Drugs for combined use in treating tumor

Abstract

Provided are a pharmaceutical combination comprising a CDK inhibitor and a selective FGFR4 inhibitor, use thereof in preparing a medicament for treating a tumor, and a method for treating a tumor. The CDK inhibitor is preferably a compound represented by formula (I) or a pharmaceutically acceptable form thereof. Studies have shown that the compound represented by formula (I) or the pharmaceutically acceptable form thereof and the selective FGFR4 inhibitor can effectively treat tumors when used in combination with a significant synergistic effect.

Description

Combination drugs for tumor treatment

[0001] Related applications

[0002] This application claims priority and related rights of Chinese Patent Application No. 202311617483.5 filed on November 30, 2023, and the entire contents of the above-mentioned Chinese patent application are incorporated herein by reference. Technical Field

[0003] The present application relates to the field of medicine, and specifically relates to a drug for treating tumors by combining a CDK inhibitor with an FGFR4 selective inhibitor and its application. Background Art

[0004] Cyclin-Dependent Kinases (CDKs) belong to the serine / threonine protein kinase family, with 21 members currently discovered, of which CDK1, CDK2, CDK4, CDK6, etc. are related to the cell cycle; CDK7-9, CDK11-13, CDK19, etc. are related to transcriptional regulation. Dysregulation of CDKs and cyclins leads to abnormal cell proliferation and the occurrence of cancers, such as breast cancer, liver cancer, lung cancer, ovarian cancer, kidney cancer, melanoma, and colorectal cancer. Targeting CDKs is an effective strategy for the development of drugs for blood and solid tumors. CDK4 / 6 regulates the cell cycle from the G1 phase to the S phase by phosphorylating its substrate retinoblastoma (Rb) protein, resulting in the dissociation of the transcription factor E2F bound to the Rb protein. Therefore, CDK4 / 6 inhibitors are usually positive for Rb expression (Rb + Palbociclib is the world's first approved CDK4 / 6 inhibitor. It is currently approved for the treatment of locally advanced or metastatic breast cancer that is hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. It is used in combination with an aromatase inhibitor as initial endocrine therapy for postmenopausal women.

[0005] The compound of formula (I) is a CDK inhibitor under investigation, with the structure shown below in formula (I). PCT application WO2021139817A1 discloses this compound and its preparation method. In vitro enzymatic assays have shown that the compound of formula (I) has inhibitory effects on multiple CDK isoforms, such as CDK2, 4, 6, and 9.

[0006] Fibroblast growth factor receptor (FGFR) is a receptor tyrosine kinase. Its family members include FGFR1, 2, 3, and 4. When continuously activated, each member can induce tumor cell proliferation, invasion, and migration, promote tumor angiogenesis, and promote tumor development and progression. FGFRs are highly expressed and abnormally activated in various tumors, with FGFR4 being the most highly expressed in human hepatocytes. Multiple FGFR4 mutations have been found in patients with liver cancer. FGF401 is a selective FGFR4 inhibitor that has entered the clinical stage. Its structure is shown in Formula (II). PCT patent application WO2015059668A1 discloses this compound and its preparation method.

[0007] Chinese patent application CN108948004A discloses a FGFR4 selective inhibitor, the structure of which is shown in formula (III-A):

[0008] Chinese patent application CN116761807A further discloses the isomers of the compound of formula (III-A), namely, the compound of formula (III-B) and the compound of formula (III-C), as well as the crystal forms, preparation methods and biological activities of the compounds.

[0009] Whether the combination of FGFR4 selective inhibitors and CDK inhibitors can provide more effective treatment for tumors needs further study. Summary of the Invention

[0010] The present application provides a drug combination for combined tumor treatment, its pharmaceutical use, and a method for treating tumors. The drug combination uses a CDK inhibitor and an FGFR4 selective inhibitor in combination, which can further enhance the effect of drug treatment of tumors compared to single drugs, exhibits synergistic effects, and is safe and tolerable, providing a new approach to providing more effective tumor treatment.

[0011] In a first aspect, the present application provides a drug or drug combination, or a pharmaceutical composition comprising a CDK inhibitor and an FGFR4 selective inhibitor.

[0012] In a second aspect, the present application provides use of a combination of a CDK inhibitor and an FGFR4 selective inhibitor in the preparation of a medicament for treating tumors.

[0013] In the above-mentioned first aspect and second aspect, the CDK inhibitor and the FGFR4 selective inhibitor can be simultaneously contained in a clinically acceptable pharmaceutical preparation (single preparation), or can be prepared into clinically acceptable dosage forms respectively, and packaged into the drug or drug combination. That is to say, the drug or drug combination described in the present application not only comprises a compound pharmaceutical preparation (single preparation), but also comprises a combination medicine package or a kit product. For the compound pharmaceutical preparation, the CDK inhibitor and the FGFR4 selective inhibitor are simultaneously contained in one preparation unit to make a clinically acceptable dosage form. For the combination medicine package or kit product, the CDK inhibitor and the FGFR4 selective inhibitor are prepared into clinically acceptable pharmaceutical preparations respectively, that is, the CDK inhibitor and the FGFR4 selective inhibitor are respectively contained in different preparation units and presented in the form of a combination package. In some embodiments, the formulation forms of the CDK inhibitor and the FGFR4 selective inhibitor may be the same or different. In some embodiments, the drug or drug formulation described in the present application is selected from oral formulations, injection formulations, topical formulations or in vitro formulations.

[0014] In a third aspect, the present application provides the use of a CDK inhibitor in the preparation of a drug for improving the effect of an FGFR4 selective inhibitor in treating tumors.

[0015] In a fourth aspect, the present application provides the use of an FGFR4 selective inhibitor in the preparation of a medicament for improving the effect of CDK inhibitors in treating tumors.

[0016] In a fifth aspect, the present application provides a method for treating tumors, comprising administering a therapeutically effective amount of a CDK inhibitor and a FGFR4 selective inhibitor to a patient or subject in need of treatment.

[0017] In a sixth aspect, the present application provides a method for improving the effect of FGFR4 selective inhibitors in treating tumors, which comprises administering a therapeutically effective amount of a CDK inhibitor to a patient or subject in need of treatment.

[0018] In a seventh aspect, the present application provides a method for improving the effect of CDK inhibitors in treating tumors, comprising administering a therapeutically effective amount of a FGFR4 selective inhibitor to a patient or subject in need of treatment.

[0019] In any one of the above-mentioned fifth to seventh aspects, the CDK inhibitor and the FGFR4 selective inhibitor can be administered simultaneously or in parallel, or can be administered separately. That is, the CDK inhibitor and the FGFR4 selective inhibitor can be contained in the same compound preparation unit and are administered simultaneously. Alternatively, the CDK inhibitor and the FGFR4 selective inhibitor are respectively contained in different preparation units, administered simultaneously or in parallel, or are sequentially administered at different times at clinically accepted time intervals within one day, or are administered separately at clinically accepted time intervals, according to the respective dosing frequency and cycle of the CDK inhibitor and the FGFR4 selective inhibitor. The CDK inhibitor and the FGFR4 selective inhibitor are not particularly limited in the order of administration, and can be used as the first treatment or the second treatment according to clinical needs. The simultaneous administration or parallel administration refers to that the first treatment and the second treatment start at the same time, or, when the second treatment delivery begins, the delivery of the first treatment is still ongoing.

