, a mitotic inhibitor, an anticancer hormone, an alkylating agent, a metal platinum, a toxin isomerase inhibitor, a hormone, an immunomodulator, a tumor suppressor gene, a cancer vaccine, or an immune checkpoint inhibitor.

[0070] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by choosing a method of co-administration with a second therapeutic activator.

[0071] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by adopting a method of administering it in sequence or simultaneously with a second therapeutic agent or by preparing a complex formulation.

[0072] In a specific embodiment, the patient or subject refers to a mammal. In a preferred embodiment, the patient or subject refers to a human.

[0073] In a second aspect of the present invention, a compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is provided for use in treating biliary tract cancer.

[0074]

[0075] Here, the definition of each variable in the above equation (I) is as defined above.

[0076] In one embodiment, Ar is a phenyl group optionally substituted by 1 to 3 R6s, each R6 being independently selected from hydrogen and halogen;

[0077] Y is CR3 and;

[0078] P is CR4 and;

[0079] W is N and;

[0080] R3 is hydrogen;

[0081] R4 is -(CH2) n -(5-6) One single heterocycle and -(CH2) n-(7-11) Selected from a condensed heterocyclic ring, where n=0~6, the ring-forming S atom of the heterocyclic ring is optionally oxidized to S(O) or S(O)2, the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic ring is optionally one to a number of C atoms. 1-3 Alkyl group and C 3-6 It is substituted by a substituent independently selected from the cycloalkyl group.

[0082] In a specific embodiment, the (5-6)-membered single heterocyclic group is a (5-6)-membered saturated single heterocyclic group, and the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated heterocyclic group. In a preferred embodiment, the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated ortho-condensed heterocyclic group, a (7-11)-membered saturated spiro-heterocyclic group, or a (7-11)-membered saturated bridge-heterocyclic group.

[0083] In one embodiment, the (5-11) original heterocycle is

[0084]

[0085]

[0086] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups. In a preferred embodiment, the (5-11)-membered heterocyclic group is

[0087] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups.

[0088] In one embodiment, the compound of formula (I) is the compound shown in Table 1 or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0089] In a preferred embodiment, the compound of formula (I) is Or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0090] In one embodiment, the biliary system cancer refers to cholangiocarcinoma.

[0091] In a specific embodiment, the cholangiocarcinoma refers to cholangiocarcinoma mediated by FGFR. In a preferred embodiment, the cholangiocarcinoma mediated by FGFR refers to cholangiocarcinoma mediated by any one of FGFR1, FGFR2, FGFR3, or a combination thereof.

[0092] In another specific embodiment, the cholangiocarcinoma refers to non-FGFR variant cholangiocarcinoma. In a preferred embodiment, the non-FGFR variant cholangiocarcinoma refers to non-FGFR2 variant cholangiocarcinoma.

[0093] In another specific embodiment, the cholangiocarcinoma refers to FGFR variant cholangiocarcinoma. In a preferred embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 and / or FGFR3 variant cholangiocarcinoma.

[0094] In a more specific embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR fusion, FGFR mutation, and FGFR overexpression. Here, FGFR mutation includes FGFR point mutations and FGFR insertion / deletion mutations.

[0095] In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 fusion, FGFR2 and / or FGFR3 mutation, and FGFR overexpression. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 and / or FGFR3 mutation. In yet another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 N549H, FGFR2 V564F, and FGFR3 K650E.

[0096] In another specific embodiment, the cholangiocarcinoma refers to a resistant cholangiocarcinoma that is positive for FGFR mutations but does not respond to an FGFR inhibitor, or refers to a resistant cholangiocarcinoma after use of an FGFR inhibitor. In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having resistance to FGFR2 and / or FGFR3 mutations.

[0097] In another specific embodiment, the cholangiocarcinoma refers to any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma, or a combination thereof. In a preferred embodiment, the cholangiocarcinoma refers to hilar cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to distal cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to FGFR2 variant intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to intrahepatic cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to non-FGFR variant intrahepatic cholangiocarcinoma.

[0098] In one embodiment, the cholangiocarcinoma further comprises cholangiocarcinoma mediated by other mechanisms, including cholangiocarcinoma mediated by Orona kinase and cholangiocarcinoma caused by an abnormality in the JAK-STAT signaling pathway mediated by IL-6.

[0099] In one embodiment, the use comprises administering a therapeutically effective amount of the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form to a patient or test subject who requires it.

[0100] In one embodiment, a therapeutically effective amount of the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form may also be prepared into any pharmaceutically acceptable drug formulation with one or more pharmaceutically acceptable vectors.

[0101] In one embodiment, the drug formulation may comprise one or more pharmaceutically acceptable vectors and may be administered to patients or subjects requiring such therapeutic regimens via oral administration, extraoral administration, rectal administration, or transpulmonary administration. When used for oral administration, the pharmaceutical composition may be prepared as a general solid formulation such as tablets, capsules, pellets, granules, etc.; or it may also be prepared as an oral liquid formulation such as an oral liquid, oral suspension, syrup, etc. When prepared as an oral formulation, appropriate amounts of fillers, thickeners, disintegrants, lubricants, etc. may be added. When used for extraoral administration, the pharmaceutical composition may be prepared as an injectable solution, an injectable sterile powder, and an injectable concentrate. When preparing the injectable, conventional methods in the pharmaceutical field may be chosen, and when formulating the injectable, additives may not be added, or appropriate additives may be added depending on the properties of the drug. When used for rectal administration, the pharmaceutical composition may be manufactured as a suppository, etc. When used for intrapulmonary administration, the pharmaceutical composition may be manufactured as an inhaler or nebulizer, etc.

[0102] In one embodiment, the use further comprises administering a therapeutically effective amount of the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form and one or more second therapeutic agents to a patient or test subject who requires it.

[0103] In a specific embodiment, the second therapeutic active agent is a metabolic antagonist, a growth factor inhibitor, a mitotic inhibitor, an anticancer hormone, an alkylating agent, a metal platinum, a toxin isomerase inhibitor, a hormone, an immunomodulator, a tumor suppressor gene, a cancer vaccine, or an immune checkpoint inhibitor.

[0104] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by choosing a method of co-administration with a second therapeutic activator.

[0105] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by adopting a method of administering it in sequence or simultaneously with a second therapeutic agent or by preparing a complex formulation.

[0106] In a specific embodiment, the patient or subject refers to a mammal. In a preferred embodiment, the patient or subject refers to a human.

[0107] In a third aspect of the present invention, a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof is provided for treating biliary tract cancer.

[0108]

[0109] Here, the definition of each variable in the above equation (I) is as defined above.

