Use of a DNA-PK inhibitor for the preparation of a medicament for the treatment of a tumor

Abstract

The present application provides the use of a DNA-PK inhibitor as an active ingredient in the manufacture of a medicament for treating a tumor.

Description

Related applications

[0001] This application claims priority to Chinese Application No. 2024103763802, filed on March 29, 2024; Chinese Application No. 2024113676389, filed on September 29, 2024; and Chinese Application No. 2024113804194, filed on September 30, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention relates to the use of DNA-PK inhibitors in the preparation of medicaments for treating tumors. Background Technology

[0003] DNA double-strand breaks (DSBs) are a highly damaging form of DNA damage in cells, and unrepaired DSBs are closely associated with cellular carcinogenesis. Non-homologous end joining (NHEJ) is one of the main pathways for repairing DNA double-strand breaks in cells. In NHEJ, the DSB ends are first recognized and bound by Ku70 / 80, and then bind to DNA-dependent protein kinase catalytic subunits (DNA-PKcs) to form DNA-dependent protein kinases (DNAPKs), namely the NHEJ initiation complex (DNAPK). Subsequently, the two DNAPKs bind to the ends of the damaged DNA, simultaneously recruiting subsequent NHEJ repair factors (XRCC4 and XLF) and DNA ligase IV (LigIV) to repair the damaged DNA. Therefore, DNA-PK inhibitors may be promising cancer treatments. However, there are currently no effective DNA-PK inhibitor drugs on the market. Summary of the Invention

[0004] Imidazolinone derivatives have been shown to exhibit high selectivity and significant inhibitory activity against DNA-PK (see, for example, WO2021 / 209055). One object of this disclosure is to provide the use of a DNA-PK inhibitor for the treatment of tumors. Therefore, the use of a DNA-PK inhibitor of formula (I) for the treatment of cancer and tumors is provided herein, wherein the daily dose of the compound of formula (I) is 25-600 mg once daily (QD). A method of treating a subject with cancer in need is also provided herein, comprising administering to said subject a therapeutically effective amount of the DNA-PK inhibitor of this disclosure, wherein the daily dose of said DNA-PK inhibitor is 25-600 mg once daily (QD). In some embodiments, the DNA-PK inhibitor is compound A. Detailed Implementation

[0005] This article provides a method for treating cancer, such as tumors, in subjects in need, comprising administering a compound of formula (I) or a stereoisomer thereof, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal: (I) The daily dose of compound (I) is 25-600 mg once daily (QD). In some embodiments, the cancer is prostate cancer or mesothelioma.

[0006] definition The definitions of the various terms used herein are listed below. These definitions apply to terms used throughout this specification and claims, unless otherwise limited individually or as part of a larger group in specific instances.

[0007] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Typically, the nomenclature used herein, as well as laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are those well-known and commonly used in the art.

[0008] As used herein, the articles “a” and “an” refer to one (or a kind) or more than one (or a kind) (i.e., at least one (or a kind)) grammatical object. For example, “an element” means one element or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0009] As used herein and throughout the disclosure, the term “about” may mean ±10%.

[0010] The term "substitution" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. Unless otherwise specified, the term "substitution" means substitution at any level, such as mono-, di-, tri-, tetra-, or penta-substitution, provided that such substitution is permitted. Substituents are chosen independently, and substitution can occur at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. It should be understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means "unsubstituted" or "substituted." The term "substitution" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as an oxo group, can substitute for two hydrogen atoms.

[0011] Term "C" n-m The indicator includes a range of endpoints, where n and m are integers, and indicates the number of carbon atoms. Examples include C.1-4 C 1-6 wait.

[0012] The term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that can be straight-chain or branched. The term "C" n-m "Alkyl" refers to an alkyl group having n to m carbon atoms. Alkyl groups formally correspond to alkane groups, where one CH bond is replaced by the alkyl group at the attachment point to the rest of the compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moiety include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; and higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc.

[0013] The term "alkoxy" used alone or in combination with other terms refers to a group of the formula -O-alkyl, wherein the alkyl group is as defined above. The term "C" n-m "Alkoxy" refers to an alkoxy group having n to m carbon atoms. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, etc. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. The term "C" n-m "Dialkoxy" refers to the formula -O-(C n-m An alkyl-O- linking group, wherein the alkyl group has n to m carbons. Exemplary dialkoxy groups include –OCH2CH2O- and OCH2CH2CH2O-. In some embodiments, C n-m The two O atoms of a diekoxy group can attach to the same B atom to form a 5- or 6-membered heterocyclic alkyl group.

[0014] The term “carboxyl” or “carbonyl”, used alone or in combination with other terms, refers to the -C(=O)- group, which can also be written as C(O).

[0015] The term "cyano" or "nitrile" refers to a group with the formula -C≡N, which can also be written as -CN.

[0016] The term "halogen" or "halogen," used alone or in combination with other terms, refers to fluorine, chlorine, bromine, and iodine. In some embodiments, "halogen" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halogen is F.

