Pharmaceutical combinations and pharmaceutical compositions for cancer treatment

Abstract

The present invention provides a pharmaceutical combination and a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, and at least one other anti-cancer agent, and use in the treatment of malignant neoplastic diseases. Here, the other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof (for example, palbociclib), lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, and formula (I) is as defined herein. TIFF2025520303000043.tif43170

Description

Technical Field

[0001] (Cross - reference to related applications) This invention claims the benefits and priority of Chinese Patent Application No. 202210597667.9, filed with the State Intellectual Property Office of the People's Republic of China on May 30, 2022, the entire content of which is incorporated herein by reference.

[0002] This invention belongs to the field of medicine, and specifically relates to the use of an FGFR4 inhibitor represented by formula (I) in combination with at least one other anti - cancer agent in the treatment of malignant neoplastic diseases.

Background Art

[0003] Fibroblast growth factor receptor 4 (FGFR4) is a protein encoded by the human FGFR4 gene. This protein is one of the fibroblast growth factor receptor family members, and throughout the process of evolution, the amino acid sequences among the family members are highly conserved. Family members 1 - 4 of the FGFR family have different ligand affinities and tissue distributions. A typical full - length protein consists of an extracellular domain composed of three immunoglobulin - like domains, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors to initiate a series of downstream signals, ultimately affecting mitosis and differentiation. The genomic structure of the FGFR4 gene contains 18 exons. Alternative splicing has been observed, but there is no evidence indicating that the structure of the C - terminal half of the IgIII domain of such a protein differs among the three alternative forms as shown in FGFR1 - 3.

[0004] To date, no potent and selective FGFR4 inhibitor has been approved. Currently, several FGFR inhibitors are being used in clinical trials for treating cancers with FGFR1-3 mutations, but many of these inhibitors exhibit promiscuous kinase activity or moderate to weak anti-FGFR4 efficacy. The lack of selectivity among kinase groups results in toxicity due to off-target effects. In particular, dose-limiting toxicity has been observed in animals and patients administered FGFR1 and FGFR3 inhibitors. For example, in rats treated with an FGFR1 inhibitor, ectopic calcification characterized by inappropriate calcium-phosphate deposition in soft tissues was observed. Also, FGFR1 and FGFR3 inhibitors cause hyperphosphatemia. This suggests the need to selectively inhibit FGFR4 without inhibiting other FGFR isoforms, including FGFR1 and FGFR3, in order to avoid any toxicity. FGFR4 preferentially binds to fibroblast growth factor 19 (FGF19). For example, aberrant signaling through the fibroblast growth factor 19 (FGF19)-FGFR4 signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and is suggested to play a similar role in humans.

[0005] Malignant tumors (cancers) are serious diseases that endanger people's lives and health. In recent years, with the rapid development of tumor biology and related disciplines, specific antitumor drugs targeting abnormal signaling systems within tumor cells have become the focus of new drug research and development. At the same time, using a combination of multiple antitumor drugs for the treatment of tumor diseases has also become a hot spot in scientific research.

[0006] Liver cancer is one of the malignant tumors with the highest incidence and mortality rates. In China, there are 466,000 new liver cancer cases and 422,000 liver cancer deaths every year. According to research, the FGF19-FGFR4 signaling system is closely related to hepatocellular carcinoma (HCC). FGFR4 is an FGFR isoform highly expressed in human hepatocytes, and various FGFR4 mutations have been discovered in liver cancer patients. In addition, its ligand FGF19 has mutations such as amplification in many liver cancers, which causes abnormal activation of the FGFR4 signaling pathway. Selectively inhibiting FGFR4 without inhibiting other isoforms of FGFR1, FGFR2, and FGFR3 can avoid certain toxicities and is likely to be an important target for liver cancer treatment. Clinical studies have shown that FGFR inhibitors can be used in the treatment of various cancers, but the development of selective FGFR4 inhibitors for the treatment of various tumors, especially liver cancer, is an urgent task.

[0007] Chinese Patent Application No. CN108948004A discloses an FGFR4 inhibitor represented by the following formula (I).

Chemical formula

[0008] Palbociclib has the chemical name (6-acetyl-8-cyclopentyl-5-methyl-2-{[5-piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one) and was approved by the FDA as an inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. Palbociclib has the following structure.

Chemical formula

[0009] Palbociclib, sold under the brand name Ibrance / IBRANCE (registered trademark), is indicated for use in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. It should be used in combination with an aromatase inhibitor as initial endocrine therapy for postmenopausal women. The recommended dose of palbociclib is 125 mg once daily for 21 consecutive days, followed by a 7-day drug-free period (3 / 1 dosing regimen), with a 28-day treatment cycle. Treatment should be continued as long as there is clinical benefit to the patient and unacceptable toxicity does not occur. In the event of an adverse reaction, it may be necessary to temporarily discontinue / delay dosing and / or reduce the dose, or permanently discontinue dosing to control it. The dose should be reduced to 100 mg / day for the first time. The dose should be reduced to 75 mg / day for the second time, and if further dose reduction to below 75 mg / day is required, treatment should be terminated. In clinical studies, the most common (20%) any-grade adverse reactions reported in patients receiving palbociclib treatment were neutropenia, infection, leukopenia, fatigue, nausea, stomatitis, anemia, alopecia, and diarrhea. The most common (2%) grade 3 or higher adverse reactions of palbociclib were neutropenia, leukopenia, anemia, fatigue, and infection. In a study comparing the safety of the combination of palbociclib (125 mg / day) and letrozole (2.5 mg / day) with the combination of placebo and letrozole, the dose was reduced due to any-grade adverse reactions in 36% of patients receiving the combination of palbociclib and letrozole. Permanent drug discontinuation related to adverse reactions occurred in 43 / 444 (9.7%) patients receiving the combination of palbociclib and letrozole and 13 / 222 (5.9%) patients receiving the combination of placebo and letrozole. Adverse reactions leading to permanent drug discontinuation in patients receiving the combination of palbociclib and letrozole included neutropenia (1.1%) and increased alanine aminotransferase (0.7%). (Source: Package Insert of Palbociclib Capsules (Brand Name: Ibrance / IBRANCE)).

[0010] Lenvatinib has the chemical name (4-[3-chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide) and is a multi-target receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs, such as those involved in pathogenic angiogenesis, tumor growth, and cancer progression in addition to normal cell function, including fibroblast growth factor (FGF) receptors FGFR1, FGFR2, FGFR3, and FGFR4, platelet-derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib has the following structure. [Chemical formula]

[0011] The mesylate salt of lenvatinib (i.e., lenvatinib mesylate) has the chemical name 4-[3-chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate and has the following structure. [Chemical formula]

[0012] Lenvatinib mesylate, with the trade name LENVIMA (registered trademark), has the following approved indications for marketing: it is for patients with unresectable hepatocellular carcinoma who have not received systemic treatment (in the main trial of this product, patients with hepatocellular carcinoma who are eligible for local treatment are excluded, and there is no relevant trial data yet). For patients weighing <60 kg, the recommended daily dose of this product is 8 mg (2 capsules of 4 mg), once a day. For patients weighing ≥60 kg, the recommended daily dose of this product is 12 mg (3 capsules of 4 mg), once a day. Treatment should be continued until the disease progresses or intolerable toxic reactions or side effects occur. In the REFLECT study, most patients (99%) in the lenvatinib group had at least one adverse reaction. The most common side effects and adverse reactions (≥20%) of lenvatinib are hypertension (45%), fatigue (44%), diarrhea (39%), anorexia (34%), weight loss (31%), arthralgia / myalgia (31%), abdominal pain (30%), hand-foot syndrome (27%), proteinuria (26%), bleeding events (25%), voice disorder (24%), hypothyroidism (21%) and nausea (20%). Among the patients in the lenvatinib group, 75% had adverse reactions of grade 3 or higher. The most common (≥5%) grade 3 or higher side effects and adverse reactions in patients treated with lenvatinib are hypertension (24%), weight loss (8%), fatigue (7%), increased blood bilirubin (7%), proteinuria (6%), thrombocytopenia (5%), hepatic encephalopathy (5%), increased γ-glutamyltransferase (5%), bleeding events (5%) and increased aspartate aminotransferase (5%).

[0013] The most common serious adverse reactions (≥2%) in patients treated with lenvatinib are bleeding events (5%), hepatic encephalopathy (5%), liver failure (3%), ascites (3%), and anorexia (2%). Adverse reactions cause dose reduction or discontinuation of lenvatinib in 62% of patients. The most common adverse reactions (≥5%) that cause dose reduction or discontinuation in the lenvatinib treatment group are fatigue (10%), anorexia (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and hand-foot syndrome (5%). The most common adverse reactions (≥1%) that cause discontinuation of lenvatinib are fatigue (2%), bleeding events (2%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and liver failure (1%). (Source: Pharmaceutical Product Label of Lenvatinib Mesylate Capsules (Trade Name: LENVIMA)).

