WO2025196671A1

WO2025196671A1 - Imidazolinone derivative combined with pd-1 or pd-l1 inhibitor for use in the treatment of tumors

Info

Publication number: WO2025196671A1
Application number: PCT/IB2025/052895
Authority: WO
Inventors: Yonggang Wei; Yi Sun; Fei Ye
Original assignee: Kangbaida Sichuan Biotechnology Co Ltd
Current assignee: Kangbaida Sichuan Biotechnology Co Ltd
Priority date: 2024-03-20
Filing date: 2025-03-19
Publication date: 2025-09-25
Anticipated expiration: 2026-09-20

Abstract

Provided is a use of a compound represented by general formula (I) in combination with PD-1 inhibitor or PD-L1 inhibitor in the preparation of an anti-cancer drug (I).

Description

IMIDAZOLINONE DERIVATIVE COMBINED WITH PD-1 OR PD-L1 INHIBITOR FOR USE IN THE TREATMENT OF TUMORS

RELATED APPLICATIONS

This application claims priority to Chinese Application No. 2024103206207, filed March 20, 2024; Chinese Application No. 2024113801321 , filed September 30, 2024; Chinese Application No. 2024108445825, filed June 27, 2024; Chinese Application No. 2024113673978, filed September 29, 2024; and Chinese Application No. 2024113808513, filed September 30, 2024, which are each incorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to the use of an imidazolinone derivative for the treatment of a tumor in combination with PD-1 or PD-L1 inhibitor.

BACKGROUND

Programmed death protein 1 (PD-1 , Pdcd-1 or CD279) is a 55 KD receptor protein associated with the CD28/CTLA4 co-stimulatory/inhibitory receptor family. Cancer cells express the ligand PD-L1 of PD-1 , which allows them to evade the host immune system. The currently available PD-1 inhibitors can significantly prolong the overall survival of patients by interfering with the immunosuppressive mechanism of tumors. However, this treatment method can only elicit a response in some patients, whereas some patients may respond well to the first dose, but the efficacy decreases or disappears after a period of administration.

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 cancer development 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 Ku70/80 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. DNA-PK inhibitors could therefore be a promising cancer treatment. However, there are still no effective DNA-PK inhibitor drugs on the market.

Therefore, there is an urgent need for new and improved therapies for the treatment of cancer. In particular, there is an urgent need for new and improved therapies to enhance the therapeutic efficacy of existing therapies. SUMMARY

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 a PD-1 inhibitor or PD- L1 inhibitor can significantly improve anti-tumor efficacy of the anti-PD-1 antibodies or anti- PD-L1 antibodies. Therefore, provided herein is the use of a imidazolinone derivative combined with a PD-1 inhibitor or PD-L1 inhibitor in the treatment of a tumor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the tumor volume change in a colon carcinoma mouse model when treated with Compound A, an anti-PD-1 antibody, or radiotherapy, and combinations thereof.

FIG. 2 shows tumor weight statistics in a colon carcinoma mouse model when treated with Compound A, an anti-PD-1 antibody, or radiotherapy, and combinations thereof.

FIG. 3 shows body weight change of mice in a colon carcinoma mouse model when treated with Compound A, an anti-PD-1 antibody, or radiotherapy, and combinations thereof.

FIG. 4 shows the rate of body weight change of mice in a colon carcinoma mouse model when treated with Compound A, an anti-PD-1 antibody, or radiotherapy, and combinations thereof.

DETAILED DESCRIPTION

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 pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor, and optionally radiotherapy. Provided herein is a combination therapy comprising a compound of Formula (I) and a PD-1 inhibitor or PD-L1 inhibitor. Also provided herein is a pharmaceutical combination comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor, and optionally radiotherapy. The combination therapies and pharmaceutical combinations of the present disclosure can be used for treating cancer, such as solid tumors.

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- , 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, 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.

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.

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.

As used herein, “pharmaceutical combination” or “combination” refers to formulations of the separate compounds with or without instructions for combined use. The combination compounds 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.

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, including two compounds, e.g., a compound of Formula (I), or pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor, 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 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 a PD-1 inhibitor or PD-L1 inhibitor and optionally 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.

