WO2025202996A1

WO2025202996A1 - Use of dna-pk inhibitor in preparation of a drug for use in the treatment of tumors

Info

Publication number: WO2025202996A1
Application number: PCT/IB2025/053309
Authority: WO
Inventors: Yonggang Wei; Yi Sun; Fei Ye; Rui Liu
Original assignee: Kangbaida Sichuan Biotechnology Co Ltd
Current assignee: Kangbaida Sichuan Biotechnology Co Ltd
Priority date: 2024-03-29
Filing date: 2025-03-28
Publication date: 2025-10-02
Anticipated expiration: 2026-09-29

Abstract

The present invention provides the use of a DNA-PK inhibitor as an active ingredient in the preparation of a drug for use in the treatment of a tumor.

Description

USE OF DNA-PK INHIBITOR

IN PREPARATION OF A DRUG FOR USE IN THE TREATMENT OF TUMORS

RELATED APPLICATIONS

This application claims priority to Chinese Application No. 2024103763802 filed March 29, 2024; Chinese Application No. 20241 13676389 filed September 29, 2024; and Chinese Application No. 2024113804194 filed September 30, 2024, the content of each of which is incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to the use of a DNA-PK inhibitor in the preparation of a drug for use in the treatment of a tumor.

BACKGROUND

DNA double-strand break (DSB) is a highly harmful form of DNA damage in cells, and DNA double-strand breaks that are not repaired in time are closely associated with the development of cancer in of cells. Non-homologous end-joining (NHEJ) is one of the main pathways for the repair of DNA double-strand breaks in cells. In NHEJ, the DSB end is first recognized and bound by Ku70/80and then binds to a DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form a DNA-dependent protein kinase (DNAPK), i.e., an NHEJ initiation complex (DNAPK). Subsequently, two DNAPKs bind to the ends of damaged DNA while recruiting subsequent NHEJ repair factors (XRCC4 and XLF) and DNA ligase IV (LiglV) to repair the damaged DNA. DNA-PK inhibitors could therefore be a promising cancer treatment. However, there are still no effective DNA-PK inhibitor drugs on the market.

SUMMARY

Imidazolinone derivatives have been shown to have high selectivity and significant inhibitory activity against DNA-PK (see, e.g., WO 2021/209055). An objective of the present disclosure is to provide the use of a DNA-PK inhibitor for the treatment of a tumor. Therefore, provided herein are uses of a DNA-PK inhibitor of formula (I) for the treatment of cancer and tumors wherein the daily dose of the compound of formula (I) is 25-600 mg once per day (QD). Also provided herein are methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a DNAPK inhibitor of the present disclosure wherein the daily dose of the DNA-PK inhibitor is 25- 600 mg once per day (QD). In certain embodiments, the DNA-PK inhibitor is Compound A. DETAILED DESCRIPTION

Provided herein is method of treating cancer, e.g., a tumor, in a subject in need thereof comprising administering a compound represented by formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: wherein the daily dose of the compound of formula (I) is 25-600 mg once per day (QD). In some embodiments, the cancer is prostate cancer or mesothelioma.

Definitions

Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

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

As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

As used herein and throughout the disclosure, the term “about” can mean ± 10%.

The term “substituted” means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group. The term “substituted,” unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule. The phrase “optionally substituted” means unsubstituted or substituted. The term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_n-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C-M, CI-6 and the like. The term “alkyl” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. The term “C_n-m alkyl,” refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1 -butyl, n-pentyl, 3-pentyl, n-hexyl, 1 ,2,2-trimethylpropyl and the like.

The term “alkoxy,” employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group is as defined above. The term “C_n-m alkoxy” refers to an alkoxy group, the alkyl group of which has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy and the like. 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 a linking group of formula -O-(C_n.m alkyl)-O-, the alkyl group of which has n to m carbons. Example dialkyoxy groups include -OCH2CH2O- and OCH2CH2CH2O-. In some embodiments, the two O atoms of a C _n-m dialkoxy group may be attached to the same B atom to form a 5- or 6- membered heterocycloalkyl group.