[0110] In one embodiment, Ar is a phenyl group optionally substituted by 1 to 3 R6s, each R6 being independently selected from hydrogen and halogen;

[0111] Y is CR3 and;

[0112] P is CR4 and;

[0113] W is N and;

[0114] R3 is hydrogen;

[0115] R4 is -(CH2) n -(5-6) One single heterocycle and -(CH2) n-(7-11) Selected from a condensed heterocyclic ring, where n=0~6, the ring-forming S atom of the heterocyclic ring is optionally oxidized to S(O) or S(O)2, the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic ring is optionally one to a number of C atoms. 1-3 Alkyl group and C 3-6 It is substituted by a substituent independently selected from the cycloalkyl group.

[0116] In a specific embodiment, the (5-6)-membered single heterocyclic group is a (5-6)-membered saturated single heterocyclic group, and the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated heterocyclic group. In a preferred embodiment, the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated ortho-condensed heterocyclic group, a (7-11)-membered saturated spiro-heterocyclic group, or a (7-11)-membered saturated bridge-heterocyclic group.

[0117] In one embodiment, the (5-11) original heterocycle is

[0118]

[0119]

[0120] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups. In a preferred embodiment, the (5-11)-membered heterocyclic group is

[0121] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups.

[0122] In one embodiment, the compound of formula (I) is the compound shown in Table 1 or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0123] In a preferred embodiment, the compound of formula (I) is Or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0124] In one embodiment, the biliary system cancer refers to cholangiocarcinoma.

[0125] In a specific embodiment, the cholangiocarcinoma refers to cholangiocarcinoma mediated by FGFR. In a preferred embodiment, the cholangiocarcinoma mediated by FGFR refers to cholangiocarcinoma mediated by any one of FGFR1, FGFR2, FGFR3, or a combination thereof.

[0126] In another specific embodiment, the cholangiocarcinoma refers to non-FGFR variant cholangiocarcinoma. In a preferred embodiment, the non-FGFR variant cholangiocarcinoma refers to non-FGFR2 variant cholangiocarcinoma.

[0127] In another specific embodiment, the cholangiocarcinoma refers to FGFR variant cholangiocarcinoma. In a preferred embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 and / or FGFR3 variant cholangiocarcinoma.

[0128] In a more specific embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR fusion, FGFR mutation, and FGFR overexpression. Here, FGFR mutation includes FGFR point mutations and FGFR insertion / deletion mutations.

[0129] In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 fusion, FGFR2 and / or FGFR3 mutation, and FGFR overexpression. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 and / or FGFR3 mutation. In yet another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 N549H, FGFR2 V564F, and FGFR3 K650E.

[0130] In another specific embodiment, the cholangiocarcinoma refers to a resistant cholangiocarcinoma that is positive for FGFR mutations but does not respond to an FGFR inhibitor, or refers to a resistant cholangiocarcinoma after use of an FGFR inhibitor. In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having resistance to FGFR2 and / or FGFR3 mutations.

[0131] In another specific embodiment, the cholangiocarcinoma refers to any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma, or a combination thereof. In a preferred embodiment, the cholangiocarcinoma refers to hilar cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to distal cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to FGFR2 variant intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to intrahepatic cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to non-FGFR variant intrahepatic cholangiocarcinoma.

[0132] In one embodiment, the cholangiocarcinoma further comprises cholangiocarcinoma mediated by other mechanisms, including cholangiocarcinoma mediated by Orona kinase and cholangiocarcinoma caused by an abnormality in the JAK-STAT signaling pathway mediated by IL-6.

[0133] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject who requires it in a therapeutically effective amount.

[0134] In one embodiment, a therapeutically effective amount of the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form may also be prepared into any pharmaceutically acceptable drug formulation with one or more pharmaceutically acceptable vectors.

[0135] In one embodiment, the drug formulation may comprise one or more pharmaceutically acceptable vectors and may be administered to patients or subjects requiring such therapeutic regimens via oral administration, extraoral administration, rectal administration, or transpulmonary administration. When used for oral administration, the pharmaceutical composition may be prepared as a general solid formulation such as tablets, capsules, pellets, granules, etc.; or it may also be prepared as an oral liquid formulation such as an oral liquid, oral suspension, syrup, etc. When prepared as an oral formulation, appropriate amounts of fillers, thickeners, disintegrants, lubricants, etc. may be added. When used for extraoral administration, the pharmaceutical composition may be prepared as an injectable solution, an injectable sterile powder, and an injectable concentrate. When preparing the injectable, conventional methods in the pharmaceutical field may be chosen, and when formulating the injectable, additives may not be added, or appropriate additives may be added depending on the properties of the drug. When used for rectal administration, the pharmaceutical composition may be manufactured as a suppository, etc. When used for intrapulmonary administration, the pharmaceutical composition may be manufactured as an inhaler or nebulizer, etc.

[0136] In one embodiment, a therapeutically effective amount of the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form may also be combined with one or more second therapeutic agents and administered to a patient or test subject who requires it.

[0137] In a specific embodiment, the second therapeutic active agent is a metabolic antagonist, a growth factor inhibitor, a mitotic inhibitor, an anticancer hormone, an alkylating agent, a metal platinum, a toxin isomerase inhibitor, a hormone, an immunomodulator, a tumor suppressor gene, a cancer vaccine, or an immune checkpoint inhibitor.

[0138] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by choosing a method of co-administration with a second therapeutic activator.

[0139] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by adopting a method of administering it in sequence or simultaneously with a second therapeutic agent or by preparing a complex formulation.

[0140] In a specific embodiment, the patient or subject refers to a mammal. In a preferred embodiment, the patient or subject refers to a human.

[0141] A fourth aspect of the present invention provides a method for treating biliary tract cancer, wherein the method comprises administering a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof to a patient in need thereof.

[0142]

[0143] Here, the definition of each variable in the above equation (I) is as defined above.

[0144] In one embodiment, Ar is a phenyl group optionally substituted by 1 to 3 R6s, each R6 being independently selected from hydrogen and halogen;

[0145] Y is CR3 and;

[0146] P is CR4 and;

[0147] W is N and;

[0148] R3 is hydrogen;

[0149] R4 is -(CH2) n -(5-6) One single heterocycle and -(CH2) n-(7-11) Selected from a condensed heterocyclic ring, where n=0~6, the ring-forming S atom of the heterocyclic ring is optionally oxidized to S(O) or S(O)2, the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic ring is optionally one to a number of C atoms. 1-3 Alkyl group and C 3-6 It is substituted by a substituent independently selected from the cycloalkyl group.

[0150] In a specific embodiment, the (5-6)-membered single heterocyclic group is a (5-6)-membered saturated single heterocyclic group, and the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated heterocyclic group. In a preferred embodiment, the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated ortho-condensed heterocyclic group, a (7-11)-membered saturated spiro-heterocyclic group, or a (7-11)-membered saturated bridge-heterocyclic group.

[0151] In one embodiment, the (5-11) original heterocycle is

[0152]

[0153]

[0154] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups. In a preferred embodiment, the (5-11)-membered heterocyclic group is

[0155] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups.

