Combination therapy including PARG inhibitors and topoisomerase inhibitors

Abstract

This invention provides a combination of a PARG inhibitor and a topoisomerase inhibitor. It also provides a method for treating diseases or disorders, such as cancer, using such a combination.

Description

[Technical Field]

[0001] Reference to related applications This application claims the interests of U.S. Provisional Application No. 63 / 457,312 filed on April 5, 2023, No. 63 / 584,013 filed on September 20, 2023, and No. 63 / 548,513 filed on November 14, 2023, each of which is incorporated herein by reference in whole for all purposes. [Background technology]

[0002] background Cancer is caused by uncontrolled and disorderly cell proliferation. This often rapid proliferation results in high levels of oxidative stress within the tumor, which damages DNA and significantly increases the mutation rate. Therefore, tumor cells are closely related to and dependent on DNA damage repair mechanisms.

[0003] Single-strand breaks (SSBs) are the most common type of damage that occurs in cells, and PARG (poly-ADP-ribose glycohydrolase), along with PARP (poly-ADP-ribose polymerase), is involved in another repair mechanism called single-strand break repair (SSBR) and base excision repair (BER), along with many other proteins.

[0004] One of the earliest events in single-strand DNA repair is the binding of PARP (poly-ADP-ribose polymerase) to the cleavage site, leading to the rapid synthesis of poly-ADP-ribose (PAR) on PARP itself. This molecular structure acts as a signal to recruit other DNA repair proteins to facilitate repair. These signals initiated by PAR chains are short-lived because they are rapidly degraded by the enzyme PARG. When PARP binds to PAR, its catalytic activity decreases, so PARG activity helps restore PARP to its catalytically active state.

[0005] PARG originates from a single gene, and isoforms exist in the nucleus, mitochondria, and cytoplasm. Another known protein with glycohydrolase activity is ARH3, which is localized in mitochondria. While PARG is primarily known for its direct role in DNA repair, it also influences PAR signaling in transcriptional and epigenetic pathways.

[0006] Cancer cells may become dependent on specific DNA repair pathways when other DNA repair mechanisms are not functioning. Tumors with mutations in proteins involved in double-strand break repair are often more sensitive to SSBR PARP inhibitors. There is already some evidence that PARG depletion inhibits SSBR and reduces the survival rate of BRCA2-deficient cells. However, other tumor mutations may cause defects in the double-strand DNA repair mechanism (so-called "BRCA-like" properties), making tumor cells sensitive to PARG inhibition.

[0007] Topoisomerases are abundant enzymes essential for altering the topology of DNA during DNA replication and transcription, and are classified into two main classes: type I and type II. Topoisomerase inhibitors, used as anticancer agents, specifically act on the topoisomerase species mentioned above. For example, topoisomerase II inhibitors include anthracyclines such as doxorubicin. Topoisomerase inhibitors induce cell death by inhibiting the activity of topoisomerase, which is usually expressed in much higher concentrations in cancer cells than in normal cells. Alternatively, topoisomerase inhibitors can covalently capture topoisomerase on DNA, causing lethal DNA strand breaks and leading to cell death.

[0008] While cancer treatment has advanced significantly in recent years, there is still a need for more effective and / or enhanced treatments for people with cancer. This disclosure addresses this need and provides relevant benefits.

[0009] overview This specification provides a combination comprising a poly-ADP-ribose glycohydrolase (PARG) inhibitor and a topoisomerase inhibitor. This combination is useful for the treatment of various cancers, including solid tumors. In one embodiment, the disease or disorder is an advanced or metastatic solid tumor. This combination is also useful for the treatment of many PARG-related diseases. This combination is also useful for the treatment of various diseases or disorders involving PARG activity. This combination is also useful for the treatment of homologous recombination deficiency (HRD) cancer. This combination is also useful for the treatment of various diseases or disorders that can be treated by inhibiting topoisomerase.

[0010] This specification provides a combination product comprising a PARG inhibitor and a topoisomerase inhibitor. This combination product is useful for the treatment of various cancers, including solid tumors. In one embodiment, the disease or disorder is a progressive or metastatic solid tumor. This combination product is also useful for the treatment of many PARG-related diseases. This combination product is also useful for the treatment of various diseases or disorders involving PARG activity. This combination product is also useful for the treatment of homologous recombination deficiency (HRD) cancer. This combination product is also useful for the treatment of various diseases or disorders that can be treated by inhibiting topoisomerase.

[0011] In one embodiment, a combination of a PARG inhibitor and a topoisomerase inhibitor is provided herein.

[0012] In one embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a PARG inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of a topoisomerase inhibitor are provided herein.

[0013] In one embodiment, a method for treating and / or preventing cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the subject's cancer.

[0014] In one embodiment, a method for treating and / or preventing cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least a pharmaceutically acceptable carrier, thereby treating the subject's cancer.

[0015] In one embodiment, a method for treating and / or preventing homologous recombination deficiency (HRD) cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the subject's cancer.

[0016] In one embodiment, a method for treating and / or preventing homologous recombination deficiency (HRD) cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject.

[0017] In yet another embodiment, cancer is characterized by decreased or absent expression of BRCA1 and / or BRCA2 genes, absence or mutation of BRCA1 and / or BRCA2 genes, impaired function of BRCA1 and / or BRCA2 proteins, or a combination thereof.

[0018] In one embodiment, a method for treating or preventing cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a PARG inhibitor and a therapeutically effective amount of a pharmaceutical composition comprising a topoisomerase inhibitor, thereby treating the subject's cancer.

[0019] In one embodiment, a method is provided herein for treating and / or preventing a disease or disorder involving PARG activity in a subject requiring such treatment, the method comprising administering to the subject a combination of a PARG inhibitor and a topoisomerase inhibitor to treat the subject's disease or disorder. In one embodiment, the disease or disorder is cancer.

[0020] In one embodiment, a method is provided herein for treating and / or preventing a disease or disorder involving PARG activity in a subject requiring such treatment, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least one pharmaceutically acceptable carrier, thereby treating the disease or disorder in the subject. In one embodiment, the topoisomerase inhibitor is doxorubicin or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or disorder is cancer. In one embodiment, the cancer is homologous recombination deficiency (HRD) cancer.

[0021] In one embodiment, the PARG inhibitor is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, where the variables in formula I are defined as follows:

[0022] In another embodiment, the PARG inhibitor has the following structural formula: [ka] Compound A having the property or a pharmaceutically acceptable salt thereof. A method for producing Compound A is described in Example 1 of this application.

[0023] Specific PARG inhibitors for use in the combination therapies described herein are described in International Publication No. 2021 / 055744 (PCT / US20 / 51486), and the general and specific compounds described herein can be used to treat the cancers described herein.

[0024] In another embodiment, a topoisomerase inhibitor is an inhibitor of type II topoisomerase (also referred to herein as a "topoisomerase II inhibitor").

[0025] In yet another embodiment, the topoisomerase II inhibitor is doxorubicin, etoposide, epirubicin, novobiocin, ciprofloxacin, or teniposide, or a pharmaceutically acceptable salt thereof. In one embodiment, the topoisomerase II inhibitor is doxorubicin or a pharmaceutically acceptable salt thereof.

[0026] In another embodiment, a topoisomerase inhibitor is an inhibitor of type I topoisomerase (also referred to herein as a "topoisomerase I inhibitor").

[0027] In one embodiment, the topoisomerase I inhibitor is topotecan or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawing]

[0028] [Figure 1] Figure 1 shows an efficacy study evaluating the combined effect of compound A and doxorubicin (compound B) in the xenograft model HCC1428 derived from HR-deficient breast cancer cell lines.

[0029] [Figure 2] Figure 2 shows an efficacy study evaluating the combined effect of compound A and topotecan (compound H) in the small cell lung cancer cell line NCI-H69.

[0030] [Figure 3] Figure 3 shows an efficacy study evaluating the combined effect of compound A and topotecan (compound H) in the Kuromachi cell line, which is a high-grade serous ovarian cancer cell line.

[0031] [Figure 4]Figure 4 shows an efficacy study evaluating the combined effect of compound A and topotecan (compound H) in the breast cancer model HCC1395.

[0032] [Figure 5] Figure 5 shows an efficacy study evaluating the combined effect of compound A and compound J (fam-trastuzumab deruxtecan-nxki) in the human lung cancer strain NCI-H650. [Modes for carrying out the invention]

[0033] Detailed explanation This specification provides a combination therapy comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. This combination therapy is useful for the treatment of various cancers, including, for example, ovarian cancer, gastric cancer, breast cancer, lung cancer, cervical cancer, pancreatic cancer, or prostate cancer. In another embodiment, this combination therapy is useful for the treatment of many PARG-related diseases.

[0034] Administering a combination of a PARG inhibitor and a topoisomerase inhibitor may yield beneficial effects in treating cancer in subjects, such as solid tumors. Such an approach (combined or simultaneous administration of the two drugs) may provide uninterrupted treatment to subjects in need over a clinically relevant treatment period.

[0035] definition The following are definitions of various terms used herein. These definitions apply to terms used herein and throughout the claims, unless, in specific cases, individually or as part of a larger group, they are not limited to others.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. Generally, the nomenclature used herein, as well as the experimental procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry, are well known and commonly used in the art.

[0037] As used herein, the articles "a" and "an" refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an element" means one or more elements. Furthermore, the use of the term "including," and its other forms "include," "includes," and "included," is not limited.

[0038] The term “about” as used herein will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. Where “about” refers to a measurable value such as quantity or duration, it means to include a variation of ±20% or ±10% (including ±5%, ±1%, and ±0.1%) from a specified value, such that it is appropriate for performing the disclosed method.

[0039] As used herein and in the claims, the term “comprising” may include embodiments such as “consisting of” and “consisting essentially of.” As used herein, the terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and their variations are intended to be unrestrictive transitional phrases, terms, or words that require the presence of a specified component / step but permit the presence of other components / steps.

[0040] Note that in this specification, ratios, concentrations, quantities, and other numerical data may be expressed in range form. Such range forms are used for convenience and conciseness, and should therefore be interpreted flexibly to include not only the numbers explicitly stated as limits of the range, but also all individual numbers or subranges contained within that range, as if each number and subrange were explicitly stated. Furthermore, the phrase "approximately x to y" includes "approximately x to approximately y".

[0041] As used herein, the terms “combination,” “therapeutic combination,” “pharmaceutical combination,” or “combination product” refer to either a fixed combination in one dosage unit form, an unfixed combination in separate dosage forms, or a kit of parts for combination administration in which two or more therapeutic agents may be administered independently, simultaneously, or separately within a time interval.

[0042] The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described herein. Such administrations include the simultaneous administration of these therapeutic agents substantially simultaneously, for example, in a single formulation having a fixed ratio of active ingredients, or in separate formulations for each active ingredient (e.g., capsules and / or intravenous formulations). Furthermore, such administrations also include the use of each type of therapeutic agent sequentially or separately, approximately simultaneously or at different times. Regardless of whether the active ingredients are administered as a single formulation or as separate formulations, the drugs are administered to the same patient as part of the same course of treatment. In any case, the treatment plan will produce a beneficial effect in treating the condition or disorder described herein.

[0043] As used herein, the terms “treating” or “treating” mean inhibiting a disease, for example, inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., preventing further progression of the pathology and / or symptoms), or improving a disease, for example, improving a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or symptoms), for example, reducing the severity of the disease.

[0044] As used herein, the terms "patient," "individual," or "subject" refer to a human being.

[0045] As used herein, the terms “effective dose,” “pharmaceutical effective dose,” and “therapeutic effective dose” refer to an amount of a drug sufficient to produce a desired biological outcome without toxicity. This outcome may be a reduction or alleviation of the signs, symptoms, or causes of a disease, or other desired changes in the biological system. The appropriate therapeutic dose in individual cases can be determined by those skilled in the art using routine experiments.

[0046] As used herein, the term "pharmaceutically acceptable" means a substance such as a carrier or diluent that does not preclude the biological activity or properties of a compound and is relatively non-toxic; that is, the substance can be administered to an individual without causing undesirable biological effects or harmful interactions with any component of a composition containing it.

[0047] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound in which the parent compound has been modified by converting an existing acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic acid salts of acidic residues such as carboxylic acids. Pharmacochemically acceptable salts described herein include conventional non-toxic salts of parent compounds, for example, formed from non-toxic inorganic or organic acids. Pharmacochemically acceptable salts discussed herein can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, and acetonitrile are used. The term “pharmaceutically acceptable salt” is not limited to monosalts, i.e., 1:1 salts. For example, “pharmaceutically acceptable salt” also includes bissalts, such as bishydrochloride salts. A list of suitable salts is provided 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.

[0048] As used herein, the terms “composition” or “pharmaceutical composition” refer to a mixture of at least one compound and a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates the administration of the composition to a patient or subject. Several techniques for administering compounds exist in the art, but are not limited to, and include intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0049] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, which is involved in carrying or transporting a compound useful to a patient so that the compound can perform its intended function. Typically, such constructs carry or transport a compound from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with other components of a formulation containing the compound disclosed herein and is not harmful to the patient. Some examples of substances that can function as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic, suitable substances used in pharmaceutical formulations.

[0050] As used herein, “pharmaceutically acceptable carriers” include any coating agents, antimicrobial agents, and antifungal agents, as well as absorption retarders, that are compatible with the activity of the compounds disclosed herein and are physiologically acceptable to the patient. Auxiliary active compounds may also be incorporated into the compositions. Other additional components that may be included in the pharmaceutical compositions are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which are incorporated herein by reference.