The term “carboxyl” or “carbonyl,” employed alone or in combination with other terms, refers to a -C(=O)- group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula -C=N, which also may be written as -CN.

The terms “halo” or “halogen,” used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, halo groups are F.

The term “cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term “C_n-m cycloalkyl” refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ringforming carbons (C3-7). 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 a C_3.6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (/.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1 ]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) or spirocyclic ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1 , 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, A/-oxide etc.) or a nitrogen atom can be quaternized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ringforming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (/.e., having a bond in common with) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include 2,5-diazabicyclo[2.2.1]heptanyl; pyrrolidinyl; hexahydropyrrolo[3,4-b]pyrrol-1 (2/7)-yl; 1 ,6- dihydropyridinyl; morpholinyl; azetidinyl; piperazinyl; and 4,7-diazaspiro[2.5]octan-7-yL

As used herein, the term “treating” or “treatment” refers to one or more of (1 ) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease. In some embodiments, the term “treating” or “treatment” refers to inhibiting or ameliorating the disease.

As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

As used herein, the term “patient,” “individual,” or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and marine mammals. Preferably, the patient, subject, or individual is human.

As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein a parent compound is modified by converting an existing acid or base moiety to 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 or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts described herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts discussed herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The phrase “pharmaceutically acceptable salt” is not limited to a mono, or 1 :1 , salt. For example, “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., 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.

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 of the composition to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound disclosed herein, and not injurious to the patient. Some examples of materials that may 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; 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 glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of a compound disclosed herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) disclosed herein. Other additional ingredients that may be included in the pharmaceutical compositions are known in the art and described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

The term “unit dose” is used herein to mean simultaneous administration of both agents together, in one dosage form, to the patient being treated. In some embodiments, the unit dose is a single formulation. In certain embodiments, the unit dose includes one or more vehicles such that each vehicle includes an effective amount of at least one of the agents along with pharmaceutically acceptable carriers and excipients. In some embodiments, the unit dose is one or more tablets, capsules, pills, or patches administered to the patient at the same time. In some embodiments, the unit dose is an intravenous (IV) injection or infusion.

Methods and Uses

In an aspect, provided herein is a DNA-PK inhibitor for use in the treatment of a tumor. Also provided herein are methods of treating cancer, such as a tumor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of DNA-PK inhibitor such as a compound of formula (I).

An example of the present disclosure is the use of a DNA-PK inhibitor, e.g., as an active ingredient, in the preparation of a drug for use in the treatment of a tumor. The DNA- PK inhibitor may be selected from M3814, AZD7648, XZP-6877, M-9831 , CC-115, BR- 101801 , XRD-0394, IMP-11 , ZL-2201 , BAY-8400, SY-7021 or a compound represented by formula (I) as defined below.

In an aspect, provided herein is the use of a compound of formula (I) for use in the treatment of a tumor, wherein the daily dose of the compound of formula (I) is 25-600 mg once per day.

In one or more embodiments of the present application, there is provided the use of a compound of general formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, e.g., as an active ingredient, in the preparation of a drug for use in the treatment of a tumor, — is a single bond or double bond; in , A, B, C, D are each independently C or N, and at least one of A,

B, C and D is N;

Ro is H, C1-6 alkyl or cyclopropyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; further substituted with 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C1-6 alkyl and C1-6 alkoxy;

Ria is H or C1-6 alkyl;

Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl; 2 is H, cyano, =0, carboxyl, -C(=O)N 2a 2b, C1-6 alkoxy, C1-6 alkyl, halogen, - S(=O)2 2a or -C(=0)0Ci-6 alkyl, wherein the C1-6 alkyl, -C(=0)0Ci-6 alkyl or C1-6 alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;

R_2a and ₂b are each independently H, Ci_₆ alkyl, or 3- to 5-membered cycloalkyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from OH, D, halogen, C1-6 alkyl and C1-6 alkoxy; alternatively, 2a and 2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 , 2 or 3 heteroatoms selected from N, O and S and is optionally further substituted with one or more substituents selected from C1-6 alkyl, OH and halogen; 3 is halogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1 ; n is 0, 1 or 2; and x and y are each independently 1 , 2 or 3; with the provisos that R₃ e, and R3 is methyl. In an embodiment, R1 is optionally further substituted with hydroxyl-substituted C1-6 alkyl.