[0014] Sorafenib is a multi-target kinase inhibitor. In vitro tests have shown that sorafenib can inhibit tumor cell proliferation and angiogenesis. Sorafenib inhibits the target sites CRAF, BRAF, BRAF V600E, c-Kit, FLT-3 of tumor cells and CRAF, VEGFR-2, VEGFR-3, PDGFR-β of the target sites of tumor blood vessels. RAF kinase is a serine / threonine kinase, and c-Kit, FLT-3, VEGFR-2, VEGFR-3, PDGFR-β are tyrosine kinases. These kinases act on the signal transduction pathways, angiogenesis, and apoptosis of tumor cells. In vivo tests have shown that sorafenib can inhibit tumor growth and angiogenesis in xenograft tumor nude mouse models of various human-derived cancer cells such as human hepatocellular carcinoma and renal cell carcinoma. Sorafenib has the following structure. [Chemical formula]

[0015] Sorafenib tosylate has the chemical name of methylamine-4-tosylate of 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid and has the following structure. [Chemical formula]

[0016] The commercially approved indications of sorafenib tosylate include inoperable or metastatic hepatocellular carcinoma (currently, due to the lack of randomized comparative clinical study data comparing sorafenib with intervention therapies such as transarterial chemoembolization (TACE) in patients with advanced hepatocellular carcinoma, the superiority or inferiority of this product compared to intervention therapies cannot be clarified, nor can it be determined whether the use of sorafenib in patients receiving intervention therapy is beneficial. It is recommended that physicians consider comprehensively according to the specific situation of the patient and select specific treatment measures). The recommended dose of sorafenib is 0.4 g (2 × 0.2 g) per administration, twice a day, and the treatment should be continued until the patient can no longer obtain clinical benefit or intolerable toxic reactions occur. The treatment of suspected adverse reactions includes temporarily suspending the use of sorafenib or reducing the dose. If the dose needs to be reduced, the dose of sorafenib should be reduced to once a day, 0.4 g (2 × 0.2 g) per administration. In the safety evaluation of a phase II clinical study including 638 patients receiving sorafenib treatment (including 202 patients with renal cell carcinoma, 137 patients with hepatocellular carcinoma, and 299 patients with other cancers), the most common drug-related adverse events reported were rash (38%), diarrhea (37%), hand-foot skin reaction (35%), and fatigue (33%). The incidence rates of drug-related adverse events of CTC (version V2.0) grade 3 and grade 4 were 37% and 3%, respectively. In a clinical study conducted by Bayer as the sponsor, the incidence rate of congestive heart failure in patients taking sorafenib was 1.9% (N = 2276). Among lung cancer patients, the mortality rate of patients receiving a chemotherapy regimen based on the combination of sorafenib and double platinum was higher than that of patients receiving a chemotherapy regimen based on double platinum alone (carboplatin / paclitaxel and gemcitabine / cisplatin). The exact cause of this result is still unclear. (Source: Pharmaceutical Product Label of Sorafenib Tosylate Tablets (Trade Name: Nexavar)).

[0017] Chinese Patent Application CN110022900A (where the specific compound is the compound of formula (1)) and Chinese Patent Application CN109803684A (where the specific compound is the compound of formula (2)) both report combinations of FGFR4 inhibitors and CDK inhibitors, especially combinations with palbociclib. Chinese Patent Application CN111787922 reports a combination of an FGFR4 inhibitor (where the specific compound is the compound of formula (2)) and lenvatinib. In liver cancer experimental models, the FGFR inhibitors reported in the above patents have large drug dosages, with a minimum of 30 mg / kg bid and a maximum of 500 mg / kg qd, posing potential risks to the safety of concomitant drugs.

Chemical formula

[0018] In view of this, in this field, there is a need for combination drugs with significant therapeutic effects and high safety for treating cancers such as liver cancer.

Summary of the Invention

[0019] The inventor has discovered that, compared with treatment using a single drug, administering an FGFR4 inhibitor represented by formula (I) (especially the compound of formula (B) shown below) in a low dosage in combination with a CDK inhibitor (such as palbociclib) or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination of these can obtain a significant therapeutic effect in treating cancer (such as liver cancer) and the administration is safe.

Chemical formula

[0020] According to a first aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, and at least one other anti-cancer agent, wherein the other anti-cancer agent is selected from the group consisting of a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof,

Chemical formula

Chemical formula

Chemical formula

[0021] In one embodiment, the pharmaceutical combination may comprise the compound of formula (I) or a pharmaceutically acceptable form thereof present as a first dosage form, and the first dosage form of the compound of formula (I) or a pharmaceutically acceptable form thereof may further comprise at least one pharmaceutically acceptable carrier, vehicle or excipient.

[0022] In one embodiment, the pharmaceutical combination may include the other anti-cancer agent present as a second dosage form, and the second dosage form of the other anti-cancer agent may further include at least one pharmaceutically acceptable carrier, vehicle, or excipient.

[0023] In one embodiment, the first dosage form and the second dosage form may be the same or different from each other.

[0024] In one embodiment, the first dosage form and the second dosage form may each be a single-dose dosage form or a divided-dose dosage form.

[0025] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable form thereof in the first dosage form and the other anti-cancer agent in the second dosage form may be administered simultaneously or separately. The administration may be oral administration, injection administration, topical administration, or in vitro administration.

[0026] In one embodiment, the pharmaceutical combination may be used for the treatment of malignant neoplastic diseases.

[0027] For example, in an embodiment, the compound of formula (I) or a pharmaceutically acceptable form thereof may improve the therapeutic effect of the other anti-cancer agent against a malignant neoplastic disease. For example, the compound of formula (I) or a pharmaceutically acceptable form thereof may (at a low dosage) improve the therapeutic effect of the other anti-cancer agent, and the compound of formula (I) or a pharmaceutically acceptable form thereof may reduce side effects of the other anti-cancer agent and the like.

[0028] Therefore, the present invention further provides the use of the pharmaceutical combination in the manufacture of a medicament for treating a malignant neoplastic disease.

[0029] For example, in the use of a compound of formula (I) or a pharmaceutically acceptable form thereof in the manufacture of a medicament for treating a malignant neoplastic disease in combination with at least one other anti-cancer agent, said other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, and formula (I) is as defined above.

[0030] Also, for example, in the use of a compound of formula (I) or a pharmaceutically acceptable form thereof in the manufacture of a medicament for treating a malignant neoplastic disease, said medicament comprises at least one other anti-cancer agent, said other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, and formula (I) is as defined above. Specifically, in the use of a compound of formula (I) or a pharmaceutically acceptable form thereof in the manufacture of a medicament for improving the therapeutic effect of another anti-cancer agent against a malignant neoplastic disease, said other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, and formula (I) is as defined above.

[0031] According to a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, at least one other anti-cancer agent, and at least one pharmaceutically acceptable carrier, vehicle or excipient, said other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, and formula (I) is as defined above.

[0032] In one embodiment, said pharmaceutical composition comprises a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable form thereof.

[0033] In one embodiment, the pharmaceutical composition may be used for the treatment of malignant neoplastic diseases.

[0034] Accordingly, the present invention further provides the use of the pharmaceutical composition in the manufacture of a drug for treating malignant neoplastic diseases.

[0035] According to a third aspect, the present invention provides a method for treating malignant neoplastic diseases, comprising administering a therapeutically effective amount of the above pharmaceutical combination or the above pharmaceutical composition to a subject in need thereof.

[0036] In one embodiment, the present invention provides a method for improving the therapeutic effect of other anti-cancer agents against malignant neoplastic diseases, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof to a subject in need thereof, wherein the other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, and formula (I) is as defined above.

[0037] In one embodiment, the method further comprises determining whether the subject has the malignant neoplastic disease or receiving information that the subject has the malignant neoplastic disease before administering the pharmaceutical combination or the pharmaceutical composition, and the malignant neoplastic disease is characterized by at least one biomarker selected from the group consisting of overexpression of fibroblast growth factor 19 (FGF19), amplified FGF19, and overexpression of fibroblast growth factor receptor 4 (FGFR4).

[0038] In one embodiment, the method further comprises identifying that the subject responds to the administration of the pharmaceutical combination or the pharmaceutical composition after determining whether the subject has the malignant neoplastic disease or receiving information that the subject has the malignant neoplastic disease.

[0039] Specifically, the present invention provides a method for treating a malignant neoplastic disease in a patient in need of treatment, the method comprising: a) determining whether the patient has a malignant neoplastic disease or receiving information that the patient has a malignant neoplastic disease, wherein the malignant neoplastic disease is characterized by at least one biomarker selected from the group consisting of overexpression of fibroblast growth factor 19 (FGF19), amplified FGF19, and overexpression of fibroblast growth factor receptor 4 (FGFR4); b) identifying the patient's response to the administered pharmaceutical combination or pharmaceutical composition; c) administering the pharmaceutical combination or pharmaceutical composition to the patient.

[0040] According to a fourth aspect, the present invention provides a kit comprising the pharmaceutical combination or pharmaceutical composition as described above and instructions for use.

[0041] In one embodiment, the kit may be used for any of the foregoing uses or methods.

[0042] In some embodiments, the kit comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof and at least one other anti-cancer agent, wherein the other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, and formula (I) is as defined above.