[0051] As used herein, the term “single formulation” refers to a single carrier or vehicle formulated to deliver therapeutically effective doses of both therapeutic agents to a patient. A single vehicle is designed to deliver therapeutically effective doses of each drug together with any pharmaceutically acceptable carrier or excipient. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

[0052] In this specification, "poly-ADP-ribose glycohydrolase inhibitor" or "PARG inhibitor" means a drug that modulates the activity of PARG.

[0053] As used herein, "topoisomerase inhibitor" means a drug that inhibits the activity of topoisomerase. Examples of topoisomerase inhibitors include, but are not limited to, doxorubicin, etoposide, epirubicin, novobiocin, ciprofloxacin, teniposide, and pharmaceutically acceptable salts thereof.

[0054] In one embodiment, a combination therapy is provided that includes a therapeutically effective amount of a PARG inhibitor and a topoisomerase inhibitor. The "therapeutically effective amount" of the combination of agents (i.e., the PARG inhibitor and the topoisomerase inhibitor) is an amount sufficient to provide an observable improvement in the clinically observable signs and symptoms of the disorder being treated, compared to baseline. Observable improvements include improvements that can be visually confirmed by a clinician, biological tests, biopsies, and assays.

[0055] The term "alkyl", alone or as part of another substituent, unless otherwise specified, means a saturated straight-chain or branched hydrocarbon group having the indicated number of carbon atoms (i.e., C 1-8 means from 1 to 8 carbon atoms). Alkyl includes a number of carbons, such as C 1-2 C 1-3 C 1-4 C 1-5 C 1-6 C 1-7 C 1-8 C 1-9 C 1-10 C 2-3 C 2-4 C 2-5 C 2-6 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 C 5-6 and can include C

[0056] Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0057] The term "cycloalkyl" refers to a saturated hydrocarbon ring having the indicated number of ring atoms (e.g., C 3-6 cycloalkyl). Cycloalkyl, unless otherwise noted, is C 1-6Alkyl, halo, hydroxy, C 1-6 Haloalkyl, C 1-6 They are optionally substituted with one, two, or three substituents independently selected from haloalkoxys or cyano compounds. Typical examples, but not limited to, include cyclopropyl, cyclobutyl, and cyclopentyl.

[0058] The term "halo" or "halogen" means, either alone or as part of another substituent, a fluorine, chlorine, bromine, or iodine atom unless otherwise specified.

[0059] The term "haloalkyl" refers to an alkyl group substituted with 1 to 5 halo atoms, as defined above, and includes monohaloalkyl and polyhaloalkyl groups. For example, the term "C 1-4 "Haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, among others.

[0060] The terms "alkoxy" and "haloalkoxy" refer to alkyl groups and haloalkyl groups, respectively, as defined herein, which are bonded to the rest of the molecule via an oxygen atom.

[0061] The term "heteroaryl" refers to a 5-10 membered aromatic ring containing 1-5 heteroatoms selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl groups can be bonded to the rest of the molecule via heteroatoms. Non-exclusive examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazolyl, isobenzofuryl, isoindolyl, indolidinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranil, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, and thienyl.

[0062] The term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated 4-10 membered monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. The nitrogen and sulfur atoms may be optionally oxidized, the nitrogen atom may be optionally quaternized, and one or two ring carbon atoms of the heterocycle may be substituted with a -C=(O) group. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, and tetrahydrothiophene. Heterocycloalkyl groups can be bonded to the rest of the molecule via a ring carbon or heteroatom. Non-limiting examples of heterocycloalkyl groups include pyridine-2(H)-one.

[0063] The term "hydroxyalkyl" refers to an alkyl group defined above, which is substituted with one or two hydroxyls. For example, "hydroxyC 1-4 The term "alkyl" includes hydroxymethyl, 1- or 2-hydroxyethyl, 1,2-dihydroxyethyl, and hydroxypropyl.

[0064] As used herein, “homologous recombination” refers to a cellular process of genetic modification in which nucleotide sequences are exchanged between two similar or identical DNA sequences.

[0065] As used herein, “homologous recombination deficiency (HRD) cancer” refers to cancer characterized by a reduction or deficiency of the functional HR repair pathway. HR deficiency can result from the absence or reduction of one or more HR-related genes, or from the presence of one or more mutations in one or more HR-related genes. Examples of HR-related genes include BRCA1, BRCA2, RAD54, RAD51B, ATM, BARD1, CHK1, CHK2, CDK12, RAD51B, RAD54L, RAD51D, PPP22A, BRIP1, CtIP (CtBP interacting protein), PALB2 (BRCA2 partner and localization factor), XRCC2 (X-ray repair complementing defect repair in Chinese fam-star cells), RECQL4 (RecQ protein-like 4), and BLM (Bloom syndrome, RecQ helicase). This includes genes encoding Fanconi anemia (FA) proteins or FA-like genes, such as FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.

[0066] The antibodies described in the antibody-drug conjugates of this disclosure mean immunoglobulins, which are molecules containing an antigen-binding site that binds immunospecifically to an antigen. The class of the antibodies of this disclosure may be any of IgG, IgE, IgM, IgD, IgA, and IgY, preferably IgG. The subclass of the antibodies of this disclosure may be any of IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, preferably IgG1 or IgG2. The antibodies may originate from any species, preferred examples of which include humans, rats, mice, and rabbits. If the antibodies originate from a non-human species, they are preferably chimerized or humanized using well-known techniques. The antibodies of this disclosure may be polyclonal or monoclonal antibodies. In some embodiments, the antibody is a monoclonal antibody. The antibodies of this disclosure can target tumor cells. Since the antibodies of this disclosure are conjugated to an antitumor compound having antitumor activity via a linker, it is preferable that the antibodies have one or more of the following properties: the property of recognizing tumor cells, the property of binding to tumor cells, the property of internalizing in tumor cells, and the property of damaging tumor cells. In one embodiment, the antibody is a monoclonal antibody that reacts with a target antigen or an epitope of an antigen expressed on cancer cells or malignant cells. Techniques for preparing monoclonal antibodies against target antigens are known in the art. Non-limited target antigens include B7-H3, B7-H4, Trop-2, PSMA, folate receptor, EGF receptor (ErbB1), ErbB2, ErbB3, HER-2, tissue factor, CD-19, VEGF, insulin-like growth factor (ILGF), MUC1, and TA-MUC1.

[0067] Combined products This specification provides a combination product comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. This combination product is useful for the treatment of various cancers, including solid tumors. In one embodiment, the disease or disorder is an advanced or metastatic solid tumor. In another embodiment, this combination product is useful for the treatment of numerous PARG-related diseases. In another embodiment, this combination product is useful for the treatment of diseases or disorders involving PARG activity. In another embodiment, this combination product is useful for the treatment of homologous recombination deficiency (HRD) cancer.

[0068] In one embodiment, a combination of a PARG inhibitor and a topoisomerase inhibitor is provided.

[0069] As used herein, the term “combination product” includes embodiments in which a PARG inhibitor and a topoisomerase inhibitor are formulated together in a single pharmaceutical composition (e.g., a tablet or capsule), and alternative embodiments in which each therapeutic agent in the combination is formulated individually in its own pharmaceutical composition, and each pharmaceutical composition is administered in the same medical treatment (e.g., the same cancer treatment). In this embodiment, each pharmaceutical composition may have the same or different carriers, diluents, or excipients. The carriers, diluents, or excipients must be acceptable in the sense that they are compatible with the other components of the formulation, are pharmaceutical formulationable, and are not harmful to the recipient.

[0070] In one embodiment, the combination product comprises a first and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises a topoisomerase inhibitor (appropriately selected from compounds B, C, D, E, F, G, or H, or pharmaceutically acceptable salts thereof), and the second pharmaceutical composition comprises compound A (or a pharmaceutically acceptable salt thereof), and both the first and second pharmaceutical compositions are administered for the treatment of cancer. The first and second pharmaceutical compositions may be administered simultaneously, separately, or sequentially, in any order. Furthermore, it is not relevant whether the compounds are administered in the same dosage form; for example, one compound may be administered by injection and the other by oral administration.

[0071] PARG inhibitors This disclosure provides PARG inhibitors. In one embodiment, the PARG inhibitor is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 is cyano, C 1-2 Alkyl and C 1-2 Selected from the group consisting of haloalkyls; Ar is a five-membered ring heteroaryl; X 2 is either CH or CF; R 2 is C 1-3 Alkyl, C 1-3 Haloalkyl, HydroxyC 1-3 Selected from the group consisting of alkyl and cyano; Ring B is R a , R b , and R c A 5-membered or 6-membered heterocycloalkyl group substituted with; R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 (is a haloalkyl); and R b and R c is hydrogen, C 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0072] In some embodiments, the PARG inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, R 1 is cyano, C1-2 Alkyl and C 1-2 Selected from the group consisting of haloalkyls; Ar is 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X 2 is CH or CF; R 2 is C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxy C 1-3 Selected from the group consisting of alkyl and cyano; Ring B is R a , R b , and R c A 5-membered or 6-membered heterocycloalkyl group substituted with; R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 (is a haloalkyl); and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0073] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is X 2 The compound is of formula (I) where is CH. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is X 2 It is a compound of formula (I) where CF is .

[0074] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 1 It is a compound of formula (I) in which is cyano.

[0075] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 1 It is a compound of formula (I) in which is methyl.

[0076] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) in which Ar is 1,2,4-thiadiazolyl or 1,3,4-thiadiazole-2-yl.

[0077] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) in which Ar is 1,3,4-thiadiazole-2-yl.

[0078] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) in which Ar is 1,2,4-thiadiazolyl.

[0079] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is R 2 It is a compound of formula (I) in which the argon atom is bonded to the argon atom in the meta position relative to the argon atom bonded to the remaining nitrogen atom of the molecule.

[0080] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), where R 2 It is bonded to Ar, which is represented as follows: , or [ka]

[0081] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), where R 2 is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), where R 2 It is difluoromethyl.

[0082] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein ring B is morpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl. In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein ring B is piperazinyl.

[0083] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R a is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)R d (where R d is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl), and R b and R c are independently selected from hydrogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halo, C 1-6 haloalkyl, and C[[ID=3e]] 1-6 haloalkoxy.

[0084] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R a is hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl, and R b and R c are independently selected from hydrogen and C 1-6 alkyl.

[0085] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R a is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or -C(O)R d (where R d is C1-6 Alkyl or C 1-6 (It is a haloalkyl) and R b and R c These are hydrogen and C, which are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkoxys.

[0086] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), where R a is hydrogen, R b and R c Each is independently either hydrogen or C 1-6 It is alkyl.

[0087] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is compound A1: [ka] or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is compound A1: [ka] That is the case.

[0089] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is compound A: [ka] or a pharmaceutically acceptable salt thereof.

[0090] In another embodiment, the PARG inhibitor is compound A: [ka] That is the case.

[0091] The preparation and activity of specific PARG inhibitors provided herein are disclosed in PCT / US20 / 51486 (WO2021 / 055744), the entire contents of which are incorporated herein by reference.

[0092] This disclosure also provides antibody-drug conjugates (ADCs) comprising an antitumor compound conjugated to an antibody via a linker. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antitumor compound is a PARG inhibitor. In some embodiments, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is a compound of formula I. In some embodiments, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is compound A. In some embodiments, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is compound A1.

[0093] Please note that references to PARG inhibitors include their pharmaceutically acceptable salts. In other words, "PARG inhibitor" is synonymous with "PARG inhibitor or its pharmaceutically acceptable salt."

[0094] Topoisomerase inhibitors This disclosure provides topoisomerase inhibitors for use in combination with PARG inhibitors. Many drugs having topoisomerase inhibitory activity and methods for producing them are known in the art. Any of these are included in this disclosure. In some embodiments, the topoisomerase inhibitor is an inhibitor of type I topoisomerase (also referred herein as a topoisomerase I inhibitor). In some embodiments, the topoisomerase inhibitor is an inhibitor of type II topoisomerase (also referred herein as a topoisomerase II inhibitor). In some embodiments, the type II topoisomerase inhibitor is selected from the group consisting of the compounds listed in Table 1 or pharmaceutically acceptable salts or hydrates thereof. [Table 1]

[0095] In some cases, type II topoisomerase inhibitors are selected from the group consisting of compounds listed in Table 1. The methods for producing and using the compounds listed in Table 1 are known in the art.

[0096] In one embodiment, the type II topoisomerase inhibitor is selected from the group consisting of doxorubicin, etoposide, epirubicin, novobiocin, ciprofloxacin, and teniposide, or pharmaceutically acceptable salts thereof. In one embodiment, the type II topoisomerase inhibitor is doxorubicin or a pharmaceutically acceptable salt thereof.

[0097] In one embodiment, the type I topoisomerase inhibitor is given by formula: [ka] The compound is topotecan (compound H) or a pharmaceutically acceptable salt thereof. Methods for producing topotecan are known in the art.

[0098] In yet another embodiment, the type I topoisomerase inhibitor is selected from the group consisting of 10-hydroxycamptothecin, irinotecan, and topotecan, hexylresorcinol, exatecan, deruxtecan, berotecan, or pharmaceutically acceptable salts thereof.

[0099] Furthermore, it should be noted that references to topoisomerase inhibitors also include references to their pharmaceutically acceptable salts. In other words, "topoisomerase inhibitor" is synonymous with "topoisomerase inhibitor or its pharmaceutically acceptable salt."

[0100] References to type II topoisomerase inhibitors in Table 1 are intended to include all variants, e.g., pharmaceutically acceptable salts, polymorphs, and solvates. References to type I topoisomerase inhibitors are intended to include all variants, e.g., pharmaceutically acceptable salts, polymorphs, and solvates.