In an aspect, provided herein is a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, wherein the daily dose of the compound of formula (I) is 25-600 mg once per day.

Ria is H or C1-6 alkyl; R2 is H, cyano, -C(=O)NR2_aR2b, C1-6 alkoxy, halogen, -S(=O)2R2a or -C(=O)OCi-6 alkyl, wherein the -C(=O)OCi-6 alkyl or C1-6 alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;

R2a and R2b are each independently H, C1-6 alkyl, or 3- to 5-membered cycloalkyl, wherein the Ci_₆ alkyl is optionally further substituted with one or more substituents selected from OH, D or halogen; alternatively, R2a and R2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 to 3 heteroatoms selected from N, O and S and is optionally further substituted with one or more substituents selected from OH and halogen;

R3 is halogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1 ; and n is 0, 1 or 2; with the provisos that when , Ro, R2, and R3 simultaneously satisfy the following conditions, and R3 is methyl.

In one or more embodiments of the present application,

Ro is H, C-1.4 alkyl or cyclopropyl, wherein the CM alkyl is optionally further substituted with one or more substituents selected from halogen and D;

Ria is H, Ci-₆ alkyl or -C(=O)Ci_₆ alkyl;

R2 is H, cyano, -C(=O)NR2aR2b, C1-6 alkoxy, halogen, -S(=O)2R2a or -C(=O)OCi-6 alkyl, wherein the -C(=O)OCi-6 alkyl or C1-6 alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;

R_2a and R₂b are each independently H, Ci_₆ alkyl, or 3- to 5-membered cycloalkyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from OH, D and halogen; alternatively, R2a and R2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 to 3 heteroatoms selected from N, O and S and is also optionally further substituted with one or more substituents selected from OH and halogen;

R3 is halogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1 ; and n is 0, 1 or 2; with the provisos that when methyl, R2 is methoxy or -

S(=O)2Me, and 3 is methyl.

In one or more embodiments of the present application, there is provided the use of a compound of general formula (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof as, e.g., an active ingredient, in the preparation of a drug for use in the treatment of a tumor: wherein

Ro is H, C1-6 alkyl or cyclopropyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and i is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, C1-6 alkyl and C1-6 alkoxy;

Ria is H or C1-6 alkyl;

Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl; 2_C is H, cyano, halogen or Ci_₆ alkoxy; 2d is H, cyano, carboxyl, -C(=O)NR_2a 2b, C1-6 alkyl, halogen, -S(=O)₂R_2a or - C(=O)OCi-6 alkyl, wherein the C1-6 alkyl and -C(=O)OCi-6 alkyl is optionally substituted with one or more substituents selected from halogen and deuterium;

R_2a and R_2b are H, Ci_₆ alkyl, or 3- to 5-membered cycloalkyl, wherein the Ci_₆ alkyl is optionally further substituted with one or more substituents selected from OH, D, halogen, C1-6 alkyl and C1-6 alkoxy; alternatively, R_2a and ₂b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 to 3 heteroatoms selected from N, O and S and is optionally further substituted with one or more substituents selected from C1-6 alkyl, OH and halogen; 3 is halogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1 ; n is 0, 1 or 2; and x and y are each independently 1 , 2 or 3; with the provisos that R₃ when Ro, 2, and 3 simultaneously satisfy the following conditions, methoxy or -S(=O)₂Me, and R3 is methyl.