[0156] In one embodiment, the compound of formula (I) is the compound shown in Table 1 or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0157] In a preferred embodiment, the compound of formula (I) is Or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0158] In one embodiment, the biliary system cancer refers to cholangiocarcinoma.

[0159] In a specific embodiment, the cholangiocarcinoma refers to cholangiocarcinoma mediated by FGFR. In a preferred embodiment, the cholangiocarcinoma mediated by FGFR refers to cholangiocarcinoma mediated by any one of FGFR1, FGFR2, FGFR3, or a combination thereof.

[0160] In another specific embodiment, the cholangiocarcinoma refers to non-FGFR variant cholangiocarcinoma. In a preferred embodiment, the non-FGFR variant cholangiocarcinoma refers to non-FGFR2 variant cholangiocarcinoma.

[0161] In another specific embodiment, the cholangiocarcinoma refers to FGFR variant cholangiocarcinoma. In a preferred embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 and / or FGFR3 variant cholangiocarcinoma.

[0162] In a more specific embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR fusion, FGFR mutation, and FGFR overexpression. Here, FGFR mutation includes FGFR point mutations and FGFR insertion / deletion mutations.

[0163] In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 fusion, FGFR2 and / or FGFR3 mutation, and FGFR overexpression. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 and / or FGFR3 mutation. In yet another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 N549H, FGFR2 V564F, and FGFR3 K650E.

[0164] In another specific embodiment, the cholangiocarcinoma refers to a resistant cholangiocarcinoma that is positive for FGFR mutations but does not respond to an FGFR inhibitor, or refers to a resistant cholangiocarcinoma after use of an FGFR inhibitor. In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having resistance to FGFR2 and / or FGFR3 mutations.

[0165] In another specific embodiment, the cholangiocarcinoma refers to any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma, or a combination thereof. In a preferred embodiment, the cholangiocarcinoma refers to hilar cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to distal cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to FGFR2 variant intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to intrahepatic cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to non-FGFR variant intrahepatic cholangiocarcinoma.

[0166] In one embodiment, the cholangiocarcinoma further comprises cholangiocarcinoma mediated by other mechanisms, including cholangiocarcinoma mediated by Orona kinase and cholangiocarcinoma caused by an abnormality in the JAK-STAT signaling pathway mediated by IL-6.

[0167] In one embodiment, the therapeutically effective amount of the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form may also be prepared into any pharmaceutically acceptable drug formulation with one or more pharmaceutically acceptable vectors.

[0168] In one embodiment, the drug formulation may comprise one or more pharmaceutically acceptable vectors and may be administered to patients or subjects requiring such therapeutic regimens via oral administration, extraoral administration, rectal administration, or transpulmonary administration. When used for oral administration, the pharmaceutical composition may be prepared as a general solid formulation such as tablets, capsules, pellets, granules, etc.; or it may also be prepared as an oral liquid formulation such as an oral liquid, oral suspension, syrup, etc. When prepared as an oral formulation, appropriate amounts of fillers, thickeners, disintegrants, lubricants, etc. may be added. When used for extraoral administration, the pharmaceutical composition may be prepared as an injectable solution, an injectable sterile powder, and an injectable concentrate. When preparing the injectable, conventional methods in the pharmaceutical field may be chosen, and when formulating the injectable, additives may not be added, or appropriate additives may be added depending on the properties of the drug. When used for rectal administration, the pharmaceutical composition may be manufactured as a suppository, etc. When used for intrapulmonary administration, the pharmaceutical composition may be manufactured as an inhaler or nebulizer, etc.

[0169] In one embodiment, the method further comprises administering a therapeutically effective amount of a compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form and one or more second therapeutic agents to a patient or test subject who requires them.

[0170] In a specific embodiment, the second therapeutic active agent is a metabolic antagonist, a growth factor inhibitor, a mitotic inhibitor, an anticancer hormone, an alkylating agent, a metal platinum, a toxin isomerase inhibitor, a hormone, an immunomodulator, a tumor suppressor gene, a cancer vaccine, or an immune checkpoint inhibitor.

[0171] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by choosing a method of co-administration with a second therapeutic activator.

[0172] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by adopting a method of administering it in sequence or simultaneously with a second therapeutic agent or by preparing a complex formulation.

[0173] In a specific embodiment, the patient or subject refers to a mammal. In a preferred embodiment, the patient or subject refers to a human.

[0174] In a fifth aspect of the present invention, a pharmaceutical composition for treating biliary tract cancer is provided, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, or crystalline form thereof, and optionally comprises a pharmaceutically acceptable vector.

[0175]

[0176] Here, the definition of each variable in the above equation (I) is as defined above.

[0177] In one embodiment, Ar is a phenyl group optionally substituted by 1 to 3 R6s, each R6 being independently selected from hydrogen and halogen;

[0178] Y is CR3 and;

[0179] P is CR4 and;

[0180] W is N and;

[0181] R3 is hydrogen;

[0182] R4 is -(CH2) n -(5-6) One single heterocycle and -(CH2) n -(7-11) Selected from a condensed heterocyclic ring, where n=0~6, the ring-forming S atom of the heterocyclic ring is optionally oxidized to S(O) or S(O)2, the ring-forming C atom is optionally oxidized to C(O), and the heterocyclic ring is optionally one to a number of C atoms. 1-3 Alkyl group and C 3-6 It is substituted by a substituent independently selected from the cycloalkyl group.

[0183] In a specific embodiment, the (5-6)-membered single heterocyclic group is a (5-6)-membered saturated single heterocyclic group, and the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated heterocyclic group. In a preferred embodiment, the (7-11)-membered condensed heterocyclic group is a (7-11)-membered saturated ortho-condensed heterocyclic group, a (7-11)-membered saturated spiro-heterocyclic group, or a (7-11)-membered saturated bridge-heterocyclic group.

[0184] In one embodiment, the (5-11) original heterocycle is

[0185]

[0186]

[0187] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups. In a preferred embodiment, the (5-11)-membered heterocyclic group is

[0188] and, n=0~3, where the above heterocycle is optionally one to a number of independently C 1-3 Alkyl group and C 3-6 It is substituted by a substituent selected from cycloalkyl groups.

[0189] In one embodiment, the compound of formula (I) is the compound shown in Table 1 or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0190] In a preferred embodiment, the compound of formula (I) is Or its pharmaceutically acceptable salt, stereoisomer, or crystalline form.

[0191] In one embodiment, the biliary system cancer refers to cholangiocarcinoma.

[0192] In a specific embodiment, the cholangiocarcinoma refers to cholangiocarcinoma mediated by FGFR. In a preferred embodiment, the cholangiocarcinoma mediated by FGFR refers to cholangiocarcinoma mediated by any one of FGFR1, FGFR2, FGFR3, or a combination thereof.

[0193] In another specific embodiment, the cholangiocarcinoma refers to non-FGFR variant cholangiocarcinoma. In a preferred embodiment, the non-FGFR variant cholangiocarcinoma refers to non-FGFR2 variant cholangiocarcinoma.

