Use of DNA-PK inhibitor for treatment of central nervous system tumors in combination with radiotherapy

Abstract

The present disclosure provides the use of a DNA-PK inhibitor (e.g., a compound represented by formula (I)) for the treatment of a tumor (e.g., central nervous system tumors) in combination with radiotherapy (I).

Description

[0001] USE OF DNA-PK INHIBITOR FOR TREATMENT OF CENTRAL NERVOUS SYSTEM TUMORS IN COMBINATION WITH RADIOTHERAPY

[0002] RELATED APPLICATIONS

[0003] This application claims priority to Chinese Application No. 202410998510.6 filed July 24, 2024, Chinese Application No. 202411355781.6 filed September 27, 2024, and Chinese Application No. 202411381044.3 filed September 30, 2024, the content of each of which is incorporated by reference in its entirety.

[0004] TECHNICAL FIELD

[0005] The present disclosure relates to the use of a DNA-PK inhibitor for the treatment of a central nervous system tumor in combination with radiotherapy.

[0006] BACKGROUND

[0007] Radiotherapy is one of the most important methods for the comprehensive treatment of malignant tumors. Neoadjuvant therapy based on conventional long-term radiotherapy has also become a standard regimen for treating various malignant tumors. However, longterm clinical studies have found that the responses to radiotherapy for patients with malignant tumors vary greatly. Although some patients can achieve complete pathological remission at the end of a treatment cycle, there remain patients who cannot benefit from long-term treatment with some experiencing continued disease progression. Studies have found that the enhanced DNA damage repair mechanism due to radiotherapy is an important reason for the tolerance mechanism of tumors to radiotherapy.

[0008] 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 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 / 80 and 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. Studies have shown that DNA-PK activity is associated with drug resistance due to radiotherapy, such that the killing effect of radiotherapy on tumor cells can be improved by inhibiting the DNA-PK activity in tumor cells. However, there are still no effective DNA-PK inhibitor drugs on the market. Therefore, developing a potent DNAPK inhibitor as a radiosensitizing drug for tumor treatment has important clinical significance. SUMMARY

[0009] Imidazolinone derivatives have been shown to have high selectivity and significant inhibitory activity against DNA-PK (see, e.g., WO 2021 / 209055). It was unexpectedly found in subsequent studies that an imidazolinone derivative combined with radiotherapy can significantly improve anti-tumor efficacy of the radiotherapy.

[0010] Therefore, provided herein is the use of a DNA-PK inhibitor, e.g., a compound of formula (I), in combination with radiotherapy, e.g., X-ray radiotherapy (e.g., IR irradiation X- ray radiotherapy), for the treatment of a tumor.

[0011] BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 shows a graph of the trend of body weight change of animals during the test using a mouse transplanted tumor model; and

[0013] FIG. 2 shows a graph of the trend of survival of animals during the test using a mouse transplanted tumor model.

[0014] DETAILED DESCRIPTION

[0015] Provided are methods of treating a tumor in a subject in need thereof comprising administering to the subject a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy. Also provided herein is a combination therapy comprising a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy. Also provided herein is a pharmaceutical combination comprising a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy. The combination therapies and pharmaceutical combinations of the present disclosure can be used for treating cancer, such as solid tumors.

[0016] Definitions

[0017] 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.

[0018] 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.

[0019] 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.

[0020] As used herein and throughout the disclosure, the term “about” can mean ± 10%.

[0021] 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.

[0022] The term “Cn.m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C- , CI-6and the like.

[0023] 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 “Cn malkyl,” 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.

[0024] 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 “Cn.malkoxy” 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 “Cn mdialkoxy” refers to a linking group of formula -O-(Cn.malkyl)-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 Cn mdialkoxy group may be attached to the same B atom to form a 5- or 6- membered heterocycloalkyl group.

[0025] 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.

[0026] 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.

[0027] 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 “Cn.mcycloalkyl” 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 C3.6monocyclic 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, cyclo pentenyl, 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.

[0028] 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, / V-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 / - / )-yl; 1 ,6- dihydropyridinyl; morpholinyl; azetidinyl; piperazinyl; and 4,7-diazaspiro[2.5]octan-7-yl.

[0029] The term “combination therapy” refers to the administration of two or more therapeutic compounds to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic compounds in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate containers (e.g., capsules or IV administration) for each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic compound in a sequential manner, either at approximately the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0030] As used herein, “pharmaceutical combination” or “combination” refers to formulations of the separate active agents with or without instructions for combined use. The combination may thus be entirely separate pharmaceutical dosage forms or in pharmaceutical compositions that are also sold independently of each other and where just instructions for their combined use are provided in the package equipment, e.g., leaflet or the like, or in other information, e.g., provided to physicians and medical staff (e.g. oral communications, communications in writing or the like), for simultaneous or sequential use for being jointly active.