In one or more embodiments of the present application, there is provided the use of a compound of general formula (III), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, e.g., as an active ingredient, in the preparation of a drug for use in the treatment of a tumor: wherein

Ro is H, C1-6 alkyl or cyclopropyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and R1 is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, C1-6 alkyl and C1-6 alkoxy;

Ria is H or C1-6 alkyl;

Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl;

R_2a and R₂b are each independently H, Ci_₆ alkyl, or 3- to 5-membered cycloalkyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from D or halogen; alternatively, R2a and R2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 to 3 heteroatoms selected from N, O and S and is optionally further substituted with one or more substituents selected from C1-6 alkyl, OH and halogen;

R_2C is H, cyano, halogen or Ci_₆ alkoxy, wherein the Ci_₆ alkoxy is optionally substituted with one or more deuterium;

R3 is halogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally further substituted with 1 to 3 substituents selected from D or halogen; m is 0 or 1 ; n is 0, 1 or 2; and x and y are each independently 1 , 2 or 3.

In an embodiment, the compound of formula (I) is a compound of formula (Illa): or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof; wherein

Ro is H, C1-6 alkyl or cyclopropyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and and R1 is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, C1-6 alkyl, C1-6 alkoxy, and hydroxyl-substituted C1-6 alkyl; each R3 is independently halogen or C1-6 alkyl; and n is 2.

In one or more embodiments of the present application, there is provided the use of a compound of general formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, e.g., as an active ingredient, in the preparation of a drug for use in the treatment of a tumor: wherein

Ro is H, C1-6 alkyl or cyclopropyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and i is -(CH)_m-4- to 7-membered carbocyclyl, -(CH)_m-4- to 7-membered heterocyclyl, - (CH)_m-8- to 12-membered bridged ring, -(CH)_m-7- to 12-membered spiro ring, wherein the - (CH)_m-4- to 7-membered carbocyclyl, -(CH)_m-4- to 7-membered heterocyclyl, -(CH)_m-8- to 12-membered bridged ring, or -(CH)_m-7- to 12-membered spiro ring is optionally further substituted with one or more substituents selected from hydroxy, cyano, halogen, =0, C1-6 alkyl, Ci-₆ alkoxy, and hydroxy substituted Ci_₆ alkyl.

In an embodiment of formula (IV), and i is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci_₆ alkyl, Ci_₆ alkoxy, and hydroxyl-substituted Ci_₆ alkyl;

Ria is H or C1-6 alkyl;

Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl; m is 0 or 1 ; and x and y are each independently 1 , 2 or 3

In one or more embodiments of the present application,

Ro is H, C1-6 alkyl or cyclopropyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and Ri is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, C1-6 alkyl and C1-6 alkoxy;

Ria is H or C1-6 alkyl;

Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl; m is 0 or 1 ; and x and y are each independently 1 , 2 or 3.

In one or more embodiments of the present application,

Ro is C1-4 alkyl, wherein the C1-4 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and

In one or more embodiments of the present application, the compound of formula (I)

(i.e., active ingredient) is selected from:

In an embodiment, the compound of formula (I) is

or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

In an embodiment, the compound of formula (I) is Compound A: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof. In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

In an embodiment, the compound of formula (I) is a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof. In an embodiment, the compound of formula (I) is administered in a capsule.

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

In one or more embodiments of the present application, the tumor is selected from neuroendocrine tumors, esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic carcinoma, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, lymphoma, nasopharyngeal cancer, ovarian cancer, breast cancer, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteoblastic sarcoma, malignant tumors of urethra, thyroid cancer, malignant tumors of anal canal, malignant tumors of bone and soft tissue, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, small cell lung cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, 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.

In an embodiment, the tumor is prostate cancer. In an embodiment, the tumor is an adenocarcinoma. In an embodiment, the tumor is androgen-sensitive prostate adenocarcinoma or hormone-sensitive prostate cancer (HSPC).

In an embodiment, the cancer is mesothelioma. In an embodiment, the tumor is lung cancer. In an embodiment, the tumor is carcinoma. In an embodiment, the tumor is lung squamous cell carcinoma.