[0194] In another specific embodiment, the cholangiocarcinoma refers to FGFR variant cholangiocarcinoma. In a preferred embodiment, the FGFR variant cholangiocarcinoma refers to FGFR2 and / or FGFR3 variant cholangiocarcinoma.

[0195] In a more specific embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR fusion, FGFR mutation, and FGFR overexpression. Here, FGFR mutation includes FGFR point mutations and FGFR insertion / deletion mutations.

[0196] In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 fusion, FGFR2 and / or FGFR3 mutation, and FGFR overexpression. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having FGFR2 and / or FGFR3 mutation. In yet another preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having any one or a combination of FGFR2 N549H, FGFR2 V564F, and FGFR3 K650E.

[0197] In another specific embodiment, the cholangiocarcinoma refers to a resistant cholangiocarcinoma that is positive for FGFR mutations but does not respond to an FGFR inhibitor, or refers to a resistant cholangiocarcinoma after use of an FGFR inhibitor. In a preferred embodiment, the cholangiocarcinoma refers to a cholangiocarcinoma having resistance to FGFR2 and / or FGFR3 mutations.

[0198] In another specific embodiment, the cholangiocarcinoma refers to any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma, or a combination thereof. In a preferred embodiment, the cholangiocarcinoma refers to hilar cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to distal cholangiocarcinoma. In a preferred embodiment, the cholangiocarcinoma refers to intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to FGFR2 variant intrahepatic cholangiocarcinoma. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to intrahepatic cholangiocarcinoma having FGFR2 fusion. In another preferred embodiment, the intrahepatic cholangiocarcinoma refers to non-FGFR variant intrahepatic cholangiocarcinoma.

[0199] In one embodiment, the cholangiocarcinoma further comprises cholangiocarcinoma mediated by other mechanisms, including cholangiocarcinoma mediated by Orona kinase and cholangiocarcinoma caused by an abnormality in the JAK-STAT signaling pathway mediated by IL-6.

[0200] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form may also be prepared into any pharmaceutically acceptable drug formulation with one or more pharmaceutically acceptable vectors.

[0201] In one embodiment, the drug formulation may comprise one or more pharmaceutically acceptable vectors and may be administered to patients or subjects requiring such therapeutic regimens via oral administration, extraoral administration, rectal administration, or transpulmonary administration. When used for oral administration, the pharmaceutical composition may be prepared as a general solid formulation such as tablets, capsules, pellets, granules, etc.; or as an oral liquid formulation such as an oral liquid, oral suspension, syrup, etc. When prepared as an oral formulation, appropriate amounts of fillers, thickeners, disintegrants, lubricants, etc. may be added. When used for parenteral administration, the pharmaceutical composition may be prepared as an injectable formulation comprising an injectable solution, an injectable sterile powder, and an injectable concentrate. When preparing the injectable formulation, conventional methods in the existing pharmaceutical field may be chosen, and when formulating the injectable formulation, additives may not be added, or appropriate additives may be added depending on the properties of the drug. When used for rectal administration, the above pharmaceutical composition may be manufactured as a suppository, etc. When used for intrapulmonary administration, the above pharmaceutical composition may be manufactured as an inhaler or a nebulizer, etc.

[0202] In one embodiment, the pharmaceutical composition further comprises one or more second therapeutic active agents.

[0203] In a specific embodiment, the second therapeutic active agent is a metabolic antagonist, a growth factor inhibitor, a mitotic inhibitor, an anticancer hormone, an alkylating agent, a metal platinum, a toxin isomerase inhibitor, a hormone, an immunomodulator, a tumor suppressor gene, a cancer vaccine, or an immune checkpoint inhibitor.

[0204] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by choosing a method of co-administration with a second therapeutic activator.

[0205] In one embodiment, the compound represented by formula (I) or its pharmaceutically acceptable salt, stereoisomer, or crystalline form is administered to a patient or test subject requiring treatment by adopting a method of administering it in sequence or simultaneously with a second therapeutic agent or by preparing a complex formulation.

[0206] In a specific embodiment, the patient or subject refers to a mammal. In a preferred embodiment, the patient or subject refers to a human.

[0207] 3. Definition

[0208] The term "halogen" as used in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.

[0209] "Halogenation" as used in the present invention refers to the substitution of any one hydrogen atom among the substituents by one or more identical or unequal halogens. "Halogen" is as defined above.

[0210] The term "cyano group" as used in the present invention refers to the -CN atomic group.

[0211] The "amino group" referred to in the present invention refers to an -NH2 atomic group.

[0212] "C" as referred to in the present invention 1-4 "Alkyl group" refers to a straight-chain or branched-chain alkyl group derived by removing one hydrogen atom from a hydrocarbon portion containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc. The above "C 1-3 "Alkyl group" refers to the alkyl group containing 1 to 3 carbon atoms.

[0213] "C" as referred to in the present invention 3-6"Cycloalkyl group" refers to a monocyclic cycloalkyl group, a dicyclic cycloalkyl group system, or a polycyclic cycloalkyl group system containing 3 to 6 carbon atoms. Such groups may be saturated but are not aromatic. Unless otherwise described, it includes all possible monocyclic and condensed ring structures. Examples include, but are not limited to, cyclopropane, cyclobutane, cyclopentyl, cyclohexyl, bicyclo[2.2.2]hexane, and bicyclo[3.2.1]hexane.

[0214] The "5-11 heterocyclic group" referred to in the present invention refers to a non-directional cyclic atomic group having 5 to 11 cyclic carbon atoms, wherein at least one cyclocarbon is substituted by one or more heteroatoms selected from O, S, and N (preferably 1 to 3 heteroatoms), and at the same time, the cyclic atoms including carbon atoms, nitrogen atoms and sulfur atoms may be oxidized.

[0215] The above "heterocyclic group" refers to a monocyclic heterocyclic group, a bicyclic heterocyclic system, or a polycyclic heterocyclic system, and includes saturated or partially saturated heterocyclic groups, but excludes directional groups. The "5-11-membered heterocyclic group" referred to in the present invention includes all possible monocyclic and condensed ring structures unless otherwise described.

[0216] The above single heterocyclic ring may be a 5-7-membered heterocyclic ring, a 5-6-membered heterocyclic ring, a 5-6-membered oxygen-containing heterocyclic ring, a 5-6-membered nitrogen-containing heterocyclic ring, a 5-6-membered saturated heterocyclic ring, etc. Examples of the 5-6 single heterocyclic groups referred to in the present invention include tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyrranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathiolanil, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, Includes, but not limited to, 2,3-dihydro-1H-pyrrolil, 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-pyranil, 4H-pyranil, 2H-thiopyranill, 4H-thiopyranill, 2,3,4,5-tetrahydropyridyl, 1,2-isoxazine, 1,4-isoxazine or 6H-1,3-oxazine.