[0020] In some embodiments, the administration can be oral administration, injection administration, topical administration or in vitro administration. Accordingly, in some embodiments, the CDK inhibitor and / or FGFR4 selective inhibitor is an oral formulation, an injection formulation, a topical formulation or an in vitro formulation.

[0021] In some specific embodiments, the method further comprises determining whether the patient or subject has the malignant neoplastic disease, or receiving information that the patient or subject has the malignant neoplastic disease, before administering the drug or drug combination. In some embodiments, the malignant neoplastic disease is characterized by: (1) at least one biomarker selected from the following: overexpression of fibroblast growth factor 19 (FGF19), amplified FGF19, overexpression of fibroblast growth factor receptor 4 (FGFR4); and / or, (2) at least one biomarker selected from the following: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb).

[0022] In some specific embodiments, the method further comprises identifying the patient or subject as responsive to administration of the drug or the drug combination after determining whether the patient or subject has the malignant neoplastic disease or receiving information that the patient or subject has the malignant neoplastic disease.

[0023] In some specific embodiments, the method comprises:

[0024] a) determining whether a patient or subject has a malignant neoplastic disease, or receiving information that a patient or subject has a malignant neoplastic disease, wherein the malignant neoplastic disease is characterized by: (1) at least one biomarker selected from the group consisting of: overexpression of fibroblast growth factor 19 (FGF19), amplified FGF19, overexpression of fibroblast growth factor receptor 4 (FGFR4); and / or, (2) at least one biomarker selected from the group consisting of: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb);

[0025] b) identifying that the patient or subject is responsive to administration of the drug or drug combination; and

[0026] c) administering the above-mentioned drug or the above-mentioned drug combination to the patient or subject.

[0027] In an eighth aspect, the present application provides a drug comprising a CDK inhibitor for improving the effect of FGFR4 selective inhibitors in treating tumors.

[0028] In a ninth aspect, the present application provides a drug comprising an FGFR4 selective inhibitor for improving the effect of CDK inhibitors in treating tumors.

[0029] In a tenth aspect, the present application provides a drug or drug combination or pharmaceutical composition comprising a CDK inhibitor and an FGFR4 selective inhibitor, which is used to treat tumors.

[0030] In any one of the above-mentioned first to tenth aspects:

[0031] In some specific embodiments, the tumor described herein is selected from a solid tumor or a hematologic tumor. In some embodiments, the solid tumor is selected from fibrosarcoma, salivary gland cancer, liver cancer, colorectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, brain tumor, lung cancer, melanoma. In some embodiments, the hematologic tumor is selected from acute myeloid leukemia. In a preferred embodiment, the tumor is a solid tumor. In a more preferred embodiment, the tumor is liver cancer.

[0032] In some specific embodiments, the tumor or neoplastic disease is characterized by: (1) at least one biomarker selected from the following: overexpression of fibroblast growth factor 19 (FGF19), amplified FGF19, overexpression of fibroblast growth factor receptor 4 (FGFR4); and / or, (2) at least one biomarker selected from the following: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb). In some embodiments, the tumor or neoplastic disease is an Rb-positive tumor or an Rb-negative tumor, preferably an Rb-positive solid tumor or an Rb-negative solid tumor, more preferably an Rb-positive liver cancer or an Rb-negative liver cancer. In a preferred embodiment, the tumor or neoplastic disease is selected from an Rb-negative solid tumor. In a more preferred embodiment, the tumor or neoplastic disease is an Rb-negative liver cancer.

[0033] In some specific embodiments, the CDK inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, G1T-38, G1T-28, AT-7519, FLX-925, avocidib, a compound of formula (I), or a pharmaceutically acceptable form of the foregoing compound. In a preferred embodiment, the CDK inhibitor is a compound of formula (I) or a pharmaceutically acceptable form thereof, wherein the structure of the compound of formula (I) is as follows:

[0034] In some specific embodiments, the FGFR4 selective inhibitor is selected from Futibatinib, Erdafitinib, Lenvatinib, Rogaratinib, IONIS-FGFR4Rx, EVER-4010001, Irpagratinib, Fisogatinib, Roblitinib, Aldafermin, Gunagratinib, JAB-6343, HS-236, HS-10340, H3B-6527, BPI-43487, ZSP-1241, U3-1784, ICP-105, SY-4798, INCB-62079, ASP-5878, LY-2874455, PRN-1371, SC-0011, ODM-203, FGF401, a compound of formula (III-A), a compound of formula (III-B), a compound of formula (III-C), etc. In a preferred embodiment, the FGFR4 selective inhibitor is selected from FGF401, a compound of formula (III-A), a compound of formula (III-B), a compound of formula (III-C), or a pharmaceutically acceptable form of the foregoing compounds. The structure of the FGF401 compound is shown in the following formula (II):

[0035] The structures of the compound of formula (III-A), the compound of formula (III-B), and the compound of formula (III-C) are shown below:

[0036] In some specific embodiments, the FGFR4 selective inhibitor is preferably a compound of formula (III-B) or a pharmaceutically acceptable form thereof.

[0037] Preferably, in any one of the above aspects 1 to 10, in some specific embodiments, the CDK inhibitor is a compound of formula (I) or a pharmaceutically acceptable form thereof, and the FGFR4 selective inhibitor is a compound of formula (III-B) or a pharmaceutically acceptable form thereof.

[0038] In the first to tenth aspects above, the CDK inhibitor and the FGFR4 selective inhibitor described herein can be combined at any clinically acceptable dose. In some specific embodiments, the CDK inhibitor is a compound of formula (I) or a pharmaceutically acceptable form thereof, and the FGFR4 selective inhibitor is FGF401 or a pharmaceutically acceptable form thereof, and the dosage ratio of the two, calculated as the free form of the compound, is selected from (1-10): (1-10), preferably (3-8): (2-5), more preferably (4-6): (2-4), and more preferably 5:3. In other specific embodiments, the CDK inhibitor is a compound of formula (I) or a pharmaceutically acceptable form thereof, and the FGFR4 selective inhibitor is a compound of formula (III-B) or a pharmaceutically acceptable form thereof. Calculated in free form, the dosage ratio of the two is selected from (1-150): (1-10), preferably (20-125): (2-8), more preferably (30-110): (2-8), more preferably (50-90): (3-7), more preferably (60-80): (4-6), and more preferably 70:5 or 14:1.