[0031] The term “treating” or “treatment” refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., arresting further development of the pathology and / or symptomology) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology) such as decreasing the severity of the 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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, e.g., a compound of formula (I), or pharmaceutically acceptable salt thereof, 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.

[0036] 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.

[0037] 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.

[0038] The combination of agents described herein may display a synergistic effect. The term “synergistic effect” as used herein, refers to action of two agents such as, for example, a compound of formula (I) and radiotherapy, producing an effect, for example, slowing the symptomatic progression of cancer or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981 )), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313- 326 (1926)) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

[0039] As used herein, the term “synergy” refers to the effect achieved when the active ingredients, i.e., Compound A and radiotherapy, used together is greater than the sum of the effects that results from using the compounds separately.

[0040] In an embodiment, provided herein is a combination therapy comprising an effective amount of a compound of formula (I) and radiotherapy. An “effective amount” of a combination of agents (i.e., a compound of formula (I) (e.g., Compound A)) and radiotherapy is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorders treated with the combination. In an embodiment, the combination therapy further comprises radiotherapy.

[0041] The term “unit dose” or “unit dosage form” 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.

[0042] Methods and Uses

[0043] In an aspect, provided herein is a DNA-PK inhibitor (e.g., a compound of formula (I)) and radiotherapy (e.g., X-ray radiotherapy) 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) and radiotherapy such as X-ray radiotherapy (e.g., IR irradiation X-ray radiotherapy).

[0044] Also provided herein is the use of a DNA-PK inhibitor, e.g., as an active ingredient, in combination with radiotherapy for the treatment of tumors, wherein the DNA-PK inhibitor is selected from M3814, AZD7648, XZP-6877, M-9831 , CC-115, BR-101801 , XRD-0394, IMP- 11 , ZL-2201 , BAY-8400, and SY-7021 , or is a compound represented by formula (I) as defined below.

[0045] The compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof has a structure as follows:

[0046] — is a single bond or double bond; , A, B, C, D are each independently C or N, and at least one of A,

[0047] B, C and D is N;

[0048] Ro is H, Ci-6 alkyl or cyclopropyl, wherein the Ci-6alkyl 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, Ci-6alkyl and Ci-6alkoxy;

[0049] Riais H or Ci-6 alkyl;

[0050] Rib is H, OH, cyano, or hydroxyl substituted C1-6 alkyl;

[0051] R2is H, cyano, =0, carboxyl, -C(=O)NR2aR2b, Ci-6alkoxy, Ci-6alkyl, halogen, - S(=O)2R2aor -C(=0)0Ci-6alkyl, wherein the Ci-6alkyl, -C(=0)0Ci.6alkyl or Ci-6alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R2aand R2bare each independently H, Ci-6alkyl, 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, Ci-6alkyl and Ci-6alkoxy; alternatively, R2aand R2btogether 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 Ci-6alkyl, OH and halogen;

[0052] R3is halogen or Ci-6alkyl, wherein the Ci-6alkyl 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 e, and R3is methyl.

[0053] In an embodiment, Ri is optionally further substituted with hydroxyl-substituted Ci-6alkyl.

[0054] 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, and radiotherapy. In an aspect, provided herein is a method of treating cancer 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, and radiotherapy.

[0055] In one or more embodiments of the present application, Ri is

[0056] Ria is H or C1-6 alkyl;

[0057] R2is H, cyano, -C(=O)NR2aR2b, Ci-6alkoxy, halogen, -S(=O)2R2aor -C(=O)OCi.6alkyl, wherein the -C(=O)OCi-6 alkyl or C1-6 alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;

[0058] R2aand R2bare each independently H, Ci-6alkyl, or 3- to 5-membered cycloalkyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from OH, D or halogen; alternatively, R2aand R2btogether 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;

[0059] R3is halogen or Ci-6alkyl, wherein the Ci-6alkyl 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 e, and R3is methyl.

[0060] In one or more embodiments of the present application,

[0061] 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;

[0062] Ria is H, C1-6 alkyl or -C(=O)Ci.6alkyl;

[0063] 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.6alkyl or Ci.6alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;

[0064] R2aand R2bare 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, R2aand R2btogether 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;

[0065] R3is halogen or Ci-6alkyl, wherein the Ci_6alkyl 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 R3simultaneously satisfy the following conditions, methyl, R2is methoxy or -

[0066] S(=O)2Me, and R3is methyl.