[0217] The above condensation heterocycle includes ortho-condensation heterocycles, spiro heterocycles, and bridge heterocycles, and may be saturated, partially saturated, or unsaturated, but does not have directionality. The 7-11 condensation heterocycle referred to in the present invention includes all formable ortho-condensation, spiro, and bridge structures unless otherwise described.

[0218] The above ortho-condensed heterocyclic group may be a 7-11-membered ortho-condensed ring group, preferably a 7-11-membered saturated ortho-condensed ring group, examples thereof include 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrole, octahydropyrrolo[3,4-b]pyrrole, octahydropyrrolo[3,4-b][1,4]oxazine, octahydro-1H-pyrrolo[3,4-c]pyridine, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indoline-1-yl, indoline-2-yl, indoline-3-yl, Includes, but not limited to, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indolyl, and octahydrobenzofuranyl.

[0219] The above spiro heterocycle may be a 7-11-membered spiro heterocycle, preferably a 7-11-membered saturated spiro heterocycle, and examples thereof include

[0220]

[0221] Includes, but is not limited to.

[0222] The above bridge heterocycle may be a 7-11 member bridge heterocycle, preferably a 7-11 member saturated bridge heterocycle, and examples thereof include

[0223]

[0224] Includes, but is not limited to.

[0225] The term "pharmaceuticalally acceptable salt" as used in the present invention refers to addition salts and solvates of acids and bases that are pharmaceutically usable. Such pharmaceutically usable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromide, sulfuric acid, sulfite, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodide, and alkanes (e.g., acetic acid, HOOC-(CH2)n-COOH (where n is 0 to 4)). Such pharmaceutically usable salts further include salts of bases such as sodium, potassium, calcium, ammonium, etc. Those skilled in the art are aware of various non-toxic, pharmaceutically usable addition salts.

[0226] All numerical ranges referred to in the present invention mean that they include both ends of the range, all integers within the range, and sub-ranges consisting of such integers. For example, "5-11 won" includes 5, 6, 7, 8, 9, 10, and 11 won; "5-6 won" includes 5 and 6 won; "7-11 won" includes 7, 8, 9, 10, and 11 won, etc.

[0227] In the present invention, the term "one to a number" regarding substituents indicates that the number of substituents may be the number of all chemically substitutable positions of the atomic group to be substituted, preferably 1 to 6, more preferably 1 to 5, more preferably 1 to 3, and more preferably 1 to 2.

[0228] The "crystalline form" referred to in the present invention can be prepared as a compound of formula (I) using conventional methods used in the field for preparing crystalline forms.

[0229] The term "stereoisomer" of the compound of formula (I) as used in the present invention refers to a case where, if an asymmetric carbon atom is present in the compound of formula (I), an enantiomer is formed; if a carbon-carbon double bond or ring structure is present, a cis-trans isomer is formed; and if a ketone or oxime is present in the compound, a tautomer is formed. All enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers, and mixtures thereof of the compound of formula (I) are included within the scope of the present invention.

[0230] For the preparation of the compound of formula (I) as described in the present invention, reference may be made to the specific embodiment portion of WO2018108079A1.

[0231] The term "therapeutic effective dose" as used in the present invention refers to an amount of the aforementioned compound or its pharmaceutically acceptable salt, stereoisomer, crystalline form, and / or drug formulation that, when administered to a patient, is capable of at least alleviating the patient's symptoms. The actual dose comprising the "therapeutic effective dose" may vary depending on various circumstances, which include, but are not limited to, the specific condition to be treated, the severity of the condition, the patient's physique and health condition, and the route of administration. A person skilled in the medical field can easily determine an appropriate dose using methods already known in the medical field.

[0232] The term "mammal" as used in the present invention refers to a group of animals belonging to the class Mammalia of the subphylum Vertebrata that secrete milk through mammary glands to feed their young. This can be divided into humans and animals. Examples of mammals include, but are not limited to, tigers, leopards, wolves, deer, giraffes, minks, monkeys, orangutans, tapirs, foxes, sloths, bears, koalas, polar bears, elephants, musk oxen, rhinoceroses, manatees, lions, red pandas, pandas, wild boars, antelopes, koalas, lynxes, pangolins, anteaters, otters, dolphins, walruses, seals, whales, platypuses, hedgehogs, kangaroos, hippos, weasels, badgers, raccoons, horses, cattle, sheep, mules, donkeys, dogs, rats, cats, and rabbits.

[0233] The "pharmaceuticalally acceptable vector" as used in the present invention includes, but is not limited to, solid vectors and liquid vectors. Suitable solid vectors include, but are not limited to, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, soluble saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragagant gum, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, low-melting point waxes, cocoa butter, etc. Suitable liquid vectors include, but are not limited to, water, ethanol, polyhydric alcohols (e.g., glycerin, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, glycerides, and mixtures thereof.

[0234] The term "FGFR inhibitor" as used in the present invention refers to a small molecule inhibitor drug that has been identified as capable of acting as a cancer treatment targeting FGFR kinase, which has already been released to the market, is currently undergoing clinical research, or is in preclinical research, and is used particularly for drugs for the treatment of cholangiocarcinoma. Examples include Erdafitinib, BGJ-398, TAS-120, and INCB-054828.

[0235] Effects of the invention

[0236] The compound represented by Formula (I) of the present invention, or its pharmaceutically acceptable salts, stereoisomers, and crystalline forms, can effectively treat biliary tract cancers and, in particular, have a significant therapeutic role for cholangiocarcinoma. Research results have revealed that it has very good therapeutic effects on non-FGFR variant cholangiocarcinoma, FGFR variant cholangiocarcinoma, various FGFR-resistant cholangiocarcinomas, and cholangiocarcinomas of various anatomical sites.

[0237] Specific details for implementing the invention

[0238] The present invention will be described in greater detail below to make the objectives, technical solutions, and advantages of the invention more clear and distinct. It is evident that the described embodiments are merely some embodiments of the present invention, not all of them. All other embodiments obtained by a person skilled in the art without creative labor based on the embodiments of the present invention are included within the scope of protection of the present invention.

[0239] The abbreviations and English notations used in this invention have the following meanings.

[0240] Table 2. Abbreviations and English Notation

[0241]

[0242] Experimental Example 1. Test of the inhibitory activity of the compound of the present invention against the FGFR wild-type enzyme

[0243] Test material: Compound of the present invention, the structure thereof as shown in Table 1, and is prepared according to the specific embodiment portion of WO2018108079A1.

[0244] Test method

[0245] (1) Compound plate preparation

[0246] A solution with a maximum concentration of 500 μM is prepared by dissolving the compound in DMSO. The compound solution is diluted with DMSO until the final concentrations are 500, 150, 50, 15, 5, 1.5, 0.5, 0.15, and 0.05 μM, thereby becoming the compound working solution (50×).