As used herein, the term “synergy” refers to the effect achieved when the active ingredients, i.e., Compound A and an anti-PD-1 antibody, used together is greater than the sum of the effects that results from using the compounds separately.

In an embodiment, provided herein is a combination therapy comprising an effective amount of a compound of Formula (I) and a PD-1 inhibitor or PD-L1 inhibitor. An “effective amount” of a combination of agents (i.e., a compound of Formula (I) (e.g., Compound A) and a PD-1 inhibitor or PD-L1 inhibitor (e.g., an anti-PD-1 antibody)) 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.

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. Methods and Uses

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) for the treatment of a tumor in combination with PD-1 inhibitor or PD-L1 inhibitor: wherein

— is a single bond or double bond; , 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 Ci-₆ alkyl is optionally further substituted with one or more substituents selected from halogen and deuterium; pyridyl, and Ri is optionally further substituted with 1 or 2 substituents selected from D, halogen, cyano, hydroxyl, Ci-₆ alkyl and Ci_₆ alkoxy;

Ria is H or Ci-6 alkyl;

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

R2 is H, cyano, =0, carboxyl, -C(=O)NR2aR2b, C1-6 alkoxy, C1-6 alkyl, halogen, - S(= O)₂R_2a or -C(=O)OCi-₆ alkyl, wherein the C1-6 alkyl, -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 R_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, Ci-₆ alkyl and Ci-₆ alkoxy; alternatively, R_2a and R_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 Ci-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 H — 4 , Ro, R₂, and R₃ simultaneously satisfy the following conditions,

Ria is H or C1-6 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;

R2a 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 R_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 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 ; and n is 0, 1 or 2; with the provisos that e, and R₃ is methyl. In an embodiment, Ri is optionally further substituted with hydroxyl-substituted Ci-₆ alkyl.

In an aspect, provided herein is a method of treating cancer (e.g., a tumor) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (described supra), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor.

In an embodiment, the method or use further comprises administering radiotherapy to the subject.

In one or more embodiments of the present application,

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;

R2 is H, cyano, -C(=O)NR2aR2b, C1-6 alkoxy, halogen, -S(=O)2R2a or -C(=0)0Ci-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 R_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 and halogen; alternatively, R_2a and R_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 also optionally further substituted with one or more substituents selected from 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 ; and n is 0, 1 or 2; with the provisos that R₃ when Ro, R2, and R₃ simultaneously satisfy the following conditions, methyl, R₂ is 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 (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof (e.g., as an active ingredient) for the treatment of a tumor in combination with PD-1 inhibitor or PD-L1 inhibitor: 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;

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_2c is H, cyano, halogen or C1-6 alkoxy;

R₂d is H, cyano, carboxyl, -C(=O)NR_2aR2b, Ci_₆ alkyl, halogen, -S(=O)₂R₂a 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 Ci-₆ alkoxy; alternatively, R_2a and R_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 Ci-₆ alkyl, OH and halogen;

R₃ when H — 4 , Ro, R₂, and R₃ simultaneously satisfy the following conditions, methyl, R₂ is 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), for the treatment of a tumor in combination with PD-1 inhibitor or PD-L1 inhibitor: 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;

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

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

R_2a and R_2b are each independently 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 D or halogen; alternatively, R_2a and R_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 Ci-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 Ci-₆ alkyl, wherein the Ci-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 of the methods and uses, the compound of Formula (I) is a compound of Formula (Illa): or a stereoisomer, solvate, or pharmaceutically acceptable salt 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

Ri 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; 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), for the treatment of a tumor in combination with a PD-1 inhibitor or a PD-L1 inhibitor: 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 -(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, C1-6 alkoxy, and hydroxy substituted C1-6 alkyl.

In an embodiment of Formula (IV), Ri 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.

In one or more embodiments of the present application,

Ro is H, C1-6 alkyl or cyclopropyl, wherein the Ci-₆ alkyl 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-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 C-i-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) (e.g., an active ingredient) is selected from:

or a stereoisomer, solvate, or pharmaceutically acceptable salt.