[0043] The kit may contain a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable form thereof, and at least one other anti-cancer agent, in individual containers (e.g., vials, ampoules, bottles, cans, syringes and / or dispenser packages, flexible packages (e.g., sealed Mylar or plastic bags) or other suitable containers), wherein the other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, and the compound of formula (I) or a pharmaceutically acceptable form thereof, and at least one other anti-cancer agent may each be formulated into individual dosage forms or into combined dosage forms. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof and at least one other anti-cancer agent may be present in separate containers or in a single container. In some embodiments, the kit provided may further preferably include one or more other containers containing one or more pharmaceutical excipients, which dilute or suspend a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable form thereof and / or at least one other anti-cancer agent. In some embodiments, prior to administration, a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable form thereof, and at least one other anti-cancer agent in individual containers are combined (preferably in a third container containing a pharmaceutical excipient for dilution or suspension) to form a unit dosage form.

[0044] In some embodiments, the kit further comprises instructions for any use or method described in the present invention. The kit may further comprise instructions for selecting an individual suitable for treatment (e.g., a compound of formula (I) or a pharmaceutically acceptable form thereof, at least one other anti-cancer agent (wherein the anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof) to form a single dosage form in combination, a type of cancer suitable for use of the kit, a frequency of administration as a single dosage form of the compound of formula (I) or a pharmaceutically acceptable form thereof, and other information regarding co-administration with the compound of formula (I) or a pharmaceutically acceptable form thereof). The kit may preferably also provide other components, such as buffers and explanatory information. The instructions provided in the kit of the present invention are generally written instructions in a label or a package insert (e.g., paper included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.

[0045] According to the foregoing first to fourth aspects, In some embodiments, in the compound of formula (I), R 2 is

Chemical formula

[0046] In some embodiments, in the compound of formula (I), U is

Chemical formula

[0047] In some embodiments, in the compound of formula (I), R 2 is

Chemical formula

[0048] In some embodiments, in the compound of formula (I), U is

Chem.

[0049] In some embodiments, in the compound of formula (I), R 2 is

Chem.

Chem.

[0050] In some embodiments, the compound of formula (I) is a compound of formula (A).

Chem.

[0051] In some embodiments, the compound of formula (I) is a compound of formula (B).

Chem.

[0052] In some embodiments, the pharmaceutically acceptable forms of the compound of formula (I) include solvates, hydrates, pharmaceutically acceptable salts, stereoisomers, tautomers, isotope derivatives, co-crystals, crystalline polymorphs, prodrugs, and metabolites of the compound of formula (I).

[0053] In some embodiments, the other anti-cancer agent is a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, such as palbociclib, ribociclib, abemaciclib, Trilaciclib, G1T-38, G1T-28, AT-7519, FLX-925, and alvocidib, or a pharmaceutically acceptable salt thereof, preferably palbociclib. In some embodiments, the other anti-cancer agent is lenvatinib mesylate. In some embodiments, the other anti-cancer agent is sorafenib tosylate. In some embodiments, the malignant tumor is a solid tumor, such as lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, epithelial cell carcinoma, pancreatic cancer, more preferably liver cancer, and the liver cancer is preferably hepatocellular carcinoma or intrahepatic cholangiocarcinoma.

[0054] In some embodiments, the malignant tumor is a refractory tumor resistant to other treatment means. In some embodiments, the malignant tumor is a recurrent tumor after receiving other treatment means. In some embodiments, the malignant tumor is an inoperable tumor. In some embodiments, the malignant tumor is a metastatic tumor. In some embodiments, the malignant tumor is a progressive tumor. In some embodiments, the malignant tumor is an FGFR4-mediated tumor. In some embodiments, the malignant tumor is a tumor with an abnormal FGFR4 signaling pathway. In some embodiments, the malignant tumor is characterized by amplified FGF19 overexpression or FGF19 overexpression. In some embodiments, the malignant tumor is characterized by overexpression of FGF19 but no statistically significant amplification of FGF19.

[0055] In some embodiments, the mass ratio of the compound of formula (I) or a pharmaceutically acceptable form thereof to the other anti-cancer agent may be 1 to 30:0.8 to 80, preferably 1 to 20:0.8 to 80, preferably 3 to 20:0.8 to 80, preferably 1 to 30:7.5 to 12.5, or 1 to 30:0.8 to 1.2, or 1 to 30:40 to 80, preferably 1 to 20:7.5 to 12.5, or 1 to 20:0.8 to 1.2, or 1 to 20:40 to 80, preferably 3 to 20:7.5 to 12.5, or 3 to 20:0.8 to 1.2, or 3 to 20:40 to 80, preferably 3 to 12:7.5 to 12.5, or 3 to 12:0.8 to 1.2, or 3 to 12:40 to 80, preferably 5:8 to 50, preferably 5:8, or 5:50.

[0056] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof and the other anti-cancer agent may be administered simultaneously or separately. The administration may be oral administration, injection administration, topical administration, or in vitro administration.

[0057] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable form thereof and the other anti-cancer agent may be included in the same pharmaceutical formulation, formulated separately as clinically acceptable formulations, manufactured as the drug in a combined packaging manner, and administered simultaneously or separately in a single formulation form. The clinically acceptable formulations include oral formulations, injection formulations, topical administration formulations, external use formulations, etc. In some embodiments, the drug is in a single-dose form or a divided-dose form.

[0058] The therapeutically effective amount or effective amount described in the present invention refers to the pharmaceutically recognized effective dosage, that is, the amount of the active compound that is sufficient to significantly improve the disease state without causing serious side effects. It may be administered once a day, divided into multiple doses per day, or used at intervals. Specific dosages and frequencies of administration should take into account factors such as the route of administration and the health status of the patient, and these can be determined by a skilled physician based on general skills. The administration method is not particularly limited, but typical administration methods include, but are not limited to, oral administration, rectal administration, parenteral administration (intravenous administration, intramuscular administration or subcutaneous administration), and topical administration.

[0059] In some embodiments, the compound of formula (I) (e.g., the compound of formula (B)) or a pharmaceutically acceptable form thereof is administered once, twice, or three times a day. In some embodiments, the compound of formula (I) (e.g., the compound of formula (B)) or a pharmaceutically acceptable form thereof is administered once a day. In some embodiments, a compound of formula (I) (e.g., a compound of formula (B)) up to 30 mg or an equivalent amount of a pharmaceutically acceptable form thereof is administered daily. For example, in some embodiments, 1 to 1000 mg, preferably 5 to 500 mg, more preferably 10 to 300 mg, or 10 to 270 mg, or 10 to 240 mg, or 10 to 210 mg, or 10 to 200 mg, or 10 to 180 mg, or 10 to 150 mg, or 10 to 120 mg, or 10 to 90 mg, or 10 to 60 mg, or 30 to 300 mg, or 30 to 270 mg, or 30 to 240 mg, or 30 to 210 mg, or 30 to 200 mg, or 30 to 180 mg, or 30 to 150 mg, or 30 to 120 mg, or 30 to 90 mg, or 30 to 60 mg, and more preferably 10 mg, 20 mg, 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, 210 mg, 240 mg, 270 mg, or 300 mg of the compound of formula (I) (e.g., the compound of formula (B)) or an equivalent amount of a pharmaceutically acceptable form thereof is administered daily. In some embodiments, a compound of formula (I) (e.g., a compound of formula (B)) less than 30 mg or an equivalent amount of a pharmaceutically acceptable form thereof is orally administered to a patient once a day. In some embodiments, the compound of formula (I) (e.g., the compound of formula (B)) or a pharmaceutically acceptable form thereof is administered in the form of tablets.

[0060] In some embodiments, 75 - 125 mg of palbociclib or an equivalent amount of its pharmaceutically acceptable salt is orally administered to a patient once a day. In some embodiments, 125 mg of palbociclib or an equivalent amount of its pharmaceutically acceptable salt is orally administered to a patient once a day. In some embodiments, less than 125 mg of palbociclib or an equivalent amount of its pharmaceutically acceptable salt is orally administered to a patient once a day, for example, 100 mg or 75 mg of palbociclib or an equivalent amount of its pharmaceutically acceptable salt is orally administered to a patient once a day.

[0061] In some embodiments, the daily dosage of lenvatinib or an equivalent amount of its pharmaceutically acceptable salt is 8 mg - 12 mg. In some embodiments, the daily dosage of lenvatinib or an equivalent amount of its pharmaceutically acceptable salt is 8 mg. For example, the daily dosage of lenvatinib or an equivalent amount of its pharmaceutically acceptable salt is 12 mg.

[0062] In some embodiments, the daily dosage of sorafenib or an equivalent amount of its pharmaceutically acceptable salt is 0.4 g - 0.8 g. In some embodiments, the daily dosage of sorafenib or an equivalent amount of its pharmaceutically acceptable salt is 0.4 g, for example, 0.4 g is administered once a day. In some embodiments, the daily dosage of sorafenib or an equivalent amount of its pharmaceutically acceptable salt is 0.8 g, for example, 0.4 g is administered twice a day.