[0247] (2) Experimental stage

[0248] a) Preparation of different reaction systems

[0249] FGFR1(h): dissolved in 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 250 μM KKKSPGEYVNIEFG;

[0250] FGFR2(h): dissolved in 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 2.5 mM MnCl2, 0.1 mg / mL poly(Glu, Tyr) 4:1;

[0251] FGFR3(h): dissolved in 8 mM MOPS, pH 7.0, 0.2 mM EDTA, 10 mM MnCl2, 0.1 mg / mL poly(Glu, Tyr) 4:1;

[0252] b) Enzymatic reaction

[0253] 10 mM magnesium acetate and 10 μM [γ- 33 The reaction is initiated by adding [P]-ATP. After incubating at room temperature for 40 min, the reaction is terminated using a 3% (v / v) phosphate solution. Take 10 μL of the reaction solution, drop it onto P30 filter paper, wash it three times with a 75 mM phosphate solution (5 min per wash), dry, and scintillate. Replace the compound solution with 2% (v / v) DMSO to use as a positive control (Max); replace the compound solution with a high concentration of cation inhibitor (10 μM staurosporine) to use as a positive control (Min).

[0254] test

[0255] Table 3. Inhibitory activity of the compounds of the present invention against wild-type FGFR (IC 50 )

[0256]

[0257] As can be seen from the experimental results in Table 3, the compound of the present invention can target FGFR1-3 and has good inhibitory activity against FGFR1-3, which explains that the compound of the present invention has relatively good clinical application potential for treating diseases mediated by FGFR1-3.

[0258] Experimental Example 2. Test of the inhibitory activity of the compound of the present invention against wild-type and mutant FGFR.

[0259] Test material: Compound of the present invention, the structure thereof as shown in Table 1, and is prepared according to the specific embodiment portion of WO2018108079A1.

[0260] Table 4. Names and Origins of Enzymes / Reagents

[0261]

[0262] Test method

[0263] (1) Compound plate preparation

[0264] After dissolving the compound solution in DMSO, it is diluted three-fold with DMSO again to obtain a solution with a concentration gradient of 10, and added to a 384-well plate system to obtain a series of compound concentrations with a gradient of 10, starting at a final concentration of 10 μM and decreasing to a three-fold gradient.

[0265] (2) Experimental stage

[0266] Prepare 2× different enzyme solutions and transfer them to a 384-well plate. After incubating with compounds of different concentrations at room temperature for 10 min, add a 2× biotin-labeled tyrosine kinase substrate / ATP mixture to initiate the activation reaction. After incubating at room temperature for 50 min, add the HTRF test reagent and the corresponding enzyme antibody cryptate. After incubating at room temperature for 1 h, test the fluorescence values ​​at 615 nm (cryptate) and 665 nm (HTRF test reagent) using an Envision 2104 multifunction microplate reader. Replace the compound solution with 10 μM BIBF-1120 to serve as a positive compound control (PC), and replace the compound solution with 0.1% (v / v) DMSO to serve as a solvent-negative control (VC).

[0267] (3) Data processing

[0268] Calculate the fluorescence ratio of 665 / 615 nm, and calculate the enzyme activity inhibition rate (%) according to the following formula.

[0269]

[0270] Based on inhibition rate values ​​at different compound concentrations, IC using GraphPad 6.0 50 The values ​​were fitted.

[0271] test

[0272] Table 5. Inhibitory activity of the compounds of the present invention against FGFR enzyme (IC10) 50 )

[0273]

[0274] As can be seen from the experimental results in Table 5, the compound of the present invention showed a significant inhibitory effect on both wild-type and mutant-type FGFR2 and FGFR3, which explains that the compound of the present invention has very good clinical application potential for diseases mediated by wild-type and / or mutant-type FGFR (e.g., cholangiocarcinoma).

[0275] Experimental Example 3. Experiment on Biliary Duct Cancer Organoids (Organ-like Organs) of the Compound of the Present Invention

[0276] Test material: Compound of the present invention, the structure thereof as shown in Table 1, and is prepared according to the specific embodiment portion of WO2018108079A1.

[0277] Organoid Information: Human distal cholangiocarcinoma (dCC), Source: Beijing Ketu Medical Technology Co., Ltd. Sample Database, Code No.: KOBD-002

[0278] Table 6. Names and Sources of Reagents and Instruments

[0279]

[0280] Test method

[0281] (1) Compound plate preparation

[0282] After dissolving the compound in DMSO, a solution with a concentration gradient of 10 (1000×) is obtained by diluting it 3-fold, and a 10× working solution is obtained by diluting it 100-fold using a GAS-Ad-BD medium incubator.

[0283] (2) Experimental stage

[0284] Once the tumor organoids become suitable for passage, melt the matrix adhesive at 4°C and prepare it for use. Collect the cultured tumor organoids using a dropper, add pancreatin to digest them, and form a monocellular suspension. After counting the cells, adjust the cell concentration to 8×10⁶ using GAS-Ad-BD medium. 4 Adjust to cells / ml and place 2ml of cell suspension on ice. Mix the cell suspension with substrate adhesive to prepare a substrate adhesive mixture, place it on ice, and prepare it for use. Add 50µl of the mixture to a 96-well plate and incubate at 37°C for 30 minutes. Then, add GAS-Ad-BD medium and culture in a 37°C cell incubator for 2 days, after which observe the formation and growth of tumor organoids.

[0285] When the tumor organoids begin to form and grow, 10 μL of 10 gradient concentrations of the 10× working solution prepared on the same day is added sequentially. Incubation is performed for 96 hours under 5% carbon dioxide conditions at 37°C. The starting concentrations of each compound are as follows: Compound 29, 10 μM; Gemcitabine, 40 μM; Cisplatin, 60 μM; and 5-Fluoruracil, 30 μM. A solution negative control (DMSO, 100% survival) and a positive control (2.5 μM BEZ235, 0% survival) are established.

[0286] After the culture is finished, add 70 μL of CellTiter-Glo® solution, perform the procedure according to the instructions, and measure the fluorescence value.

[0287] (3) Data processing

[0288] Using GraphPad Prism 5 software, the corresponding compound concentration at a 50% viability, i.e., the IC of the corresponding compound in these cells. 50 Value (absolute IC 50 Calculate the value.

[0289] test

[0290] Table 7. Inhibitory activity of the compounds of the present invention against KOBD-002 distal cholangiocarcinoma organoids.

[0291]

[0292] As can be seen from the experimental results in Table 7, the compound of the present invention exhibits good inhibitory activity against KOBD-002 distal cholangiocarcinoma organoids and is superior to gemcitabine, cisplatin, and 5-fluorouracil, which explains that the compound of the present invention has relatively good clinical application potential for treating cholangiocarcinoma, particularly distal cholangiocarcinoma.

[0293] Experimental Example 4. HuPrime of the compound of the present invention ® In vivo efficacy test of CC6204 subcutaneous xenograft tumor model of ductal cholangiocarcinoma

[0294] Test material: Compound of the present invention, the structure thereof as shown in Table 1, prepared according to the specific embodiment portion of WO2018108079A1; gemcitabine hydrochloride, purchased from the market.