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

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

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

In an embodiment of the methods and uses, the compound of Formula (I) is a compound of Formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

In an embodiment of the methods and uses, the PD-1 inhibitor or PD-L1 inhibitor is an anti-PD-1 antibody. In another embodiment, the PD-1 or PD-L1 inhibitor is selected from Pembrolizumab, Nivolumab, Serplulimab, Pidilizumab, Lambrolizumab, Atezolizumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab, Penpulimab, Zimberelimab, Envafolimab, Sugemalimab, Dostarlimab, Cadonilimab, Cemiplimab, Retifanlimab, BMS- 986213, HX-008, Geptanolimab, Prolgolimab, Socazolimab, Avelumab, Adebrelimab, and Durvalumab.

In an embodiment, the compound of Formula (I) is Compound A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and the PD-1 inhibitor or PD-L1 inhibitor is an anti-PD-1 antibody.

In an embodiment of the methods and uses, the compound of Formula (I) is administered simultaneously with the PD-1 or PD-L1 inhibitor. In an embodiment, the compound of Formula (I) is administered prior to the PD-1 or PD-L1 inhibitor. In an embodiment, the PD-1 or PD-L1 inhibitor is administered prior to the compound of Formula (I).

In an embodiment of the methods and uses, the method and use further comprises administering radiotherapy (i.e., IR) to the subject. In an embodiment of the methods and uses, the method or use comprises a compound of Formula (I), a PD-1 or PD-L1 inhibitor, and radiotherapy.

In one or more embodiments of the present application, the DNA-PK inhibitor (e.g., active ingredient such as a compound of Formula (I) and Compound A) exhibits obvious synergistical therapeutic effects when used in combination with PD-1 inhibitor or PD-L1 inhibitor.

In one or more embodiments of the present application, the tumor is selected from a solid tumor.

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 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 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.

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 lymphocytic 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 lymphocytic 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.

Combination Therapies and Pharmaceutical Combinations

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 a PD-1 inhibitor or PD-L1 inhibitor.

In an embodiment, the combination therapy comprises a compound of Formula (I )l, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor.

In an embodiment, the combination therapy comprises a compound of Formula (III), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor.

In an embodiment, the combination therapy comprises a compound of Formula (IV), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor.

In an embodiment, the combination therapy further comprises radiotherapy.

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 a PD-1 inhibitor or PD-L1 inhibitor. In an embodiment, the pharmaceutical combination comprises a compound of Formula (II), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor.

In an embodiment, the pharmaceutical combination comprises a compound of Formula (III), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor.

In an embodiment, the pharmaceutical combination comprises a compound of Formula (IV), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a PD-1 inhibitor or PD-L1 inhibitor.

In an embodiment, the pharmaceutical combination further comprises radiotherapy.

In an embodiment of the formulae of the combination therapies and pharmaceutical combinations:

Ri 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 Ci-6 alkyl;

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

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

In another embodiment, the compound of Formulae (I), (II), (III), or (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), or (IV) 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 PD-1 or PD-L1 inhibitor is an anti-PD-1 antibody. In an embodiment, the PD-1 inhibitor or PD-L1 inhibitor is selected from Pembrolizumab, Nivolumab, Serplulimab, Pidilizumab, Lambrolizumab, Atezolizumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab, Penpulimab, Zimberelimab, Envafolimab, Sugemalimab, Dostarlimab, Cadonilimab, Cemiplimab, Retifanlimab, BMS-986213, HX-008, Geptanolimab, Prolgolimab, Socazolimab, Avelumab, Adebrelimab, and Durvalumab.

In an embodiment, the pharmaceutical combination comprises Compound A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody.

In an embodiment, the pharmaceutical combination is for use in the treatment of a tumor. In an embodiment, the combination therapy comprises Compound A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody.

In an embodiment, the combination therapy further comprises radiotherapy.

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

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

In an embodiment, the pharmaceutical combination comprises: a compound of Formulae (I), (II), (III), or (IV), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and a PD-1 inhibitor or PD-L1 inhibitor, and a pharmaceutically acceptable carrier.

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.

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, a PD-1 inhibitor or PD-L1 inhibitor, and a pharmaceutically acceptable carrier.