Brief Description of the Drawings

[0063]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0064] 〔Definitions and Explanations of Terms〕 As used herein, the term "pharmaceutically acceptable" refers to compounds, substances, compositions and / or dosage forms that are within the scope of reasonable medical judgment, are free of excessive toxicity, irritation, allergic response or other problems or complications, and are suitable for use in contact with human and animal tissues, having a reasonable benefit / risk ratio commensurate therewith. Unless otherwise specified, the term "pharmaceutically acceptable salt" or "medicinally acceptable salt" refers to a salt that is within the scope of reasonable medical judgment, is free of excessive toxicity, irritation, allergic response, etc., and has a reasonable benefit / risk ratio suitable for contact with mammalian, especially human, tissues. For example, pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are known in the art. Such salts can be prepared in situ during the final separation and purification of the compounds of the present invention, or by separately reacting the free alkali or free acid with a suitable reagent.

[0065] Unless otherwise specified, the term "isotope derivative" means that the compounds of the present invention contain one or more atoms with an atomic weight or mass number different from that of the most abundant atoms found in nature, and can exist in the form of isotope tracing or enrichment. The isotopes may be radioactive or non-radioactive isotopes. Usually, the isotopes used as isotope labels are hydrogen isotopes ( 2 H and 3 H), carbon isotopes ( 13 C and 14 C), chlorine isotopes ( 35 Cl and 37 Cl), fluorine isotopes ( 18 F), iodine isotopes ( 123 I and 125 I), nitrogen isotopes ( 13 N and 15 N), oxygen isotopes ( 15 O, 17 O and 18 O) and sulfur isotopes ( 35S). These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, 3 H and 13 C are more easily labeled and detected, so they have a wider range of applications. Substitution with specific heavy isotopes, such as deuterium ( 2 H), can improve metabolic stability, extend the half-life, achieve the purpose of reducing the dose, and provide the advantage of therapeutic effect. Isotope-labeled compounds are generally synthesized from labeled starting materials in the same manner as the synthesis of non-isotope-labeled compounds using known synthetic techniques.

[0066] Unless otherwise specified, the terms "solvate" and "solvent compound" refer to a physical association of a compound of the present invention with one or more solvent molecules (regardless of whether organic or inorganic). The physical association includes hydrogen bonds. In some cases, a solvent compound can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in a solvent compound can exist in a regular arrangement and / or a disordered arrangement. A solvate can contain a stoichiometric or non-stoichiometric amount of solvent molecules. The solvate can be a solvate of the invented compound or its pharmaceutically acceptable salt. "Solvate" includes solvates in the solution phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are, for example, complexes containing from 1 to about 100, or 1 to about 10, or 1 to about 2, about 3 or about 4 solvent or water molecules. It should be understood that the term "compound" as used herein includes the compound, the solvate of the compound, and mixtures thereof. Solvation methods are well known in the art.

[0067] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereoisomers, conformational isomers (rotational isomers), geometric isomers (cis-trans isomers), atropisomers, etc. Any mixture of obtained stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers based on the differences in the physicochemical properties of the components by, for example, chromatographic methods and / or fractional crystallization methods. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can be interconverted by a low energy barrier. When tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called proton-transfer tautomers) include mutual conversions by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions by the reorganization of some bonding electrons.

[0068] Unless otherwise indicated, all structural formulas described in the present invention include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational)), including, for example, the R and S configurations about chiral centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Accordingly, both a single stereochemical isomer of a compound of the present invention and a mixture thereof with its enantiomers, diastereoisomers, or geometric isomers are within the scope of the present invention.

[0069] "Enantiomers" or "mirror images" refer to a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of any proportion of a pair of enantiomers may be called a "racemic mixture". If necessary, the term "(±)" is used to designate a racemic mixture. "Diastereoisomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be designated as R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) according to the direction (dextrorotatory or levorotatory) in which it rotates plane-polarized light at the wavelength of the sodium D line. Specific compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomers that can be designated as (R)- or (S)- from the perspective of the absolute stereochemistry at each asymmetric atom. The chemical substances, pharmaceutical compositions, and methods of the present invention are meant to include all such possible isomers, including racemic mixtures, optically substantially pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents and may be resolved using conventional techniques.

[0070] In some embodiments, the isomer / enantiomer may not substantially contain the corresponding enantiomer and may be referred to as "optically enriched", "enantiomerically enriched", "enantiomerically pure", and "non-racemic" (used interchangeably herein). These terms refer to a composition in which the amount of one enantiomer exceeds the amount of that enantiomer in a control mixture of the racemic composition (e.g., exceeds 1:1 by weight). For example, an enantiomerically enriched product of the S enantiomer refers to a compound product having the S enantiomer in an amount of at least about 75% by weight, or for example at least about 80% by weight, relative to the total weight of the product (e.g., the total weight of the S isomer and the R isomer), which exceeds about 50% by weight. In some embodiments, the enrichment can far exceed about 80% by weight, providing a "substantially enantiomerically enriched", "substantially enantiomerically pure", or "substantially non-racemic" product, which refers to a product of a composition having one enantiomer in an amount of at least about 85% by weight, such as at least about 90% by weight, and even at least about 95% by weight relative to the total weight of the product. In certain embodiments, the compounds provided herein are composed of at least about 90% by weight of one enantiomer. In some other embodiments, the compound is composed of at least about 95% by weight, about 98% by weight, or about 99% by weight of one enantiomer.

[0071] In some embodiments, the compound is a racemic mixture of the (S)-isomer and the (R)-isomer. In some other embodiments, provided herein is a mixture of compounds, wherein the individual compounds of the mixture are present predominantly in the (S)- or (R)-isomeric configuration. For example, in some embodiments, the mixture of compounds has an (S)-enantiomeric excess of greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 55%, greater than about 60%, greater than about 65%, greater than about 70%, greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, or greater than about 99%. In some embodiments, the mixture of compounds has an (S)-enantiomeric excess of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 99.5%, or more. In some embodiments, the mixture of compounds has an (S)-enantiomeric excess of from about 55% to about 99.5%, from about 60% to about 99.5%, from about 65% to about 99.5%, from about 70% to about 99.5%, from about 75% to about 99.5%, from about 80% to about 99.5%, from about 85% to about 99.5%, from about 90% to about 99.5%, from about 95% to about 99.5%, from about 96% to about 99.5%, from about 97% to about 99.5%, from about 98% to about 99.5%, or from about 99% to about 99.5%, or greater than about 99.5%.

[0072] Unless otherwise specified, the terms "cocrystal" or "co-crystal" are used to describe the case where neutral molecular components are present in a crystalline compound in a defined stoichiometric ratio. The production of pharmaceutical co-crystals can change the crystal form of the active pharmaceutical ingredient, thereby changing its physicochemical properties without impairing its desired biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters and L. Quere, RSC Publishing, 2012).

[0073] Unless otherwise specified, the term "crystalline polymorph" or "crystalline polymorphic form" refers to different arrangements of a chemical drug molecule and is generally expressed as the form in which a drug raw material exists in a solid state. A single drug can exist as multiple crystalline substances. Different crystalline forms of the same drug may have different dissolution and absorption in vivo and may affect the elution and release of the formulation. In certain embodiments, the "crystalline polymorph" or "crystalline polymorphic form" described herein is also intended to include all crystalline or amorphous forms of a compound or its pharmaceutically acceptable salts, unless otherwise referring to a crystalline or amorphous form, and this includes, for example, crystalline forms, crystalline polymorphic forms, pseudopolymorphic forms, solvates, hydrates, co-crystals, non-solvated crystalline polymorphs (including anhydrides), conformational crystalline polymorphs, tautomeric forms, irregular crystalline forms and amorphous forms, as well as mixtures thereof.

[0074] Unless otherwise specified, the term "metabolite" refers to a product generated by the metabolism of a specific compound or its pharmaceutically acceptable salt in vivo. The metabolites of a compound can be identified using the known techniques in the relevant field, and their activities can be characterized by the test methods as described in the present invention. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compound and metabolites generated by contacting the compound of the present invention with a mammal for a sufficient period of time.

[0075] Unless otherwise specified, the term "prodrug" refers to a drug that is converted in vivo to the parent drug. Prodrugs are generally useful and can improve certain undesirable physical or biological properties. Physical properties are typically related solubility (excessive or insufficient lipid or water solubility) or stability, and problematic biological properties include being metabolized too rapidly or having low bioavailability, which may itself be related to physicochemical properties. A prodrug may be bioavailable, for example, by oral administration, while the parent drug is not. A prodrug has improved solubility in a pharmaceutical composition compared to the parent drug. A (non-limiting) example of a prodrug may be any compound herein, which is administered as an ester ("prodrug") to facilitate permeation through cell membranes (where water solubility is disadvantageous for mobility but advantageous once inside the cell), and is then metabolically hydrolyzed to the carboxylic acid, which is the active substance. Another example of a prodrug may be a short peptide (polyamino acid) in which the peptide is metabolized to bind to an acidic group at the active site.