[0067] 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, e.g., as an active ingredient, in combination with radiotherapy for the treatment of a tumor: wherein

[0068] Ro is H, Ci-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0069] Ri is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, C1-6 alkyl and C1-6 alkoxy;

[0070] Ria is H or C1-6 alkyl;

[0071] Rib is H, OH, cyano, or hydroxyl substituted Ci-6alkyl;

[0072] R2Cis H, cyano, halogen or Ci-6alkoxy; R2d is H, cyano, carboxyl, -C(=O)NR2a 2b, Ci_6alkyl, halogen, -S(=O)2R2aor - 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;

[0073] R2aand R2bare 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, R2aand R2btogether 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;

[0074] R3is halogen or Ci-6alkyl, wherein the Ci-6alkyl 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

[0075] R3when , Ro, R2, and R3simultaneously satisfy the following conditions,

[0076] R1 is not r methyl, R2is methoxy or -S(=O)2Me, and R3is methyl.

[0077] 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 combination with radiotherapy for the treatment of a tumor: wherein Ro is H, C1-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; pyridyl, and Ri is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-6alkyl and Ci-6alkoxy;

[0078] Ria is H or Ci-6 alkyl;

[0079] Rib is H, OH, cyano, or hydroxyl substituted Ci-6alkyl;

[0080] R2a and R2b are each independently H, Ci-6 alkyl, or 3- to 5-membered cycloalkyl, wherein the Ci-6alkyl 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 Ci-6alkyl, OH and halogen; is H, cyano, halogen or Ci-6 alkoxy, wherein the Ci-6 alkoxy is optionally substituted with one or more deuterium;

[0081] R3is halogen or Ci-6alkyl, wherein the Ci-6alkyl 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.

[0082] In an embodiment, the compound of formula (I) is a compound of formula (Illa): or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof; wherein

[0083] 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 and Ri is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-6alkyl, Ci-6alkoxy, and hydroxyl-substituted Ci-6alkyl; each R3is independently halogen or Ci-6alkyl; and n is 2.

[0084] 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 combination with radiotherapy for the treatment of a tumor: wherein

[0085] Ro is H, C1-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and

[0086] Ri 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, Ci-6alkyl, C1-6 alkoxy, and hydroxy substituted Ci_6alkyl; and m is 0 or 1 .

[0087] In an embodiment of formula (IV), and Ri is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-6alkyl, Ci-6alkoxy, and hydroxyl-substituted Ci-6alkyl;

[0088] Ria is H or Ci-6 alkyl;

[0089] Rib is H, OH, cyano, or hydroxyl substituted Ci-6alkyl; m is 0 or 1 ; and x and y are each independently 1 , 2 or 3.

[0090] In one or more embodiments of the present application,

[0091] Ro is H, Ci-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium;

[0092] Ri is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-6alkyl and Ci-6alkoxy;

[0093] Ria is H or Ci-6 alkyl;

[0094] Rib is H, OH, cyano, or hydroxyl substituted Ci-6alkyl; m is 0 or 1 ; and x and y are each independently 1 , 2 or 3.

[0095] In one or more embodiments of the present application,

[0096] Ro is C-i-4 alkyl, wherein the C1-4 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and

[0097] In one or more embodiments of the present application, the compound of formula (I), i.e., active ingredient, is selected from: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0098] In an embodiment, the compound of formula (I) is Compound A: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0099] In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0100] In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0101] In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0102] In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0103] In an embodiment, the radiotherapy is X-ray radiotherapy. In an embodiment, the radiotherapy is X-ray therapy. In an embodiment, the X-ray radiotherapy is IR irradiation X- ray radiotherapy. In one or more embodiments of the present application, the tumor is selected from central nervous system tumors, neuroendocrine tumors, esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic carcinoma, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, 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, 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, astrocytoma, craniopharyngioma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, glioblastoma, melanoma, neuroblastoma, retinoblastoma, leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia or heavy chain disease, or any combination thereof.

[0104] In an embodiment, the tumor is a central nervous system cancer.

[0105] In an embodiment, the tumor is a neuroendocrine tumor. In an embodiment, the tumor is a gastroenteropancreatic neuroendocrine tumor (GEP-NET).

[0106] In an embodiment, the tumor is selected from leukemia, breast cancer, lung cancer, and adenocarcinoma. In an embodiment, the tumor is lung cancer.

[0107] In an embodiment, the tumor is selected from glioma, CNS metastatic breast cancer, CNS metastatic lung cancer, neuroendocrine tumors, pulmonary large-cell neuroendocrine carcinoma, prostate cancer, and pleural mesothelioma.

[0108] In an embodiment, the tumor is selected from non-small cell lung cancer, colon cancer, lung adenocarcinoma.

[0109] 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).

[0110] In an embodiment, the tumor 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.

[0111] In an embodiment, the tumor is metastatic.

[0112] In one or more embodiments of the present application, the central nervous system tumor is selected from neuroepithelia I tumors, meningioma, cranial and paraspinal nerve tumors, CNS metastatic tumors, glioma, neuronal tumors, medulloblastoma, ependymoma, skull tumors, choroid plexus tumors, pineal region tumors, embryonal tumors, lymphoma, histiocytic tumors, germ cell tumors, and tumors of the sellar region; 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 castrationresistant prostate cancer, metastatic neuroendocrine prostate cancer, metastatic castrationresistant prostate cancer without chemotherapy, and progressive metastatic castrationresistant 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, CNS metastatic lung cancer, pulmonary sarcomatoid carcinoma, and / or lung squamous cell carcinoma; 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.