In an embodiment, the pharmaceutical composition comprises a compound of Formula (II), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, a PD-1 inhibitor or PD-L1 inhibitor, and a pharmaceutically acceptable carrier. In an embodiment, the pharmaceutical composition comprises a compound of Formula (III), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, a PD-1 inhibitor or PD-L1 inhibitor, and a pharmaceutically acceptable carrier.

In an embodiment, the pharmaceutical composition comprises a compound of Formula (IV), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, a PD-1 inhibitor or PD-L1 inhibitor, and a pharmaceutically acceptable carrier.

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

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

In another embodiment, the PD-1 inhibitor or PD-L1 inhibitor is an anti-PD-1 antibody. In an embodiment, the PD-1 inhibitor or PD-L1 inhibitor is selected from Pembrolizumab, Nivolumab, Serplulimab, Pidilizumab, Lambrolizumab, Atezolizumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab, Penpulimab, Zimberelimab, Envafolimab, Sugemalimab, Dostarlimab, Cadonilimab, Cemiplimab, Retifanlimab, BMS- 986213, HX-008, Geptanolimab, Prolgolimab, Socazolimab, Avelumab, Adebrelimab, and Durvalumab.

In an embodiment, the pharmaceutical composition comprises Compound A, or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, an anti-PD-1 antibody, and a pharmaceutically acceptable carrier.

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 carcinoma. In an embodiment, the tumor is colon cancer.

In an embodiment, the pharmaceutical composition is used in combination with radiotherapy. 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 combination of a compound of Formula (I) and a PD-1 inhibitor or PD-L1 inhibitor. 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.

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 PD-1 inhibitor or PD-L1 inhibitor are in a unit dose form. In an embodiment, the compound of Formula (I) and PD-1 inhibitor or PD-L1 inhibitor are in separate unit dose forms.

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.

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.

In all of the foregoing the combination of components of the present disclosure can be administered alone, as mixtures, or with additional active agents, such as radiotherapy.

Administration, Dosage, and Formulations

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

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.

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.

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 certain embodiments, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 antibody) 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 PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 antibody) is administered at a dose per day of about 1-1000 mg/kg. In certain embodiments, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 antibody) 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, a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 antibody) is administered at a dose per day of about 1-15 mg/kg (e.g., about 15 mg/kg, about 10 mg/kg, or about 5 mg/kg).

The total daily dose of the PD-1 or PD-L1 inhibitor 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 PD-1 or PD-L1 inhibitor is administered twice a week.

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., a compound of Formula 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 a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 antibody). 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., a compound of Formula A), for example, wherein the therapeutically effective amount of a compound of Formula (I) is a dose of about 1-2000 mg (e.g., about 1- 1000 mg), and (2) a single dose (once within a 24-hour period) to deliver about 1-1000 mg of a PD-1 or PD-L1 inhibitor (e.g., an anti-PD-1 antibody) intravenously twice a week.

The combination components provided herein (for example, a compound of Formula (I) and a PD-1 or PD-L1 inhibitor) are present in the combinations, dosage forms, pharmaceutical compositions and pharmaceutical formulations disclosed herein in a ratio in the range of 100:1 to 1 :100. The optimum ratios, individual and combined dosages, and concentrations of the drug compounds that yield efficacy without toxicity are based on the kinetics of the active ingredients’ availability to target sites, and are determined using methods known to those of skill in the art.

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.

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.

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

Example 1. Efficacy test of Compound A in combination with a PD-1 inhibitor in CT26 transplanted tumor model

Experimental steps

Test materials

SPF 5-week-old BALB/c female mice, purchased from BEIJING HFK BIOSCIENCE Co., LTD. Colon cancer CT26 cells (purchased from BeNa Culture Collection); and antimouse PD-1 (CD279) (InVivoPlus anti-mouse PD-1 , purchased from BioXCell, Clone: RMPI- 14; Lot Number: BP0146; see, e.g., Liang, S. C., et al. (2003). Eur J Immunol 33(10): 2706- 2716).

Cell culture and inoculation

CT26 cells in a logarithmic growth phase were collected and washed with pre-chilled PBS twice for later use. BALB/c mice were adapted to the laboratory environment for 5 days and inoculated subcutaneously with CT26 cells in the right flank at an inoculation amount of 1 x 1 o⁶ cells/mouse. When the tumor volume reached about 50 mm³, the efficacy experiment was performed.