[0017] The term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic ring system (monocyclic, bicyclic, or polycyclic), including cyclized alkyl and alkenyl groups. The term "C" n-m"Cycloalkyl" refers to a cycloalkyl group having n to m ring member carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. Cycloalkyl groups can have 3, 4, 5, 6, or 7 cyclic carbons (C1, C2, C3, C4, C5, C6, C7, C8, C9 ... 3-7 In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C16-3 ... 3-6 Monocyclic cycloalkyl groups. The cycloforming carbon atom of a cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Also included in the definition of cycloalkyl groups are portions having one or more aromatic rings fused to the cycloalkyl ring (i.e., having shared bonds), such as benzo or thiophene derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings can be attached by any cycloforming atom, including the cycloforming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0018] The term "heterocyclic alkyl" as used alone or in combination with other terms refers to a non-aromatic ring or cyclic system that optionally contains one or more alkenyl groups as part of a ring structure, has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and has 4-10, 4-7, or 4-6 ring members. The term "heterocyclic alkyl" includes monocyclic 4, 5, 6, and 7-membered heterocyclic alkyl groups. Heterocyclic alkyl groups may comprise monocyclic or bicyclic (e.g., having two fused or bridged rings) or spirocyclic systems. In some embodiments, a heterocyclic alkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atoms and heteroatoms of a heterocyclic alkyl group may optionally be oxidized to form an oxo group or a thio group or other oxidative bonds (e.g., C(O), S(O), C(S), or S(O)2). N-Oxides, etc.), or the nitrogen atom may be quaternized. Heterocyclic alkyl groups may be attached by cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. Also included in the definition of heterocyclic alkyl groups are portions having one or more aromatic rings fused with the heterocyclic alkyl ring (i.e., having shared bonds), such as benzo or thiophene derivatives of piperidine, morpholine, aziridine, etc. Heterocyclic alkyl groups containing fused aromatic rings may be attached by any cyclic atom, including the cyclic atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include 2,5-diazabicyclo[2.2.1]heptyl; pyrrolidinyl; hexahydropyrrolo[3,4-b]pyrrole-1(2 H )-yl; 1,6-dihydropyridyl; morpholinyl; aziridine-butyl; piperazine; and 4,7-diazaspiro[2.5]octane-7-yl.

[0019] As used herein, the term “treating” or “treatment” means one or more of the following: (1) preventing disease; for example, preventing disease, illness, or condition in an individual who is susceptible to disease, illness, or symptom but has not yet experienced or exhibited the pathology or symptoms of the disease; (2) suppressing disease; for example, suppressing disease, illness, or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, illness, or symptom (i.e., preventing further development of the pathology and / or symptoms); and (3) alleviating disease; for example, alleviating disease, illness, or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, illness, or symptom (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease. In some embodiments, the term “treating” or “treatment” means suppressing or alleviating disease.

[0020] As used herein, the terms “prevent” or “prevention” mean the absence of symptoms or disease development (if not yet occurring), or the absence of further symptoms or disease development (if symptoms or disease have already developed). The ability to treat and prevent some or all of the symptoms associated with the symptoms or disease is also considered.

[0021] As used herein, the terms “patient,” “individual,” or “subject” refer to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is a human.

[0022] As used herein, the terms "effective amount," "pharmaceutical effective amount," and "therapeutic effective amount" refer to an amount of an agent that is non-toxic but sufficient to provide the desired biological outcome. This outcome may be the reduction or alleviation of signs, symptoms, or causes of disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case can be determined by a person skilled in the art using routine laboratory methods.

[0023] As used herein, the term “pharmaceutically acceptable” refers to a material such as a carrier or diluent that does not eliminate the biological activity or properties of a compound and is relatively nontoxic, i.e., that the material can be applied to an individual without causing undesirable biological effects or interacting with any component of the composition containing it in a harmful manner.

[0024] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts described herein include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts discussed herein can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts are prepared by reacting the free acidic or basic form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typically used. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0025] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration to a patient or subject. Various techniques for administering compounds exist in the art, including but not limited to intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0026] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting a compound useful to a patient and enabling the compound to perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of compatibility with other components of the formulation, including the compounds disclosed herein, and harmless to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic, compatible substances used in pharmaceutical formulations.

[0027] As used herein, "pharmaceuticalally acceptable carrier" also includes any and all coatings, antimicrobial and antifungal agents, and absorption delayers that are compatible with the activity of the compounds disclosed herein and are physiologically acceptable to patients. Complementary active compounds may also be incorporated into the composition. "Pharmaceuticalally acceptable carrier" may also include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that may be included in the pharmaceutical composition are known in the art and described, for example, in Remington's Pharmaceutical Sciences (edited by Genaro, Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0028] The term "unit dose" is used herein to mean the simultaneous administration of two pharmaceutical agents, in one dosage form, to a patient to be treated. In some embodiments, a unit dose is a single formulation. In some embodiments, a unit dose includes one or more mediators, such that each mediator contains an effective amount of at least one agent along with a pharmaceutically acceptable carrier and excipients. In some embodiments, a unit dose is one or more tablets, capsules, pills, or patches administered simultaneously to a patient. In some embodiments, a unit dose is administered intravenously (IV) by injection or infusion.