[0113] In an aspect, provided herein is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

[0114] In an embodiment, the cancer is a central nervous system cancer.

[0115] In an embodiment, the cancer is selected from leukemia, breast cancer, lung cancer, and adenocarcinoma. In an embodiment, the cancer is lung cancer. In an embodiment, the cancer is selected from glioma, CNS metastatic breast cancer, CNS metastatic lung cancer, neuroendocrine tumors, pulmonary large-cell neuroendocrine carcinoma, prostate cancer, and pleural mesothelioma.

[0116] In an embodiment, the cancer is selected from non-small cell lung cancer, colon cancer, lung adenocarcinoma.

[0117] In an embodiment, the cancer is a neuroendocrine tumor. In an embodiment, the cancer is a gastroenteropancreatic neuroendocrine tumor (GEP-NET).

[0118] In an embodiment, the cancer is prostate cancer. In an embodiment, the cancer is an adenocarcinoma. In an embodiment, the cancer is androgen-sensitive prostate adenocarcinoma or hormone-sensitive prostate cancer (HSPC).

[0119] In an embodiment, the cancer is mesothelioma. In an embodiment, the cancer is lung cancer. In an embodiment, the cancer is carcinoma. In an embodiment, the cancer is lung squamous cell carcinoma.

[0120] In an embodiment, the cancer is metastatic.

[0121] Combination Therapies and Pharmaceutical Combinations

[0122] In an aspect, provided herein is a combination therapy comprising a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

[0123] In an embodiment, the combination therapy comprises a compound of formula (II), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

[0124] In an embodiment, the combination therapy comprises a compound of formula (III), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

[0125] In an embodiment, the combination therapy comprises a compound of formula (IV), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

[0126] In another aspect, provided herein is a pharmaceutical combination comprising a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

[0127] In an embodiment, the pharmaceutical combination comprises a compound of formula (II), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

[0128] In an embodiment, the pharmaceutical combination comprises a compound of formula (III), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

[0129] In an embodiment, the pharmaceutical combination comprises a compound of formula (IV), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy. In an embodiment of the formulae of the combination therapies and pharmaceutical combinations:

[0130] Ro is H, C1-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; dyl, and

[0131] Ri is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-6alkyl, Ci-6alkoxy, and hydroxyl-substituted Ci-6alkyl;

[0132] Ria is H or Ci-6 alkyl;

[0133] Rib is H, OH, cyano, or hydroxyl substituted Ci-6alkyl; m is 0 or 1 ; and x and y are each independently 1 , 2 or 3.

[0134] In another embodiment of the formulae of the pharmaceutical combinations and combination therapies,

[0135] Ro is C-i-4 alkyl, wherein the C1-4 alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and

[0136] In another embodiment, the compound of formulae (I), (II), (III), and (IV) in the pharmaceutical combinations and combination therapies is selected from the compounds disclosed supra. In another embodiment, the compound of formulae (I), (II), (III), and (IV) is or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0137] In an embodiment, the compound of formula (I) is Compound A: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0138] In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0139] In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0140] In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0141] In an embodiment, the compound of formula (I) is: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

[0142] In an embodiment, the radiotherapy is X-ray radiotherapy. In an embodiment, the X- ray radiotherapy is IR irradiation X-ray radiotherapy.

[0143] In an embodiment, the pharmaceutical combination is for use in the treatment of a tumor.

[0144] In an embodiment, the combination therapy is for use in the treatment of a tumor.

[0145] In an embodiment, the tumor is a solid tumor. In an embodiment, the tumor is carcinoma. In an embodiment, the tumor is colon cancer.

[0146] In an embodiment, the tumor is a neuroendocrine tumor. In an embodiment, the tumor is a gastroenteropancreatic neuroendocrine tumor (GEP-NET).

[0147] In an embodiment, the tumor is selected from central nervous system tumors, neuroendocrine tumors, esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic carcinoma, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, 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, 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 tumors, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, small cell lung cancer, epithelial cancer, astrocytoma, craniopharyngioma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, glioblastoma, melanoma, neuroblastoma, retinoblastoma, leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease, or any combination thereof.

[0148] In another embodiment, the central nervous system (CNS) tumor is selected from neuroepithelia I tumors, meningioma, cranial and paraspinal nerve tumors, CNS metastatic tumors, glioma, neuronal tumors, medulloblastoma, ependymoma, skull tumors, choroid plexus tumors, pineal region tumors, embryonal tumors, lymphoma, histiocytic tumors, germ cell tumors, and tumors of the sellar region; 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, CNS metastatic lung cancer, pulmonary sarcomatoid carcinoma, and / or lung squamous cell carcinoma; 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, and ovarian serous carcinoma.