Administration method

The animals that had successfully developed tumors were randomly divided into 3 groups, with 8 mice in each group (n = 8), including: a control mouse group (Vehicle), the anti-mouse PD-1 (5 mg/kg, BIW) group, and the anti-mouse PD-1 (5mg/kg, BIW) + Compound A (20 mg/kg, QD) group. The Vehicle group was given a solvent (30% HP-p-CD) by intragastric administration for 14 days. Compound A was given once a day (QD) by intragastric administration for 14 consecutive days. The anti-mPD-1 drug was administered intraperitoneally twice a week for a total of 4 time.

Test indicators

Tumor volume

The diameter of tumors was measured twice a week using a vernier caliper to calculate the volume of tumors, and a tumor growth curve was plotted. The calculation formula of the tumor volume (V) is:

V = 1/2 x a x b² where a and b represent the long and short diameters of the tumor, respectively.

At the end of the experiment, the relative tumor proliferation rate T/C (%) and tumor growth inhibition TGI (%) were calculated, with calculation formulae as follows:

T/C (%) = TRTV/CRTV x 100%; and

TGI (%) = 1 - T/C;

TRTV: RTV of treatment group, CRTV: RTV of negative control group; RTV = Vt/Vo, where V_o is the tumor volume measured when the mice are placed in separate cages for administration (i.e., PG-D0), and Vt is the tumor volume at each measurement.

Body weight

The body weight of a mouse was measured twice a week during a drug treatment cycle, and the data were recorded. Statistical analysis of the body weight and weight changes (%) of mice was conducted.

The experimental results show that Compound A has a relatively good synergistic effect when used in combination with a PD-1 inhibitor. Example 2. Efficacy test of Compound A in combination with radiotherapy (IR) and/or a PD-1 inhibitor in CT26 transplanted tumor model

Experimental steps

Test materials

SPF 35-48-day-old BALB/c mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Colon cancer CT26 cells were purchased from BeNa Culture Collection); and anti-mouse PD-1 (CD279) was purchased from BioXCell as described in Example 1.

Cell culture and inoculation

CT26 cells in a logarithmic growth phase were collected and washed with pre-chilled PBS twice for later use. BALB/c mice were adapted to the laboratory environment for 5 days and inoculated subcutaneously with CT26 cells in the right flank at an inoculation amount of 1 x 10⁶ cells/mouse (100 pL). When the average volume reached 120-150 mm³, the mice were randomly divided into groups based on the tumor volume for the efficacy test.

Administration method

The animals that had successfully developed tumors were randomly divided into eight groups, with eight mice in each group (n = 8), including: control mouse Group 1 (Vehicle), Group 2 (IR 1 Gy+Vehicle), Group 3 (PD-1 5 mg/kg), Group 4 (IR 1 Gy + PD-1 5 mg/kg), Group 5 (IR 1 Gy + Compound A 20 mg/kg + PD-1 5 mg/kg), Group 6 (IR 1 Gy+ M3814 20 mg/kg+PD-1 5 mg/kg), Group 7 (IR 1 Gy + Compound A 20 mg/kg), and Group 8 (IR 1Gy+ M3814 20 mg/kg). M3814 is a previously disclosed DNA-PK inhibitor (see, e.g., Zenke, F. T., et al., Mol Cancer Ther. 2020 May;19(5):1091-1101 ).

Table 1 : Grouping information

The administration information is shown in Table 2 below:

Table 2: Administration information Test indicators

Tumor volume

The diameter of tumors was measured twice a week using a vernier caliper to calculate the volume of tumors, and a tumor growth curve was plotted. The calculation formula of the tumor volume (V) is: V = 1/2 x _a x b², where a and b represent the long and short diameters of the tumor, respectively.

T/C (%) = TRTV/CRTV x 100%; and TGI (%) = 1 - T/C; TRTV: RTV of treatment group, CRTV: RTV of negative control group; RTV = Vt/V₀, where Vo is the tumor volume measured when the mice are placed in separate cages for administration (i.e., PG-D0), and Vt is the tumor volume at each measurement.