[0039] In some specific embodiments, the compound of formula (I) is selected from the free form of the compound of formula (I) or a pharmaceutically acceptable salt thereof, such as sulfate, methanesulfonate, tartrate, benzenesulfonate, hydrochloride, p-toluenesulfonate, fumarate, citrate, and malate. In a preferred embodiment, the pharmaceutically acceptable salt is selected from benzenesulfonate, hydrochloride, p-toluenesulfonate, fumarate, citrate, and malate. In a more preferred embodiment, the pharmaceutically acceptable salt is hydrochloride or benzenesulfonate.

[0040] In some specific embodiments, the compound of formula (III-A), (III-B), (III-C) is selected from the free form of the compound of formula (III-A), (III-B), (III-C) or a pharmaceutically acceptable salt thereof, for example, salts with acidic groups (e.g., potassium salts, sodium salts, magnesium salts, calcium salts) or salts with basic groups (e.g., sulfates, hydrochlorides, phosphates, nitrates, carbonates).

[0041] In some embodiments, the drug, drug combination, pharmaceutical composition or pharmaceutical preparation described herein further comprises a pharmaceutically acceptable excipient or excipient. The drug, drug combination, pharmaceutical composition or pharmaceutical preparation can be a single-dose preparation or a split-dose preparation.

[0042] The combined administration of a CDK inhibitor and an FGFR4 selective inhibitor in the present application can significantly inhibit the growth of tumors (especially liver cancer), achieve a synergistic effect, and produce unexpected technical effects. DETAILED DESCRIPTION

[0043] Definitions and Explanation of Terms

[0044] The term "pharmaceutically acceptable" is used herein to refer to compounds, substances, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, and that are consistent with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. The term "pharmaceutically acceptable form" of a compound herein is selected from the group consisting of solvates, hydrates, pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic derivatives, cocrystals, polymorphs, prodrugs and metabolites of the compound; preferably pharmaceutically acceptable salts, stereoisomers, tautomers; more preferably pharmaceutically acceptable salts.

[0045] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with mammalian tissues, particularly human tissues, without excessive toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base or free acid with a suitable reagent. In some embodiments, "pharmaceutically acceptable salts" refer to salts formed by the compounds of the present invention with pharmaceutically acceptable inorganic acids and organic acids, wherein preferred inorganic acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1,5), oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.

[0046] Unless otherwise specified, the term "isotopic derivative" means that the compounds disclosed herein may exist in an isotopically labeled or enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom found in the largest amount in nature. Isotopes may be radioactive or non-radioactive. Isotopes commonly used as isotopic labels are: Hydrogen isotopes: 2 H and 3 H; Carbon isotope: 13 C and 14 C; Chlorine isotope: 35 Cl and 37 Cl; Fluorine isotope: 18 F; Iodine isotope: 123 I and 125 I; Nitrogen isotopes: 13N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. 3 H and 13 C, because they are easy to label and detect, they are more widely used. Some heavy isotopes, such as deuterium ( 2 H) substitution can enhance metabolic stability and prolong half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques similar to those used for synthesizing non-isotope-labeled compounds.

[0047] Unless otherwise specified, the terms "solvate" and "solvate" refer to a physical association of a compound disclosed herein with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be capable of isolation. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. The solvate may be a solvate of the disclosed compound or a pharmaceutically acceptable salt thereof. "Solvate" encompasses solution-phase and isolatable 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 complexes that may, for example, include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It is to be understood that the term "compound" as used herein includes the compound and solvates of the compound and mixtures thereof. Solvation methods are well known in the art.

[0048] Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that are interconvertible across a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0049] Unless otherwise indicated, the structural formulas described in the present disclosure include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformers. Therefore, single stereochemical isomers of the compounds disclosed herein or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are within the scope of the present disclosure.

[0050] "Enantiomers" or "enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of any ratio of a pair of enantiomers can be referred to as a "racemic" mixture. Where appropriate, the term "(±)" is used to designate a racemic mixture. "Diastereomers" or "diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry can be specified according to the Cahn Ingold Prelog RS system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) according to the direction (right-handed or left-handed) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore produce enantiomers, diastereomers, and other stereoisomeric forms that can be designated as (R) or (S) according to the absolute stereochemistry at each asymmetric atom. The chemical entities, pharmaceutical compositions and methods disclosed herein are intended to include all such possible isomers, including racemic mixtures, optically substantially pure forms and intermediate mixtures. Optically active (R) and (S) isomers can be prepared, for example, using chiral synthons or chiral reagents or resolved using conventional techniques.

[0051] Isomers / enantiomers may, in some embodiments, be substantially free of the corresponding enantiomer and may also be referred to as "optically enriched," "enantiomerically enriched," "enantiomerically pure," and "non-racemic" (used interchangeably herein). These terms refer to compositions in which the amount of one enantiomer is greater than the amount of that enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the S enantiomer refers to a preparation of a compound having greater than about 50% by weight, such as at least about 75% by weight, and further, for example, at least about 80% by weight of the S enantiomer relative to the total weight of the preparation (e.g., the total weight of the S and R isomers). In some embodiments, the enrichment may be significantly greater than about 80% by weight to provide a "substantially enantiomerically enriched," "substantially enantiomerically pure," or "substantially non-racemic" preparation, which refers to a preparation of a composition having at least about 85% by weight of one enantiomer, such as at least about 90% by weight, and further, for example, at least about 95% by weight, relative to the total weight of the preparation. In certain embodiments, the compounds provided herein are composed of at least about 90% by weight of one enantiomer. In other embodiments, the compound is made up of at least about 95%, about 98%, or about 99% by weight of one enantiomer.

[0052] In some embodiments, the compound is a racemic mixture of (S) and (R) isomers. In other embodiments, provided herein is a mixture of compounds, wherein each compound of the mixture exists primarily as (S) or (R) isomers. For example, in some embodiments, the compound mixture has an enantiomeric excess of (S) 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 compound mixture 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 greater. In some embodiments, the compound mixture has an (S) enantiomeric excess of about 55% to about 99.5%, about 60% to about 99.5%, about 65% to about 99.5%, about 70% to about 99.5%, about 75% to about 99.5%, about 80% to about 99.5%, about 85% to about 99.5%, about 90% to about 99.5%, about 95% to about 99.5%, about 96% to about 99.5%, about 97% to about 99.5%, about 98% to about 99.5%, or about 99% to about 99.5%, or greater than about 99.5%.

[0053] Unless otherwise specified, the term "co-crystal" or "co-crystal" is used to describe a situation in which the neutral molecular components are present in a crystalline compound in a well-defined stoichiometric ratio. The preparation of pharmaceutically acceptable co-crystals enables changes to be made to the crystalline form of the active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its desired biological activity (see Pharmaceutical Salts and Co-crystals, edited by J. Wouters and L. Quere, RSC Publishing, 2012).