[0029] Methods and uses In one aspect, this article provides a DNA-PK inhibitor for the treatment of tumors. This article also provides a method for treating a subject with cancer (such as a tumor) in need, comprising administering to the subject a therapeutically effective amount of a DNA-PK inhibitor, such as a compound of formula (I).

[0030] One example of this disclosure is the use of a DNA-PK inhibitor in the preparation of a medicament for treating tumors, for example, as an active ingredient. The DNA-PK inhibitor may be selected from compounds represented by M3814, AZD7648, XZP-6877, M-9831, CC-115, BR-101801, XRD-0394, IMP-11, ZL-2201, BAY-8400, SY-7021, or those represented by formula (I) as defined below.

[0031] In one aspect, this article provides the use of compounds of formula (I) for the treatment of tumors, wherein the daily dose of compounds of formula (I) is 25-600 mg once daily.

[0032] In one or more embodiments of this application, the use of compounds of general formula (I) or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals is provided, for example, as an active ingredient, in the preparation of medicaments for the treatment of tumors: (I) in yes , or ; Is it a single bond or a double bond? exist In the given information, A, B, C, and D are each independently either C or N, and at least one of A, B, C, and D is N; R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; R1 is , , , , , , , , , , , Or pyridyl, and R1 is optionally further selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 One or two substituents of the alkoxy group are substituted; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; R2 represents H, cyano, =O, carboxyl, or -C(=O)NR. 2a R 2b C 1-6 Alkoxy, C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl, wherein the C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens and deuterium; R 2a and R 2b H and C are independent of each other. 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 Alkyl groups are optionally further surrounded by one or more elements selected from OH, D, halogen, C. 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally further surrounded by one or more heteroatoms selected from C. 1-6 Alkyl, OH, and halogen substituents; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogens; m is 0 or 1; n is 0, 1, or 2; and x and y are each independently 1, 2 or 3; The condition is when R1 is not R0 when R0, R2 and R3 simultaneously satisfy the following conditions. , or : yes n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0033] In one embodiment, R1 is optionally further substituted with a hydroxyl group of C. 1-6 Alkyl substitution.

[0034] In one aspect, this article provides a method for treating a tumor in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof, a solvate or a pharmaceutically acceptable salt thereof, wherein the daily dose of the compound of formula (I) is 25-600 mg once daily.

[0035] In one or more embodiments of this application, R1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R 1a Is it H or C? 1-6 alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b C 1-6 Alkyl groups, halogens, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl group, wherein -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens and deuterium; R 2a and R 2b H and C are independent of each other. 1-6Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 The alkyl group may optionally be further substituted by one or more substituents selected from OH, D or halogen; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and optionally further substituted by one or more substituents selected from OH and halogens; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogens; m is 0 or 1; and n is 0, 1, or 2; The condition is when R1 is not R0 when R0, R2 and R3 simultaneously satisfy the following conditions. , or : yes n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0036] In one or more embodiments of this application, yes or ; R0 is H, C 1-4 alkyl or cyclopropyl, wherein the C 1-4 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and D; R1 is , , , , , , , , , , or ; R 1a It is H, C 1-6 Alkyl or -C(=O)C 1-6 alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b C1-6 Alkyl groups, halogens, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl group, wherein -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens and deuterium; R 2a and R 2b H and C are independent of each other. 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from OH, D and halogens; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and optionally further substituted by one or more substituents selected from OH and halogens; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogens; m is 0 or 1; and n is 0, 1, or 2; The condition is when R1 is not R0 when R0, R2 and R3 simultaneously satisfy the following conditions. , or : when yes When n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0037] In one or more embodiments of this application, the use of compounds of general formula (II) or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals is provided, for example, as an active ingredient, in the preparation of medicaments for the treatment of tumors: (II) in R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; R1 is , , , , , , , , , , , Or pyridyl, and R1 optionally further contains one to two groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; R 2c It is H, cyano, halogen or C 1-6 Alkoxy; R 2d It consists of H, cyano, carboxyl, and -C(=O)NR. 2a R 2b C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl, wherein the C 1-6 Alkyl groups and -C(=O)OC 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogens and deuterium; R 2a and R 2b It is H, C 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 Alkyl groups are optionally further surrounded by one or more elements selected from OH, D, halogen, C. 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, and optionally further surrounded by one or more heteroatoms selected from C. 1-6 Alkyl, OH, and halogen substituents; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogens; m is 0 or 1; n is 0, 1, or 2; and x and y are each independently 1, 2 or 3; The condition is when R1 is not R0 when R0, R2 and R3 simultaneously satisfy the following conditions. , or ; Selected from n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

[0038] In one or more embodiments of this application, the use of compounds of general formula (III) or their stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals is provided, for example, as an active ingredient, in the preparation of medicaments for the treatment of tumors: (III) in R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; R1 is , , , , , , , , , , , Or pyridyl, and R1 optionally further contains one to two groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; R 2a and R 2b H and C are independent of each other. 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from D or halogens; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, and optionally further surrounded by one or more heteroatoms selected from C.1-6 Alkyl, OH, and halogen substituents; R 2c It is H, cyano, halogen or C 1-6 Alkoxy, wherein the C 1-6 The alkoxy group may optionally be substituted with one or more deuterium groups; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one to three substituents selected from D or halogens; m is 0 or 1; n is 0, 1, or 2; and x and y are each independently 1, 2, or 3.