[0101] This disclosure also provides an antibody-drug conjugate (ADC) comprising at least two antitumor compounds conjugated to an antibody via a linker. In one embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase inhibitor. In one embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase inhibitor, where the PARG inhibitor is a compound of formula I. In one embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase inhibitor, where the PARG inhibitor is compound A. In one embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase I inhibitor. In one embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase I inhibitor, where the PARG inhibitor is a compound of formula I. In one embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase I inhibitor, where the PARG inhibitor is compound A. In one embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase II inhibitor. In one embodiment, the antitumor compound is selected from a PARG inhibitor and a topoisomerase II inhibitor, where the PARG inhibitor is a compound of formula I. In another embodiment, the antitumor compound is selected from a PARG inhibitor and a topoisomerase II inhibitor, where the PARG inhibitor is compound A.

[0102] This disclosure also provides antibody-drug conjugates (ADCs) containing a topoisomerase inhibitor for use in combination with a PARG inhibitor. Many ADCs containing topoisomerase inhibitors and methods for producing the same are known in the art. Each of these is included in this disclosure. In one embodiment, the ADC containing a topoisomerase inhibitor is a type I topoisomerase inhibitor. In yet another embodiment, the ADC containing a topoisomerase inhibitor is fam-trastuzumab deruxtecan-nxki (compound J). In yet another embodiment, the ADC containing a topoisomerase inhibitor is AZD8205. In yet another embodiment, the ADC containing a topoisomerase inhibitor is DS-1062 (also known as datopotamab deruxtecan). In one embodiment, the PARG inhibitor is a compound of formula (I). In one embodiment, the PARG inhibitor is compound A. Combination therapy of PARG inhibitors and topoisomerase inhibitors

[0103] In another embodiment, a combination product comprising compound A or a pharmaceutically acceptable salt thereof and compound B, C, D, E, F, or G or a pharmaceutically acceptable salt thereof is provided herein. In another embodiment, a combination product comprising compound A or a pharmaceutically acceptable salt thereof and compound H or a pharmaceutically acceptable salt thereof is provided herein.

[0104] In another embodiment, a combination product comprising compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof is provided herein.

[0105] In another embodiment, a combination product comprising compound A1 or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof is provided herein.

[0106] In another embodiment, a combination product comprising compound A or a pharmaceutically acceptable salt thereof and compound H or a pharmaceutically acceptable salt thereof is provided herein.

[0107] In another embodiment, a combination product comprising compound A1 or a pharmaceutically acceptable salt thereof and compound H or a pharmaceutically acceptable salt thereof is provided herein.

[0108] In another embodiment, the Specified Reference Indicators provide a combination product comprising compound A or a pharmaceutically acceptable salt thereof and a compound selected from the group consisting of compound C, compound D, compound E, compound F, and compound G, or a pharmaceutically acceptable salt thereof.

[0109] In another embodiment, the Specified Reference Indicators provide a combination product comprising compound A1 or a pharmaceutically acceptable salt thereof and a compound selected from the group consisting of compound C, compound D, compound E, compound F, and compound G, or a pharmaceutically acceptable salt thereof.

[0110] The administration of the combination therapies provided herein may produce beneficial effects, for example, synergistic therapeutic effects, such as symptom relief, delay or inhibition of progression, and may also produce remarkable beneficial effects, such as reduced side effects, improved quality of life, or lower morbidity compared to monotherapy using only one of the active pharmaceutical ingredients used in the combination therapy of this disclosure.

[0111] Treatment method In one embodiment, a method for treating cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a therapeutically effective dose of a PARG inhibitor and administering to the subject a therapeutically effective dose of a topoisomerase inhibitor, thereby treating the subject's cancer.

[0112] In one embodiment, a method for treating cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least a pharmaceutically acceptable carrier, thereby treating the subject's cancer.

[0113] In one embodiment, a method for treating and / or preventing homologous recombination deficiency (HRD) cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent the subject's cancer.

[0114] In one embodiment, a method for treating and / or preventing homologous recombination deficiency (HRD) cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least a pharmaceutically acceptable carrier, thereby treating and / or preventing the subject's cancer. In one embodiment, the HRD cancer is breast cancer. In one embodiment, the HRD cancer is ovarian cancer.

[0115] In one embodiment, a method for treating and / or preventing cancer in a subject requiring it is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent cancer in the subject, wherein the cancer is homologous recombination deficiency (HRD) cancer and estrogen receptor (ER) positive. In one embodiment, a method for treating cancer in a subject requiring it is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat cancer in the subject, wherein the cancer is homologous recombination deficiency (HRD) cancer and estrogen receptor (ER) positive.

[0116] In one embodiment, a method for treating and / or preventing cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent cancer in the subject, wherein the cancer is HRD cancer, ER-positive, and optionally progesterone receptor (PR)-positive.

[0117] In one embodiment, a method for treating and / or preventing cancer in a subject requiring such treatment is provided herein, comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent cancer in the subject, wherein the cancer is HRD cancer, ER-positive, and optionally human epidermal growth factor receptor 2 (HER2)-negative. In one embodiment, a method for treating cancer in a subject requiring such treatment is provided herein, comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat cancer in the subject, wherein the cancer is HRD cancer, ER-positive, and optionally human epidermal growth factor receptor 2 (HER2)-negative.

[0118] In one embodiment, a method for treating and / or preventing cancer in a subject requiring it is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent cancer in the subject, wherein the cancer is HRD cancer, ER-positive, optionally PR-positive, and optionally HER2-negative. In one embodiment, a method for treating cancer in a subject requiring it is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat cancer in the subject, wherein the cancer is HRD cancer, ER-positive, optionally PR-positive, and optionally HER2-negative. In one embodiment, the cancerous tumor is a breast cancer or ovarian cancer tumor.

[0119] In one embodiment, a method for treating and / or preventing breast cancer in a subject requiring it is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent the subject's cancer, wherein the cancer is HRD cancer, ER-positive, optionally PR-positive, and optionally HER2-negative. In one embodiment, a method for treating breast cancer in a subject requiring it is provided herein, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat the subject's cancer, wherein the cancer is HRD cancer, ER-positive, optionally PR-positive, and optionally HER2-negative.

[0120] In one embodiment, HRD cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer. In one embodiment, HRD cancer is breast cancer or ovarian cancer. In one embodiment, HRD cancer is small cell lung cancer, kidney cancer, renal cancer, urothelial carcinoma, melanoma, liver cancer, bladder cancer, gastric cancer, carcinoma, lymphoma, glioblastoma, sarcoma, leukemia, myeloma, or lymphoid malignancy.

[0121] In yet another embodiment, the cancer is characterized by decreased or absent expression of the BRCA1 and / or BRCA2 genes, absence or mutation of the BRCA1 and / or BRCA2 genes, impaired function of the BRCA1 and / or BRCA2 proteins, or a combination thereof.

[0122] In one embodiment, a method for treating cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a PARG inhibitor and a therapeutically effective amount of a pharmaceutical composition comprising a topoisomerase inhibitor, thereby treating the subject's cancer.

[0123] In one embodiment, the use of a combination of a PARG inhibitor and a topoisomerase inhibitor for the manufacture of a pharmaceutical product is provided. In one embodiment, the PARG inhibitor is compound A. In one embodiment, the PARG inhibitor is compound A1. In one embodiment, the topoisomerase inhibitor is compound B. In one embodiment, the use of a combination of compound A and compound B for the manufacture of a pharmaceutical product is provided. In one embodiment, the topoisomerase inhibitor is compound H. In one embodiment, the use of a combination of compound A and compound H for the manufacture of a pharmaceutical product is provided. In one embodiment, the use of a combination of compound A and compound C, compound D, compound E, compound F, or compound G for the manufacture of a pharmaceutical product is provided.

[0124] Another embodiment provides the use of a combination of a PARG inhibitor and a topoisomerase inhibitor for the treatment of cancer. In one embodiment, the PARG inhibitor is a compound of formula I. In one embodiment, the PARG inhibitor is compound A. In one embodiment, the use of a combination of compound A and compound B for the treatment of cancer is provided. In one embodiment, the use of a combination of compound A and compound H for the treatment of cancer is provided. In one embodiment, the use of a combination of compound A and compound C, compound D, compound E, compound F, or compound G for the treatment of cancer is provided.

[0125] In one embodiment, the PARG inhibitor is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, where the variables are defined above.

[0126] In another embodiment, the PARG inhibitor is compound A1 or a pharmaceutically acceptable salt thereof.

[0127] In another embodiment, the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0128] In one embodiment, the topoisomerase inhibitor is selected from the group consisting of the compounds listed in Table 1 or pharmaceutically acceptable salts or hydrates thereof.

[0129] In another embodiment, the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0130] In another embodiment, the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0131] In another embodiment, the topoisomerase inhibitor is compound C, compound D, compound E, compound F, or compound G, or a pharmaceutically acceptable salt thereof.

[0132] In another embodiment, a method for treating cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and administering to the subject a therapeutically effective amount of compound B or a pharmaceutically acceptable salt thereof.

[0133] In another embodiment, a method for treating cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and administering to the subject a therapeutically effective amount of compound H or a pharmaceutically acceptable salt thereof.

[0134] In yet another embodiment, a method for treating cancer in a subject requiring such treatment is provided herein, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and administering to the subject a therapeutically effective amount of compound C, compound D, compound E, compound F, compound G, or a pharmaceutically acceptable salt thereof.

[0135] In another embodiment, a product is provided comprising a PARG inhibitor and a topoisomerase inhibitor as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, the PARG inhibitor is a compound of formula I. In one embodiment, the PARG inhibitor is compound A. In one embodiment, a product is provided comprising compound A and compound B as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, a product is provided comprising compound A and compound H as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, a product is provided comprising compound A and compound C, compound D, compound E, compound F, or compound G as a combination product for simultaneous, separate, or sequential use in pharmaceuticals.

[0136] In another embodiment, a product is provided comprising a PARG inhibitor and a topoisomerase inhibitor as a combination product for simultaneous, separate, or sequential use in the treatment of a subject's cancer. In one embodiment, the PARG inhibitor is a compound of formula I. In one embodiment, the PARG inhibitor is compound A. In one embodiment, a product is provided comprising compound A and compound B as a combination product for simultaneous, separate, or sequential use in the treatment of a subject's cancer. In one embodiment, a product is provided comprising compound A and compound H as a combination product for simultaneous, separate, or sequential use in the treatment of a subject's cancer. In one embodiment, a product is provided comprising compound A and compound C, compound D, compound E, compound F, or compound G as a combination product for simultaneous, separate, or sequential use in the treatment of a subject's cancer.

[0137] In yet another embodiment, the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, and esophageal cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer.

[0138] In one embodiment, cancer is breast cancer. In one embodiment, cancer is ovarian cancer. In one embodiment, cancer is endometrial cancer. In one embodiment, cancer is pancreatic cancer. In one embodiment, cancer is colorectal cancer. In one embodiment, cancer is non-small cell lung cancer (NSCLC). In one embodiment, cancer is small cell lung cancer. In one embodiment, cancer is kidney cancer, renal cancer, urothelial carcinoma, melanoma, liver cancer, bladder cancer, gastric cancer, carcinoma, lymphoma, glioblastoma, sarcoma, leukemia, myeloma, or lymphoid malignancy.

[0139] In yet another embodiment, the cancer is metastatic. In one embodiment, the disease or disorder is a progressive or metastatic solid tumor.

[0140] In yet another embodiment, cancer is a solid malignant tumor.

[0141] In certain embodiments, the PARG inhibitor and the topoisomerase inhibitor are present in separate dosage forms. In another embodiment, the PARG inhibitor and the topoisomerase inhibitor are present in the same dosage form.

[0142] In another embodiment, the treatment comprises administering a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof substantially simultaneously. In yet another embodiment, the treatment comprises administering a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof at different times.

[0143] In yet another embodiment, a PARG inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject, followed by administration of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. In certain embodiments, a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof is administered to a subject, followed by administration of a PARG inhibitor or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are administered orally.

[0145] In certain aspects, a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are provided herein for use in therapy.

[0146] In certain aspects, a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are used for the treatment of cancer in a subject that needs it.

[0147] In an embodiment of the method, the method comprises administering a therapeutically effective amount of a combination or composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof to a subject (including, but not limited to, humans or animals) that needs treatment (including a subject identified as needing treatment).

[0148] In another embodiment of the method, the treatment comprises co-administering an amount of a PARG inhibitor or a pharmaceutically acceptable salt thereof and an amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. In certain embodiments, the amount of the PARG inhibitor or a pharmaceutically acceptable salt thereof and the amount of the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are present in a single formulation or unit dosage form. In yet another embodiment, the amount of the PARG inhibitor or a pharmaceutically acceptable salt thereof and the amount of the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are present in separate formulations or unit dosage forms.

[0149] In the aforementioned method, the treatment may comprise administering an amount of a PARG inhibitor or a pharmaceutically acceptable salt thereof and an amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof substantially simultaneously, or administering an amount of a PARG inhibitor or a pharmaceutically acceptable salt thereof and an amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the aforementioned method, the amount of the PARG inhibitor or a pharmaceutically acceptable salt thereof and / or the amount of the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are administered at a dosage that is not effective when either the PARG inhibitor or a pharmaceutically acceptable salt thereof or the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof is administered alone, but is effective when combined.

[0150] In another embodiment of the method described above, the treatment involves the simultaneous administration of an amount of compound A or a pharmaceutically acceptable salt thereof and an amount of compound B or a pharmaceutically acceptable salt thereof. In one embodiment, the amounts of compound A or a pharmaceutically acceptable salt thereof and the amounts of compound B or a pharmaceutically acceptable salt thereof are present in a single formulation or unit dosage form. In yet another embodiment, the amounts of compound A or a pharmaceutically acceptable salt thereof and the amounts of compound B or a pharmaceutically acceptable salt thereof are present in separate formulations or unit dosage forms.