[0054] Unless otherwise specified, the term "polymorph" or "polymorph" refers to different arrangements of chemical drug molecules, generally manifested as the existence form of drug raw materials in the solid state. A drug can exist in multiple crystalline material states, and different crystalline forms of the same drug may have different solubility and absorption in the body, which will affect the dissolution and release of the formulation. In certain embodiments, "polymorph" or "polymorph" as used herein is also intended to include all crystalline and amorphous forms of the compound or its pharmaceutically acceptable salt, including, for example, crystalline forms, polymorphs, pseudopolymorphs, solvates, hydrates, co-crystals, non-solvated polymorphs (including anhydrates), conformational polymorphs, tautomeric forms, disordered crystalline forms and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is mentioned.

[0055] Unless otherwise specified, the term "metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or a pharmaceutically acceptable salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present disclosure encompasses metabolites of the compound, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient period of time.

[0056] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are often related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include rapid metabolism or poor bioavailability, which themselves may be related to physicochemical properties. For example, they may be bioavailable orally, whereas the parent drug is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example (but not limited to) of a prodrug is any of the compounds described herein, administered as an ester ("prodrug") to facilitate transport across cell membranes (where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial), which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug is a short peptide (polyamino acid) conjugated to an acid group, where the peptide is metabolized to reveal the active moiety.

[0057] As used herein, "combination" administration or "combination" administration refers to administering two (or more) different treatments to a patient or subject while the patient or subject is suffering from a condition, for example, administering two or more drugs to the patient or subject after the patient or subject is diagnosed with the condition and before the condition is cured or eliminated or treatment is stopped for other reasons. In some embodiments, when the delivery of the second treatment begins, the delivery of the first treatment is still ongoing, so there is overlap in terms of administration. This situation is sometimes referred to as "simultaneous" or "parallel delivery" herein. In other embodiments, the delivery of one treatment ends before the delivery of the other treatment begins. In some embodiments of either case, the treatments are more effective due to combined administration. For example, the same effect is observed with less of the second treatment, or the same dose can provide greater relief of symptoms, or a similar situation is observed with the first treatment, compared to the results observed when the second treatment is administered in the absence of the first treatment. In some embodiments, the delivery results in a greater relief of symptoms or other parameters associated with the condition than when the other treatment is delivered in the absence of one treatment. The effects of the two (or more) treatments may be partially additive, fully additive, or greater than additive, i.e., synergistic. The delivery may be such that the effect of the first treatment delivered is still detectable when the second treatment is delivered.

[0058] As used herein, the term "single formulation" refers to a single carrier or vehicle formulated to deliver effective amounts of both therapeutic agents to a patient or subject. A single vehicle is designed to deliver effective amounts of each of the agents and any pharmaceutically acceptable carriers or excipients. In some embodiments, the vehicle is a tablet, capsule, pill, or patch.

[0059] The term "pharmaceutically acceptable excipient" or "pharmaceutical excipient" can be selected from carriers, binders, suspending agents, glidants, flavorings, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, stabilizers, penetration enhancers, defoaming agents, antioxidants, preservatives, solvents or combinations thereof commonly used in the art.

[0060] The term "dose range" refers to the upper and lower limits of acceptable variation in the amount of a given pharmaceutical agent. Generally, a dosage of any amount within the given range can be administered to a patient or subject being treated.

[0061] The term "treat" means to alleviate, reduce or alleviate at least one symptom of a disease in a subject. For example, with respect to a malignant neoplastic disease, the term "treat" may mean to prevent, delay the onset of the disease (i.e., the period before the clinical manifestation of the disease or symptoms of the disease) and / or reduce the risk of the occurrence or worsening of disease symptoms. The term, when used in conjunction with a disease such as cancer, includes, but is not limited to, one or more of the following: preventing the growth of the cancer; causing the cancer to shrink in weight or volume; extending the expected survival time of the patient or subject; inhibiting tumor growth; reducing the tumor mass; reducing the size or number of metastatic lesions; inhibiting the development of new metastatic lesions; extending survival; extending progression-free survival; extending the time to progression; and / or improving the quality of life.

[0062] The terms "treat," "alleviate," and "improve" are used interchangeably herein. These terms refer to methods for obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or preventive benefit. A therapeutic benefit refers to the eradication or improvement of the underlying disorder being treated. The eradication or improvement of one or more physiological symptoms associated with the underlying disorder also achieves a therapeutic benefit, such that an improvement is observed in the patient or subject, even though the patient or subject may still be suffering from the underlying disorder. With regard to preventive benefit, the pharmaceutical composition can be administered to a patient or subject at risk of developing a particular disease, or to a patient or subject who has reported one or more physiological symptoms of a disease, even though the disease may not yet have been diagnosed. In one embodiment, these terms also refer to partially or completely inhibiting or alleviating the condition suffered by an individual. In one embodiment, these terms refer to actions taken to reduce the severity of the condition or to delay or slow the progression of the condition when the patient or subject is suffering from the condition or has been diagnosed with the condition. Treatment does not need to result in a complete cure of the condition; this term includes partial inhibition or alleviation of the condition. Treatment is intended to include prevention or prophylaxis.

[0063] The term "subject" or "patient" is intended to include animals that are capable of having or suffering from a malignant neoplastic disease. Examples of subjects or patients include mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject is a human, such as a human that has, is at risk of, or is potentially capable of having a malignant neoplastic disease.

[0064] The term "enhanced effect" refers to the effect of two agents administered together that provides a greater or improved result than when the individual agents are administered alone without the other agent. Administering the agents together can provide an enhanced effect when they are administered simultaneously or sequentially. Administering the agents sequentially includes administration separated by seconds, minutes, hours, or days. Administering the agents together can provide an enhanced effect when the agents are administered as part of a single formulation or when administered in separate formulations.

[0065] The term "amplified" means that extra copies of a gene or chromosome segment are produced in a cancer cell that may confer a growth or survival advantage. Those skilled in the art can use conventional techniques in the art, such as fluorescence in situ hybridization (FISH) comparative genomic hybridization, and utilize a high-resolution array-based test to measure the copy number of a gene or chromosome segment, wherein the high-resolution array-based test is based on: array comparative genomic hybridization (or aCGH), SNP array technology, and high-resolution microarrays including copy number probes and SNPs, and whole genome (WGS) or whole exome DNA sequencing (WES) using next-generation sequencing (NGS) technology.

[0066] The term "FGFR4" or "FGFR4 protein" refers to any form of FGFR4 protein, including wild type and all variant forms (including but not limited to mutant form and splice variants). FGFR4 protein is the product of FGFR4 gene, so FGFR4 protein includes any protein encoded by any form of FGFR4 gene including any aberration (such as point mutation, insertion / deletion, translocation fusion and focal amplification). The term "overexpression" means that the output of gene product in the sample is higher than the output observed in control sample group (such as, normal tissue). If gene product is not produced in control sample conventionally, overexpression includes expression. The output of gene product can use the routine techniques of this area, and for example immunohistochemistry is measured. In one aspect, FGF19 gene product overexpression is FGF19 protein expression ≥1%.