[0039] In one embodiment, the compound of formula (I) is the compound of formula (IIIa): (IIIa) Or its stereoisomers, solvates or pharmaceutically acceptable salts; in R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; and R1 is , , , , , , , , , , , Or pyridyl, and R1 optionally further contains one to two groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 alkoxy and hydroxy substituted C 1-6 Alkyl substituents; Each R3 is independently halogen or C. 1-6 Alkyl; and n is 2.

[0040] In one or more embodiments of this application, the use of a compound of formula (IV) or its stereoisomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals is provided, for example, as an active ingredient, in the preparation of a medicament for the treatment of tumors: (IV) in R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; and R1 is -(CH) m -4 to 7-membered carbon cyclogroups, -(CH) m -4 to 7-membered heterocyclic groups, -(CH) m -8 to 12 yuan bridge ring, -(CH) m -7 to 12-membered spirorings, where -(CH) m -4 to 7-membered carbon cyclogroups, -(CH) m -4 to 7-membered heterocyclic groups, -(CH) m -8 to 12 yuan bridge ring or -(CH) m -7 to 12-membered spirocyclic rings may optionally be further composed of one or more elements selected from hydroxyl, cyano, halogen, =O, C 1-6 Alkyl, C 1-6 alkoxy and hydroxy substituted C 1-6 Alkyl substituents.

[0041] In one implementation of formula (IV), R1 is , , , , , , , , , , , Or pyridyl, and R1 optionally further contains one to two groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 alkoxy and hydroxy substituted C 1-6 Alkyl substituents; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; m is 0 or 1; and x and y are each independently 1, 2, or 3.

[0042] In one or more embodiments of this application, R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; R1 is , , , , , , , , , , , Or pyridyl, and R1 optionally further contains one to two groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; m is 0 or 1; and x and y are each independently 1, 2, or 3.

[0043] In one or more embodiments of this application, R0 is C 1-4 Alkyl, wherein the C 1-4 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; and R1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0044] In one or more embodiments of this application, the compound of formula (I) (i.e., the active ingredient) is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0045] In one implementation, the compound of formula (I) is , , , or ; Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

[0046] In one implementation, the compound of formula (I) is compound A: ; Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

[0047] In one embodiment, the compound of formula (I) is: ; Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

[0048] In one embodiment, the compound of formula (I) is: ; Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

[0049] In one embodiment, the compound of formula (I) is: ; Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

[0050] In one embodiment, the compound of formula (I) is: ; Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

[0051] In one embodiment, the compound of formula (I) is a compound of formula (I) or a stereoisomer thereof, a solvate, or a pharmaceutically acceptable salt. In one embodiment, the compound of formula (I) is administered in capsule form.

[0052] In one or more embodiments of this application, the tumor is selected from esophageal tumors, lung tumors, head and neck tumors, or pleural mesothelioma.

[0053] In one or more embodiments of this application, the tumor is selected from neuroendocrine tumors, esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic carcinoma, renal cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, lymphoma, nasopharyngeal carcinoma, ovarian cancer, breast cancer, fibrosarcoma, myoma, liposarcoma, chondrosarcoma, osteosarcoma, urethral malignant tumors, thyroid cancer, anal canal malignant tumors, bone and soft tissue malignant tumors, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor. Tumor), leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatocellular carcinoma, cholangiocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, small cell lung cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or heavy chain disease, or any combination thereof.

[0054] In one embodiment, the tumor is prostate cancer. In one embodiment, the tumor is adenocarcinoma. In one embodiment, the tumor is androgen-sensitive prostate adenocarcinoma or hormone-sensitive prostate cancer (HSPC).

[0055] In one embodiment, the cancer is mesothelioma. In one embodiment, the tumor is lung cancer. In one embodiment, the tumor is carcinoma. In one embodiment, the tumor is squamous cell carcinoma of the lung.