[0076] As used herein, "combination" administration or "co - administration" refers to administering two (or more) different treatments to a subject while the subject is suffering from a medical condition. For example, after a subject is diagnosed with a medical condition and before the condition is cured or resolved, or before treatment is discontinued for other reasons, two or more drugs are delivered to the subject. In some embodiments, delivery in the first treatment is still ongoing when delivery in the second treatment is initiated, so there is overlap with respect to administration. This is sometimes referred to herein as "simultaneous" or "co - delivery". In other embodiments, delivery in one treatment ends before delivery in the other treatment begins. In some embodiments in either case, the combination administration is more effective for the treatment. For example, the second treatment is more effective, e.g., equivalent effects are seen with fewer doses of the second treatment, or the second treatment significantly reduces symptoms more than when the second treatment is administered without the first treatment, or similar situations are seen with the first treatment. In some embodiments, the above - mentioned delivery results in a greater decrease in symptoms or other parameters related to the symptoms than is observed when one treatment is administered without the other treatment. The effects of two (or more) treatments can be sub - additive, fully additive, or supra - additive. The delivery can be such that the effect of the first treatment delivered is still detectable when the second treatment is delivered.

[0077] As used herein, the term "single formulation" refers to a single carrier or vehicle (medium) formulated to deliver an effective amount of both therapeutic agents to a patient. The single vehicle is designed to deliver an effective amount of each drug, along with any pharmaceutically acceptable carrier or excipient. In some embodiments, the vehicle is a tablet, capsule, pill, or patch.

[0078] As used herein, the term "unit dose" means administering both drugs together to a patient being treated in one dosage form simultaneously. In some embodiments, the unit dose is a single formulation. In certain embodiments, the unit dose comprises one or more vehicles, each vehicle being adapted to contain an effective amount of at least one of the above-mentioned drugs (e.g., a compound of formula (I), or a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof) together with a pharmaceutically acceptable carrier and excipient. In some embodiments, the unit dose is one or more tablets, capsules, pills, or patches administered to the patient simultaneously.

[0079] The term "pharmaceutically acceptable excipient" or "pharmaceutical excipient" may be selected from the group consisting of common carriers, adhesives, suspending agents, glidants, flavoring agents, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizing agents, wetting agents, stabilizers, penetration enhancers, defoaming agents, antioxidants, preservatives, solvents, and combinations thereof in the art.

[0080] The term "dose range" refers to the upper and lower limits of the acceptable variation in the amount of a particular drug. Usually, any dose of the drug within the specified range can be administered to the patient being treated.

[0081] The term "treatment" means reducing, alleviating or mitigating at least one symptom of a disease in a subject. For example, with respect to a malignant neoplastic disease, the term "treatment" means preventing or delaying the onset (i.e., the period before the symptoms of the disease or the clinical manifestations of the disease appear) and / or reducing the risk of progression or worsening of the symptoms of the disease. When the term is used in combination with a disease such as cancer, it means inhibiting the growth of cancer, reducing the weight or volume of cancer, prolonging the expected survival time of the patient, inhibiting tumor proliferation, reducing the tumor mass, reducing the size or number of metastases, inhibiting the progression of new metastases, prolonging the survival period, prolonging the progression-free survival period, prolonging the time to progression, and / or improving the quality of life, including but not limited to one or more of these.

[0082] The terms "treatment", "alleviation" and "improvement" may be used interchangeably herein. These terms refer to a way of obtaining a beneficial or desired result (including but not limited to a therapeutic effect and / or a prophylactic effect). A therapeutic effect means eradicating or improving the underlying disorder being treated. Also, a therapeutic effect can be obtained by observing an improvement in the patient by eradicating or improving one or more physiological symptoms associated with the underlying disorder, even though the patient may still be susceptible to the pain of the underlying disorder. For a prophylactic effect, although a diagnosis for a particular disease may not have been made, the pharmaceutical composition can be administered to a patient at risk of developing the particular disease or to a patient in whom one or more physiological symptoms of the disease have been reported. In one embodiment, these terms also refer to inhibiting or alleviating some or all of the medical conditions suffered by an individual. In one embodiment, these terms refer to an action that is used when a patient has or has been diagnosed with the medical condition, and that reduces the severity of the medical condition or delays or alleviates the progression of the medical condition. Treatment does not necessarily require complete cure of the medical condition, and the term includes partial inhibition or alleviation of the medical condition. Treatment is intended to include prevention or prophylaxis.

[0083] The term "subject" or "patient" is intended to include an animal suffering from or afflicted with a malignant neoplastic disease. Examples of subjects or patients include mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, and transgenic non-human animals. In certain embodiments, the subject is a human, e.g., a human suffering from a malignant neoplastic disease, a human at risk of suffering from a malignant neoplastic disease, or a human who may be suffering from a malignant neoplastic disease.

[0084] The term "about" or "approximately" generally means within 20% of a given value or range, more preferably within 10%, and most preferably within 5% further. Alternatively, particularly in biological systems, the term "about" means within about one logarithm (i.e., one order of magnitude) of a given value, preferably within a factor of two.

[0085] The term "synergistic effect" refers to the case where administering two agents together gives a higher or improved effect than administering a single agent alone without co-administering the other agent. The agents administered together can provide a synergistic effect when administered simultaneously or sequentially. Administering the agents sequentially includes administering them at intervals of seconds, minutes, hours, or days. Administering the agents together when one of the agents is administered as part of a single administration or as a single formulation can provide a synergistic effect. Examples of agents administered together include a compound of formula (I) and a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof.

[0086] The term "amplification" means, in cancer cells, the generation of additional copies of a gene or chromosomal segment that confers a growth or survival advantage. A person skilled in the art can compare genomic hybridization using common techniques in this field, such as fluorescence in situ hybridization (FISH), measure the copy number of a gene or chromosomal segment by high-resolution array-based tests, and the above high-resolution array-based tests are based on array comparative genomic hybridization (or aCGH), SNP array technology, and high-resolution microarrays containing copy number probes and SNPs, and are performed using next-generation sequencing (NGS) technology whole genome (WGS) or whole exon DNA sequencing (WES).

[0087] The term "FGFR4" or "FGFR4 protein" refers to any form of the FGFR4 protein, including wild-type forms and all mutant forms (including, but not limited to, mutant forms and splice variants). Since the FGFR4 protein is the product of the FGFR4 gene, the FGFR4 protein includes any protein encoded by any form of the FGFR4 gene that contains any mutation (e.g., point mutation, insertion / deletion, translocation fusion, and local amplification). The term "overexpression" means that the production level of a gene product in a sample is higher than the production level observed in a control sample group (e.g., normal tissue). If the gene product is not normally produced in the control sample, overexpression includes expression. The production level of the gene product can be measured using common techniques in this field, such as immunohistochemistry. According to one aspect, overexpression of the FGF19 gene product is FGF19 protein expression ≧ 1%.

[0088] The term "therapeutic effect" refers to the beneficial local or systemic effect induced in an animal, such as a mammal (e.g., a human), by administration of a compound or composition of the present invention. The phrase "therapeutically effective amount" refers to the amount of a compound or composition of the present invention that effectively treats a disease or medical condition at a reasonable benefit / risk ratio. The therapeutically effective amount of the above compound or composition varies depending on the subject being treated and the disease or medical condition, the weight and age of the subject, the severity of the disease or medical condition, the mode of administration, etc., and such therapeutically effective amount can be readily determined by those skilled in the art.

[0089] The term "combination therapy" refers to an administration regimen in which it is necessary to administer to a patient at least two different compounds (e.g., a compound of formula (I) and a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof). The above at least two different compounds can be administered simultaneously or at different times within one day. The administration regimen of the above at least two different compounds may be repeated, but not necessarily.

[0090] The term "total daily dose" or "daily administration dose" refers to the amount of a compound administered to a subject within a 24-hour time window.

[0091] The term "co - administration" refers to having a subject receive two or more treatment regimens (e.g., two or more compounds) simultaneously. In some embodiments, two or more compounds may be administered simultaneously. In some embodiments, two or more compounds may be administered sequentially (in a dosing regimen with no complete overlap). In some embodiments, two or more compounds may be administered in a dosing regimen with partial overlap. In some embodiments, "administration" in combination therapy may include administering one or more compounds to a subject to whom one or more other compounds have been administered. For clarity, in combination therapy, it is not required (or not necessary) to administer each compound together in the form of a single composition, but in some embodiments, two or more compounds may be administered together in the form of a single composition. In some embodiments, the co - administered compounds are in individual dosage forms but are packaged together (e.g., in a blister pack or other container) to facilitate co - administration.

[0092] As used herein, when referring to "treating a disease by using A and B in combination", "treating a disease by using A and B in combination / association" or "manufacturing a drug for treating a disease by using A and B in combination", generally, A and B can produce a synergistic effect in the treatment of the disease, that is, the combined treatment effect of A and B is higher than the individual treatment effect of A or B, or the side effects / adverse reactions of the combination of A and B are lower than the side effects / adverse reactions of A or B alone. This includes, but is not limited to, that A improves the treatment effect of B at the same dose, so that the combined treatment effect of A and B is higher than the sum of the individual treatment effects of A and B; A can reduce the dose of B under the premise of producing the same treatment effect, so as to reduce the side effects / adverse reactions caused by the use of a high dose of B; A can directly reduce or avoid the side effects / adverse reactions caused by the use of B.

[0093] It should be understood that the examples or embodiments described in this specification are for illustrative purposes only and not for purposes of limitation. The description of features in each example or embodiment should generally be regarded as applicable to other similar features in other examples or embodiments. Those skilled in the art should understand that various changes in form and detail can be made without departing from the spirit and scope defined by the claims.