[0067] The term "therapeutic effect" refers to a beneficial local or systemic effect in an animal, such as a mammal (e.g., a human), caused by the administration of a compound or composition disclosed herein. The phrase "therapeutically effective amount" refers to the amount of a compound or composition disclosed herein that effectively treats a disease or condition at a reasonable benefit / risk ratio. The therapeutically effective amount of the compound or composition will vary depending on the subject and disease or condition being treated, the subject's weight and age, the severity of the disease or condition, the mode of administration, and the like, and is readily determined by those skilled in the art.

[0068] The term "combination therapy" refers to a dosing regimen that requires administering at least two different compounds to a patient or subject. The at least two different compounds can be administered simultaneously or concurrently, or sequentially at different times of the day at clinically accepted intervals, or separately at clinically accepted intervals, at the respective dosing frequencies and cycles of the CDK inhibitor and the FGFR4 selective inhibitor. The dosing regimens of the at least two compounds may, but need not, overlap.

[0069] The term "co-administration" means exposing a subject to two or more treatment regimens (e.g., two or more compounds) at the same time. In some embodiments, two or more compounds can be administered simultaneously; in some embodiments, two or more compounds can be administered sequentially (in a completely non-overlapping dosing regimen); in some embodiments, two or more compounds can be administered in a partially overlapping dosing regimen. In some embodiments, the "administration" of a combination therapy may involve administering one or more compounds to a subject who has already received other compounds (one or more). For clarity, combination therapy does not require that each compound be administered together in a single composition (or even not necessarily administered simultaneously), but in some embodiments, two or more compounds can be administered together in a single composition. In some embodiments, the compounds to be co-administered are separate dosage forms, but are packaged together (e.g., in blister packs or other medicine boxes) to facilitate their co-administration.

[0070] In this document, when reference is made to "A combined with B for treating a disease", "A and B combined / combined for treating a disease" or "A combined with B for preparing a medicament for treating a disease", etc., it generally means that A and B can produce a synergistic effect in treating the disease, that is, the combined therapeutic effect of A and B is better than the individual therapeutic effect of A or B, or the combined side effects / adverse reactions of A and B are lower than the individual side effects / adverse reactions of A or B, including but not limited to, A can enhance the therapeutic effect of an equivalent dose of B, so that the combined therapeutic effect of A and B can be better than the sum of the individual therapeutic effects of A and B; A can reduce the dose of B while producing equivalent therapeutic effects, thereby reducing the side effects / adverse reactions that may be caused by the use of high doses of B; A can directly reduce or avoid the side effects / adverse reactions that may be caused by B; etc.

[0071] In order to provide a more concise description, some quantitative data herein do not use the term "about". It should be understood that, regardless of whether the term "about" is explicitly used or not, each numerical value given here not only includes the actual value given (given value), but also means including the approximate value of such given value reasonably inferred based on a person of ordinary skill in the art, including the equivalents and approximate values ​​of such given value produced due to experimental and / or measurement conditions. In some embodiments, the given value is obtained by rounding off based on the measured value obtained by experiment or measurement or the calculated data based on the measured value. In some embodiments, the approximate value is preferably ± 20%, ± 15%, ± 10%, ± 8%, ± 6%, ± 5%, ± 4%, ± 3%, 2%, ± 1% based on the given value.

[0072] It should be understood that the embodiments or implementations described herein should be considered in a descriptive sense only and not for limiting purposes. The description of features in each embodiment or implementation should generally be considered to be applicable to other similar features in other embodiments or implementations. It should be understood by those of ordinary skill in the art that various changes in form and detail may be made without departing from the spirit and scope defined by the claims.

[0073] Example

[0074] The present disclosure is further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present disclosure only and are not intended to limit the scope of the present disclosure. Experimental methods in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or as recommended by the manufacturer. All raw materials and reagents used, unless otherwise specified, were commercially available.

[0075] The compound of formula (I) of the present application can be prepared by referring to the method disclosed in patent application WO2021139817A1.

[0076] The compound of formula (II) of the present application can be prepared by referring to the method disclosed in patent application WO2015059668A1.

[0077] The compound of formula (III-B) of the present application can be prepared by referring to the method disclosed in patent application CN116761807A.

[0078] Example 1: Study on the efficacy of the compound of formula (I) and FGF401 combined with Nu / Nu mice in human liver cancer Huh-7 cell xenograft tumors

[0079] This study used a Nu / Nu mouse human liver cancer Huh-7 cell xenograft tumor model to evaluate the inhibitory effect of the compound of formula (I) on the growth of Huh-7 transplanted tumors, and also examined the tumor inhibitory effect of the compound of formula (I) in combination with FGF401.

[0080] 1. Materials and Methods

[0081] 1.1 Drugs and preparation methods

[0082] 1.1.1 Medicines

[0083] The compound of formula (I) was prepared according to the method described in patent application WO2021139817A1 and provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.

[0084] FGF401 was prepared according to the method described in patent application WO2015059668A1 and provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.

[0085] 1.1.2 Preparation method

[0086] (1) Solvent: Aqueous solution of 0.4% Tween 80 and 0.5% methylcellulose.

[0087] (2) FGF401 solution: Weigh a certain amount of FGF401, add solvent, add magnetic beads, vortex, and sonicate until a uniform suspension is obtained with a concentration of 1.5 mg / mL.

[0088] (3) Solution of the compound of formula (I): Weigh a certain amount of the compound of formula (I), add solvent, add magnetic beads, vortex, and sonicate until a uniform suspension is obtained with a concentration of 2.5 mg / mL.

[0089] All drugs in this experiment were prepared every 3 days and stored at 4°C in the dark.

[0090] 1.2 Cell sources and experimental animals

[0091] Huh-7 cells (human hepatocellular carcinoma cells) were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

[0092] Experimental animals: 90 female Nu / Nu mice, SPF grade, 6-8 weeks old / 18-20 g, provided by Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0093] 1.3 Test methods

[0094] Huh-7 cells were revived and passaged to the desired cell number. The cells were diluted with serum-free DMEM medium and Matrigel (Corning, Cat. No. 356237) (1:1) and counted using a cell counter. The number of tumor cells was adjusted to approximately 5 × 10 7 The cell suspension was kept in an ice bath.

[0095] Huh-7 cell suspension was drawn with a sterile syringe and inoculated into the subcutaneous tissue on the right side of the back of Nu / Nu mice. The inoculation volume was 0.1 mL / mouse, containing approximately 5×10 tumor cells. 6 Nu / Nu mice Huh-7 xenograft tumor model was established. On day 27 after inoculation, the tumor volume grew to an average of 100-200 mm 3 At the same time, mice with well-growing tumors were selected and divided into 4 groups (G1 to G4) according to tumor volume. Each group was given the drug by gavage once a day at a volume of 10 mL / kg for 6 consecutive days.

[0096] The administration follows the following principles: when the animal body weight drops below 85% (<85%) of the group body weight, the administration is suspended; when it returns to 90% (≥90%), the administration is resumed.

[0097] 1.4 Observation and evaluation indicators

[0098] 1.4.1 General Observations

[0099] All animals were observed once a day during the experimental period, and any abnormalities in their body parts and behavioral changes were recorded.