[0149] In an embodiment, the tumor is selected from leukemia, breast cancer, lung cancer, colon cancer, prostate cancer, and mesothelioma.

[0150] In an embodiment, the pharmaceutical combination comprises: a compound of formulae (I), (II), (III), and (IV), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and radiotherapy, and a pharmaceutically acceptable carrier.

[0151] In an embodiment, the radiotherapy is X-ray radiotherapy. In an embodiment, the radiotherapy is X-ray therapy. In an embodiment,

[0152] The administration of a pharmaceutical combination provided herein may result in a beneficial effect, e.g. a synergistic therapeutic effect, e.g., with regard to alleviating, delaying progression of or inhibiting the symptoms, and may also result in further surprising beneficial effects, e.g., fewer side-effects, an improved quality of life or a decreased morbidity, compared with a monotherapy applying only one of the pharmaceutically active ingredients used in the combination of the invention.

[0153] Pharmaceutical Formulations

[0154] 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 combination of a compound of formula (I) and radiotherapy. The combination in formulated form 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.

[0155] In certain embodiments the pharmaceutical formulation (e.g., packaged pharmaceutical formulation) or pharmaceutical product contains the combination described herein in a container with instructions for administering the dosage forms on a fixed schedule. In some of these embodiments, the combination is provided in separate unit dosage forms. In an embodiment, the compound of formula (I) and radiotherapy are in a unit dose form. In an embodiment, the compound of formula (I) and radiotherapy are in separate unit dose forms.

[0156] In a particular embodiment, the combination components can be dosed on the same schedule, whether by administering a single formulation or unit dosage form containing all of the components of the combination, or by administering separate formulations or unit dosage forms of the components of the combination. However, some of the components used in the combination may be administered more frequently than once per day, or with different frequencies that other components in the combination. Therefore, in one embodiment the pharmaceutical formation (e.g., packaged pharmaceutical formulation) contains a formulation or unit dosage form containing all of the components in the combination, and an additional formulation or unit dosage form that includes one of the components in the combination, with no additional active compound, in a container, with instructions for administering the dosage forms on a fixed schedule.

[0157] 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.

[0158] In all of the foregoing the combination of components of the present disclosure can be administered alone, as mixtures, or with additional active agents. Administration, Dosage, and Formulations

[0159] In another aspect, provided herein is a pharmaceutical composition or pharmaceutical combination comprising the components disclosed herein, together with a pharmaceutically acceptable carrier.

[0160] Administration of the combination includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurrently but separately, or administration of the individual agents of the combination sequentially by any suitable route. The dosage of the individual agents of the combination may require more frequent administration of one of the agent(s) as compared to the other agent(s) in the combination. Therefore, to permit appropriate dosing, packaged pharmaceutical products may contain one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the combination of agents, but not the other agent(s) of the combination.

[0161] 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.

[0162] 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.

[0163] A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed agent at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0164] 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).

[0165] 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.

[0166] Provided herein are methods of administering a therapeutically effective amount of a radiotherapy in combination with a therapeutically effective amount of the compound of formula (I). In particular embodiments, the dosing of radiotherapy to be administered to a human or other mammal host in single or divided doses may be referred to as administered activity to be delivered to the subject (e.g., human or other mammal host). Administered activity of radiotherapy is given in units of radioactive disintegrations per unit time (SI units Becquerels (BQ), imperial units Curies (Ci)). The total dose will vary depending on a variety of factors, such as the purpose, i.e., for imaging and / or therapy, and the number of cycles of administration. Dosing may also be based on energy deposited per unit of mass, i.e., the absorbed dose, usually given in J / kg or Gy).

[0167] In some embodiments, the total dose (over the course of a treatment regimen, also referred to herein as a “cumulative dose”) of the radiotherapy is from about 1 GBq to about 200 GBq. In some embodiments, the radiotherapy is administered in a total dose to deliver from 40 to 100 GBq of radiation. In some embodiments, the radiotherapy is administered in a single dose (once within a 24-hour period) to deliver from about 1 to about 20 GBq of radiation. In some embodiments, the radiotherapy is administered in a single dose (once within a 24-hour period) to deliver from about 3 to about 15 GBq of radiation. In some embodiments, the radiotherapy is administered in a single dose (once within a 24-hour period) to deliver from about 5 to about 10 GBq of radiation. In some embodiments, the radiotherapy is administered in a single dose (once within a 24-hour period) to deliver about 7.4 GBq (e.g., 7.4 GBq) of radiation.