In one or more embodiments of the present application, the neuroendocrine tumor comprises SSTR-positive neuroendocrine tumors of the gastrointestinal tract and pancreas, an SSTR-positive bronchial neuroendocrine tumors, unresectable or metastatic SSTR- positive neuroendocrine tumors, aggressive neuroendocrine tumors of the gastrointestinal tract and pancreas, neuroendocrine tumors of the gastrointestinal tract 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 comprises PSMA-positive metastatic castration-resistant prostate cancer, metastatic neuroendocrine prostate cancer, metastatic castration-resistant prostate cancer without chemotherapy, and progressive metastatic castration-resistant prostate cancer; the neuroblastoma comprises SSTR-positive refractory or relapsed neuroblastoma; the glioblastoma comprises newly diagnosed glioblastoma, progressive glioblastoma, and relapsed glioblastoma; the leukemia is selected from acute lymphocitic leukemia or acute myeloblastic leukemia, and the acute myeloblastic leukemia comprises myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia and/or erythroleukemia; the chronic leukemia comprises chronic myelogenous/granulocytic leukemia and/or chronic lymphocitic leukemia; the lymphoma comprises Hodgkin lymphoma and/or non-Hodgkin lymphoma; the gastric cancer comprises gastric adenocarcinoma; the head and neck cancer comprises tongue adenoid cystic carcinoma and/or adenoid cystic carcinoma; the lung cancer comprises limited-stage small cell lung cancer, extensive-stage small-cell lung cancer, non-small cell lung cancer, pulmonary large-cell neuroendocrine carcinoma, lung adenocarcinoma, pulmonary sarcomatoid carcinoma, and/or lung squamous cell carcinoma and CNS metastatic lung cancer; the cervical cancer comprises cervical squamous cell carcinoma; the breast cancer comprises invasive ductal carcinoma, ductal carcinoma, relapsed breast cancer, and CNS metastatic breast cancer; and the ovarian cancer comprises ovarian clear cell carcinoma or ovarian serous carcinoma.

In an aspect, provided herein is a method of treating adenocarcinoma in a subject in need thereof comprising administering to the subject 500 mg (QD) Compound A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof. In an embodiment, the adenocarcinoma is prostate cancer. In an embodiment, the cancer is androgen-sensitive prostate adenocarcinoma or hormone-sensitive prostate cancer (HSPC). In an embodiment, the subject has received one or more treatments selected from abiraterone, prednisone, methylprednisolone, enzalutamide, olaparib, and chemical castration prior to the treatment with Compound A.

In an aspect, provided herein is a method of treating mesothelioma in a subject in need thereof comprising administering to the subject 300 mg (QD) Compound A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof. In an embodiment, the subject has received one or more treatments selected from pemetrexed, cisplatin, bevacizumab, anti-tumor herbal medicine, cadonilimab (PD-1/CTLA-4), etoposide, and apatinib prior to the treatment with Compound A.

In an aspect, provided herein is a method of treating carcinoma in a subject in need thereof comprising administering to the subject 300 mg (QD) Compound A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof. In an embodiment, the carcinoma is lung cancer. In an embodiment, carcinoma is tumor is lung squamous cell carcinoma

In an embodiment of the methods and uses, the method or use involves the administration of a therapeutically effective amount of a compound provided herein, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, or a composition comprising a compound provided herein, to a subject (including, but not limited to a human or animal) in need of treatment (including a subject identified as in need).

Pharmaceutical Compositions

In an aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In an embodiment, the compound of formula (I) is a compound of formula (II). In an embodiment, the compound of formula (I) is a compound of formula (III). In an embodiment, the compound of formula (I) is a compound of formula (Illa). In an embodiment, the compound of formula (I) is a compound of formula (IV).

In another embodiment, the compound of formulae (I), (II), (III), and (IV) is selected from the compounds disclosed supra. In another embodiment, the compound of formulae (I), or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of formulae (I), (II), (III), and (IV) is Compound A.

In an embodiment, the pharmaceutical composition is for use in the treatment of a tumor. In an embodiment, the tumor is a solid tumor. In an embodiment, the tumor is prostate cancer. In an embodiment, the tumor is mesothelioma.

Pharmaceutical Formulations

Pharmaceutical formulations or pharmaceutical products are included herein. Such pharmaceutical formulations (e.g., packaged pharmaceutical formulation) include, for example, one or more pharmaceutical formulations comprising a compound of formula (I). The pharmaceutical formulation is contained in a container. The package typically contains instructions for using the formulation to treat an animal (typically a human patient) suffering from cancer.