[0056] In one or more embodiments of this application, neuroendocrine tumors include SSTR-positive gastrointestinal and pancreatic neuroendocrine tumors, SSTR-positive bronchial neuroendocrine tumors, unresectable or metastatic SSTR-positive neuroendocrine tumors, invasive gastrointestinal and pancreatic neuroendocrine tumors, gastrointestinal neuroendocrine tumors with liver metastases, bronchial neuroendocrine tumors with liver metastases, neuroendocrine tumors of unknown primary site with liver metastases, and other SSTR-positive neuroendocrine tumors; prostate cancer includes PSMA-positive metastatic castration-resistant prostate cancer, metastatic neuroendocrine prostate cancer, and metastatic castration-resistant prostate cancer that has not received chemotherapy. Resistant prostate cancer and progressive metastatic castration-resistant prostate cancer; neuroblastoma including SSTR-positive refractory or relapsed neuroblastoma; glioblastoma including newly diagnosed glioblastoma, progressive glioblastoma, and relapsed glioblastoma; leukemia selected from acute lymphoblastic leukemia or acute myeloid leukemia, with acute myeloid leukemia including myeloid leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, and / or erythroleukemia; chronic leukemia including chronic myeloid / granulocytic leukemia and / or chronic lymphocytic leukemia; lymphoma including Hodgkin lymphoma. Lymphoma and / or non-Hodgkin's lymphoma; gastric cancer including gastric adenocarcinoma; head and neck cancer including adenoid cystic carcinoma and / or adenoid cystic carcinoma of the tongue; lung cancer including limited-stage small cell lung cancer, extensive-stage small cell lung cancer, non-small cell lung cancer, large cell neuroendocrine carcinoma of the lung, lung adenocarcinoma, sarcomatoid carcinoma of the lung and / or squamous cell carcinoma of the lung, as well as CNS metastatic lung cancer; cervical cancer including cervical squamous cell carcinoma; breast cancer including invasive ductal carcinoma, ductal carcinoma, recurrent breast cancer and CNS metastatic breast cancer; and ovarian cancer including clear cell carcinoma of the ovary or serous carcinoma of the ovary.

[0057] In one aspect, this article provides a method of treating adenocarcinoma in a subject of need, comprising administering to the subject 500 mg (QD) of compound A or its stereoisomers, solvates, or pharmaceutically acceptable salts. In some embodiments, the adenocarcinoma is prostate adenocarcinoma. In one embodiment, the cancer is androgen-sensitive prostate adenocarcinoma or hormone-sensitive prostate cancer (HSPC). In one embodiment, the subject has received one or more treatments selected from abiraterone, prednisone, methylprednisolone, enzalutamide, olaparib, and chemical castration prior to treatment with compound A.

[0058] In one aspect, this article provides a method for treating a subject with mesothelioma in need, comprising administering to the subject 300 mg (QD) of compound A or its stereoisomers, solvates, or pharmaceutically acceptable salts. In one embodiment, the subject has received one or more treatments selected from pemetrexed, cisplatin, bevacizumab, antitumor herbal remedies, cadonilimab (PD-1 / CTLA-4), etoposide, and apatinib prior to treatment with compound A.

[0059] In one aspect, this article provides a method for treating cancer in a subject of need, comprising administering to the subject 300 mg (QD) of compound A or its stereoisomers, solvates, or pharmaceutically acceptable salts. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is a tumor, specifically squamous cell carcinoma of the lung.

[0060] In one embodiment of the method and use, the method or use involves administering a therapeutically effective amount of the compound provided herein or its stereoisomers, solvates or pharmaceutically acceptable salts, or compositions comprising the compound provided herein to a subject requiring treatment (including, but not limited to, human or animal subjects, including those identified as requiring treatment).

[0061] Pharmaceutical Composition In one aspect, this article provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof, a solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0062] In one embodiment, compound (I) is compound (II). In one embodiment, compound (I) is compound (III). In one embodiment, compound (I) is compound (IIIa). In one embodiment, compound (I) is compound (IV).

[0063] In another embodiment, compounds of formulas (I), (II), (III), and (IV) are selected from the compounds disclosed above. In another embodiment, compounds of formulas (I), (II), (III), and (IV) are... , , , or ; Or its pharmaceutically acceptable salt.

[0064] In one embodiment, compounds of formulas (I), (II), (III) and (IV) are compound A.

[0065] In one embodiment, the pharmaceutical composition is used to treat a tumor. In one embodiment, the tumor is a solid tumor. In one embodiment, the tumor is prostate cancer. In one embodiment, the tumor is mesothelioma.

[0066] Drug formulation This article includes pharmaceutical formulations or pharmaceutical products. Such pharmaceutical formulations (e.g., packaged pharmaceutical formulations) include, for example, pharmaceutical formulations containing one or more compounds of formula (I). The pharmaceutical formulation is contained in a container. The packaging typically includes instructions for using the formulation to treat animals (or typically human patients) with cancer.

[0067] In some embodiments, the pharmaceutical formulation (e.g., packaged pharmaceutical formulation) or pharmaceutical product contains the compounds described herein in a container and is accompanied by instructions for use in a dosage form according to a fixed schedule. In some of these embodiments, the formulation is in unit dose form.

[0068] The packaged pharmaceutical formulations described herein include, for example, prescribing information for patients or healthcare providers, or as a label on the packaged pharmaceutical formulation. Prescribing information may include, for example, information regarding the efficacy, dosage and administration, contraindications, and adverse reactions of the pharmaceutical formulation.

[0069] Application / Dosage On the other hand, this article provides a pharmaceutical composition or a compound of formula (I) or a stereoisomer thereof, a solvate or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0070] In some embodiments, the compound of formula (I) (e.g., compound A) is administered at a dose of about 1-3000 mg daily, such as about 1-2000 mg (e.g., about 1-1000 mg, or about 1-500 mg). In some embodiments, the compound of formula (I) (e.g., compound A) is administered at a dose of about 1-1000 mg / kg daily. In some embodiments, the compound of formula (I) (e.g., compound A) is administered at a dose of about 1-100 mg / kg daily (e.g., about 1-50 mg / kg, about 1-25 mg / kg, about 1-15 mg / kg, about 1-10 mg / kg, or about 1-5 mg / kg). In some embodiments, the compound of formula (I) (e.g., compound A) is administered at a dose of about 1-25 mg / kg daily (e.g., about 25 mg / kg, about 20 mg / kg, about 15 mg / kg, about 10 mg / kg, or about 5 mg / kg).