[0168] In some embodiments, the total dose (over the course of a treatment regimen) of the radiotherapy is from about 1 MBq to about 100 MBq. In some embodiments, the radiotherapy) is administered in a total dose of from about 20 to about 80 MBq of radiation. In some embodiments, the radiotherapy is administered in a single dose (once within a 24- hour period) to deliver from about 1 to about 40 MBq of radiation. In some embodiments, the radiotherapy is administered in a single dose (once within a 24-hour period) to deliver from about 5 to about 40 MBq of radiation. In some embodiments, the radiotherapy is administered in a single dose (once within a 24-hour period) to deliver from about 5 to about 25 MBq of radiation.

[0169] In some embodiments, the radiotherapy is administered at 2 Gy. In some embodiments, the radiotherapy is administered for five consecutive days. In some embodiments, the radiotherapy is administered at 2 Gy for five consecutive days.

[0170] In some embodiments, the radiotherapy is administered on alternate days, weeks, or months. For example, the radiotherapy described herein may be administered every two days, or every three days, or every four days, or every five days, or every six days, or every week, or every month. The radiotherapy described herein may be administered every two weeks, or every three weeks, or every four weeks, or every five weeks, or every six weeks, or every seven weeks, or every eight weeks, or every nine weeks, or every ten weeks. In some embodiments, the radiotherapy is administered once about every 2 weeks to 10 weeks. In some embodiments, the radiotherapy is administered once about every 3 weeks to 4 weeks. In some embodiments, the radiotherapy is administered once about every 4 weeks to 6 weeks (e.g., once about every four weeks, once about every 5 weeks, or once about every 6 weeks).

[0171] In some embodiments, provided are methods of treating a tumor in a subject in need thereof, wherein the method comprises administering to the subject: (1 ) a therapeutically effective amount of a compound of formula (I) (e.g., Compound A), for example, wherein the therapeutically effective amount of a compound of formula (I) is a dose per day of about 1 - 2000 mg (e.g., about 1-1000 mg), and (2) a therapeutically effective amount of radiotherapy.

[0172] Routes of administration of any of the compositions discussed herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0173] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions are not limited to the particular formulations and compositions that are described herein. For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or 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.

[0174] For parenteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.

[0175] EXAMPLES

[0176] The implementation process and beneficial effects of the present disclosure are described in detail below by way of specific examples, which are intended to help readers better understand the essence and characteristics of the present disclosure but not to limit the scope of implementation of the present disclosure.

[0177] 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.

[0178] 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.

[0179] 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 (e.g., the paragraph bridging pages 68 and 69)

[0180] I. Pharmacokinetic studies of mouse brain tissue

[0181] An appropriate amount of the test article (Compound A) was weighed and formulated into a 5 mg / mL suspension using 10% DMSO + 5% HS-15 + 85% Saline for intraperitoneal administration. Nine Balb / c nude tumor-bearing mice (from Jicui Gempharmatech Co., Ltd., SPF grade) were taken, with three animals per time point. The test article (50 mg / kg) was administered via intraperitoneal injection, and blood and brain tissue were collected at 30 min, 1 h, and 3 h after administration. The blood sample was anticoagulated using EDTA-K2, then 6000 g of the sample was centrifuged at 4 °C for 5 min to separate plasma, which was stored at -70 °C for testing. After blood collection, the animal was sacrificed to collect brain tissue, which was stored at -70 °C for testing. The brain tissue was flushed with ice-cold physiological saline to remove the residual blood and stored at -70 °C for testing after absorbing the moisture using absorbent paper. The drug concentration of Compound A in the plasma / brain tissue was determined using an LC-MS / MS method (with an internal standard being Gliclazide); and the main pharmacokinetic parameters were calculated using a Winnolin 8.3 noncompartmental model. The results are shown in Table 1 below: Table 1 Drug concentration statistics

[0182] The experimental results show that Compound A of the present application has good ability to pass through the blood-brain barrier.

[0183] II. Mouse transplanted tumor model experiment

[0184] Cell culture

[0185] The NCI-H1299 tumor cells were cultured in vitro using a DMEM medium containing 10% fetal bovine serum in an incubator with 5% CO2at 37 °C. The cells were treated with pancreatin every 3 to 4 days after the cells grew to fill the culture dish, then split into separate vials for subculture, with no more than 4-5 passages. The tumor cells in the logarithmic growth phase were used for in vivo tumor inoculation. Tumor cell inoculation and grouping

[0186] The animal was anesthetized by intraperitoneal injection of pentobarbital and then fixed on a bench in the prone position. The skin on the head of the animal was disinfected with iodine tincture and 75% alcohol, respectively, and was cut approximately 0.5 cm along the midline of the head to expose the coronary and sagittal lines. A position about 1 mm above the coronal line and about 2 mm to the right of the sagittal line was localized using a stereotaxic apparatus, where a hole was drilled with a 1 mL syringe needle and a microsampler was inserted perpendicularly to a depth of 3 mm to slowly (about 1 minute) inject 2 x 105 NCI-H1299 tumor cells / 2 pL suspension. After injection, the needle was retained for 1 minute and then withdrew, the needle hole was quickly sealed with bone wax, and the wound was sutured. Approximately 18 days after tumor cell inoculation, animals were randomly divided into four groups according to body weight with eight animals in each group. The specific administration regimen is shown in Table 2 where “IR” refers to X-ray radiotherapy (RAD Source RS2000 irradiator).