Example

[0094] Hereinafter, the present invention will be further described with reference to specific examples. It should be understood that these examples are only for explaining the present invention and do not limit the scope of the present invention. In the following examples, experimental methods for which specific conditions are not specified are generally carried out according to general conditions or according to the conditions proposed by the manufacturer. The raw materials and reagents used are all commercially available unless otherwise specified. The compound of formula (I) of the present invention can be prepared with reference to the method disclosed in Chinese Patent Application CN108948004A.

[0095] Production Example: Production of the Compound of Formula (B)

Chemical Formula

[0096] Compound B-3 (1.5 g, 2.7 mmol) was dissolved in tetrahydrofuran (30 mL), and then HCl (2 M, aqueous solution) (20 mL) was added dropwise to the solution at room temperature. The reaction solution was stirred at room temperature for 3 hours to react. The reaction solution was poured into an appropriate amount of saturated sodium bicarbonate solution, extracted three times with dichloromethane, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was separated and purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain an off-white solid compound of formula (B) (0.44 g, yield 32%). 1HNMR(500MHz,CDCl3)δ 13.56(s,1H),10.17(s,1H),8.11(s,1H),7.85(s,1H),7.57(s,1H),5.21(s,1H),5.00(dd,J=46.1,15.7Hz,2H),4.07 - 3.96(m,2H),3.45(ddd,J=12.3,9.6,4.8Hz,1H),3.23(ddd,J=16.8,10.7,6.3Hz,2H),2.98(dt,J=12.2,4.3Hz,1H),2.91(ddd,J=9.5,7.6,4.8Hz,1H),2.85(t,J=6.3Hz,2H),2.79 - 2.69(m,1H),2.61 - 2.51(m,2H),2.23 - 2.14(m,1H),2.00 - 1.94(m,2H),1.94 - 1.69(m,3H),0.93 - 0.85(m,2H),0.63 - 0.55(m,2H).MS515.20[M + H] + 。

Example

[0097] In vitro pharmacological efficacy test of the compound of formula (B) 1. FGFR4 kinase activity inhibition experiment The FGFR4 protein kinase activity was measured using the Caliper mobility shift assay. After dissolving the compound in DMSO, it was diluted with kinase buffer, and 5 μL of the compound at a 5-fold reaction final concentration (10% DMSO) was added to a 384-well plate. After adding 10 μL of a 2.5-fold enzyme (FGFR4) solution, it was incubated at room temperature for 10 minutes, and then 10 μL of a 2.5-fold substrate (FAM-labeled peptide and ATP) solution was added. After incubating at 28 °C for 30 - 60 minutes, 25 μL of the stop solution was added to stop the reaction. The conversion rate data was read using a Caliper EZ Reader II (Caliper Life Sciences). The conversion rate was converted to inhibition rate data (% inhibition rate = (max - sample conversion rate) / (max - min) × 100). Here, max refers to the conversion rate of the DMSO control, and min refers to the conversion rate of the enzyme-inactive control. With the compound concentration and inhibition rate as the abscissa and ordinate respectively, a curve was made, and the curve was fitted by the XLFit excel add-in version 4.3.1 software to calculate the IC 50 value.

[0098] The results show that the inhibition (IC 50 , nM) of the compounds of formula (B) of the present invention against FGFR4 kinase activity is <5 nM.

[0099] 2. Huh-7 Tumor Cell Proliferation Inhibition Test The Huh-7 cell suspension was adjusted to 5×10 4 / mL or 2×10 4Adjusted to / mL. In a 96-well cell culture plate, 100 μL of the cell suspension was added to each well, and the final cell concentration was set to 5000 cells / well (72 hours) or 2000 cells / well (168 hours). The test compound (compound of formula (B)) was dissolved in DMSO to form a 10 mM stock solution. A 200-fold final concentration of the compound was prepared with the stock solution and DMSO, and a 3-fold serial dilution was prepared, and then each was diluted 20-fold with the medium. Finally, 10 μL of the corresponding 10-fold solution was added to each cell well so that each drug concentration was in a single well. Finally, the treatment concentrations of each compound were 3000 nM, 1000 nM, 333.3 nM, 111.1 nM, 37.04 nM, 12.35 nM, 4.12 nM, 1.37 nM, respectively, and the final DMSO concentration in each well was 0.5%. The cells were cultured in a 37 °C, 5% CO2 incubator for 72 hours or 168 hours. After treatment with the drug for 72 hours or 168 hours, according to the CTG (Cell Titer Glo) instruction manual, 100 μL of the CTG solution that had been pre-melted and brought to room temperature was added to each well, mixed uniformly with a microplate shaker for 2 minutes, left at room temperature for 10 minutes, and then the chemiluminescence signal value was measured with an EnSpire plate reader. The cell viability was calculated by the formula (V sample -V blank ) / (V vehicle control -V blank )×100%. In the formula, V sample is the value of the drug treatment group, V vehicle control is the average value of the solvent control group, and V blank is the average value of the blank control well. Using GraphPad Prism 5.0 software, an S-shaped dose-viability curve was created using a non-linear regression model, and the value of IC 50 was calculated.

[0100] The results show that the inhibition (IC 50 , nM) of the compound of formula (B) of the present invention on Huh-7 tumor cell proliferation is <10 nM.

Example

[0101] Pharmacodynamic study on the combined administration of the compound of formula (B) with lenvatinib mesylate or palbociclib against transplanted tumors of NU / NU mice with Hep3B (human hepatocellular carcinoma cell line) 1. Test animals NU / NU mice, female, 42 - 48 days old, body weight 22 - 26 g, 42 animals.

[0102] 2. Test purpose To investigate the pharmacodynamic effects of the combined administration of the compound of formula (B) with lenvatinib mesylate or palbociclib against Hep3B transplanted tumors.

[0103] 3. Drugs Compound of formula (B), lenvatinib mesylate, palbociclib.

[0104] Solvent: For the compound of formula (B): Aqueous solution of 0.5% methylcellulose containing 0.4% polysorbate 80 Lenvatinib mesylate / palbociclib: A solution of castor oil, absolute ethanol and ultrapure water with a volume ratio of 1:1:6.

[0105] 4. Test method 4.1 Model establishment Resuscitate in vitro - passaged Hep3B cells until the required number of cells is reached, count them under a microscope, dilute the cells with serum - free medium and Matrigel (1:1), and adjust the number of tumor cells to approximately 5×10 7 cells / mL. Place the cell suspension in an ice bath.

[0106] Extract the Hep3B cell suspension with a sterile syringe and inoculate it subcutaneously into the anterior flank subcutaneous tissue of NU / NU mice. Set the inoculation volume to 0.1 mL / animal, and set the number of tumor - containing cells to approximately 5.0×10 6 cells to establish a NU / NU mouse Hep3B transplanted tumor model.

[0107] 4.2 Administration method The single - administration group (compound of formula (B), lenvatinib mesylate, palbociclib) and the combined - administration group (compound of formula (B)+lenvatinib mesylate, compound of formula (B)+palbociclib) were administered intragastrically once a day, with the administration volume set at 10 mL / kg. The solvent group was administered the solvent at the same frequency and the same administration volume, and the administration was continued for 14 consecutive days.

[0108] 4.3 Observation Indexes and Evaluation Indexes (1) Observation of general condition: All animals were observed once a day during the test period, and abnormalities in each part of the body and changes in behavior were recorded.

[0109] (2) Body weight: All animals were weighed once before the test, and animals with appropriate body weights were selected for use in the test. After the start of administration, the body weight of the animals was measured once a day at a fixed time to monitor the body weight, and the body weight statistics were consistent with the tumor volume statistics.

[0110] (3) Death and near - death: For dead animals, the death time was recorded. For near - death animals, the observation frequency was increased to determine the death time.

[0111] (4) Tumor evaluation After the animals were grouped, the length and short diameter of the tumors were measured twice a week. (1) Tumor volume: V = 1 / 2×a×b 2 (2) Relative tumor volume:

Number

Number

Number

[0112] (5) Tumor weight At the end of the experiment, the animals were sacrificed by cervical dislocation, and the tumors were dissected and weighed. Difference in tumor weight between groups: Tumor weight inhibition rate % = (1 - tumor weight of treatment group / tumor weight of solvent (model) group) × 100%

[0113] 5 Statistical methods SPSS 19.0 statistical software was used for data processing. In the Repeated Measure procedure, the changes in tumor volume between groups over time were measured and analyzed multiple times. In the Multivariate procedure, the differences in tumor volume between groups measured each time were compared. The differences in tumor weight between groups were analyzed using the LSD method of One-way ANOVA.

[0114] 6 Results 6.1 Effect on tumor growth The results are shown as follows. Compared with the corresponding time points in the solvent (model) group, from d5 to d14, the group of compound (B) 5 mg / kg qd + palbociclib 50 mg / kg qd significantly inhibited the increase in tumor volume (P ≤ 0.05 or P ≤ 0.001). From d8 to d14, the compound (B) 5 mg / kg qd + lenvatinib mesylate 8 mg / kg qd significantly inhibited the increase in tumor volume (P ≤ 0.01 or P ≤ 0.001). From d12 to d14, the compound (B) 5 mg / kg qd + lenvatinib mesylate 8 mg / kg qd could significantly inhibit the increase in tumor volume (P ≤ 0.01 or P ≤ 0.001).