[0071] The total daily dose of compound (I) may be administered according to, but is not limited to, the following regimens: once daily, twice daily, three times daily, four times daily, five times daily, once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or ten times or more monthly. In some embodiments, compound (I) is administered once daily.

[0072] In one or more embodiments of this application, the daily dose of the compound of formula (I) or its stereoisomers, solvates or pharmaceutically acceptable salts is about 25-600 mg once daily, about 50-400 mg once daily or about 100-300 mg once daily.

[0073] In one or more embodiments of this application, the daily dose of the active ingredient is 25-600 mg once daily, preferably 50-400 mg once daily, and more preferably 100-300 mg once daily.

[0074] In one or more embodiments of this application, the daily dose of the compound of formula (I) or its stereoisomers, solvates or pharmaceutically acceptable salts is about 25 mg once daily, about 50 mg once daily, about 75 mg once daily, about 300 mg once daily or about 500 mg once daily.

[0075] In one or more embodiments of this application, the daily dose of the active ingredient is 25 mg once daily, or 50 mg once daily, or 75 mg once daily, or 500 mg once daily, or 300 mg once daily.

[0076] In one or more embodiments of this application, the daily dose of the compound of formula (I) or its stereoisomers, solvates or pharmaceutically acceptable salts is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg or about 600 mg.

[0077] In one implementation, the compound of formula (I) or its stereoisomers, solvates or pharmaceutically acceptable salts are administered in capsule form.

[0078] The actual dose level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of the active ingredient that effectively achieves the desired therapeutic response for a particular patient, composition, and administration mode without being toxic to the patient.

[0079] In particular, the selected dose level will depend on a variety of factors, including the activity of the specific agent used, the time of administration, the rate of excretion of the agent, the duration of treatment, other drugs, compounds or materials used in combination with the agent, the age, sex, weight, condition, general health and medical history of the patient being treated, and similar factors well known in the medical field.

[0080] For oral applications, tablets, sugar-coated pills, liquids, drops, suppositories, capsules, pouches, and gelatin capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically effective excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated using known techniques for aesthetic purposes or to delay the release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0081] Example The following detailed description of the implementation process and beneficial effects of the present invention through specific examples is intended to help readers better understand the essence and features of the present invention, but is not intended to limit the scope of implementation of the present invention.

[0082] Those skilled in the art will recognize or be able to determine numerous equivalents of the particular procedures, implementations, claims, and embodiments described herein using only conventional experiments. Such equivalents are considered to be within the scope of this disclosure and are covered by the appended claims. For example, it should be understood that modifications to experimental conditions using art-recognized alternatives and employing experiments no more than conventional are within the scope of this application.

[0083] It should be understood that wherever values ​​and ranges are provided herein, all values ​​and ranges covered by such values ​​and ranges are intended to be covered within the scope of this disclosure. Furthermore, all values ​​falling within these ranges, as well as the upper or lower limits of the ranges of values, are also covered by this application.

[0084] The following examples further illustrate various aspects of this disclosure. However, they in no way constitute a limitation on the teachings of this disclosure.

[0085] The synthesis and activity of the compounds of formula (I) disclosed herein (including compound A) are described in WO 2021 / 209055, which is incorporated herein by reference in its entirety. Compound A is referred to as compound 62 in WO 2021 / 209055.

[0086] Compound A is available in capsules in 25 mg, 100 mg, 300 mg or 500 mg strengths.

[0087] Clinical trial administration protocol Single-dose period (C0D1-C0D3): Compound A is administered once on day 1, followed by a 2-day break; if no dose-limiting toxicity (DLT) event occurs, the first cycle of multiple-dose administration (C1D1-C1D28) begins: Compound A is administered once daily for 28 days, with each cycle lasting 28 days; if no DLT event occurs, administration continues until the subject experiences disease progression, withdraws from the group, or becomes intolerant of the drug. The dose for each administration is determined based on the dose group the subject is assigned to (e.g., the dose may be 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg), and the drug should be taken half an hour before breakfast each day.

[0088] Clinical results After evaluation, one patient with squamous cell carcinoma of the lung was assessed as having a stable disease (SD), and one patient with pleural mesothelioma was assessed as having a partial response (PR) (Table 2).

[0089] As shown in the following clinical data, the DNA-PK inhibitor compound A of this application is effective as an active ingredient in anti-tumor therapy, and has good safety and tolerability.

[0090] Table 1. Clinical outcomes in patients with prostate cancer

[0091] Note: TPSA stands for total prostate-specific antigen; and ALP stands for alkaline phosphatase.

[0092] Table 2. Clinical outcomes of patients with mesothelioma

[0093] The clinical data above show that compound A is well-tolerated in cancer patients, with no DLT or SAE observed. Compound A also demonstrates promising activity in prostate cancer patients by reducing TPSA and ALP levels.