The tumor volume results are shown in Table 3 and FIG. 1. Table 3: Tumor volume statistics (Mean ± SEM, mm³)

Notes: the day of grouping is DO; * indicates P < 0.05 compared to animals in the

Vehicle group; ** indicates P < 0.01 compared to animals in the Vehicle group; *** indicates P < 0.001 compared to animals in the Vehicle group.

Table 3 continued Notes: the day of grouping is DO; * indicates P < 0.05 compared to animals in the

Vehicle group; ** indicates P < 0.01 compared to animals in the Vehicle group; *** indicates P < 0.001 compared to animals in the Vehicle group; # indicates P < 0.05 compared to animals in the “IR 1Gy+Vehicle” group (exclude two mice with tumor regression); ## indicates P < 0.01 compared to animals in the “IR 1 Gy+Vehicle” group; ### indicates P < 0.001 compared to animals in the “IR 1Gy+Vehicle” group.

The tumor inhibition rates are shown in Table 4. Table 4: Relative tumor inhibition rate (%)

Table 4 continued data were not collected; Two mice with tumor regression were excluded from the (IR 1Gy + Vehicle) group.

The tumor weight results are shown in Table 5 and FIG. 2.

Table 5: Tumor weight statistics (Mean±SEM, mg)

Notes: two mice with tumor regression were excluded from the (IR 1 Gy + Vehicle) group.

Body weight The body weight of a mouse was measured twice a week during a drug treatment cycle, and the data were recorded. Statistical analysis of the body weight and weight changes (%) of mice was conducted.

The body weight results are shown in Table 6 and FIG. 3.

Table 6: Body weight statistics (Mean±SEM, g)

Table 6 continued

Notes: the day of grouping is DO; 7” indicates that the mice were euthanized, and data were not collected The body weight change rates are shown in Table 7 and FIG. 4.

Table 7: Body weight change rate (%)

Table 7 continued

Notes: the day of grouping is DO; 7” indicates that the mice were euthanized, and data were not collected

As can be seen, Compound A can significantly enhance the anti-tumor efficacy of a model of radiotherapy in combination with a PD-1 inhibitor. Furthermore, Compound A is well-tolerated by animals in the CT26 subcutaneous tumor model. Compound A has better antitumor efficacy than M3814 and has a significantly less effect on animal body weight than M3814, indicating better safety.

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

1 . Use of a compound represented by formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the preparation of an anti-tumor drug in combination with PD-1 inhibitor or PD-L1 inhibitor: ch 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; pyridyl, and Ri is optionally further substituted with 1 or 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 Ci-₆ alkyl;

R₂ is H, cyano, =0, carboxyl, -C(=O)NR_2aR2b, Ci-₆ alkoxy, Ci-₆ alkyl, halogen, - S(=O)₂R_2a or -C(=0)0Ci-₆ alkyl, wherein the Ci-₆ alkyl, -C(=0)0Ci.₆ alkyl or Ci-₆ alkoxy is optionally substituted with one or more substituents selected from halogen and deuterium; R_2a and R_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, Ci-₆ alkyl and Ci-₆ alkoxy; alternatively, R_2a and R_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 Ci-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 e, and R₃ is methyl.

2. The use according to claim 1 , wherein

Ria is H or C1-6 alkyl;

R_2a and R_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 or halogen; alternatively, R_2a and R_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 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 ; and n is 0, 1 or 2; with the provisos that e, and R₃ is methyl.

3. The use according to claim 1 , wherein

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

R₂ is H, cyano, -C(=O)NR_2aR2b, C1-6 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;

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 ; and n is 0, 1 or 2; with the provisos that when methyl, R₂ is methoxy or -

S(=O)₂Me, and R₃ is methyl.