[0100] Animals of appropriate weight were selected for the experiment. After the start of drug administration, the animals were weighed once a day at a fixed time for weight monitoring. The weight statistics were consistent with the tumor volume statistics.

[0101] For dead animals, the time of death was recorded; for dying animals, the frequency of observation was increased to determine the time of death.

[0102] 1.4.2 Tumor Evaluation

[0103] After the animals were divided into groups, the long and short diameters of the tumors were measured twice a week.

[0104] ①Tumor volume: V = 1 / 2 × a × b 2

[0105] ②Relative tumor volume:

[0106] ③Relative tumor volume growth rate:

[0107] ④Tumor inhibition rate: Note: V: tumor volume

[0108] a: tumor length b: tumor width

[0109] RTV: relative tumor volume

[0110] TV nd : Tumor volume on day n

[0111] TV 1d : Tumor volume on day 1

[0112] RTV xnd : Average relative tumor volume on day n

[0113] TV Xn : Average tumor volume on day n in the drug-treated group

[0114] TV X1 : Average tumor volume on day 1 of the drug-treated group

[0115] TV Mn : Average tumor volume on day n in the model group

[0116] TV M1 : Average tumor volume of the model group on day 1

[0117] 1.4.3 Evaluation of drug synergy

[0118] Burgi correction formula: Q = E(a+b) / [E(a)+E(b)-E(a)*E(b)]

[0119] Evaluation criteria: Q < 0.85 is antagonistic, 0.85 ≤ Q ≤ 1.15 is additive, and Q > 1.15 is synergistic.

[0120] E(a+b): Tumor inhibition rate after combined administration of drugs a and b

[0121] E(a): Tumor inhibition rate when a is administered alone

[0122] E(b): Tumor inhibition rate when b is administered alone

[0123] 1.5 Statistical analysis

[0124] Data were analyzed using SPSS 19.0, with a significance level of 0.05 or P < 0.05. T-tests were used for comparisons between two groups, and one-way ANOVA was used for comparisons between three or more groups. If the F value showed a significant difference, the Games-Howell method was used for analysis; if the F value showed no significant difference, the Dunnet (two-sided) method was used for analysis.

[0125] 2. Results

[0126] 2.1 Body weight and mortality

[0127] No mice in any group died. During the experiment, the body weight of mice in both the solvent and treatment groups increased slowly, indicating that Huh-7 tumor-bearing mice tolerated FGF401 and the compound of formula (I) well. There were no statistically significant differences in body weight between the single-drug and combination-treated groups compared with the solvent group (P>0.05). See Table 1 for details.

[0128] Table 1 Effect on the body weight of tumor-bearing mice (g)

[0129] 2.2 Effects of compounds on tumor growth

[0130] The tumor observation indicators of each group are shown in Table 2. As can be seen from Table 2, on the 6th day (D6) of administration, the tumor growth inhibition rates (TGI%) of the FGF40115 mg / kg, the compound of formula (I) 25 mg / kg, and the combined administration of FGF40115 mg / kg and the compound of formula (I) 25 mg / kg groups were 106.2%, 102.0%, and 163.7%, respectively; the relative tumor volume proliferation rates (T / C%) were 54.2%, 56.2%, and 30.1%, respectively. As can be seen from Table 2, compared with the solvent group, FGF401 and the compound of formula (I) alone and in combination significantly inhibited tumor growth (G2, G3P<0.05; G4P<0.001). Calculated by the tumor volume on the 6th day of administration, the tumor inhibition effect of combined administration was significantly better than that of either alone, and the efficacy had an additive effect (0.85 <Q<1.15)。

[0131] One week after drug withdrawal (Day 13, D13), compared with the solvent group, the compound of formula (I) alone and the compound of formula (I) combined with FGF401 still had significant tumor inhibitory effects (P<0.05), and the effect of the combination group was significantly better than that of the single-dose group.

[0132] Human hepatocellular carcinoma Huh-7 cells are Rb +The above experimental results indicate that the compound of formula (I) alone or in combination with the FGFR4 selective inhibitor (FGF401) has a significant growth inhibitory effect on Rb+ tumors.

[0133] Table 2 Effects on tumor volume Note: Compared with the solvent group: * P<0.05, ** P<0.01, *** P<0.001.

[0134] Example 2 Pharmacodynamic Study on the Combined Administration of the Compound of Formula (I) and the Compound of Formula (III-B) on Human Hepatocellular Carcinoma Hep3b Cell Xenografts in Nu / Nu Mice

[0135] This study used a Nu / Nu mouse human liver cancer cell (Hep3b) transplanted tumor model to verify the anti-tumor effects of the compound of formula (I) alone and in combination with the compound of formula (III-B).

[0136] 1. Materials and Methods

[0137] 1.1 Drugs and preparation methods

[0138] 1.1.1 Medicines

[0139] The compound of formula (I) was prepared according to the method described in patent WO2021139817A1 and provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.

[0140] The compound of formula (III-B) was prepared according to the method of CN116761807A and provided by CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.

[0141] 1.1.2 Drug preparation method

[0142] Drug preparation method Note: The solvent is an aqueous solution containing 5% anhydrous ethanol, 0.4% Tween 80 and 0.5% methylcellulose.

[0143] 1.2 Cell line sources and experimental animals

[0144] Hep3b cells (human hepatocellular carcinoma cells) were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

[0145] 80 female Nu / Nu mice, SPF grade, weighing 18-20 g, were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0146] 1.3 Test methods

[0147] Hep3b cells were revived and passaged in vitro to the desired cell number, counted under a microscope, and diluted with MEM serum-free medium and Matrigel (BD Biosciences, catalog number: 354262) (1:1) to adjust the tumor cell number to approximately 5 × 10 7 The cell suspension was kept in an ice bath.

[0148] Hep3b cell suspension was drawn with a sterile syringe and inoculated subcutaneously into the subcutaneous tissue of the axilla of the forelimb of Nu / Nu mice. The inoculation volume was 0.1 mL / mouse, containing approximately 5×10 tumor cells. 6 Nu / Nu mouse Hep3b xenograft tumor model was established.

[0149] The tumor grew to 160 mm 3 Around 6 s, mice with well-grown tumors were selected and divided into groups according to tumor volume, with 6 animals in each group. The drug was administered orally once a day at a volume of 10 mL / kg for 17 days.

[0150] 1.4 Observation indicators

[0151] 1.4.1 General Status

[0152] All animals were observed once a day during the experimental period, and any abnormalities in their body parts and behavioral changes were recorded.

[0153] Body weight: All animals were weighed once before the experiment, and animals of appropriate weight were selected for the experiment. After the start of drug administration, the animals were weighed once a day at a fixed time.

[0154] Death and dying: For dead animals, record the time of death. For dying animals, increase the frequency of observation to determine the time of death.

[0155] 1.4.2 Tumor volume evaluation

[0156] After the animals were divided into groups, the long and short diameters of the tumors were measured twice a week.