[0187] Table 2 Administration regimen

[0188] The irradiated group received 2 Gy of radiation treatment at the tumor inoculation site on the head for 5 consecutive days, and Compound A was formulated into a 5 mg / mL suspension using 10% DMSO + 5% HS-15 + 85% Saline for intraperitoneal administration, with an administration volume of 10 mL / kg. During administration, the body weight of animals was measured weekly and their survival was observed. The results are shown in Table 3 and FIGS. 1 and 2.

[0189] Table 3 Median survival time

[0190] The experimental results show that in this brain orthotopic model, Compound A of the present application exhibits the advantage of increasing the efficacy of irradiation and prolonging the survival time of tumor-bearing mice; meanwhile, Compound A is safe and controllable with less impact on body weight. Further clinical study results show that for indications, including glioma, CNS metastatic breast cancer, CNS metastatic lung cancer, neuroendocrine tumors, pulmonary large-cell neuroendocrine carcinoma, prostate cancer, and pleural mesothelioma, the growth of tumors in patients within the radiotherapy field is all significantly inhibited, and the safety and tolerability of the treatment process are both excellent.

[0191] Specific embodiments are described in detail in the description of the present invention. A person skilled in the art should recognize that the embodiments described above are exemplary and cannot be construed as limiting the present invention. Additionally, a person skilled in the art can make several improvements and modifications to the present invention without departing from the principle of the present invention, and the technical solutions obtained based on these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

CLAIMS1 . Use of a compound of formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, in combination with radiotherapy for the treatment of a tumor wherein the compound of formula (I) is:— is a single bond or double bond; in, A, B, C, D are each independently C or N, and at least one ofA, B, C and D is N;Ro is H, C1-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium;optionally further substituted with 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-6alkyl, Ci-6alkoxy, and hydroxyl-substituted Ci-6alkyl;Ria is H or Ci-6 alkyl;Rib is H, OH, cyano, or hydroxyl substituted Ci-6 alkyl;R2is H, cyano, =0, carboxyl, -C(=O)NR2aR2b, Ci-6alkoxy, Ci-6alkyl, halogen, - S(=O)2R2aor -C(=O)OCi-6alkyl, wherein the Ci-6alkyl, -C(=O)OCi_6alkyl or Ci-6alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;R2aand R2bare each independently H, Ci-6alkyl, 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, Ci-6alkyl and Ci-6alkoxy; alternatively, R2aand R2btogether 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 Ci-6alkyl, OH and halogen;R3is halogen or Ci-6alkyl, wherein the Ci-6alkyl 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 whensimultaneously satisfy the following conditions,S(=O)2Me, and R3is methyl.

2. The use according to claim 1 , whereinRia is H or C1-6 alkyl;R2is H, cyano, -C(=O)NR2aR2b, Ci-6alkoxy, halogen, -S(=O)2R2aor -C(=O)OCi.6alkyl, wherein the -C(=O)OCi.6alkyl or Ci-6alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;R2aand R2bare each independently H, Ci-6alkyl, or 3- to 5-membered cycloalkyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from OH, D or halogen; alternatively, R2aand R2btogether 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;R3is 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 ; and n is 0, 1 or 2; with the provisos that whenRo, R2, and R3simultaneously satisfy the following conditions,S(=O)2Me, and R3is methyl.

3. The use according to claim 1 , whereinRo 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.6alkyl;R2is H, cyano, -C(=O)NR2aR2b, Ci-6alkoxy, halogen, -S(=O)2R2aor -C(=O)OCi.6alkyl, wherein the -C(=O)OCi.6alkyl or Ci-6alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium;R3is 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 that4. 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:whereinRo is H, Ci-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium;pyridyl, and Ri is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-6alkyl and Ci-6alkoxy;Ria is H or Ci-6 alkyl;Rib is H, OH, cyano, or hydroxyl substituted Ci-6alkyl;R2Cis H, cyano, halogen or Ci-6alkoxy;R2d is H, cyano, carboxyl, -C(=O)NR2aR2b, Ci-6alkyl, halogen, -S(=O)2R2aor - C(=0)0Ci-6 alkyl, wherein the Ci-6 alkyl and -C(=0)0Ci-6 alkyl is optionally substituted with one or more substituents selected from halogen and deuterium;R2aand R2bare H, Ci-6alkyl, or 3- to 5-membered cycloalkyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from OH, D, halogen, Ci-6 alkyl and Ci-6 alkoxy; alternatively, R2aand R2btogether 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 Ci-6alkyl, OH and halogen;R3is halogen or Ci-6alkyl, wherein the Ci-6alkyl 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 thatwhensimultaneously satisfy the following conditions,S(=O)2Me, and R3is 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:whereinRo is H, Ci-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium;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 Ci-6alkyl;R2aand R2b are each independently H, C1-6 alkyl, or 3- to 5-membered cycloalkyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from D or halogen;alternatively, R2aand R2btogether 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 Ci-6alkyl, OH and halogen;R2Cis H, cyano, halogen or Ci-6alkoxy, wherein the Ci-6alkoxy is optionally substituted with one or more deuterium;R3is halogen or Ci-6alkyl, wherein the Ci-6alkyl 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.