Claims

1. Use of a compound of formula (I) for the treatment of tumors, wherein the daily dose of said compound of formula (I) is 25-600 mg once daily: (I) in yes , or ; Is it a single bond or a double bond? exist In the given information, A, B, C, and D are each independently either C or N, and at least one of A, B, C, and D is N; R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; R1 is , , , , , , , , , , , Or pyridyl, and R1 is optionally further selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 One or two substituents of the alkoxy group are substituted; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; R2 represents H, cyano, =O, carboxyl, or -C(=O)NR. 2a R 2b C 1-6 Alkoxy, C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl, wherein the C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens and deuterium; R 2a and R 2b H and C are independent of each other. 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 Alkyl groups are optionally further surrounded by one or more elements selected from OH, D, halogen, C. 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, and optionally further surrounded by one or more heteroatoms selected from C. 1-6 Alkyl, OH, and halogen substituents; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogens; m is 0 or 1; n is 0, 1, or 2; and x and y are each independently 1, 2 or 3; The condition is when R1 is not R0 when R0, R2 and R3 simultaneously satisfy the following conditions. , or : yes n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

2. The use according to claim 1, wherein R1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R 1a Is it H or C? 1-6 alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b C 1-6 Alkyl groups, halogens, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl group, wherein -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens and deuterium; R 2a and R 2b H and C are independent of each other. 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 The alkyl group may optionally be further substituted by one or more substituents selected from OH, D or halogen; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and optionally further substituted by one or more substituents selected from OH and halogens; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogens; m is 0 or 1; and n is 0, 1, or 2; The condition is when R1 is not R0 when R0, R2 and R3 simultaneously satisfy the following conditions. , or : yes n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

3. The use according to claim 1, wherein yes or ; R0 is H, C 1-4 alkyl or cyclopropyl, wherein the C 1-4 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and D; R1 is , , , , , , , , , , or ; R 1a It is H, C 1-6 Alkyl or -C(=O)C 1-6 alkyl; R2 is H, cyano, -C(=O)NR 2a R 2b C 1-6 Alkyl groups, halogens, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl group, wherein -C(=O)OC 1-6 Alkyl or C 1-6 The alkoxy group is optionally substituted by one or more substituents selected from halogens and deuterium; R 2a and R 2b H and C are independent of each other. 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from OH, D and halogens; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, and optionally further substituted by one or more substituents selected from OH and halogens; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogens; m is 0 or 1; and n is 0, 1, or 2; The condition is when R1 is not R0 when R0, R2 and R3 simultaneously satisfy the following conditions. , or : when yes When n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

4. The use according to claim 1, wherein the compound of formula (I) is a compound of formula (II) or a stereoisomer thereof, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal: (II) in R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; R1 is , , , , , , , , , , , Or pyridyl, and R1 optionally further contains one to two groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; R 2c It is H, cyano, halogen or C 1-6 Alkoxy; R 2d It consists of H, cyano, carboxyl, and -C(=O)NR. 2a R 2b C 1-6 Alkyl, halogen, -S(=O)2R 2a or -C(=O)OC 1-6 Alkyl, wherein the C 1-6 Alkyl groups and -C(=O)OC 1-6 The alkyl group is optionally substituted with one or more substituents selected from halogens and deuterium; R 2a and R 2b It is H, C 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 Alkyl groups are optionally further surrounded by one or more elements selected from OH, D, halogen, C. 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, and optionally further surrounded by one or more heteroatoms selected from C. 1-6 Alkyl, OH, and halogen substituents; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally further substituted with 1 to 3 substituents selected from D and halogens; m is 0 or 1; n is 0, 1, or 2; and x and y are each independently 1, 2 or 3; The condition is when R1 is not R0 when R0, R2 and R3 simultaneously satisfy the following conditions. , or : Selected from n is 1, R0 is H or methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

5. The use according to claim 4, wherein the compound of formula (II) is a compound of formula (III) or a stereoisomer thereof, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal: (III) in R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; R1 is , , , , , , , , , , , Or pyridyl, and R1 optionally further contains one to two groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; R 2a and R 2b H and C are independent of each other. 1-6 Alkyl or 3- to 5-membered cycloalkyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from D or halogens; Or, R 2a and R 2b Together with the atoms to which they are attached, they form a 5- to 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O, and S, and optionally further surrounded by one or more heteroatoms selected from C. 1-6 Alkyl, OH, and halogen substituents; R 2c It is H, cyano, halogen or C 1-6 Alkoxy, wherein the C 1-6 The alkoxy group may optionally be substituted with one or more deuterium groups; R3 is a halogen or C. 1-6 Alkyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one to three substituents selected from D or halogens; m is 0 or 1; n is 0, 1, or 2; and x and y are each independently 1, 2, or 3.