[0157] (1) Tumor volume: V = 1 / 2 × A × B 2

[0158] (2) Relative tumor volume:

[0159] (3) Relative tumor volume growth rate:

[0160] (4) Tumor inhibition rate:

[0161] Note: V: tumor volume

[0162] A: Tumor growth

[0163] B: Tumor width

[0164] RTV: relative tumor volume

[0165] TVnd: tumor volume on day n

[0166] TV0d: tumor volume on day 0

[0167] RTVxnd: average relative tumor volume on day n

[0168] TVXn: Average tumor volume on day n in the treatment group

[0169] TVX0: average tumor volume on day 0 of the treatment group

[0170] TVMn: average tumor volume on day n in the solvent group

[0171] TVM0: average tumor volume on day 0 in the vehicle group

[0172] 1.4.3 Evaluation of tumor weight and drug synergy

[0173] At the end of the experiment, the animals were killed by dislocation, and the tumors were removed and weighed.

[0174] (1) Tumor weight inhibition rate (%) = (1 - tumor weight of drug-treated group / tumor weight of solvent group) × 100%

[0175] (2) The evaluation method of drug synergy was the same as that in Example 1.

[0176] 1.5 Statistical methods

[0177] SPSS 19.0 statistical software was used for data processing. The RepeatedMeasure procedure was used to analyze the changes in tumor volume between groups over time. The Multivariate procedure was used to compare the differences in tumor volume between groups at each measurement. The differences in tumor weight between groups were analyzed using the LSD method of One-way ANOVA.

[0178] 2. Results

[0179] 2.1 General Observation and Weight

[0180] No mice in any group died. Compared with the solvent control group, the 105 mg / kg group receiving the compound of formula (I) and the 5 mg / kg group receiving the compound of formula (III-B) showed less weight gain, with statistically significant differences observed on days 14 and 17 (P<0.05). At the endpoint, all groups showed varying degrees of weight loss, with the solvent control group showing a slight decrease, which may be related to the Hep3b tumor type. See Table 3 for details.

[0181] Table 3 Effects on the body weight of tumor-bearing mice (g)

[0182] Compared with the solvent control group: *P<0.05, **P<0.01, ***P<0.001

[0183] 2.2 Effects of compounds on tumor volume

[0184] Tumor volume results showed that the combination of compound (III-B) (5 mg / kg) and compound (I) (70 mg / kg) significantly inhibited tumor growth compared to the solvent control group (P < 0.001). While the 5 mg / kg group receiving compound (III-B) alone, or the 70 mg / kg or 105 mg / kg group receiving compound (I) alone, showed varying degrees of tumor growth inhibition, no statistically significant difference was observed compared to the solvent control group. Calculated by tumor volume on day 17 (D17), the combined administration demonstrated significantly superior tumor inhibition compared to either compound alone, demonstrating a synergistic effect (Q > 1.15). See Table 4 for details.

[0185] Table 4 Effects on tumor volume

[0186] Compared with the solvent control: ***P < 0.001.

[0187] 2.3 Effects of compounds on tumor weight

[0188] The medium and high dose groups (70 mg / kg or 105 mg / kg) of the compound of formula (I) inhibited tumor growth in a dose-dependent manner, but there was no statistical difference between the two groups and the solvent control group.

[0189] Compared with the solvent control group, the combined administration of the compound of formula (III-B) (5 mg / kg) and the compound of formula (I) (70 mg / kg) significantly inhibited tumor growth (P<0.001), showing a synergistic effect (Q>1.15). The tumor weight and inhibition rate of each group are shown in Table 5.

[0190] Table 5 Effects on tumor weight in mice

[0191] Compared with the solvent control: ***P < 0.001.

[0192] Human hepatocellular carcinoma Hep3b cells are Rb - The above experimental results show that although the compound of formula (I) or the compound of formula (III-B) alone did not significantly inhibit the growth of human liver cancer Hep3b, the combined use of these two active ingredients had a tumor growth inhibition rate of up to 90%, producing a significant synergistic effect.

[0193] The above research results show that the combination of a CDK inhibitor such as a compound of formula (I) and a FGFR4 selective inhibitor such as a compound of formula (III-B) can significantly improve the anti-tumor effect and have a synergistic effect.

Claims

1. A drug combination comprising a CDK inhibitor and a FGFR4 selective inhibitor, Preferably, the CDK inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, G1T-38, G1T-28, AT-7519, FLX-925, avocidib, a compound of formula (I), or a pharmaceutically acceptable form of the foregoing compound; wherein the structure of the compound of formula (I) is shown below: And / or preferably, the FGFR4 selective inhibitor is selected from Futibatinib, Erdafitinib, Lenvatinib, Rogaratinib, IONIS-FGFR4Rx, EVER-4010001, Irpagratinib, Fisogatinib, Roblitinib, Aldafermin, Gunagratinib, JAB-6343, HS-236, HS-10340, H3B-6527, BPI-43487, ZSP-1241, U3-1784, ICP-105, SY-4798, INCB-62079, ASP-5878, LY-2874455, PRN-1371, SC-0011, ODM-203, FGF401, a compound of formula (III-A), a compound of formula (III-B), or a compound of formula (III-C); wherein, The structure of the FGF401 compound is shown in the following formula (II): The structures of the compound of formula (III-A), the compound of formula (III-B), and the compound of formula (III-C) are shown below: Preferably, the CDK inhibitor is a compound of formula (I), or a pharmaceutically acceptable form thereof; and / or the FGFR4 selective inhibitor is selected from FGF401, a compound of formula (III-A), a compound of formula (III-B), a compound of formula (III-C), or a pharmaceutically acceptable form of the foregoing compounds; more preferably, the FGFR4 selective inhibitor is a compound of formula (III-B) or a pharmaceutically acceptable form thereof.

2. The drug combination according to claim 1, wherein the CDK inhibitor and the FGFR4 selective inhibitor are simultaneously contained in a clinically acceptable pharmaceutical preparation; or, the CDK inhibitor and the FGFR4 selective inhibitor are separately prepared into clinically acceptable preparations and packaged in combination into a drug; preferably, the preparation is selected from an oral preparation, an injectable preparation, a topical preparation or an in vitro preparation.

3. Use of the drug combination according to claim 1 in the preparation of a drug for treating tumors, preferably, wherein the tumor is selected from a solid tumor or a blood tumor; preferably, the solid tumor is selected from fibrosarcoma, salivary gland cancer, liver cancer, colorectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, brain tumor, lung cancer, melanoma, and / or the blood tumor is selected from acute myeloid leukemia; more preferably, the tumor is liver cancer.