In certain embodiments the pharmaceutical formulation (e.g., packaged pharmaceutical formulation) or pharmaceutical product contains the compound described herein in a container with instructions for administering the dosage forms on a fixed schedule. In some of these embodiments, the formulation is in a unit dose form.

The packaged pharmaceutical formulations provided herein include comprise prescribing information, for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.

Administration / Dosage

In another aspect, provided herein is a pharmaceutical composition or comprising a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

In certain embodiments, a compound of formula (I) (e.g., Compound A) is administered at a dose per day of about 1-3000 mg, for example, about 1-2000 mg (e.g., about 1-1000 mg, or about 1-500 mg). In certain embodiments, a compound of formula (I) (e.g., Compound A) is administered at a dose per day of about 1-1000 mg/kg. In certain embodiments, a compound of formula (I) (e.g., Compound A) is administered at a dose per day of about 1-100 mg/kg (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 certain embodiments, compound of formula (I) (e.g., Compound A) is administered at a dose per day of about 1-25 mg/kg (e.g., about 25 mg/kg, about 20 mg/kg, about 15 mg/kg, about 10 mg/kg, or about 5 mg/kg).

The total daily dose of the compound of formula (I) may be administered according to, but not limited to, the following regimen of once a day, twice a day, three times a day, four times a day, five times a day, once a week, twice a week, three times per week, four times per week, five times per week, six times per week, once a month, twice per month, three times per month, four times per month, five times per month, six times per month, seven times per month, eight times per month, nine times per month, or ten or more times per month. In certain embodiments, the compound of formula (I) is administered once a day.

In one or more embodiments of the present application, the daily dose of the compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, is about 25-600 mg once per day, about 50-400 mg once per day, or about 100-300 mg once per day. In one or more embodiments of the present application, the daily dose of the active ingredient is 25-600 mg once per day, preferably 50-400 mg once per day, more preferably 100-300 mg once per day.

In one or more embodiments of the present application, the daily dose of the compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, is about 25 mg once per day, about 50 mg once per day, about 75 mg once per day, about 300 mg once per day, or about 500 mg once per day.

In one or more embodiments of the present application, the daily dose of the active ingredient is 25 mg once per day, or 50 mg once per day, or 75 mg once per day, or 500 mg once per day, or 300 mg once per day.

In one or more embodiments of the present application, the daily dose of the compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, 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.

In an embodiment, the compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, is administered in a capsule.

Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular agent employed, the time of administration, the rate of excretion of the agent, the duration of the treatment, other drugs, compounds or materials used in combination with the agent, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, capsules, caplets and gel caps. The compositions intended for oral use may 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 excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. EXAMPLES

The implementation process and beneficial effects of the present invention are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present invention, and are not intended to limit the scope of implementation of the present invention.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in experimental conditions with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings of the present disclosure as set forth.

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

Compound A is provided in a capsule with a specification of 25 mg, 100 mg, 300 mg, or 500 mg.

Administration regimen of clinical trials

Single administration period (C0D1 - C0D3): Compound A is administered once on day 1 , followed by 2 days of drug discontinuation; if no dose limiting toxicity (DLT) event occurs, the first cycle (C1 D1 - C1 D28) of multiple administration begins: Compound A is administered once a day for 28 days in total, with 28 days per cycle; and if no DLT event occurs, administration is continued until the subject develops disease progression, leaves the group, or cannot tolerate the drug. The dose for each administration is determined based on the dose group to which the subject is assigned (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 every day. Clinical results

After evaluation, one patient with lung squamous cell carcinoma was evaluated as stable disease (SD), and one patient with pleural mesothelioma was evaluated as partial response (PR) (Table 2). As can be seen in the clinical data below, the DNA-PK inhibitor of the present application, Compound A, is effective as an active ingredient in the anti-tumor therapy, with good safety and tolerability.

Table 1 . Clinical results for patient with prostate cancer phosphatase.