[0151] In the above method, the treatment may include administering a substantially simultaneous dose of compound A or a pharmaceutically acceptable salt thereof and a substantially simultaneous dose of compound B or a pharmaceutically acceptable salt thereof, or administering a pharmaceutically acceptable dose of compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof at different times. In some embodiments of the above method, the doses of compound A or a pharmaceutically acceptable salt thereof and / or compound B or a pharmaceutically acceptable salt thereof are administered in doses that are ineffective when administered individually or in combination with compound A or a pharmaceutically acceptable salt thereof and compound B or a pharmaceutically acceptable salt thereof, but are effective when administered together.

[0152] In another embodiment of this method, the treatment involves the simultaneous administration of an amount of compound A or a pharmaceutically acceptable salt thereof and an amount of compound H or a pharmaceutically acceptable salt thereof. In one embodiment, the amounts of compound A or a pharmaceutically acceptable salt thereof and compound H or a pharmaceutically acceptable salt thereof are present in a single formulation or unit dosage form. In yet another embodiment, the amounts of compound A or a pharmaceutically acceptable salt thereof and compound H or a pharmaceutically acceptable salt thereof are present in separate formulations or unit dosage forms.

[0153] In the above method, the treatment may include administering a substantially simultaneous dose of compound A or a pharmaceutically acceptable salt thereof and a substantially simultaneous dose of compound H or a pharmaceutically acceptable salt thereof, or administering a pharmaceutically acceptable dose of compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof at different times. In some embodiments of the above method, the doses of compound A or a pharmaceutically acceptable salt thereof and / or compound H or a pharmaceutically acceptable salt thereof are administered in doses that are ineffective when administered individually or in combination with compound H or a pharmaceutically acceptable salt thereof, but effective when administered together.

[0154] Non-exclusive exemplary embodiments: In the following further embodiments 1 to 93, the disclosure includes the following:

[0155] Embodiment 1. In one embodiment, a method is provided for treating cancer in a subject requiring the treatment thereof, the method comprising administering to the subject a therapeutically effective dose of a poly-ADP-ribose glycohydrolase (PARG) inhibitor and administering to the subject a therapeutically effective dose of a topoisomerase inhibitor.

[0156] Embodiment 1A. Embodiment 1A provides a method for treating cancer in a subject requiring such treatment, the method comprising administering to the subject a therapeutically effective dose of a poly-ADP-ribose glycohydrolase (PARG) inhibitor and administering to the subject an antibody-drug conjugate (ADC) containing a therapeutically effective dose of a topoisomerase inhibitor.

[0157] Embodiment 1A1. Embodiment 1A1 provides a method according to Embodiment 1A, comprising a topoisomerase inhibitor in which the ADC is a type I topoisomerase inhibitor.

[0158] Embodiment 1A2. Embodiment 1A2 provides the method of Embodiment 1A, wherein the ADCfam-trastuzumab deruxtecan-nxki comprises a topoisomerase inhibitor.

[0159] Embodiment 1A3. Embodiment 1A3 provides the method according to Embodiment 1A, wherein the ADC containing the topoisomerase inhibitor is AZD8205.

[0160] Embodiment 1A4. Embodiment 1A4 provides the method of Embodiment 1A, wherein the ADC containing the topoisomerase inhibitor is DS-1062 (also known as datopotamab deruxtecan).

[0161] Embodiment 2. In one embodiment, a method is provided for treating cancer in a subject requiring it, the method comprising administering to the subject a therapeutically effective amount of a poly-ADP-ribose glycohydrolase (PARG) inhibitor, wherein the subject is simultaneously administered a topoisomerase inhibitor.

[0162] Embodiment 2A. Embodiment 2A provides a method for treating cancer in a subject requiring such treatment, the method comprising administering a therapeutically effective dose to the subject of a poly-ADP-ribose glycohydrolase (PARG) inhibitor, wherein the subject is simultaneously administered an antibody-drug conjugate (ADC) containing the topoisomerase inhibitor.

[0163] Embodiment 2A1. Embodiment 2A1 provides the method described in Embodiment 2A, wherein the ADC containing the topoisomerase inhibitor is an ADC containing a type I topoisomerase inhibitor.

[0164] Embodiment 2A2. Embodiment 2A2 provides the method of Embodiment 2A, wherein the ADC comprising a topoisomerase inhibitor is fam-trastuzumab deruxtecan-nxki.

[0165] Embodiment 2A3. Embodiment 2A3 provides the method described in Embodiment 2A, wherein the ADC containing the topoisomerase inhibitor is AZD8205.

[0166] Embodiment 2A4. In Embodiment 2A4, the method described in Embodiment 2A is provided, where the ADC containing a topoisomerase inhibitor is DS-1062 (also known as datopotamab deruxtecan).

[0167] Embodiment 3. In certain embodiments, a method of treating cancer in a subject that needs it is provided, the method comprising administering to the subject a therapeutically effective amount of a poly ADP-ribose glycohydrolase (PARG) inhibitor, where the subject is undergoing treatment with a topoisomerase inhibitor.

[0168] Embodiment 3A. In Embodiment 3A, a method of treating cancer in a subject that needs it is provided, the method comprising administering to the subject a therapeutically effective amount of a poly ADP-ribose glycohydrolase (PARG) inhibitor, where the subject is undergoing treatment with an antibody-drug conjugate (ADC) containing a topoisomerase inhibitor.

[0169] Embodiment 3A1. In Embodiment 3A1, the method described in Embodiment 3A is provided, where the ADC containing a topoisomerase inhibitor is an ADC containing a type I topoisomerase inhibitor.

[0170] Embodiment 3A2. In Embodiment 3A2, the method described in Embodiment 3A is provided, where the ADC containing a topoisomerase inhibitor is fam-trastuzumab deruxtecan-nxki.

[0171] Embodiment 3A3. In Embodiment 3A3, the method described in Embodiment 3A is provided, where the ADC containing a topoisomerase inhibitor is AZD8205.

[0172] Embodiment 3A4. In Embodiment 3A4, the method described in Embodiment 3A is provided, where the ADC containing a topoisomerase inhibitor is DS-1062 (also known as datopotamab deruxtecan).

[0173] Embodiment 4. Embodiment 4 provides a method according to any one of Embodiments 1 to 3, wherein the PARG inhibitor is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 is cyano, C 1-2 Alkyl and C 1-2 Selected from the group consisting of haloalkyls, Ar is a five-membered heteroaryl; X 2 is either CH or CF; R 2 C 1-3 Alkyl, C 1-3 Haloalkyl, HydroxyC 1-3 Selected from the group consisting of alkyl and cyano; Ring B is R a , R b , and R c A 5-membered or 6-membered heterocycloalkyl group substituted with; R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 (is a haloalkyl); and R b and R c is hydrogen, C 1-6 Alkyl, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0174] Embodiment 5. In Embodiment 5, the method described in Embodiment 4 is provided, Here, R 1 is cyano, C 1-2 Alkyl and C 1-2Selected from the group consisting of haloalkyls; Ar is 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X 2 is either CH or CF; R 2 C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxy C 1-3 Selected from the group consisting of alkyl and cyano; Ring B is R a , R b , and R c A 5-membered or 6-membered heterocycloalkyl group substituted with; R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 (is a haloalkyl); and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0175] Embodiment 6. Embodiment 6 provides a method according to Embodiment 4 or 5, where X 2 It is CH.

[0176] Embodiment 7. Embodiment 7 provides a method according to Embodiment 4 or 5, where X 2 It is CF.

[0177] Embodiment 8. Embodiment 8 provides a method according to any one of Embodiments 4 to 7, where R 1 It is methyl.

[0178] Embodiment 9. Embodiment 9 provides a method according to any one of Embodiments 4 to 7, where R 1 It is cyano.

[0179] Embodiment 10. Embodiment 10 provides a method according to any one of Embodiments 4 to 9, wherein Ar is 1,2,4-thiadiazolyl or 1,3,4-thiadiazol-2-yl.

[0180] Embodiment 11. Embodiment 11 provides a method according to any one of Embodiments 4 to 10, where Ar is 1,3,4-thiadiazole-2-yl.

[0181] Embodiment 12. Embodiment 12 provides a method according to any one of Embodiments 4 to 10, where Ar is 1,2,4-thiadiazolyl.

[0182] Embodiment 13. Embodiment 13 provides a method according to any one of Embodiments 4 to 12, where R 2 It is bonded to the carbon atom of Ar that is in the meta position relative to the Ar atom bonded to the remaining nitrogen atom of the molecule.

[0183] Embodiment 14. Embodiment 14 provides a method according to any one of Embodiments 4 to 13, where R 2 These are methyl, ethyl, difluoromethyl, trifluoromethyl, and cyanomethyl.

[0184] Embodiment 15. Embodiment 15 provides a method according to any one of Embodiments 4 to 14, where R 2 It is difluoromethyl.

[0185] Embodiment 16. Embodiment 16 provides a method according to any one of Embodiments 4 to 15, wherein ring B is morpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl.

[0186] Embodiment 17. Embodiment 17 provides a method according to any one of Embodiments 4 to 16, where ring B is piperazinyl.

[0187] Embodiment 18. Embodiment 18 provides a method according to any one of Embodiments 4 to 17, where R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl; and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0188] Embodiment 19. Embodiment 19 provides a method according to any one of Embodiments 4 to 17, where R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl; and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0189] Embodiment 20. Embodiment 20 provides a method according to any one of Embodiments 4 to 17, where R a is hydrogen, C 1-4 Alkyl or C1-4 It is a haloalkyl; and R b and R c is hydrogen and C 1-6 It is selected independently of alkyl.

[0190] Embodiment 21. Embodiment 21 provides a method according to any one of Embodiments 4 to 17, where R a is hydrogen or C 1-4 It is alkyl; and R b and R c C 1-6 It is independently selected from alkyl and hydrogen.

[0191] Embodiment 22. Embodiment 22 provides a method according to any one of Embodiments 4 to 17, where R a is hydrogen; and R b and R c Each of them is independently C 1-6 It is alkyl or hydrogen.

[0192] Embodiment 23. Embodiment 23 provides a method according to any one of Embodiments 4 to 22, wherein the PARG inhibitor is compound A1 or a pharmaceutically acceptable salt thereof.

[0193] Embodiment 24. Embodiment 24 provides a method according to any one of Embodiments 4 to 23, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0194] Embodiment 25. Embodiment 25 provides a method according to any one of Embodiments 4 to 24, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0195] Embodiment 25A. Embodiment 25A provides the method of Embodiment 25, wherein the topoisomerase I inhibitor is compound H or a pharmaceutically acceptable salt or hydrate thereof.

[0196] Embodiment 26. Embodiment 26 provides a method according to any one of Embodiments 4 to 24, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

[0197] Embodiment 27. Embodiment 27 provides the method described in Embodiment 26, wherein the topoisomerase II inhibitor is selected from the group consisting of compound B, compound C, compound D, compound E, compound F, and compound G, or pharmaceutically acceptable salts or hydrates thereof.

[0198] Embodiment 28. Embodiment 28 provides the method described in Embodiment 27, wherein the topoisomerase II inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0199] Embodiment 29. Embodiment 29 provides a method according to any one of Embodiments 1 to 28, wherein the cancer is homologous recombination deficiency (HRD) cancer.

[0200] Embodiment 30. Embodiment 30 provides a method according to any one of Embodiments 1 to 29, wherein the cancer is characterized by decreased or absent BRCA1 gene expression, absence or mutation of the BRCA1 gene, or impaired function of the BRCA1 protein.

[0201] Embodiment 31. Embodiment 31 provides a method according to any one of Embodiments 1 to 30, wherein the cancer is characterized by reduced or absent BRCA2 gene expression, absence or mutation of the BRCA2 gene, or impaired function of the BRCA2 protein.

[0202] Embodiment 32. Embodiment 32 provides a method according to any one of Embodiments 1 to 31, wherein the cancer is ER-positive.

[0203] Embodiment 33. Embodiment 33 provides a method according to any one of Embodiments 1 to 32, wherein the cancer is PR-positive.

[0204] Embodiment 34. Embodiment 34 provides a method according to any one of Embodiments 1 to 33, wherein the cancer is HER2-negative.

[0205] Embodiment 35. Embodiment 35 provides a method according to any one of Embodiments 1 to 34, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and prostate cancer.

[0206] Embodiment 35A. Embodiment 35A provides a method according to any one of Embodiments 1 to 34, wherein cancer is breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer.

[0207] Embodiment 36. Embodiment 36 provides a method according to any one of Embodiments 1 to 35, wherein the cancer is breast cancer or ovarian cancer.

[0208] Embodiment 37. Embodiment 37 provides a method according to any one of Embodiments 1 to 36, wherein the PARG inhibitor and the topoisomerase inhibitor are present in separate dosage forms.

[0209] Embodiment 38. Embodiment 38 provides a method according to any one of Embodiments 1 to 36, wherein the PARG inhibitor and the topoisomerase inhibitor are present in the same dosage form.

[0210] Embodiment 39. Embodiment 39 provides a combination product comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof and a poisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0211] Embodiment 40. In Embodiment 40, the PARG inhibitor described in Embodiment 39 is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0212] Embodiment 41. In Embodiment 41, the PARG inhibitor described in Embodiment 40 is a compound of formula (I) as defined in any one of Embodiments 4 to 22, or a pharmaceutically acceptable salt thereof.

[0213] Embodiment 42. In Embodiment 42, the PARG inhibitor described in Embodiment 39 or 40 is compound A1 or a pharmaceutically acceptable salt thereof.