4. Use of the drug combination according to claim 1 in the preparation of a drug for treating a tumor, wherein the tumor is characterized by: (1) at least one biomarker selected from the group consisting of: fibroblast growth factor 19 (FGF19) overexpression, amplified FGF19, fibroblast growth factor receptor 4 (FGFR4) overexpression; and / or, (2) at least one biomarker selected from the following: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb); Preferably, the tumor is an Rb expression-positive tumor or an Rb expression-negative tumor, preferably an Rb expression-positive solid tumor or an Rb expression-negative solid tumor; more preferably, the tumor is an Rb expression-negative tumor, preferably an Rb expression-negative solid tumor, more preferably an Rb expression-negative liver cancer.

5. The pharmaceutical combination according to claim 1, for treating a tumor, wherein the tumor is preferably selected from a solid tumor or a blood tumor; preferably, the solid tumor is selected from fibrosarcoma, salivary gland cancer, liver cancer, colorectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, brain tumor, lung cancer, melanoma, and / or the blood tumor is selected from acute myeloid leukemia; more preferably, the tumor is liver cancer; and / or wherein the tumor is characterized by: (1) at least one biomarker selected from the group consisting of: fibroblast growth factor 19 (FGF19) overexpression, amplified FGF19, fibroblast growth factor receptor 4 (FGFR4) overexpression, and / or, (2) at least one biomarker selected from the following: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb); Preferably, the tumor is an Rb expression-positive tumor or an Rb expression-negative tumor, preferably an Rb expression-positive solid tumor or an Rb expression-negative solid tumor; more preferably, the tumor is an Rb expression-negative tumor, preferably an Rb expression-negative solid tumor, more preferably an Rb expression-negative liver cancer.

6. Use of a combination of a CDK inhibitor and a FGFR4 selective inhibitor in the preparation of a medicament for treating tumors.

7. Use of CDK inhibitors in the preparation of drugs for improving the effect of FGFR4 selective inhibitors in treating tumors.

8. Use of a FGFR4 selective inhibitor in the preparation of a drug for improving the effect of CDK inhibitors in treating tumors.

9. The use according to any one of claims 6 to 8, wherein: The CDK inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, G1T-38, G1T-28, AT-7519, FLX-925, avocidib, a compound of formula (I), or a pharmaceutically acceptable form of the foregoing compound; The structure of the compound of formula (I) is shown below: And / or the FGFR4 selective inhibitor is selected from Futibatinib, Erdafitinib, Lenvatinib, Rogaratinib, IONIS-FGFR4Rx, EVER-4010001, Irpagratinib, Fisogatinib, Roblitinib, Aldafermin, Gunagratinib, JAB-6343, HS-236, HS -10340, H3B-6527, BPI-43487, ZSP-1241, U3-1784, ICP-105, SY-4798, INCB-62079, ASP-5878, LY-2874455, PRN-1371, SC-0011, ODM-203, FGF401, compound of formula (III-A), compound of formula (III-B), compound of formula (III-C), etc.; wherein, the structure of the FGF401 compound is shown in the following formula (II): The structures of the compound of formula (III-A), the compound of formula (III-B), and the compound of formula (III-C) are shown below: Preferably, the CDK inhibitor is a compound of formula (I), or a pharmaceutically acceptable form thereof; and / or the FGFR4 selective inhibitor is selected from FGF401, a compound of formula (III-A), a compound of formula (III-B), a compound of formula (III-C), or a pharmaceutically acceptable form of the foregoing compounds; more preferably, the FGFR4 selective inhibitor is a compound of formula (III-B) or a pharmaceutically acceptable form thereof.

10. The use according to any one of claims 6 to 9, wherein the tumor is selected from a solid tumor or a hematological tumor; preferably, the solid tumor is selected from fibrosarcoma, salivary gland cancer, liver cancer, colorectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, brain tumor, lung cancer, melanoma; and / or the hematological tumor is selected from acute myeloid leukemia; more preferably, the tumor is liver cancer.

11. The use according to any one of claims 6 to 9, wherein the tumor is characterized by: (1) at least one biomarker selected from the group consisting of: fibroblast growth factor 19 (FGF19) overexpression, amplified FGF19, fibroblast growth factor receptor 4 (FGFR4) overexpression; and / or, (2) at least one biomarker selected from the following: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb); Preferably, the tumor is an Rb expression-positive tumor or an Rb expression-negative tumor, preferably an Rb expression-positive solid tumor or an Rb expression-negative solid tumor; more preferably, the tumor is an Rb expression-negative tumor, preferably an Rb expression-negative solid tumor, more preferably an Rb expression-negative liver cancer.

12. A method for treating a tumor, comprising administering a therapeutically effective amount of a CDK inhibitor and a FGFR4 selective inhibitor to a patient or subject in need of treatment, preferably, wherein the CDK inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, dalpiciclib, G1T-38, G1T-28, AT-7519, FLX-925, avocidib, a compound of formula (I), or a pharmaceutically acceptable form of the foregoing compound; wherein the structure of the compound of formula (I) is as follows: And / or preferably, the FGFR4 selective inhibitor is selected from Futibatinib, Erdafitinib, Lenvatinib, Rogaratinib, IONIS-FGFR4Rx, EVER-4010001, Irpagratinib, Fisogatinib, Roblitinib, Aldafermin, Gunagratinib, JAB-6343, HS-236, HS-10340, H3B-6527, BPI-43487, ZSP-1241, U3-1784, ICP-105, SY-4798, INCB-62079, ASP-5878, LY-2874455, PRN-1371, SC-0011, ODM-203, FGF401, a compound of formula (III-A), a compound of formula (III-B), or a compound of formula (III-C); wherein, The structure of the FGF401 compound is shown in the following formula (II): The structures of the compound of formula (III-A), the compound of formula (III-B), and the compound of formula (III-C) are shown below: Preferably, the CDK inhibitor is a compound of formula (I), or a pharmaceutically acceptable form thereof; the FGFR4 selective inhibitor is selected from FGF401, a compound of formula (III-A), a compound of formula (III-B), a compound of formula (III-C), or a pharmaceutically acceptable form of the foregoing compounds; more preferably, the FGFR4 selective inhibitor is a compound of formula (III-B) or a pharmaceutically acceptable form thereof.

13. The method of claim 12, wherein the tumor is selected from a solid tumor or a hematological tumor; preferably, the solid tumor is selected from fibrosarcoma, salivary gland cancer, liver cancer, colorectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, brain tumor, lung cancer, melanoma, and / or the hematological tumor is selected from acute myeloid leukemia; more preferably, the tumor is liver cancer; and / or wherein the tumor is characterized by: (1) at least one biomarker selected from the group consisting of: fibroblast growth factor 19 (FGF19) overexpression, amplified FGF19, fibroblast growth factor receptor 4 (FGFR4) overexpression, and / or, (2) at least one biomarker selected from the following: positive expression of hormone receptor (HR), positive or negative expression of retinoblastoma protein (Rb); Preferably, the tumor is an Rb expression-positive tumor or an Rb expression-negative tumor, preferably an Rb expression-positive solid tumor or an Rb expression-negative solid tumor; more preferably, the tumor is an Rb expression-negative tumor, preferably an Rb expression-negative solid tumor, more preferably an Rb expression-negative liver cancer.

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