[0115] At the test endpoint (d14), in the 5 mg / kg qd group of the compound of formula (B), the 8 mg / kg qd group of lenvatinib mesylate, the 50 mg / kg qd group of palbociclib, the 5 mg / kg qd + 8 mg / kg qd group of lenvatinib mesylate of the compound of formula (B), and the 5 mg / kg qd + 50 mg / kg qd group of palbociclib of the compound of formula (B), the tumor growth inhibition rate (TGI%) was 49.1%, 57.4%, 11.0%, 72.8% and 88.3% respectively, and the relative tumor volume growth rate (T / C%) was 55.8%, 50.9%, 95.8%, 36.2% and 24.2% respectively.

[0116] The results are shown as follows. At the test dose, single administration of palbociclib could not inhibit the growth of transplanted tumors (P>0.05), while single administration of the compound of formula (B) (P≤0.01), single administration of lenvatinib mesylate (P≤0.01), and combined administration of the compound of formula (B) with lenvatinib mesylate or palbociclib (P≤0.001) could all significantly inhibit the growth of transplanted tumors. The combined administration of the compound of formula (B) with lenvatinib mesylate or palbociclib had a significantly better tumor inhibitory effect than single administration. The details of the tumor observation indicators for each group are shown in Table 1 and Figure 1. Also, in the case of combined administration of the compound of formula (B) with lenvatinib mesylate or palbociclib, the change rate of animal body weight was significantly smaller than that of the solvent group and the single administration group.

[0117]

Table 1

[0118] 6.2 Tumor weight Compared with the solvent group, in the 5 mg / kg qd group of the compound of formula (B), the 8 mg / kg qd group of lenvatinib mesylate, the 5 mg / kg qd + 8 mg / kg qd group of the compound of formula (B) + lenvatinib mesylate, and the 5 mg / kg qd + 50 mg / kg qd group of the compound of formula (B) + palbociclib, the tumor weights were all significantly decreased (P≤0.01), and the tumor weight inhibition rates (%) were 43.8%, 58.0%, 77.9% and 89.2% respectively. Compared with the solvent group, there was no statistically significant difference in tumor weight in the 50 mg / kg qd group of palbociclib (P>0.05), and the tumor weight inhibition rate (%) was only 2.1%.

[0119] The results are shown as follows. At the test dosage, single administration of palbociclib could not inhibit tumor growth (P>0.05), while single administration of the compound of formula (B) (P≤0.01), single administration of lenvatinib mesylate (P≤0.001), and combined administration of the compound of formula (B) with lenvatinib mesylate or palbociclib (P≤0.001) could all significantly inhibit tumor growth. The combined administration of the compound of formula (B) with lenvatinib mesylate or palbociclib had a significantly better tumor inhibitory effect than single administration. The details are shown in Table 2.

[0120]

Table 2

[0121] 7 Conclusions The experimental results show that the combined administration of the compound of formula (B) with lenvatinib mesylate or palbociclib has an inhibitory effect on NU / NU mouse Hep3B (human liver cancer cell line) transplanted tumors, which is significantly higher than that of any single administration, indicating a synergistic effect or enhancement effect.

Examples

[0122] Pharmacodynamic study on the combined administration of the compound of formula (B) with sorafenib tosylate or palbociclib against transplanted tumors of BALB / c Nude mouse Hep3B (human liver cancer cell line) 1. Test animals 36 female BALB / c Nude mice, weighing 18 - 20 g

[0123] 2. Test Objectives To investigate the efficacy of the combined administration of the compound of formula (B) with sorafenib tosylate or palbociclib against Hep3B transplanted tumors

[0124] 3. Drugs The compound of formula (B), sorafenib tosylate, palbociclib

[0125] Solvent: For the compound of formula (B): An aqueous solution of 0.5% methylcellulose containing 0.4% polysorbate 80 For sorafenib tosylate / palbociclib: A solution of castor oil, absolute ethanol and ultrapure water with a volume ratio of 1:1:6

[0126] 4. Test Methods 4.1 Model Preparation Same as Example 2

[0127] 4.2 Administration Method For the single administration groups (the compound of formula (B), sorafenib tosylate, palbociclib) and the combined administration groups (the compound of formula (B) + sorafenib tosylate, the compound of formula (B) + palbociclib), they were administered intragastrically once a day with a volume of 10 mL / kg. The solvent group was administered the solvent at the same frequency and the same volume for 16 consecutive days

[0128] 4.3 Observation and Evaluation Indicators: Same as Example 2

[0129] 5. Statistical Method Same as Example 2

[0130] 6. Results 6.1 Effect on Tumor Growth The results are shown as follows. Compared with the corresponding time points of the model (solvent) group, at d13 - d16, 5 mg / kg qd of the compound of formula (B) can significantly inhibit the increase in tumor volume (P < 0.05); at d3 - d6, d10 - d16, the combined administration of 5 mg / kg qd of the compound of formula (B) + 8 mg / kg qd of sorafenib tosylate can significantly inhibit the increase in tumor volume (P < 0.05); at d6 - d16, the combined administration of 5 mg / kg qd of the compound of formula (B) + 50 mg / kg qd of palbociclib can significantly inhibit the increase in tumor volume (P < 0.01). At the end of the test, for the single - administration group of the compound of formula (B), the single - administration group of sorafenib tosylate, the single - administration group of palbociclib, the combined administration of the compound of formula (B) and sorafenib tosylate, and the combined administration of the compound of formula (B) and palbociclib, the tumor growth inhibition rate (TGI%) is 30.9%, 31.4%, 44.5%, 51.0% and 87.7% respectively, and the relative tumor volume growth rate (T / C%) is 84.5%, 91.3%, 75.1%, 68.5% and 30.9% respectively. The details of the tumor observation indexes of each group are shown in Table 3 and Figure 2.

[0131] The results show that, under the test doses, neither the single administration of sorafenib tosylate nor the single administration of palbociclib can significantly inhibit the growth of transplanted tumors (P > 0.05), while the single administration of the compound of formula (B) (P ≤ 0.05), and the combined administration of the compound of formula (B) with sorafenib tosylate or palbociclib (P ≤ 0.05 or P ≤ 0.001) can all significantly inhibit the growth of transplanted tumors, indicating that the tumor - inhibiting effect of the combined administration of the compound of formula (B) with sorafenib tosylate or palbociclib is significantly higher than that of single administration. Also, in the case of the combined administration of the compound of formula (B) with sorafenib tosylate or palbociclib, the change rate of animal body weight is significantly smaller than that of the solvent group and the single - administration groups.

[0132]

Table 3

[0133] 6.2 Tumor weight Compared with the solvent (model) group, the tumor weight in the group administered with the compound of formula (B) alone and the group administered with the compound of formula (B) in combination with sorafenib tosylate or palbociclib both significantly decreased (P<0.05 or P<0.01). The tumor weight inhibition rates (%) of the group administered with the compound of formula (B) alone, the group administered with sorafenib tosylate alone, the group administered with palbociclib alone, the group administered with the compound of formula (B) in combination with sorafenib tosylate, and the group administered with the compound of formula (B) in combination with palbociclib were 27.8%, 19.1%, 46.4%, 57.5% and 89.2% respectively.

[0134] The results showed that, at the test doses, neither the administration of sorafenib tosylate alone nor the administration of palbociclib alone could significantly inhibit tumor growth (P>0.05), while the administration of the compound of formula (B) alone (P<0.05) and the administration of the compound of formula (B) in combination with sorafenib tosylate or palbociclib (P<0.01) could both significantly inhibit tumor growth, indicating that the tumor inhibitory effect of the combined administration of the compound of formula (B) with sorafenib tosylate or palbociclib was higher than that of the single administration. Details are shown in Table 4.

[0135]

Table 4

[0136] 7 Conclusion The experimental results showed that the combined administration of the compound of formula (B) with sorafenib tosylate or palbociclib had an inhibitory effect on Hep3B (human liver cancer cell line) transplanted tumors, which was significantly higher than that of any single administration, indicating a synergistic effect or improvement effect.

[0137] All publications and patents mentioned in the content described in this specification are hereby incorporated by reference into this specification. Various modifications and variations of the methods, compositions, and their uses described in the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been described with reference to specific embodiments, those skilled in the art should understand that the present invention is not limited to these specific embodiments. In fact, it will be apparent to those skilled in the art that various modifications of the embodiments described for carrying out the present invention are intended to be included within the scope of the appended claims.

Claims

1. A pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, and at least one other anti-cancer agent, wherein the other anti-cancer agent is selected from the group consisting of a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, 【Chemical 1】 wherein, T １ is CR １ and R １ is a cyano group T ２ is CR ２ and R ２ is [Chemical 2] selected from the group consisting of, Z is CH, Y is NR and R is hydrogen, W is hydrogen, V is CH ２ and U is [Chemical Formula 3] selected from the group consisting of, X ５ is a C １－４ alkyl group, m is 1, a pharmaceutical combination.