[0214] Embodiment 43. In Embodiment 43, the PARG inhibitor described in Embodiment 39 or 40 is compound A or a pharmaceutically acceptable salt thereof.

[0215] Embodiment 44. In Embodiment 44, the topoisomerase inhibitor described in any one of Embodiments 39 to 43 is a type I topoisomerase inhibitor.

[0216] Embodiment 44A. In Embodiment 44A, the topoisomerase inhibitor described in Embodiment 44 is compound H or a pharmaceutically acceptable salt or hydrate thereof.

[0217] Embodiment 44B. In Embodiment 44A, the topoisomerase inhibitor described in Embodiment 44 is 10-hydroxycamptothecin, irinotecan, and topotecan, hexylresorcinol, exatecan, deruxtecan, berotecan, or a pharmaceutically acceptable salt thereof.

[0218] Embodiment 45. In Embodiment 45, the topoisomerase inhibitor described in any one of Embodiments 39 to 43 is a type II topoisomerase inhibitor.

[0219] Embodiment 46. In Embodiment 46, the topoisomerase inhibitor described in Embodiment 45 is compound B, compound C, compound D, compound E, compound F, or compound G, or a pharmaceutically acceptable salt thereof.

[0220] Embodiment 47. In Embodiment 47, the topoisomerase inhibitor described in Embodiment 46 is compound B or a pharmaceutically acceptable salt thereof.

[0221] Embodiment 48. Embodiment 48 provides a combination product comprising a first pharmaceutical composition containing a therapeutically effective amount of a PARG inhibitor and a second pharmaceutical composition containing a therapeutically effective amount of a topoisomerase inhibitor.

[0222] Embodiment 49. In Embodiment 49, the PARG inhibitor described in Embodiment 48 is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0223] Embodiment 50. In Embodiment 50, the PARG inhibitor described in Embodiment 49 is a compound of formula (I) as defined in any one of Embodiments 4 to 22 or a pharmaceutically acceptable salt thereof.

[0224] Embodiment 51. In Embodiment 51, the PARG inhibitor described in Embodiment 48 or 49 is compound A1 or a pharmaceutically acceptable salt thereof.

[0225] Embodiment 52. In Embodiment 52, the PARG inhibitor described in Embodiment 48 or 49 is compound A or a pharmaceutically acceptable salt thereof.

[0226] Embodiment 53. In Embodiment 53, the topoisomerase inhibitor described in any one of Embodiments 48 to 52 is a type I topoisomerase inhibitor.

[0227] Embodiment 53A. In Embodiment 53A, the topoisomerase inhibitor described in Embodiment 53 is compound H or a pharmaceutically acceptable salt or hydrate thereof.

[0228] Embodiment 54. In Embodiment 54, the topoisomerase inhibitor described in any one of Embodiments 48 to 52 is a type II topoisomerase inhibitor.

[0229] Embodiment 55. In Embodiment 55, the topoisomerase inhibitor described in Embodiment 54 is compound B, compound C, compound D, compound E, compound F, or compound G, or a pharmaceutically acceptable salt thereof.

[0230] Embodiment 56. In Embodiment 56, the topoisomerase inhibitor described in Embodiment 55 is compound B or a pharmaceutically acceptable salt thereof.

[0231] Embodiment 57. Embodiment 57 provides a combination product comprising a first pharmaceutical composition containing a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition containing a therapeutically effective amount of compound B or a pharmaceutically acceptable salt thereof.

[0232] Embodiment 57A. Embodiment 57A provides a combination product comprising a first pharmaceutical composition containing a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition containing a therapeutically effective amount of compound H or a pharmaceutically acceptable salt thereof.

[0233] Embodiment 58. Embodiment 58 provides a PARG inhibitor for use in the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor.

[0234] Embodiment 59. In Embodiment 59, the PARG inhibitor described in Embodiment 58 is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0235] Embodiment 60. In Embodiment 60, the PARG inhibitor described in Embodiment 59 is a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of Embodiments 4 to 22.

[0236] Embodiment 61. In Embodiment 61, the PARG inhibitor described in Embodiment 58 or 59 is compound A1 or a pharmaceutically acceptable salt thereof.

[0237] Embodiment 62. In Embodiment 62, the PARG inhibitor described in Embodiment 58 or 59 is compound A or a pharmaceutically acceptable salt thereof.

[0238] Embodiment 63. In Embodiment 63, the topoisomerase inhibitor described in any one of Embodiments 58 to 62 is a type I topoisomerase inhibitor.

[0239] Embodiment 63A. In Embodiment 63A, the topoisomerase inhibitor described in Embodiment 63 is compound H or a pharmaceutically acceptable salt or hydrate thereof.

[0240] Embodiment 64. In Embodiment 64, the topoisomerase inhibitor described in any one of Embodiments 58 to 62 is a type II topoisomerase inhibitor.

[0241] Embodiment 65. In Embodiment 65, the topoisomerase inhibitor described in Embodiment 64 is compound B, compound C, compound D, compound E, compound F, or compound G, or a pharmaceutically acceptable salt thereof.

[0242] Embodiment 66. In Embodiment 66, the topoisomerase inhibitor described in Embodiment 65 is compound B or a pharmaceutically acceptable salt thereof.

[0243] Embodiment 67. Embodiment 67 provides a PARG inhibitor for use in the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0244] Embodiment 67A. Embodiment 67A provides a PARG inhibitor for use in the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0245] Embodiment 68. Embodiment 68 provides the use described in any one of Embodiments 58 to 67, wherein the cancer is homologous recombination deficiency (HRD) cancer.

[0246] Embodiment 69. Embodiment 69 provides a use described in any one of Embodiments 58 to 68, wherein the cancer is characterized by reduced or absent BRCA1 gene expression, absence or mutation of the BRCA1 gene, or impaired function of the BRCA1 protein.

[0247] Embodiment 70. Embodiment 70 provides a use described in any one of Embodiments 58 to 69, wherein the cancer is characterized by reduced or absent BRCA2 gene expression, absence or mutation of the BRCA2 gene, or impaired function of the BRCA2 protein.

[0248] Embodiment 71. Embodiment 71 provides the use described in any one of Embodiments 58 to 70, wherein the cancer is ER-positive.

[0249] Embodiment 72. In Embodiment 72, the use described in any one of Embodiments 58 to 71 is provided, wherein the cancer is PR-positive.

[0250] Embodiment 73. Embodiment 73 provides the use described in any one of Embodiments 58 to 72, wherein the cancer is HER2-negative.

[0251] Embodiment 74. Embodiment 74 provides a use described in any one of Embodiments 58 to 73, wherein cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and prostate cancer.

[0252] Embodiment 74A. Embodiment 74A provides a use described in any one of Embodiments 58 to 73, wherein cancer is breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer.

[0253] Embodiment 75. In Embodiment 75, the use described in any one of Embodiments 58 to 74 is provided, wherein the cancer is breast cancer or ovarian cancer.

[0254] Embodiment 76. Embodiment 76 provides the use of a PARG inhibitor in the manufacture of a pharmacopoeci for the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor.

[0255] Embodiment 77. In Embodiment 77, the PARG inhibitor described in Embodiment 76 is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0256] Embodiment 78. In Embodiment 78, the PARG inhibitor described in Embodiment 77 is a compound of formula (I) as defined in any one of Embodiments 4 to 22 or a pharmaceutically acceptable salt thereof.

[0257] Embodiment 79. In Embodiment 79, the PARG inhibitor described in Embodiment 76 or 77 is compound A1 or a pharmaceutically acceptable salt thereof.

[0258] Embodiment 80. In Embodiment 80, the PARG inhibitor described in Embodiment 76 or 77 is compound A or a pharmaceutically acceptable salt thereof.

[0259] Embodiment 81. In Embodiment 81, the topoisomerase inhibitor described in any one of Embodiments 76 to 80 is a type I topoisomerase inhibitor.

[0260] Embodiment 81A. In Embodiment 81A, the topoisomerase inhibitor described in Embodiment 81 is compound H or a pharmaceutically acceptable salt or hydrate thereof.

[0261] Embodiment 82. In Embodiment 82, the topoisomerase inhibitor described in any one of Embodiments 76 to 80 is a type II topoisomerase inhibitor.

[0262] Embodiment 83. In Embodiment 83, the topoisomerase inhibitor described in Embodiment 82 is compound B, compound C, compound D, compound E, compound F, or compound G, or a pharmaceutically acceptable salt thereof.

[0263] Embodiment 84. In Embodiment 84, the topoisomerase inhibitor described in Embodiment 83 is compound B or a pharmaceutically acceptable salt thereof.

[0264] Embodiment 85. Embodiment 85 provides the use of a PARG inhibitor in the manufacture of a pharmacopoeci for the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0265] Embodiment 85A. Embodiment 85A provides the use of a PARG inhibitor in the manufacture of a pharmacopoeci for the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0266] Embodiment 86. Embodiment 86 provides the use described in any one of Embodiments 76 to 85A, wherein the cancer is homologous recombination deficiency (HRD) cancer.

[0267] Embodiment 87. Embodiment 87 provides the use described in any one of Embodiments 76 to 86, wherein the cancer is characterized by reduced or absent BRCA1 gene expression, absence or mutation of the BRCA1 gene, or impaired function of the BRCA1 protein.

[0268] Embodiment 88. Embodiment 88 provides the use described in any one of Embodiments 76 to 87, wherein the cancer is characterized by reduced or absent BRCA2 gene expression, absence or mutation of the BRCA2 gene, or impaired function of the BRCA2 protein.

[0269] Embodiment 89. Embodiment 89 provides the use described in any one of Embodiments 76 to 88, wherein the cancer is ER-positive.

[0270] Embodiment 90. In Embodiment 90, the use described in any one of Embodiments 76 to 89 is provided, wherein the cancer is PR-positive.

[0271] Embodiment 91. Embodiment 91 provides the use described in any one of Embodiments 76 to 90, wherein the cancer is HER2-negative.

[0272] Embodiment 92. Embodiment 92 provides a use described in any one of Embodiments 76 to 91, wherein cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and prostate cancer.

[0273] Embodiment 92A. Embodiment 92A provides a use described in any one of Embodiments 76 to 91, wherein cancer is breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer.

[0274] Embodiment 93. Embodiment 93 provides the use described in any one of Embodiments 76 to 92, wherein the cancer is breast cancer or ovarian cancer.

[0275] In the above embodiment, when referring to a prior embodiment, the reference also includes embodiments having a textual notation or combination. For example, when referring to embodiments 1 to 3, embodiments 1, 1A, 1A1, 1A2, 1A3, 1A4, 2, 2A, 2A1, 2A2, 2A3, 2A4, 3, 3A, 3A1, 3A2, 3A3, and 3A4 are included.

[0276] Additional non-limiting embodiments: Embodiment 1. Embodiment 1 provides a method for treating cancer in a subject requiring such treatment, the method comprising administering a therapeutically effective dose of a PARG inhibitor to the subject and administering a therapeutically effective dose of a topoisomerase inhibitor to the subject, wherein the PARG inhibitor is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof [in the formula, R 1 is cyano, C 1-2 Alkyl and C 1-2 Selected from the group consisting of haloalkyls; Ar is 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X 2 is either CH or CF; R 2 C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxy C 1-3 Selected from the group consisting of alkyl and cyano; Ring B is R a , R b , and R c A 5-membered or 6-membered heterocycloalkyl group substituted with; R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 (is a haloalkyl); and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 [Selected independently from haloalkoxys].

[0277] Embodiment 2. Embodiment 2 provides the method described in Embodiment 1, where X 2 It is CH.

[0278] Embodiment 3. Embodiment 3 provides a method according to Embodiment 1 or 2, where R 1 It is methyl.

[0279] Embodiment 4. Embodiment 4 provides a method according to Embodiment 1 or 2, where R 1 It is cyano.

[0280] Embodiment 5. Embodiment 5 provides a method according to any one of Embodiments 1 to 4, where Ar is 1,3,4-thiadiazole-2-yl.

[0281] Embodiment 6. Embodiment 6 provides a method according to any one of Embodiments 1 to 5, where R 2 It is bonded to the carbon atom of Ar that is in the meta position relative to the Ar atoms bonded to the nitrogen atoms of the rest of the molecule.

[0282] Embodiment 7. Embodiment 7 provides a method according to any one of Embodiments 1 to 6, where R 2 These are methyl, ethyl, difluoromethyl, trifluoromethyl, or cyanomethyl.

[0283] Embodiment 8. Embodiment 8 provides a method according to any one of Embodiments 1 to 7, where R 2 It is difluoromethyl.

[0284] Embodiment 9. Embodiment 9 provides a method according to any one of Embodiments 1 to 8, wherein ring B is morpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl.

[0285] Embodiment 10. Embodiment 10 provides a method according to any one of Embodiments 1 to 9, wherein ring B is piperazinyl.

[0286] Embodiment 11. Embodiment 11 provides a method according to any one of Embodiments 1 to 10, where R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 It is a haloalkyl; and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0287] Embodiment 12. Embodiment 12 provides a method according to any one of Embodiments 1 to 11, where R a is hydrogen, C 1-4 Alkyl, or C 1-4 It is a haloalkyl; and R b and R c C 1-6 It is independently selected from alkyl and hydrogen.

[0288] Embodiment 13. Embodiment 13 provides a method according to any one of Embodiments 1 to 12, where R a is hydrogen, R b and R c Each is independently C 1-6It is alkyl or hydrogen.