Table 2. Clinical results for patient with mesothelioma

As can be seen by the clinical data above, Compound A was well-tolerated in cancer patients resulting in no DLTs or SAEs. Compound A also showed promising activity in the prostate cancer patient by lowering TPSA and ALP levels.

Claims

1 . Use of a compound of formula (I) for use in the treatment of a tumor, wherein the daily dose of the compound of formula (I) is 25-600 mg once per day:

— is a single bond or double bond; in , A, B, C, D are each independently C or N, and at least one of A, B, C and D is N;

Ro is H, Ci-₆ alkyl or cyclopropyl, wherein the Ci_₆ alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; further substituted with 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, C1-6 alkyl and Ci_₆ alkoxy;

Ria is H or C1-6 alkyl;

Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl; 2 is H, cyano, =0, carboxyl, -C(=O)N 2a 2b, C1-6 alkoxy, C1-6 alkyl, halogen, - S(=O)₂ 2a or -C(=O)OCi-₆ alkyl, wherein the Ci_₆ alkyl, -C(=O)OCi.₆ alkyl or Ci_₆ alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; 2a and 2b are each independently H, C1-6 alkyl, or 3- to 5-membered cycloalkyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from OH, D, halogen, C1-6 alkyl and C1-6 alkoxy; alternatively, R2a and R2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 , 2 or 3 heteroatoms selected from N, O and S and is optionally further substituted with one or more substituents selected from C1-6 alkyl, OH and halogen;

R₃ is halogen or Ci_₆ alkyl, wherein the Ci_₆ alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1 ; n is 0, 1 or 2; and x and y are each independently 1 , 2 or 3; with the provisos that

R₃ when , Ro, 2, and ₃ simultaneously satisfy the following conditions, 1 is not methyl, R2 is methoxy or -S(=O)2Me, and R3 is methyl.

2. The use according to claim 1 , wherein

Ria is H or C1-6 alkyl;

R₂ is H, cyano, -C(=O)NR_2aR2b, Ci_₆ alkoxy, halogen, -S(=O)₂R_2a or -C(=O)OCi_₆ alkyl, wherein the -C(=O)OCi-6 alkyl or C1-6 alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;

R_2a and R₂b are each independently H, C1-6 alkyl, or 3- to 5-membered cycloalkyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from OH, D or halogen; alternatively, R_2a and R₂b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 to 3 heteroatoms selected from N, O and S and is optionally further substituted with one or more substituents selected from OH and halogen;

R3 is halogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1 ; and n is 0, 1 or 2; with the provisos that when Ro, R2, and R3 simultaneously satisfy the following conditions, and R3 is methyl.

The use according to claim 1 , wherein

Ro is H, C1-4 alkyl or cyclopropyl, wherein the C1-4 alkyl is optionally further substituted with one or more substituents selected from halogen and D;

Ria is H, C1-6 alkyl or -C(=O)Ci-6 alkyl;

R_2a and R₂b are each independently H, C1-6 alkyl, or 3- to 5-membered cycloalkyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from OH, D and halogen; alternatively, R_2a and R₂b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 to 3 heteroatoms selected from N, O and S and is also optionally further substituted with one or more substituents selected from OH and halogen;

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, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: wherein

Ro is H, C1-6 alkyl or cyclopropyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and i is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci_₆ alkyl and Ci_₆ alkoxy;

Ria is H or C1-6 alkyl;

Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl;

R_2c is H, cyano, halogen or Ci-6 alkoxy; 2d is H, cyano, carboxyl, -C(=O)NR_2a 2b, Ci_₆ alkyl, halogen, -S(=O)₂R_2a or - C(=O)OCi-6 alkyl, wherein the C1-6 alkyl and -C(=O)OCi-6 alkyl is optionally substituted with one or more substituents selected from halogen and deuterium;

R_2a and ₂b are H, C1-6 alkyl, or 3- to 5-membered cycloalkyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from OH, D, halogen, C1-6 alkyl and C1-6 alkoxy; alternatively, R_2a and ₂b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 to 3 heteroatoms selected from N, O and S and is optionally further substituted with one or more substituents selected from C1-6 alkyl, OH and halogen; 3 is halogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally further substituted with 1 to 3 substituents selected from D and halogen; m is 0 or 1 ; n is 0, 1 or 2; and x and y are each independently 1 , 2 or 3; with the provisos that R₃ when Ro, 2, and 3 simultaneously satisfy the following conditions, 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, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: wherein