6. The use according to claim 1, wherein the compound of formula (I) is a compound of formula (IV) or a stereoisomer thereof, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt, or a cocrystal: (IV) in R0 is H, C 1-6 alkyl or cyclopropyl, wherein the C 1-6 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; and R1 is , , , , , , , , , , , Or pyridyl, and R1 optionally further contains one to two groups selected from D, halogen, cyano, hydroxyl, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups; R 1a Is it H or C? 1-6 alkyl; R 1b C is substituted with H, OH, cyano or hydroxyl groups. 1-6 alkyl; m is 0 or 1; and x and y are each independently 1, 2, or 3.

7. The use according to claim 6, wherein... R0 is C 1-4 Alkyl, wherein the C 1-4 The alkyl group may optionally be further substituted with one or more substituents selected from halogens and deuterium; and R1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

8. The use according to any one of claims 1 to 7, wherein the compound of formula (I) is selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

9. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is compound A: ； Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

10. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is: ； Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

11. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is: ； Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

12. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is: ； Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

13. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is: ； Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

14. The use according to any one of claims 1 to 13, wherein the tumor is selected from solid tumors.

15. The use according to any one of claims 1 to 14, wherein the tumor is selected from neuroendocrine tumors, esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic carcinoma, renal cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, lymphoma, nasopharyngeal carcinoma, ovarian cancer, breast cancer, fibrosarcoma, myoma, liposarcoma, chondrosarcoma, osteosarcoma, urethral malignant tumors, thyroid cancer, anal canal malignant tumors, bone and soft tissue malignant tumors, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, etc. Cellular carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, nephroblastoma, cervical cancer, testicular tumor, small cell lung cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenström macroglobulinemia or heavy chain disease, or any combination thereof.

16. The use according to any one of claims 1 to 14, wherein the tumor is prostate cancer.

17. The use according to any one of claims 1 to 14, wherein the tumor is a mesothelioma.

18. The use according to claim 15, wherein the neuroendocrine tumor includes SSTR-positive gastrointestinal and pancreatic neuroendocrine tumors, SSTR-positive bronchial neuroendocrine tumors, unresectable or metastatic SSTR-positive neuroendocrine tumors, invasive gastrointestinal and pancreatic neuroendocrine tumors, gastrointestinal neuroendocrine tumors with liver metastases, bronchial neuroendocrine tumors with liver metastases, neuroendocrine tumors of unknown primary site with liver metastases, and other SSTR-positive neuroendocrine tumors; the prostate cancer includes PSMA-positive metastatic castration-resistant prostate cancer, metastatic neuroendocrine prostate cancer, metastatic castration-resistant prostate cancer that has not received chemotherapy, and progressive metastatic castration-resistant prostate cancer; the neuroblastoma includes SSTR-positive refractory or recurrent neuroblastoma; the glioblastoma includes newly diagnosed glioblastoma, progressive glioblastoma, and recurrent glioblastoma. Lymphoma; the leukemia is selected from acute lymphoblastic leukemia or acute myeloid leukemia, and the acute myeloid leukemia includes myeloid leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia and / or erythroleukemia; the chronic leukemia includes chronic myeloid / granulocytic leukemia and / or chronic lymphocytic leukemia; the lymphoma includes Hodgkin lymphoma and / or non-Hodgkin lymphoma; the gastric cancer includes gastric adenocarcinoma; the head and neck cancer The cancer includes adenoid cystic carcinoma and / or adenoid cystic carcinoma of the tongue; the lung cancer includes limited-stage small cell lung cancer, extensive-stage small cell lung cancer, non-small cell lung cancer, large cell neuroendocrine carcinoma of the lung, lung adenocarcinoma, lung sarcomatoid carcinoma and / or lung squamous cell carcinoma and CNS metastatic lung cancer; the cervical cancer includes cervical squamous cell carcinoma; the breast cancer includes invasive ductal carcinoma, ductal carcinoma, recurrent breast cancer and CNS metastatic breast cancer; and the ovarian cancer includes clear cell carcinoma of the ovary or serous carcinoma of the ovary.

19. The use according to any one of claims 1 to 18, wherein the daily dose of the compound of formula (I) is about 50-400 mg once daily.

20. The use according to any one of claims 1 to 18, wherein the daily dose of the compound of formula (I) is about 100-300 mg once daily.

21. The use according to any one of claims 1 to 20, wherein the daily dose of the compound of formula (I) is about 25 mg once daily, about 50 mg once daily, about 75 mg once daily, about 300 mg once daily, or about 500 mg once daily.

22. The use according to any one of claims 1 to 21, wherein the compound of formula (I) is administered in capsule form.

23. A method for treating a tumor in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof, a solvate or a pharmaceutically acceptable salt thereof, wherein the daily dose of the compound of formula (I) is 25-600 mg once daily.

24. The method according to claim 23, wherein the compound of formula (I) is , , , or ; Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

25. The method according to claim 23 or 24, wherein the compound of formula (I) is compound A: ； Or its stereoisomers, solvates, or pharmaceutically acceptable salts.

26. The method according to any one of claims 23 to 25, wherein the tumor is a solid tumor.

27. The method according to any one of claims 23 to 26, wherein the tumor is prostate cancer.

28. The method according to any one of claims 23 to 26, wherein the tumor is a mesothelioma.

29. The method according to any one of claims 23 to 28, wherein the compound of formula (I) is administered in capsule form.

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