[0289] Embodiment 14. Embodiment 14 provides a method according to any one of Embodiments 1 to 13, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof. Embodiment 15. Embodiment 15 provides a method according to any one of claims 1 to 14, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

[0290] Embodiment 16. Embodiment 16 provides a method according to any one of Embodiments 1 to 15, wherein the topoisomerase inhibitor is selected from the group consisting of compound B, compound C, compound D, compound E, compound F, and compound G, or pharmaceutically acceptable salts or hydrates thereof.

[0291] Embodiment 17. Embodiment 17 provides a method according to any one of Embodiments 1 to 16, wherein the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0292] Embodiment 18. Embodiment 18 provides a method according to any one of Embodiments 1 to 14, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0293] Embodiment 19. Embodiment 19 provides a method according to any one of Embodiments 1 to 14, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0294] Embodiment 20. Embodiment 20 provides a method according to any one of Embodiments 1 to 19, wherein the cancer is homologous recombination deficiency (HRD) cancer.

[0295] Embodiment 21. Embodiment 21 provides a method according to any one of Embodiments 1 to 20, wherein the cancer is characterized by reduced or absent BRCA1 and / or BRCA2 gene expression, absence or mutation of the BRCA1 and / or BRCA2 gene, or impaired function of the BRCA1 and / or BRCA2 protein.

[0296] Embodiment 22. Embodiment 22 provides a method according to any one of Embodiments 1 to 21, wherein the cancer is breast cancer, lung cancer, or ovarian cancer.

[0297] Embodiment 23. Embodiment 23 provides a method according to any one of Embodiments 1 to 22, wherein the PARG inhibitor and the topoisomerase inhibitor are present in separate dosage forms.

[0298] Embodiment 24. Embodiment 24 provides a method according to any one of Embodiments 1 to 22, wherein the PARG inhibitor and the topoisomerase inhibitor are present in the same dosage form.

[0299] Embodiment 25. Embodiment 25 provides a combination comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0300] Embodiment 26. In Embodiment 26, a combination of Embodiment 25 is provided, where the PARG inhibitor is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, in the formula: R 1 is cyano, C 1-2 Alkyl and C 1-2 Selected from the group consisting of haloalkyls; Ar is 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X 2 is either CH or CF; R 2 C1-3 Haloalkyl, C 1-3 Alkyl, hydroxy C 1-3 Selected from the group consisting of alkyl and cyano; Ring B is R a , R b , and R c A 5-membered or 6-membered heterocycloalkyl group substituted with; R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 (is a haloalkyl); and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0301] Embodiment 27. In Embodiment 27, a combination of Embodiment 25 or 26 is provided, where the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0302] Embodiment 28. Embodiment 28 provides a combination described in any one of Embodiments 25 to 27, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[0303] Embodiment 29. Embodiment 29 provides a combination described in any one of Embodiments 25 to 28, wherein the topoisomerase inhibitor is selected from the group consisting of compound B, compound C, compound D, compound E, compound F, and compound G, or pharmaceutically acceptable salts thereof.

[0304] Embodiment 30. Embodiment 30 provides a combination described in any one of Embodiments 25 to 29, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0305] Embodiment 31. Embodiment 31 provides a combination described in any one of Embodiments 25 to 27, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0306] Embodiment 32. Embodiment 32 provides a combination described in any one of Embodiments 25 to 27, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 33. Embodiment 33 provides a PARG inhibitor for use in the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor.

[0308] Embodiment 34. In Embodiment 34, the use of Embodiment 33 is provided, where the PARG inhibitor is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, in the formula: R 1 is cyano, C 1-2 Alkyl and C 1-2 Selected from the group consisting of haloalkyls; Ar is 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X 2 is either CH or CF; R 2 C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxy C 1-3 Selected from the group consisting of alkyl and cyano; Ring B is R a , R b , and Rc A 5-membered or 6-membered heterocycloalkyl group substituted with; R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, R d is hydrogen, C 1-6 Alkyl, or C 1-6 (is a haloalkyl); and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0309] Embodiment 35. In Embodiment 35, the use described in Embodiment 33 or 34 is provided, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0310] Embodiment 36. In Embodiment 36, the use described in any one of Embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[0311] Embodiment 37. Embodiment 37 provides the use described in any one of Embodiments 33 to 36, wherein the topoisomerase inhibitor is selected from the group consisting of compound B, compound C, compound D, compound E, compound F, and compound G, or pharmaceutically acceptable salts thereof.

[0312] Embodiment 38. Embodiment 38 provides the use described in any one of Embodiments 33 to 37, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0313] Embodiment 39. In Embodiment 39, the use described in any one of Embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0314] Embodiment 40. In Embodiment 40, the use described in any one of Embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0315] Embodiment 41. Embodiment 41 provides the use of a PARG inhibitor in the manufacture of a pharmacopoeci for the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor.

[0316] Embodiment 42. In Embodiment 42, the use of Embodiment 41 is provided, where the PARG inhibitor is a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, in the formula: R 1 is cyano, C 1-2 Alkyl and C 1-2 Selected from the group consisting of haloalkyls; Ar is 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X 2 is either CH or CF; R 2 C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxy C 1-3 Selected from the group consisting of alkyl and cyano; Ring B is R a , R b , and R c A 5-membered or 6-membered heterocycloalkyl group substituted with; R a is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, halo, hydroxy, or -C(O)R d (Here, Rd is hydrogen, C 1-6 Alkyl, or C 1-6 (is a haloalkyl); and R b and R c C 1-6 Alkyl, hydrogen, hydroxy, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl and C 1-6 It is selected independently of haloalkoxys.

[0317] Embodiment 43. In Embodiment 43, the use described in Embodiment 41 or 42 is provided, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0318] Embodiment 44. In Embodiment 44, the use described in any one of Embodiments 41 to 43 is provided, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[0319] Embodiment 45. In Embodiment 45, the use described in any one of Embodiments 41 to 44 is provided, wherein the topoisomerase inhibitor is selected from the group consisting of compound B, compound C, compound D, compound E, compound F, and compound G, or pharmaceutically acceptable salts thereof.

[0320] Embodiment 46. Embodiment 46 provides the use described in any one of Embodiments 41 to 45, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0321] Embodiment 47. In Embodiment 47, the use described in any one of Embodiments 41 to 43 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0322] Embodiment 48. Embodiment 48 provides the use described in any one of Embodiments 41 to 43, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 49. Embodiment 49 provides the use described in any one of Embodiments 33 to 48, wherein the cancer is homologous recombination deficiency (HRD) cancer.

[0324] Embodiment 50. Embodiment 50 provides a use described in any one of Embodiments 33 to 49, wherein cancer is characterized by reduced or absent BRCA1 and / or BRCA2 gene expression, absence or mutation of the BRCA1 and / or BRCA2 gene, or impaired function of the BRCA1 and / or BRCA2 protein.

[0325] Embodiment 51. In Embodiment 51, the use described in any one of Embodiments 33 to 50 is provided, wherein the cancer is breast cancer, lung cancer, or ovarian cancer.

[0326] Pharmaceutical composition In one embodiment, a pharmaceutical composition comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof, a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier is provided herein.

[0327] In one embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a PARG inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of a topoisomerase inhibitor are provided.

[0328] In another embodiment, a combination product comprising a first pharmaceutical composition containing a therapeutically effective amount of a PARG inhibitor and a second pharmaceutical composition containing a therapeutically effective amount of a topoisomerase inhibitor is provided herein.

[0329] In one embodiment, the PARG inhibitor is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, where the variables are defined above.

[0330] In another embodiment, the topoisomerase inhibitor is a type II topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is a type I topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0331] In another embodiment, the topoisomerase inhibitor is selected from the group consisting of the compounds listed in Table 1 or their pharmaceutically acceptable salts or hydrates.

[0332] In another embodiment, the topoisomerase inhibitor is topotecan (compound H) or a pharmaceutically acceptable salt or hydrate thereof.

[0333] In another embodiment, the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0334] In another embodiment, the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound C or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound D or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound E or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound F or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound G or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0335] In yet another embodiment, a combination product is provided herein comprising a first pharmaceutical composition comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of compound B or a pharmaceutically acceptable salt thereof.

[0336] In yet another embodiment, a combination product is provided herein comprising a first pharmaceutical composition comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of compound H or a pharmaceutically acceptable salt thereof.

[0337] In yet another embodiment, the Specified Reference Indicators provide a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of compound C, compound D, compound E, compound F, or compound G, or a pharmaceutically acceptable salt thereof.

[0338] In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, compound B or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is provided herein.

[0339] In another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, compound H or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is provided herein.

[0340] In yet another embodiment, a pharmaceutical composition comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, compound C, compound D, compound E, compound F, or compound G or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is provided herein.

[0341] Dosage / Prescription In another embodiment, the compounds disclosed herein may be combined with a pharmaceutically acceptable carrier. Pharmaceutical compositions or combination pharmaceutical products are provided herein.

[0342] In one embodiment of the combination product, a PARG inhibitor or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are present in the same formulation. In another embodiment of the combination product, the PARG inhibitor and the topoisomerase inhibitor are present in separate formulations. In a further embodiment of this embodiment, these formulations are for simultaneous or sequential administration.

[0343] Administration of concomitant medications may include administering the concomitant medication as a single formulation or unit dosage form, administering the individual drugs of the concomitant medication simultaneously but separately, or administering the individual drugs of the concomitant medication sequentially via any appropriate route. Depending on the dosage of the individual drugs in the concomitant medication, it may be necessary to administer one drug more frequently than the other drugs in the concomitant medication. Therefore, to enable appropriate administration, packaged medications may contain one or more dosage forms that include the concomitant medication and one or more dosage forms that include one drug of the concomitant medication but do not include the other drug.

[0344] The actual dosage level of the active ingredient in a pharmaceutical composition can be modified to obtain an effective amount of the active ingredient for achieving the desired therapeutic response without causing toxicity to the patient, for a particular patient, composition, and method of administration.

[0345] In particular, the selected dosage level depends on a variety of factors, including the activity of the specific compound used, the timing of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, or substances used in combination with the compound, the age, sex, weight, condition, overall health status, and medical history of the patient being treated, as well as similar factors known in the medical field.

[0346] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start administering the pharmaceutical composition by administering the disclosed compound at a lower level than required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0347] In certain embodiments, it is particularly advantageous to formulate the compound in dose unit form for ease of administration and uniformity of dosage. As used herein, dose unit form refers to a physically distinct unit suitable as a unit dose for a patient under treatment, each unit containing a predetermined amount of the disclosed compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical vehicle. The dose unit form is determined and directly depends on (a) the inherent properties of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations of the technology for formulating / manufacturing such disclosed compound for the treatment of a patient's pain, depression, or drug addiction.

[0348] In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition provided herein comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0349] The optimal ratio, individual and combined dosages, and concentrations of drug compounds that exert efficacy without toxicity are based on the dynamics of the utilization of the active ingredient to the target site.

[0350] The routes of administration of any composition discussed herein include oral, nasal, rectal, vaginal, parenteral, oral cavity, sublingual, or topical administration. Compounds can be formulated for any suitable route, e.g., oral or parenteral, e.g., transdermal, transmucosal (e.g., sublingual, via the tongue, (trans)oral, (trans)urethral, ​​intravaginal (e.g., via the vagina and perivacial), nasal (intra) and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

[0351] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, lozenges, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma preparations, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosols for inhalation, and compositions and formulations for intravesical administration. It should be understood that these formulations and compositions are not limited to the specific formulations and compositions described herein.

[0352] Tablets, sugar-coated tablets, liquids, infusions, suppositories, or capsules, caplets, and gel capsules are particularly suitable for oral administration. Compositions for oral administration can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of inert and non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose, granulators and disintegrants such as corn starch, binders such as starch, and lubricants such as magnesium stearate. Tablets may be uncoated or coated by known techniques to improve appearance or to delay the release of the active ingredient. Formulations for oral administration may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0353] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or for bolus or continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous vehicles (optionally including other formulation agents such as suspending agents, stabilizers, or dispersants) may be used.

[0354] In one embodiment, particularly when the topoisomerase inhibitor is doxorubicin, it can be administered by injection. In one embodiment, doxorubicin is administered in capsule form. In another embodiment, doxorubicin is administered intravenously.

[0355] kit In one embodiment, the Disclosure provides a kit for treating cancer comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0356] In certain embodiments, the kit includes a pharmaceutical composition comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, and a pharmaceutical comprising a pharmaceutically acceptable composition comprising a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

[0357] In some embodiments, the kit comprises a pharmaceutical composition comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof, a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

[0358] In additional embodiments, a pharmaceutical kit is provided. The kit includes a sealed container approved for the storage of a pharmaceutical composition, the container containing one of the pharmaceutical compositions described above. In some embodiments, the sealed container, such as an airless bottle, minimizes contact between the ingredients and air. In another embodiment, the sealed container is a sealed tube. Instructions for use of the composition and information about the composition are included in the kit.

[0359] In certain embodiments, the combination compounds can be administered on the same schedule by administering a single formulation or unit dosage form containing all of the combination compounds, or by administering separate formulations or unit dosage forms of the combination compounds. However, some of the compounds used in the combination may be administered more frequently than once a day, or at a different frequency than the other compounds used in the combination. Therefore, in one embodiment, the kit contains a formulation or unit dosage form containing all of the compounds in the combination, and an additional formulation or unit dosage form containing one of the compounds in the combination, along with instructions for administering the dosage forms on a fixed schedule, without including additional active compounds, in a container.

[0360] The kits provided herein include prescribing information, for example, on the label of a patient or healthcare provider, or on a packaged pharmaceutical product. Prescribing information may include, for example, information on the efficacy, dosage and method of administration, contraindications and side effects of the pharmaceutical product.