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

Ria is H or C1-6 alkyl;

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

R_2C is H, cyano, halogen or Ci-6 alkoxy;

R_2d is H, cyano, carboxyl, -C(=O)NR_2aR₂b, Ci_₆ alkyl, halogen, -S(=O)₂R_2a or - C(=O)OCi-₆ alkyl, wherein the Ci-₆ alkyl and -C(=O)OCi_₆ alkyl is optionally substituted with one or more substituents selected from halogen and deuterium;

R_2a and R₂b 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, Ci-6 alkyl and Ci-₆ alkoxy; alternatively, R_2a and R_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;

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 ; n is 0, 1 or 2; and x and y are each independently 1 , 2 or 3; with the provisos that when , Ro, R2, and R₃ simultaneously satisfy the following conditions,

R1 is not , n is 1 , Ro is H or methyl, R₂ is methoxy or -S(=O)₂Me, and R₃ is methyl.

5. The use according to claim 4, wherein the compound of Formula (II) is a compound of Formula (III), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof: wherein

yl, and

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

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 Ci-₆ alkyl, wherein the Ci-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.

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

Ri 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.

7. The use according to claim 6, wherein

Ria is H or C1-6 alkyl;

8. The use according to claim 7, wherein

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

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

15. The use according to any one of claims 1 to 14, wherein the PD-1 or PD-L1 inhibitor is an anti-PD-1 antibody.

16. The use according to any one of claims 1 to 15, wherein the PD-1 or PD-L1 inhibitor is selected from Pembrolizumab, Nivolumab, Serplulimab, Pidilizumab, Lambrolizumab, Atezolizumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab, Penpulimab, Zimberelimab, Envafolimab, Sugemalimab, Dostarlimab, Cadonilimab, Cemiplimab, Retifanlimab, BMS-986213, HX-008, Genolimzumab, Prolgolimab, Socazolimab, Avelumab, Adebrelimab, and Durvalumab.

17. The use according to any one of claims 1 to 16, wherein the tumor is selected from a solid tumor.

18. The use according to any one of claims 1 to 17, 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 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 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.

19. The use according to any one of claims 1 to 17, wherein the tumor is colon cancer.

20. The use according to claim 18, wherein 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 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 lymphocytic 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 lymphocytic 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.

21 . The use according to any one of claims 1 to 20, wherein the combination further comprises radiotherapy.

22. A pharmaceutical combination comprising a compound of Formula (I), or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor.

23. The pharmaceutical combination of claim 22, wherein the compound of Formula (I) is or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

24. The pharmaceutical combination according to claim 22 or 23, wherein the compound of Formula (I) is Compound A: or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof.

25. The pharmaceutical combination according to any one of claims 22 to 24, wherein the PD-1 or PD-L1 inhibitor is an anti-PD-1 antibody.

26. The pharmaceutical combination according to any one of claims 22 to 25, wherein the PD-1 or PD-L1 inhibitor is selected from Pembrolizumab, Nivolumab, Serplulimab, Pidilizumab, Lambrolizumab, Atezolizumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab, Penpulimab, Zimberelimab, Envafolimab, Sugemalimab, Dostarlimab, Cadonilimab, Cemiplimab, Retifanlimab, BMS-986213, HX-008, Genolimzumab, Prolgolimab, Socazolimab, Avelumab, Adebrelimab, and Durvalumab.

27. The pharmaceutical combination according to any one of claims 22 to 26, wherein the pharmaceutical combination further comprises radiotherapy.

28. 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 a PD-1 or PD-L1 inhibitor.

29. The method according to claim 28, wherein the compound of Formula (I) is or 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 PD-1 or PD-L1 inhibitor is an anti-PD-1 antibody.

32. The method according to any one of claims 28 to 31 , wherein the PD-1 or PD-L1 inhibitor is selected from Pembrolizumab, Nivolumab, Serplulimab, Pidilizumab, Lambrolizumab, Atezolizumab, Toripalimab, Sintilimab, Tislelizumab, Camrelizumab, Penpulimab, Zimberelimab, Envafolimab, Sugemalimab, Dostarlimab, Cadonilimab, Cemiplimab, Retifanlimab, BMS-986213, HX-008, Genolimzumab, Prolgolimab, Socazolimab, Avelumab, Adebrelimab, and Durvalumab.

33. The method according to any one of claims 28 to 32, wherein the method further comprises administering radiotherapy to the subject.

34. The method according to any one of claims 28 to 33, wherein the tumor is a solid tumor.

35. The method according to any one of claims 28 to 33, wherein the tumor is colon cancer.