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:whereinRo is H, Ci-6 alkyl or cyclopropyl, wherein the Ci-6alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium;dyl, andRi is optionally further substituted with 1 to 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-6alkyl, Ci-6alkoxy, and hydroxyl-substituted Ci-6alkyl;Ria is H or C1-6 alkyl;Rib is H, OH, cyano, or hydroxyl substituted Ci-6alkyl; m is 0 or 1 ; and x and y are each independently 1 , 2 or 3.

7. The use according to claim 6, whereinRo is C1-4 alkyl, wherein the C-M alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; and8. The use according to any one of claims 1 to 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 radiotherapy is X-ray therapy.

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

16. The use according to any one of claims 1 to 15, wherein the tumor is a gastroenteropancreatic neuroendocrine tumor (GEP-NET).

17. The use according to any one of claims 1 to 14, wherein the tumor is selected from central nervous system tumors, neuroendocrine tumors, esophageal cancer, lung cancer, head and neck cancer, gastric cancer, pleural mesothelioma, thymic carcinoma, kidney cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, 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, 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, astrocytoma, craniopharyngioma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, glioblastoma, melanoma, neuroblastoma, retinoblastoma, leukemia, chronic leukemia, polycythemia vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia and heavy chain disease, or any combination thereof.

18. The use according to claim 17, wherein the central nervous system tumor is selected from neuroepithelia I tumors, meningioma, cranial and paraspinal nerve tumors, CNS metastatic tumors, glioma, neuronal tumors, medulloblastoma, ependymoma, skull tumors, choroid plexus tumors, pineal region tumors, embryonal tumors, lymphoma, histiocytic tumors, germ cell tumors, and tumors of the sellar region; 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, CNS metastatic lung cancer, pulmonary sarcomatoid carcinoma, and / or lung squamous cell carcinoma; 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 to 14, wherein the cancer is a central nervous system cancer.

20. The use according to any one of claims 1 to 19, wherein the tumor is a solid tumor.21 . The use according to any one of claims 1 to 14, wherein the tumor is lung cancer.

22. The use according to any one of claims 1 to 14, wherein the tumor is selected from glioma, CNS metastatic breast cancer, CNS metastatic lung cancer, neuroendocrine tumors, pulmonary large-cell neuroendocrine carcinoma, prostate cancer, and pleural mesothelioma.

23. The use according to any one of claims 1 to 22, wherein the tumor is metastatic.

24. A pharmaceutical combination comprising a compound of formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and radiotherapy.

25. The pharmaceutical combination of claim 24, wherein the compound of formula (I) isor a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

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

27. The pharmaceutical combination according to any one of claims 24 to 26, wherein the radiotherapy is X-ray radiotherapy.

28. A method of treating cancer 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, and radiotherapy.

29. The method according to claim 28, wherein the compound of formula (I) isor a stereoisomer, solvate, or pharmaceutically acceptable salt.

30. The method according to claim 28 or 29, wherein the compound of formula (I) is Compound A:or a stereoisomer, solvate, or pharmaceutically acceptable salt.31 . The method according to any one of claims 28 to 30, wherein the radiotherapy is X- ray radiotherapy.

32. The method according to any one of claims 28 to 31 , wherein the cancer is a solid tumor.

33. The method according to any one of claims 28 to 32, wherein the cancer is a neuroendocrine tumor.

34. The method according to any one of claims 28 to 33, wherein the cancer a gastroenteropancreatic neuroendocrine tumor (GEP-NET).

35. The method according to any one of claims 28 to 32, wherein the cancer is lung cancer.

36. The method according to any one of claims 28 to 32, wherein the cancer is a central nervous system cancer.

37. The method according to any one of claims 28 to 32 and 36, wherein the cancer is selected from glioma, CNS metastatic breast cancer, CNS metastatic lung cancer, neuroendocrine tumors, pulmonary large-cell neuroendocrine carcinoma, prostate cancer, and pleural mesothelioma.

38. The method according to any one of claims 28 to 37, wherein the cancer is metastatic.

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