[0361] In all of the foregoing, the combination compounds of this disclosure may be administered alone, as a mixture, or in combination with additional active agents.

[0362] The kits provided in this invention can be designed to meet the conditions necessary to properly maintain the components contained therein (e.g., refrigeration or freezing). The kits may include labels or accompanying documents containing identifying information of the components therein, and instructions for use (e.g., administration parameters, clinical pharmacology of the active ingredient including mechanism of action, pharmacokinetics and pharmacodynamics, side effects, contraindications, etc.).

[0363] Each component of the kit can be sealed in an individual container, or all of the various containers can be placed in a single package. The label or accompanying information may include manufacturer information such as lot number and expiration date. The label or accompanying information may be incorporated into the physical structure containing the components, housed separately within the physical structure, or affixed to the components of the kit (e.g., ampoules, syringes, or vials).

[0364] Those skilled in the art will be able to recognize or confirm, by ordinary experimentation alone, any equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are deemed to be within the scope of this disclosure and to be encompassed by the claims appended herein.

[0365] Where values ​​and ranges are indicated in this specification, it should be understood that all values ​​and ranges encompassed within those values ​​and ranges are intended to be included within the scope of this disclosure. Furthermore, all values ​​included within these ranges, as well as any upper or lower limits on the ranges of values, are also assumed by this application.

[0366] The following embodiments further illustrate aspects of the present disclosure. However, they do not in any way limit the teachings of the present disclosure described herein. [Examples]

[0367] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limitations. In carrying out this disclosure, unless otherwise specified, the usual techniques of organic synthesis, cell biology, cell culture, and molecular biology in the art are used. Example 1 Preparation of compound A [ka] Step 1: Preparation of 2,6-difluoro-4-iodobenzaldehyde [ka]

[0368] To a stirred solution of 1,3-difluoro-5-iodobenzene (compound 1) (50 g, 208.3 mmol, Oakwood Chemical, CAS 2265-91-0, catalog number 024566) in THF (500 mL), LDA (80 mL, 625.0 mmol) and DMF (48.3 mL, 625 mmol) were added at -78°C, and the mixture was stirred at -78°C for 2 hours. After the starting material was completely consumed, the reaction mixture was diluted with water (500 mL), extracted with ethyl acetate (2 × 300 mL), washed with saline solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product as an oil. The crude product was purified by column chromatography using silica gel (100-200), and eluted using a 20% ethyl acetate / hexane gradient. The product was eluted using a 30% ethyl acetate / hexane gradient. The purified fraction was concentrated under reduced pressure to obtain 2,6-difluoro-4-iodobenzaldehyde (compound 2) (23 g) as a solid. 1 ¹H NMR (500 MHz, chloroform-d) δ: 10.29 (s, 1H), 7.37-7.46 (m, 2H). Step 2: Preparation of 4-fluoro-6-iodo-1H-indazole [ka]

[0369] To a stirred solution of 2,6-difluoro-4-iodobenzaldehyde (compound 2) (5 g, 18.6 mmol) in 1,4-dioxane (110 mL), hydrazine hydrate (18.6 mL, 373.1 mmol) was added at room temperature, and the resulting mixture was stirred at 100 °C for 24 hours. The reaction mixture was concentrated under reduced pressure, and ice-cold water (100 mL) was added. The mixture was stirred for 30 minutes, during which time a solid precipitate formed. The mixture was filtered. The solid was washed with water (100 mL) and n-pentane (50 mL), and dried under vacuum to obtain the product 4-fluoro-6-iodo-1H-indazole (compound 3) (2.3 g) as a solid. MS ESI [M+H] of C7H4FIN2 + The theoretical value is 262.94, and the measured value is 262.99. 1H NMR (CDCl3, 400 MHz): 10.12 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.15 (dd, J = 9 Hz, 1H). Step 3: Preparation of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazole-1-yl)-1,3,4-thiadiazole [ka]

[0370] To a stirred solution of 4-fluoro-6-iodo-1H-indazole (compound 3) (5 g, 19.0 mmol) in DMF (50 mL), cesium carbonate (18.6 g, 57.24 mmol) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (compound 4) (3.8 g, 18.1 mmol, Enamine Stock Building Blocks, CAS 1340313-49-6, catalog number EN300-108825) were added. The resulting mixture was stirred at 60°C for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (50 mL) and stirred for 30 minutes, during which time a solid precipitate formed. The mixture was filtered. The recovered solid was washed with water (100 mL), followed by washing with n-pentane (100 mL), and then dried under vacuum to obtain 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazole-1-yl)-1,3,4-thiadiazole (compound 5) (4.2 g) as a solid. 10 MS ESI [M+H] for H4F3IN4S + The theoretical value is 396.92, and the measured value is 396.91. 1 H NMR (CDCl3, 500 MHz): 8.87 (s, 1H), 8.29 (s, 1H), 7.40 (dd, J = 17 Hz, 1H), 7.0 (t, J = 53.5 Hz, 1H). Step 4: Preparation of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-fluoro-1H-indazole-6-yl)benzothioate [ka]

[0371] To a stirred solution of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazole-1-yl)-1,3,4-thiadiazole (compound 5) (100 mg, 0.25 mmol) in toluene (1 mL) degassed for 5 minutes, CuI (5 mg, 0.025 mmol), 1,10-phenanthroline (phen) (11 mg, 0.05 mmol), and potassium thiobenzoate (67 mg, 0.378 mmol) were added at room temperature. The resulting mixture was stirred at 100°C for 16 hours. The reaction was monitored by LC-MS. The crude mixture was purified by column chromatography using silica gel (100-200), and eluted using 10% ethyl acetate / hexane as a gradient solution. The purified fraction was recovered and concentrated under reduced pressure to obtain S-(1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-fluoro-1H-indazole-6-yl)benzothioate (compound 6) (55 mg) as a solid. 17 MS ESI [M+H] for H9F3N4OS2 + The theoretical value is 407.02, and the measured value is 407.01. 1 H NMR (CDCl3, 400 MHz): 8.68 (s, 1 H), 8.39 (s, 1H), 8.03 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.27 (s, 1H), 6.99 (t, J = 53.2 Hz, 1H). Step 5: Preparation of N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-fluoro-1H-indazole-6-sulfonamide [ka]

[0372] To a stirred solution of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-fluoro-1H-indazole-6-yl)benzothioate (compound 6) (500 mg, 1.23 mmol) in acetonitrile (10 mL) at 0°C, a solution of BnMe3NCl (682 mg, 3.69 mmol) and TCCA (trichloroisocyanuric acid) (370 mg, 1.59 mmol) in acetonitrile (40 mL) was added. The reaction mixture was stirred for 20 minutes. Next, a solution of 1-methylcyclopropan-1-amine (1.71 g, 7.38 mmol, Combi-Blocks, CAS22936-83-0, catalog number QH-3639) in pyridine (2.5 mL) and cesium carbonate (198 mg, 0.61 mmol) were added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction was tracked by LC-MS. LC-MS showed that the starting material (S-(1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-fluoro-1H-indazole-6-yl)benzothioate) (compound 6) was completely consumed. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with saline solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography using silica gel (100-200) and eluted using 5-50% ethyl acetate / hexane as a gradient solution. The product was eluted with 20% ethyl acetate / hexane. The purified fraction was collected and concentrated under reduced pressure to obtain 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound 7) (90 mg) as a solid. 14 MS ESI [M+H] for H9F3N6O2S2 + The theoretical value is 404.04, and the measured value is 404.18. 1H NMR (CDCl3, 400 MHz): 9.00 (s, 1 H), 8.80 (s, 1H), 8.54 (s, 1H), 7.63 (t, J= 48.8 Hz, 2H), 1.10 (s, 3 H), 0.65 (s, 2 H), 0.44 (s, 2H). Step 6: Preparation of (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazole-4-yl)-2,6-dimethylpiperazine-1-carboxylate tert-butyl [ka]

[0373] To a stirred solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound 7) (80 mg, 0.19 mmol) in DMSO (dimethyl sulfoxide) (2 mL), (2S,6S)-2,6-dimethylpiperazine-1-carboxylate tert-butyl (85 mg, 0.39 mmol, BLD Pharmatech, CAS 574007-66-2, catalog number BD233798) and DIPEA (N,N-diisopropylethylamine) (0.1 mL, 0.59 mmol) were added, and the reaction mixture was stirred at 130°C for 2 hours. The reaction mixture was quenched with ice-cold water (20 mL) and stirred for 30 minutes. The obtained solid was filtered, washed with water (10 mL), dried under vacuum, purified by silica gel (100-200) column chromatography, eluted using 50% ethyl acetate / hexane as a gradient solution, and the purified fraction was concentrated under reduced pressure to obtain (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazole-4-yl)-2,6-dimethylpiperazine-1-carboxylate tert-butyl (compound 8) (110 mg, yield: 92%) as a solid. 25 H 33MS ESI [M+H] for F2N7O4S2 + The theoretical value is 598.20, and the measured value is 598.26. Step 7: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-((3S,5S)-3,5-dimethylpiperazine-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (Compound A) [ka]

[0374] To a stirred solution of (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazole-4-yl)-2,6-dimethylpiperazine-1-carboxylate tert-butyl (compound 8) (100 mg, 0.16 mmol) in DCM (3 mL), trifluoroacetic acid (0.07 mL, 0.98 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (preparative HPLC conditions: mobile phase - water: 10 mM ammonium bicarbonate in a MeCN column, -Inertsil ODS (20 x 250) mm, 5 u, flow rate - 18 ml / min, gradient method - 0 / 50, 9.5 / 82, 9.55 / 99, 11.5 / 99, 11.55 / 50, 14.5 / 50, solubility: CAN, fraction volume: 100 mL) to obtain 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-4-((3S,5S)-3,5-dimethylpiperazine-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound A) (18 mg, yield: 21%) as a solid. 20 H 25 MS ESI [M+H] for F2N7O2S2 + The theoretical value is 498.15, and the measured value is 498.34. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.75 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.59 (t, J = 52.8 Hz, 1H), 7.10 (d, J = 1.0 Hz, 1H), 3.37 (br dd, J = 11.5, 2.9 Hz, 2H), 3.22-3.30 (m, 2H), 3.08 (br dd, J = 11.7, 6.1 Hz, 2H), 1.17 (d, J = 6.4 Hz, 6H), 1.08 (s, 3H), 0.58-0.76 (m, 2H), 0.29-0.49 (m, 2H). Example 2 Efficacy study to evaluate the combined effect of compound A and doxorubicin (compound B) in the HCC1428 xenograft model derived from HR-deficient breast cancer cell lines.

[0375] The combined effect of compound A and doxorubicin was evaluated using a xenograft (CDX) model derived from the HCC1428 breast cancer cell line, which possesses a BRCA2 mutation. In this study, cells were grown in RPMI medium containing 10% fetal bovine serum and transplanted into BALB / c nude mice. As shown in Table 2, the average tumor volume was approximately 180 mm². 3 Once the target was reached, the animals were randomly assigned to the treatment group, and the experimental treatment period was set to 35 days. In this xenograft, estradiol benzoate (40 μg / 20 μl / mouse) was administered subcutaneously twice a week, starting one week before cell transplantation and continuing until the end of treatment.

[0376] When compound A was administered once daily (QD) at 30 mg / kg and 100 mg / kg, tumor growth inhibition (TGI) was 63.2% and 102.5%, respectively. When doxorubicin 5 mg / kg was administered intravenously once weekly for 5 weeks, the TGI was 57%. Combination therapy yielded a more potent and sustained response, with TGIs of 85% and 110% in the groups administered compound A at 30 mg / kg and 100 mg / kg, respectively. In the combination therapy group administered 100 mg / kg of compound A, 50% of animals achieved complete regression. Statistically significant differences in TGI were observed between the monotherapy and combination therapy groups at both 30 mg / kg and 100 mg / kg doses of compound A, highlighting the enhanced antitumor effect of this combination therapy (Table 3 and Figure 1 (Figure 1)). No deaths were observed in this study, however, weight loss exceeding 10% was observed in the high-dose combination therapy group. [Table 2] [Table 3] Example 3 Efficacy study to evaluate the combined effect of compound A and topotecan (compound H) in the small cell lung cancer cell line NCI-H69.

[0377] The combined effect of compound A and topotecan was evaluated using a xenograft (CDX) model derived from the NCI-H69 small cell lung cancer cell line, which possesses an ATM variant of unknown significance. In this study, NCI-H69 cells were grown in RPMI medium containing 10% fetal bovine serum and transplanted into NOD SCID mice. The average tumor volume was approximately 100-150 mm². 3 Upon reaching a certain threshold, the mice were randomly assigned to a different treatment group. This study consisted of six treatment groups, each containing 10 mice, and the treatment period was 42 days. TGI was calculated on day 21, when the vehicle group was discontinued due to reaching the maximum tolerable tumor burden.

[0378] When compound A was administered at 100 mg / kg, the TGI was 53%, while with topotecan administered at 0.25 mg / kg and 1 mg / kg, the TGI values ​​were 79% and 80%, respectively (see Table 4 for administration schedule). Topotecan showed a combined effect at both doses, with a TGI of 79% at the 0.25 mg / kg dose and a TGI of 105% at the 1 mg / kg dose, and complete regression was observed in 7 out of 10 animals by day 42. These results highlight the potent anticancer effect of compound A when used in combination with topotecan, a topoisomerase I inhibitor (see Figure 2). [Table 4] Example 4 Efficacy study to evaluate the combined effect of compound A and topotecan (compound H) in the Kuromachi cell line, a high-grade serous ovarian cancer cell line.