Ro is H, Ci-6 alkyl or cyclopropyl, wherein the Ci_₆ alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and R1 is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci_₆ alkyl and Ci_₆ alkoxy;

Ria is H or C1-6 alkyl;

Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl;

R2a and R2b are each independently H, C1-6 alkyl, or 3- to 5-membered cycloalkyl, wherein the Ci_₆ alkyl is optionally further substituted with one or more substituents selected from D or halogen; alternatively, R2a and R2b together with the atoms to which they are attached form a 5- to 6-membered heterocyclyl, which contains 1 to 3 heteroatoms selected from N, O and S and is optionally further substituted with one or more substituents selected from C1-6 alkyl, OH and halogen;

6. The use according to claim 1 , wherein the compound of formula (I) is a compound of formula (IV), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: wherein

Ro is H, C1-6 alkyl or cyclopropyl, wherein the C1-6 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and and R1 is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci_₆ alkyl and Ci_₆ alkoxy;

Ria is H or C1-6 alkyl;

7. The use according to claim 6, wherein

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

9. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is Compound A: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

10. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

11. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

12. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

13. The use according to any one of claims 1 to 8, wherein the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

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

15. The use according to any one of claims 1-14, wherein the tumor is selected from neuroendocrine tumors, esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic carcinoma, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, lymphoma, nasopharyngeal cancer, ovarian cancer, breast cancer, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteoblastic sarcoma, malignant tumors of urethra, thyroid cancer, malignant tumors of anal canal, malignant tumors of bone and soft tissue, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelioma sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, small cell lung cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, 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.

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 mesothelioma.

18. The use according to claim 15, wherein the neuroendocrine tumor comprises SSTR- positive neuroendocrine tumors of the gastrointestinal tract and pancreas, an SSTR-positive bronchial neuroendocrine tumors, unresectable or metastatic SSTR-positive neuroendocrine tumors, aggressive neuroendocrine tumors of the gastrointestinal tract and pancreas, neuroendocrine tumors of the gastrointestinal tract 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 comprises PSMA-positive metastatic castration-resistant prostate cancer, metastatic neuroendocrine prostate cancer, metastatic castration-resistant prostate cancer without chemotherapy, and progressive metastatic castration-resistant prostate cancer; the neuroblastoma comprises SSTR-positive refractory or relapsed neuroblastoma; the glioblastoma comprises newly diagnosed glioblastoma, progressive glioblastoma, and relapsed glioblastoma; the leukemia is selected from acute lymphocitic leukemia or acute myeloblastic leukemia, and the acute myeloblastic leukemia comprises myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia and/or erythroleukemia; the chronic leukemia comprises chronic myelogenous/granulocytic leukemia and/or chronic lymphocitic leukemia; the lymphoma comprises Hodgkin lymphoma and/or non-Hodgkin lymphoma; the gastric cancer comprises gastric adenocarcinoma; the head and neck cancer comprises tongue adenoid cystic carcinoma and/or adenoid cystic carcinoma; the lung cancer comprises limited-stage small cell lung cancer, extensive-stage small-cell lung cancer, non-small cell lung cancer, pulmonary large-cell neuroendocrine carcinoma, lung adenocarcinoma, pulmonary sarcomatoid carcinoma, and/or lung squamous cell carcinoma and CNS metastatic lung cancer; the cervical cancer comprises cervical squamous cell carcinoma; the breast cancer comprises invasive ductal carcinoma, ductal carcinoma, relapsed breast cancer, and CNS metastatic breast cancer; and the ovarian cancer comprises ovarian clear cell carcinoma or ovarian serous carcinoma.

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

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

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

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

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

24. The method according to claim 23, wherein the compound of formula (I) is or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

25. The method according to claim 23 or 24, wherein the compound of formula (I) is Compound A: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

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 mesothelioma.

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