2. R ２ is 【Chemical Formula 4】 wherein, U is 【Chemical Formula 5】 The pharmaceutical combination according to claim 1.

3. The pharmaceutical combination according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (A). 【Chemical Formula 6】

4. The pharmaceutical combination according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (B). [Chemical Formula 7]

5. The pharmaceutically acceptable forms of the compound of formula (I) include solvates, hydrates, pharmaceutically acceptable salts, stereoisomers, tautomers, isotope derivatives, co-crystals, crystal polymorphs, prodrugs, and metabolites of the compound of formula (I), the pharmaceutical combination according to any one of claims 1 to 4.

6. The other anti-cancer agent is a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, preferably selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, G1T-38, G1T-28, AT-7519, FLX-925 and albosidib, and pharmaceutically acceptable salts thereof, more preferably palbociclib, the pharmaceutical combination according to any one of claims 1 to 5.

7. The other anti-cancer agent is lenvatinib mesylate or sorafenib tosylate, the pharmaceutical combination according to any one of claims 1 to 5.

8. Comprising the compound of formula (I) or a pharmaceutically acceptable form thereof present as a first dosage form, wherein the first dosage form of the compound of formula (I) or a pharmaceutically acceptable form thereof further comprises at least one pharmaceutically acceptable carrier, vehicle or excipient, the pharmaceutical combination according to any one of claims 1 to 7.

9. The pharmaceutical combination according to any one of claims 1 to 8, comprising the other anticancer agent present as the second dosage form, wherein the second dosage form of the other anticancer agent further comprises at least one pharmaceutically acceptable carrier, vehicle or excipient.

10. The pharmaceutical combination according to any one of claims 1 to 9, which is used for the treatment of malignant neoplastic diseases.

11. The pharmaceutical combination according to claim 10, wherein the compound of formula (I) or a pharmaceutically acceptable form thereof improves the therapeutic effect of the other anticancer agent against malignant neoplastic diseases.

12. The pharmaceutical combination according to claim 10 or 11, wherein the malignant tumor is a solid tumor, preferably selected from the group consisting of lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, epithelial cell cancer, and pancreatic cancer.

13. The pharmaceutical combination according to any one of claims 10 to 12, wherein the malignant tumor is hepatocellular carcinoma or intrahepatic cholangiocarcinoma.

14. The pharmaceutical combination according to any one of claims 10 to 13, wherein the malignant tumor is a progressive tumor, a refractory tumor resistant to other treatment means, a recurrent tumor after receiving other treatment means, a metastatic tumor, an FGFR4-mediated tumor, a tumor with an abnormal FGFR4 signaling pathway, and a tumor with amplified FGFR19 or overexpressed FGFR19.

15. The mass ratio of the compound of formula (I) or a pharmaceutically acceptable form thereof to the other anticancer agent is 1 to 30:0.8 to 80, preferably 3 to 20:0.8 to 80, more preferably 3 to 12:0.8 to 1.2, 3 to 12:7.5 to 12.5 or 3 to 12:40 to 80, and even more preferably 5:8 to 50. The pharmaceutical combination according to any one of claims 1 to 14.

16. The daily dosage of the compound of formula (I) or a pharmaceutically acceptable form thereof is 1 to 1000 mg, preferably 5 to 500 mg, more preferably 10 to 300 mg, even more preferably 30 to 200 mg, and even more preferably 30 to 120 mg. The pharmaceutical combination according to any one of claims 1 to 15.

17. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable form thereof, at least one other anti-cancer agent, and at least one pharmaceutically acceptable carrier, vehicle or excipient, wherein the other anti-cancer agent is a CDK inhibitor or a pharmaceutically acceptable salt thereof, lenvatinib or a pharmaceutically acceptable salt thereof, sorafenib or a pharmaceutically acceptable salt thereof, or any combination thereof, 【Chemical Formula 8】 wherein, T １ is CR １ and R １ is a cyano group T ２ is CR ２ and R ２ is 【Chemical Formula 9】 selected from the group consisting of, Z is CH, Y is NR and R is hydrogen, W is hydrogen, V is CH ２ and U is 【Chemical Formula 10】 selected from the group consisting of, X ５ is a C １－４ alkyl group, m is 1, a pharmaceutical composition.

18. R ２ is 【Chemical 11】 and, U is 【Chemical 12】 The pharmaceutical composition according to claim 17.

19. The pharmaceutical composition according to claim 17 or 18, wherein the compound of formula (I) is a compound of formula (A). 【Chemical Formula 13】

20. The pharmaceutical composition according to claim 17 or 18, wherein the compound of formula (I) is a compound of formula (B). 【Chemical 14】

21. The pharmaceutically acceptable form of the compound of formula (I) includes a solvate, hydrate, pharmaceutically acceptable salt, stereoisomer, tautomer, isotope derivative, co-crystal, crystal polymorph, prodrug, and metabolite of the compound of formula (I). The pharmaceutical composition according to any one of claims 17 to 20.

22. The other anti-cancer agent is a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, preferably selected from the group consisting of palbociclib, ribociclib, abemaciclib, trilaciclib, G1T-38, G1T-28, AT-7519, FLX-925 and albosidib, and pharmaceutically acceptable salts thereof, more preferably palbociclib. The pharmaceutical composition according to any one of claims 17 to 21.

23. The other anti-cancer agent is lenvatinib mesylate or sorafenib tosylate. The pharmaceutical composition according to any one of claims 17 to 21.

24. The pharmaceutical composition according to any one of claims 17 to 23, which is used for the treatment of malignant neoplastic diseases.

25. The malignant tumor is a solid tumor, preferably selected from the group consisting of lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, epithelial cell cancer, and pancreatic cancer. The pharmaceutical composition according to claim 24.

26. The malignant tumor is hepatocellular carcinoma or intrahepatic cholangiocarcinoma. The pharmaceutical composition according to claim 24 or 25.

27. The malignant tumor is selected from the group consisting of a progressive tumor, a refractory tumor resistant to other treatment means, a recurrent tumor after receiving other treatment means, a metastatic tumor, an FGFR4-mediated tumor, a tumor with an abnormal FGFR4 signaling pathway, and a tumor with amplified FGFR19 or overexpressed FGFR19, and is the pharmaceutical composition according to any one of claims 24 to 26.

28. The pharmaceutical composition according to any one of claims 17 to 27, comprising a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable form thereof, and the other anti-cancer agent.

29. The mass ratio of the compound of formula (I) or a pharmaceutically acceptable form thereof to the other anti-cancer agent is 1 to 30:0.8 to 80, preferably 3 to 20:0.8 to 80, more preferably 3 to 12:0.8 to 1.2, 3 to 12:7.5 to 12.5 or 3 to 12:40 to 80, and still more preferably 5:8 to 50, and is the pharmaceutical composition according to any one of claims 17 to 28.

30. A method for treating a malignant tumor disease, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical combination according to any one of claims 1 to 16, or the pharmaceutical composition according to any one of claims 17 to 29.

31. A method further comprising determining whether the subject has the malignant tumor disease or receiving information that the subject has the malignant tumor disease before administering the pharmaceutical combination or the pharmaceutical composition, wherein the malignant tumor disease is characterized by at least one biomarker selected from the group consisting of overexpression of fibroblast growth factor 19 (FGF19), amplified FGF19, and overexpression of fibroblast growth factor receptor 4 (FGFR4), and is the method according to claim 30.

32. The method according to claim 31, further comprising identifying that the subject responds to the administration of the pharmaceutical combination or the pharmaceutical composition after determining whether the subject has the malignant tumor disease or receiving information that the subject has the malignant tumor disease.

33. The method according to any one of claims 30 to 32, which is used to improve the therapeutic effect of the other anti-cancer agent on the malignant tumor disease.

34. The malignant tumor is a solid tumor, preferably selected from the group consisting of lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, epithelial cell carcinoma, and pancreatic cancer, according to any one of claims 30 to 33.

35. The malignant tumor is hepatocellular carcinoma or intrahepatic cholangiocarcinoma, according to any one of claims 30 to 34.

36. The malignant tumor is selected from the group consisting of a progressive tumor, a refractory tumor resistant to other treatment means, a recurrent tumor after receiving other treatment means, a metastatic tumor, an FGFR4-mediated tumor, a tumor with an abnormal FGFR4 signaling pathway, and a tumor with amplified FGFR19 or overexpressed FGFR19, according to any one of claims 30 to 35.

37. A kit comprising the pharmaceutical combination according to any one of claims 1 to 16, or the pharmaceutical composition according to any one of claims 17 to 29, and an instruction manual.

38. The kit according to claim 37, which is used for the treatment of malignant tumor diseases.

39. The malignant tumor is a solid tumor, preferably selected from the group consisting of lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, epithelial cell carcinoma, and pancreatic cancer, according to claim 38.

40. The malignant tumor is hepatocellular carcinoma or intrahepatic cholangiocarcinoma, according to claim 38 or 39.

41. The malignant tumor is selected from the group consisting of a progressive tumor, a refractory tumor resistant to other treatment means, a recurrent tumor after receiving other treatment means, a metastatic tumor, an FGFR4-mediated tumor, a tumor with an abnormal FGFR4 signaling pathway, and a tumor with amplified FGFR19 or overexpressed FGFR19, according to any one of claims 38 to 40.

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