[0295] Tumor Source: CC6204 is a HuPrime® xenograft model constructed from a female patient with cholangiocarcinoma. The pathological diagnosis is intrahepatic cholangiocarcinoma with an FGFR2-BICC1 fusion mutation.

[0296] Animal: Balb / c nude mouse, 5–6 weeks (mouse age at inoculation), female.

[0297] Test method:

[0298] (1) Establishment of tumor-bearing mice and group division

[0299] HuPrime ® Tumor tissue was taken from CC6204 tumor-carrying mice, a cholangiocarcinoma xenograft model, sliced ​​into tumor fragments 2–3 mm in diameter, and subcutaneously inoculated into the right scapula of Balb / c nude mice; subsequently, the average tumor volume was 133 mm² 3 When the condition is reached, administer the medication by group. Group division method: Measure the animal's body weight and tumor volume before administration. Based on tumor volume, divide the animals into groups using a compartmentalization design, with 6 mice per group.

[0300] (2) Medication Plan

[0301] Table 8. Medication Plan

[0302]

[0303] main: a Gemcitabine hydrochloride administered once a week, for a total of 10 doses.

[0304] (3) Experimental observation indicators

[0305] The health and mortality status of animals are monitored daily, body weight and tumor volume are measured twice a week, and samples are collected after the last medication administration. The therapeutic effect on tumor volume is evaluated as TGI%, and the relative tumor inhibition rate TGI(%) is given by TGI = 1 - T / C(%). T / C% represents the relative tumor growth rate, i.e., the percentage of the relative tumor volume between the treatment group and the control group at a given time point. T and C are the relative tumor volume (RTV) of the treatment group and the control group, respectively, at a specific time point.

[0306] Calculation formula: T / C % = T RTV / C RTV ×100%(T RTV : Mean RTV of treatment group; C RTV : Mean RTV of solvent control group; RTV=V t / V0, V0 is the tumor volume of the animal when dividing into groups, and V t (This is the tumor volume of the animal after treatment). According to the National Institutes of Health (NIH) guidelines, if TGI ≥ 58%, the drug is considered effective.

[0307] test

[0308] Table 9. Compounds of the present invention versus HuPrime ® Human Bile Duct Cancer CC6204

[0309] Effect of tumor growth in subcutaneous xenograft tumor model mice

[0310]

[0311] main: a: Tumor volume is statistical data from day 21 of medication. b: TGI: Relative tumor suppression rate, statistical data for 21 days of treatment. c : P<0.05 indicates a statistical difference, P<0.01 indicates a significant statistical difference, and P<0.001 indicates a very significant statistical difference.

[0312] Table 10. Compounds of the present invention versus HuPrime ®Human Bile Duct Cancer CC6204

[0313] Effect on survival rate of subcutaneous xenograft tumor model mice

[0314]

[0315] main: a : Surviving animals data statistics after the last administration (Day 67). b : P<0.05 indicates a statistical difference, P<0.01 indicates a significant statistical difference, and P<0.001 indicates a very significant statistical difference.

[0316] As can be seen from the experimental results in Tables 9 and 10, the compound of the present invention is HuPrime ® It has a significant inhibitory role against the human cholangiocarcinoma CC6204 subcutaneous xenograft tumor model, effectively extends the survival cycle of tumor-bearing animals, and is significantly superior to gemcitabine, the clinical standard treatment, which explains that the compound of the present invention can be used for the clinical treatment of intrahepatic cholangiocarcinoma tumors with FGFR2 mutations and has relatively good potential for clinical application.

[0317] Experimental Example 5. HuPrime of the compound of the present invention ® In vivo efficacy test of the human cholangiocarcinoma CC6639 subcutaneous xenograft tumor model

[0318] Test material: Compound of the present invention, the structure thereof as shown in Table 1, and is prepared according to the specific embodiment portion of WO2018108079A1.

[0319] Tumor Source: CC6639 is a HuPrime® xenograft model constructed from a male patient with cholangiocarcinoma. The pathological diagnosis is intrahepatic cholangiocarcinoma, and there is no FGFR2 mutation.

[0320] Animal: Balb / c nude mouse, 4–5 weeks (mouse age at inoculation) female.

[0321] Test method

[0322] (1) Establishment of tumor-bearing mice and group division

[0323] HuPrime ® Tumor tissue was taken from CC6639 tumor-carrying mice, a cholangiocarcinoma xenograft model, sliced ​​into tumor fragments 2–3 mm in diameter, and subcutaneously inoculated into the right scapula of Balb / c nude mice; subsequently, the average tumor volume was 202 mm² 3 When [the condition] is reached, administer the drug by group. Group division method: Measure the animal's body weight and tumor volume before administration. Based on tumor volume, divide the animals into groups using a compartmentalization design, with 5 mice per group.

[0324] (2) Refer to Table 11 for the medication plan.

[0325] Table 11. Medication Plan

[0326]

[0327] (3) Experimental observation indicators

[0328] The health and mortality status of animals are monitored daily, body weight and tumor volume are measured twice a week, and samples are collected after the last medication administration. The therapeutic effect on tumor volume is evaluated as TGI%, and the relative tumor inhibition rate TGI(%) is calculated as TGI = 1 - T / C(%). T / C% represents the relative tumor growth rate, i.e., the percentage of the relative tumor volume between the treatment group and the control group at a specific time point. T and C are the relative tumor volume (RTV) of the treatment group and the control group, respectively, at a specific time point. Calculation formula: T / C% = T RTV / C RTV ×100%(T RTV : Mean RTV of treatment group; C RTV : Mean RTV of solvent control group; RTV=V t / V0, V0 is the tumor volume of the animal when dividing into groups, and V t (This is the tumor volume of the animal after treatment). According to NIH guidance principles, if TGI ≥ 58%, the drug is considered effective.

[0329] test:

[0330] Table 12. Compound of the present invention 29 vs. HuPrime ® Human bile duct cancer CC6639

[0331] Effects on tumor growth in a subcutaneous xenograft tumor model

[0332]

[0333] main: a : Statistical data after the last dose; TGI: Relative tumor suppression rate. b : P<0.05 indicates a statistical difference, P<0.01 indicates a significant statistical difference, and P<0.001 indicates a very significant statistical difference.

[0334] As can be seen from the experimental results in Table 12, Compound 29 is HuPrime ® It exhibits a significant inhibitory role against the human cholangiocarcinoma CC6639 subcutaneous xenograft tumor model, which explains that the compound of the present invention can be used in the clinical treatment of intrahepatic cholangiocarcinoma tumors with non-FGFR2 mutations and has relatively good potential for clinical application.

[0335] Experimental Example 6. In vivo pharmacokinetic test of the compound of the present invention on a PDTX subcutaneous xenograft tumor model of human hilar cholangiocarcinoma.

[0336] Test material: Compound of the present invention, the structure thereof as shown in Table 1, and is prepared according to the specific embodiment portion of WO2018108079A1.