[0379] The combined effect of compound A and topotecan was evaluated using a xenograft (CDX) model derived from the Kuromachi cell line, a highly malignant serous ovarian cancer cell line with a BRCA2 gene mutation (nonsense mutation). In this study, Kuromachi cells were grown in RPMI containing 10% fetal bovine serum and transplanted into NOD SCID mice. The average tumor volume was approximately 100-150 mm². 3 Once the maximum tolerable tumor burden was reached, the mice were randomly assigned to different treatment groups. This study consisted of four treatment groups, each containing 6-8 mice, and the treatment period was 63 days. TGI was calculated on day 41, when the vehicle group was discontinued due to reaching the maximum tolerable tumor burden.

[0380] When compound A was administered at 100 mg / kg, the TGI was 103%, while with topotecan administered at 1 mg / kg, the TGI was 77% (see Table 5 for administration schedule). In the combination group, the TGI was 108%, and complete remission was observed in all 6 animals by day 52. ​​These results highlight the potent anticancer effect of compound A when used in combination with topotecan, a topoisomerase I inhibitor (Figure 3). [Table 5] Example 5 PARG enzyme inhibition assay (TR-FRET)

[0381] enzyme EC 50 Assay The PARG enzyme was incubated in a microtiter plate with a compound or vehicle (DMSO) and a biotinylated PAR-modified PARP-1 substrate. After adding the detection antibody and streptavidin-europium, the plates were incubated again, and the fluorescence intensity of the plates was read. Low-intensity controls (DMSO) showed no inhibition of enzyme activity, while high-intensity controls (no enzyme) showed complete inhibition of enzyme activity. material: Enzyme: PARG • hPARG: 250 pM, 1-976, His tagged, Proteos, 2.0 mg / mL (17.9 μM) ·Substrate: 30nM • Test compound / enzyme pre-incubation time: 1 hour • Enzyme / substrate reaction time: 10 minutes Substrate: hPARP1, His6-TEV tagged, 1.2 mg / mL (10.3 μM) Detected antibody: Anti-His monoclonal antibody - ULight, Perkin Elmer, catalog number TRF0134-M Streptoavidin-Europium: Perkin Elmer Catalog Number AD0062 Assay buffer: 50 mM Tris-HCl, pH 7.4, 50 mM KCl, 3 mM EDTA, 0.4 mM EGTA, 1 mM DTT, 0.01% Tween 20, 0.01% BSA Temperature: 23℃ Total reaction volume: 20 μL Contrast: • 0% inhibition: DMSO • 100% inhibition: No enzyme Enzyme reactions and detection: Place 200 μL of a 100-fold concentration compound or DMSO into each appropriate well of a 1.384-well white polystyrene microtiter plate (Corning, catalog no. 3574). Place either twice the final concentration of enzyme in 2.10 μL of assay buffer, or only the assay buffer, into the appropriate wells. 3. Centrifuge the plate at 1000 rpm for 30 seconds. 4. Incubate the plate at room temperature for 1 hour. Add 10 μL each of the 2x concentration substrate in 5.10 μL of assay buffer to each test well. 6. Incubate the plate at room temperature for 10 minutes. Add 10 μL each of a 3-fold mixture of 42 nM detection antibody in 7.50 mM Tris-HCl (pH 7.4) and 2.25 nM streptavidin-europium to each test well. 8. Incubate the plate at room temperature for 1 hour. 9. Measure the fluorescence of the plate using a plate reader (Envision). Excitation: 317nm Fluorescence: 620nm Fluorescence: 665nm

[0382] Data analysis: EC 50 The values ​​were calculated by the Collaborative Drug Discovery Vault (CDD). The curves were fitted by the CDD as response rate (%) versus compound concentration (uM) using a four-parameter inhibition model with Equation 1.

[0383] Formula 1: A. Fit=(A+((BA) / (1+((C / x)^D)))) B.Res=(y-fit)

[0384] TR-FRET EC of compound A 50 The values ​​are shown in Table 6 below.

[0385] TR-FRET:**** ≤0.1μM [Table 6] Example 6 Efficacy study to evaluate the combined effect of compound A and topotecan (compound H) in the breast cancer model HCC1395.

[0386] The combined efficacy of compound A and topotecan was evaluated using a xenograft (CDX) model derived from the HCC1395 cell line of breast cancer (TMBC) with BRCA1 and BRCA2 mutations. In this study, HCC1395 cells were grown in RPMI containing 10% fetal bovine serum and transplanted into NOG mice. The average tumor volume was approximately 100-150 mm². 3 Once the target was reached, the mice were randomly assigned to a different treatment group. This study consisted of four treatment groups, each containing eight mice, and the treatment period was 35 days. TGI was calculated on day 35.

[0387] When compound A was administered at 100 mg / kg, the TGI was 56%, while with topotecan administered at 1 mg / kg, the TGI was 98% (see Table 7 for administration schedule). The TGI in the combination group was 102%. These results highlight the potent anticancer effect of the combination of topotecan, a topoisomerase I inhibitor, and compound A (Figure 4). [Table 7] Example 7 Efficacy study to evaluate the combined effect of compound A and compound J (fam-trastuzumab deruxtecan-nxki) in the human lung cancer cell line NCI-H650.

[0388] The combined efficacy of compound A and compound J (fam-trastuzumab deruxtecan-nxki) was evaluated using a xenograft (CDX) model derived from the non-small cell lung cancer cell line NCI-H650. In this study, NCI-H650 cells were grown in RPMI medium containing 10% fetal bovine serum and transplanted into BALB / c nude mice. The average tumor volume was approximately 100-150 mm². 3 Once the mice reached a certain stage, they were randomly assigned to a different treatment group. This study consisted of four treatment groups, each containing eight mice, and the treatment period was 26 days.

[0389] When compound A was administered at a dose of 100 mg / kg, the TGI was 5%, and when compound J was administered as a single dose at 10 mg / kg, the TGI was 100%, with complete regression achieved in 3 out of 8 animals (see Table 8 for administration schedule). In the combination group, the TGI was 106%, and complete regression was observed in 6 out of 8 animals by day 26. These results highlight the potent anticancer effect of the combination of compound A and compound J (Figure 5). [Table 8]

[0390] Specific embodiments of the Disclosure, including the best mode for carrying out the Disclosure known to the inventors, are described herein. By reading the above description, modifications of the disclosed embodiments will be obvious to those skilled in the art, and it is expected that those skilled in the art will be able to adopt such modifications as appropriate. Accordingly, the Disclosure is intended to be carried out in ways other than those specifically described herein, and to include all modifications and equivalents of the subject matter described in the appended claims, to the extent permitted by applicable law. Furthermore, unless otherwise stated herein, or unless it is clearly inconsistent with the context, all combinations of the above elements in all possible modifications are incorporated herein.

[0391] All patent applications, patents, and print publications referenced herein are incorporated herein by reference in their entirety, except for definitions, abandonment or denial of subject matter, and unless the incorporated material conflicts with the express disclosure herein, where the language of this disclosure shall prevail in the event of any conflict.

[0392] Other embodiments are within the scope of the following claims.

Claims

1. A method for treating cancer in a subject requiring such treatment, comprising administering a therapeutically effective amount of a PARG inhibitor to the subject and administering a therapeutically effective amount of a topoisomerase inhibitor to the subject, wherein the PARG inhibitor is a compound of formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, a method [in the formula, R １ is cyano, C １－２ Alkyl and C １－２ Selected from the group consisting of haloalkyls; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazolyl; X ２ is CH or CF; R ２ C １－３ Haloalkyl, C １－３ Alkyl, hydroxy C １－３ Selected from the group consisting of alkyl and cyano; Ring B is a 5- or 6-membered heterocycloalkyl substituted with R ａ , R ｂ , and R ｃ ; R ａ is hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, halo, hydroxy, or -C(O)R ｄ And here, R ｄ is hydrogen, C １－６ Alkyl, or C １－６ It is a haloalkyl; and R ｂ and R ｃ C １－６ Alkyl, hydrogen, hydroxy, C １－６ Alkoxy, Halo, C １－６ Haloalkyl and C １－６ [Selected independently from haloalkoxys].

2. X ２ The method according to claim 1, wherein is CH.

3. R １ The method according to claim 1 or 2, wherein is methyl.

4. R １ The method according to claim 1 or 2, wherein is cyanoacrylate.

5. The method according to any one of claims 1 to 4, wherein Ar is 1,3,4-thiadiazole-2-yl.

6. R ２ The method according to any one of claims 1 to 5, wherein the Ar carbon atom is bonded to the Ar atom bonded to the nitrogen atom of the rest of the molecule, and is located at the meta position of the Ar carbon atom.

7. R ２ The method according to any one of claims 1 to 6, wherein is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano.

8. R ２ The method according to any one of claims 1 to 7, wherein is difluoromethyl.

9. The method according to any one of claims 1 to 8, wherein ring B is morpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazinyl.

10. The method according to any one of claims 1 to 9, wherein ring B is piperazinyl.

11. A method according to any one of claims 1 to 10, wherein R ａ However, hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, halo, hydroxy, or -C(O)R ｄ (Here, R ｄ is hydrogen, C １－６ Alkyl, or C １－６ (It is a haloalkyl) and R ｂ and R ｃ However, C １－６ Alkyl, hydrogen, hydroxy, C １－６ Alkoxy, Halo, C １－６ Haloalkyl and C １－６ A method selected independently of haloalkoxys.

12. R ａ However, hydrogen, C １－４ Alkyl, or C １－４ It is a haloalkyl, and also R ｂ and R ｃ C １－６ The method according to any one of claims 1 to 11, independently selected from alkyl and hydrogen.

13. R ａ is hydrogen, R ｂ and R ｃ However, each is independent of C １－６ The method according to any one of claims 1 to 12, wherein the hydrogen is alkyl or hydrogen.

14. A method according to any one of claims 1 to 13, wherein the PARG inhibitor is compound A; 【Chemistry 2】 A method, or a pharmaceutically acceptable salt thereof.

15. The method according to any one of claims 1 to 14, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

16. The method according to any one of claims 1 to 15, wherein the topoisomerase inhibitor is selected from the group consisting of compound B, compound C, compound D, compound E, compound F, and compound G, or pharmaceutically acceptable salts or hydrates thereof.

17. The method according to any one of claims 1 to 16, wherein the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

18. The method according to any one of claims 1 to 14, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

19. The method according to any one of claims 1 to 14, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

20. The method according to any one of claims 1 to 14, wherein the topoisomerase inhibitor is 10-hydroxycamptothecin and topotecan, hexylresorcinol, exatecan, deruxtecan, or berotecan.

21. The method according to any one of claims 1 to 20, wherein the cancer is homologous recombination deficiency (HRD) cancer.

22. The method according to any one of claims 1 to 20, wherein the cancer is characterized by decreased or absent expression of the BRCA1 and / or BRCA2 gene, absence or mutation of the BRCA1 and / or BRCA2 gene, or impaired function of the BRCA1 and / or BRCA2 protein.

23. The method according to any one of claims 1 to 20, wherein the cancer is breast cancer, lung cancer, or ovarian cancer.

24. The method according to any one of claims 1 to 21, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer.

25. The method according to any one of claims 1 to 24, wherein the PARG inhibitor and the topoisomerase inhibitor are present in separate dosage forms.

26. The method according to any one of claims 1 to 24, wherein the PARG inhibitor and the topoisomerase inhibitor are present in the same dosage form.

27. A PARG inhibitor for use in the treatment of cancer, wherein the PARG inhibitor is administered simultaneously with or sequentially with a topoisomerase inhibitor.

28. The use of PARG inhibitors in the manufacture of pharmaceuticals for the treatment of cancer, in which PARG inhibitors are administered simultaneously or sequentially with topoisomerase inhibitors.

29. The aforementioned PARG inhibitor is a compound of formula I: 【Transformation 3】 or a pharmaceutically acceptable salt thereof, the use according to claim 27 or 28 [in the formula, R １ is cyano, C １－２ Alkyl and C １－２ Selected from the group consisting of haloalkyls; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazolyl; X ２ is CH or CF; R ２ C １－３ Haloalkyl, C １－３ Alkyl, hydroxy C １－３ Selected from the group consisting of alkyl and cyano; Ring B is R ａ , R ｂ , and R ｃ A 5-membered or 6-membered heterocycloalkyl substituted with; R ａ is hydrogen, C １－４ Alkyl, C １－４ Haloalkyl, halo, hydroxy, or -C(O)R ｄ And here, R ｄ is hydrogen, C １－６ Alkyl, or C １－６ It is a haloalkyl; and R ｂ and R ｃ C １－６ Alkyl, hydrogen, hydroxy, C １－６ Alkoxy, Halo, C １－６ Haloalkyl and C １－６ [Selected independently from haloalkoxys].

30. The use according to any one of claims 27 to 29, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof.

31. The use according to any one of claims 27 to 30, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

32. The use according to any one of claims 27 to 31, wherein the topoisomerase inhibitor is selected from the group consisting of compound B, compound C, compound D, compound E, compound F, and compound G, or pharmaceutically acceptable salts thereof.

33. The use according to any one of claims 27 to 32, wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

34. The use according to any one of claims 27 to 30, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

35. The use according to any one of claims 27 to 30 and 34, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

36. The use according to any one of claims 27 to 35, wherein the cancer is homologous recombination deficiency (HRD) cancer.

37. The use according to any one of claims 27 to 36, wherein the cancer is characterized by decreased or absent expression of the BRCA1 and / or BRCA2 gene, absence or mutation of the BRCA1 and / or BRCA2 gene, or impaired function of the BRCA1 and / or BRCA2 protein.

38. The use according to any one of claims 27 to 37, wherein the cancer is breast cancer, lung cancer, or ovarian cancer.

39. The use according to any one of claims 27 to 37, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer.

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