[0337] Tumor Source: The human hilar cholangiocarcinoma tumor sample was taken from a female patient.

[0338] Animal: NCG mouse, 5–8 weeks, male.

[0339] Test method:

[0340] (1) Establishment of tumor-bearing mice and group division

[0341] Tumor samples excised from surgical resection are used to evaluate drug efficacy when inoculated into mice as the P0 series, and subsequent passages are used as the P1 series. Tumors are inoculated onto the right back of mice, with an average tumor volume of approximately 100 mm³3 When this is reached, drug administration begins by group. Group division method: Before drug administration, the animals' body weight and tumor volume are measured. Based on tumor volume, a compartmentalization design is adopted to divide the groups, with 6 mice per group.

[0342] (2) Administer medication according to the medication plan in Table 13.

[0343] Table 13. Medication Plan

[0344]

[0345] (3) Experimental observation indicators

[0346] The health and mortality status of animals are monitored daily, body weight and tumor volume are measured twice a week, and samples are collected after the last medication administration. The therapeutic effect on tumor volume is evaluated as TGI%, and the relative tumor inhibition rate TGI(%) is calculated as TGI = 1 - T / C(%). T / C% represents the relative tumor growth rate, i.e., the percentage of the relative tumor volume between the treatment group and the control group at a specific time point. T and C are the relative tumor volume (RTV) of the treatment group and the control group, respectively, at a specific time point. Calculation formula: T / C% = T RTV / C RTV ×100%(T RTV : Mean RTV of treatment group; C RTV : Mean RTV of solvent control group; RTV=V t / V0, V0 is the tumor volume of the animal when dividing into groups, and V t (This is the tumor volume of the animal after treatment). According to NIH guidance principles, if TGI ≥ 58%, the drug is considered effective.

[0347] test

[0348] Table 14. Compound 29 of the present invention vs. HuPrime ® Human Bile Duct Cancer CC6204

[0349] Effects on tumor growth in a subcutaneous xenograft tumor model

[0350]

[0351] main: a: Tumor volume is statistical data from day 21 of medication; b: TGI: Relative tumor suppression rate, statistical data for 21 days of treatment. c : P<0.05 indicates a statistical difference, P<0.01 indicates a significant statistical difference, and P<0.001 indicates a very significant statistical difference.

[0352] As can be seen from the experimental results in Table 14, compound 29 has a significant inhibitory role against a human cholangiocarcinoma PDTX subcutaneous xenograft tumor model and is significantly superior to the clinical standard treatment of gemcitabine + cisplatin, which explains that the compound of the present invention can be used in the clinical treatment of cholangiocarcinoma tumors and has relatively good potential for clinical application.

[0353] The above description is merely a relatively preferred embodiment of the present invention and is not intended to limit the invention; all modifications, equivalent substitutions, improvements, etc., in accordance with the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

Claim 1 A pharmaceutical composition for treating biliary tract cancer comprising a compound represented by formula (I), a pharmaceutically acceptable salt or stereoisomer thereof: Here, Ar is a phenyl group optionally substituted by 1 to 3 R6s, each R6 being independently selected from hydrogen and halogen; Y is CR3; P is CR4; W is N; R3 is hydrogen; and R4 is -(CH2) n -(6) A heterocyclic ring, wherein n=0, and the heterocyclic ring contains two heteroatoms independently selected from N and O, and the heterocyclic ring is optionally C 1-3 Alkyl group and C 3-6 It is substituted by one to a number of substituents independently selected from the cycloalkyl group. Claim 2 In paragraph 1, where R4 is and n=0, where the heterocycle is optionally C 1-3 Alkyl group and C 3-6 A pharmaceutical composition substituted by one to a number of substituents independently selected from cycloalkyl groups. Claim 3 A pharmaceutical composition according to paragraph 2, wherein the compound is selected from a compound having the following structure, a pharmaceutically acceptable salt thereof, and a stereoisomer. Claim 4 In paragraph 3, the above compound is , a pharmaceutically acceptable salt, or a stereoisomer thereof, a pharmaceutical composition. Claim 5 A pharmaceutical composition according to any one of claims 1 to 4, wherein the biliary tract cancer is cholangiocarcinoma, or cholangiocarcinoma mediated by FGFR, or cholangiocarcinoma mediated by any one of FGFR1, FGFR2, and FGFR3 or a combination thereof. Claim 6 A pharmaceutical composition according to claim 5, wherein the cholangiocarcinoma is a non-FGFR variant cholangiocarcinoma. Claim 7 A pharmaceutical composition according to claim 5, wherein the cholangiocarcinoma is an FGFR variant cholangiocarcinoma, or an FGFR2 variant cholangiocarcinoma and / or an FGFR3 variant cholangiocarcinoma. Claim 8 A pharmaceutical composition according to claim 7, wherein the cholangiocarcinoma is a cholangiocarcinoma having any one of FGFR fusion, FGFR mutation, and FGFR overexpression, or a combination thereof. Claim 9 A pharmaceutical composition according to claim 8, wherein the cholangiocarcinoma is a cholangiocarcinoma having any one or a combination of FGFR2 fusion, FGFR2 and / or FGFR3 mutation, and FGFR overexpression. Claim 10 A pharmaceutical composition according to claim 5, wherein the cholangiocarcinoma refers to resistant cholangiocarcinoma that is FGFR mutation-positive but does not respond to an FGFR inhibitor, or refers to resistant cholangiocarcinoma after administration of an FGFR inhibitor. Claim 11 A pharmaceutical composition according to claim 5, wherein the cholangiocarcinoma is any one of intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, and distal cholangiocarcinoma, or a combination thereof. Claim 12 A pharmaceutical composition according to any one of claims 1 to 4, wherein, in addition to containing a compound represented by formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof, the pharmaceutical composition further contains a pharmaceutically acceptable carrier. Claim 13 A pharmaceutical composition according to any one of claims 1 to 4, wherein, in addition to containing a compound represented by formula (I), a pharmaceutically acceptable salt, or a stereoisomer thereof, the pharmaceutical composition further contains one or more second therapeutic agents, wherein the second therapeutic agent is any one or a combination thereof of a metabolic antagonist, a growth factor inhibitor, a mitotic inhibitor, an anticancer hormone, an alkylating agent, a metal platinum, a focal isomerase inhibitor, a hormone, an immunomodulator, a tumor suppressor gene, a cancer vaccine, and an immune checkpoint inhibitor. Claim 14 A pharmaceutical composition according to claim 13, wherein the compound represented by formula (I), its pharmaceutically acceptable salt, or stereoisomer is administered to a patient or test subject requiring treatment by adopting a method of administering it sequentially or simultaneously with the second therapeutic agent or by preparing it as a complex formulation. Claim 15 A pharmaceutical composition according to claim 14, wherein the patient or test subject refers to a mammal. Claim 16 A pharmaceutical composition according to claim 15, wherein the patient or test subject refers to a person. Claim 17 delete

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