Combination therapy comprising a PARG inhibitor and a topoisomerase inhibitor to treat cancer.

Description

1 / 93 Combination therapy comprising a PARG inhibitor and a topoisomerase inhibitor to treat cancer. CROSS-REFERENCES TO RELATED REQUESTS

[001] This application claims the benefit of Provisional Applications US Nos. 63 / 457,312, filed April 5, 2023; 63 / 584,013, filed September 20, 2023; and 63 / 548,513, filed November 14, 2023, each of which is incorporated herein in its entirety and for all purposes. BACKGROUND

[002] Cancer is caused by uncontrolled and unregulated cell proliferation. The consequence of this proliferation, often rapid, is a high level of oxidative stress within the tumor, which damages DNA and leads to a greatly increased mutation rate. Tumor cells, therefore, utilize and rely heavily on DNA damage repair mechanisms.

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

[004] One of the first events during single-strand DNA repair is the binding of PARP (poly ADP-ribose polymerase) to the break and the rapid synthesis of poly ADP-ribose (PAR) on PARP itself. This molecular structure serves as a signal to recruit other DNA repair proteins to facilitate repair. The signal initiated by these PAR chains is short-lived, as they are rapidly degraded by the PARG enzyme. When PARP binds to PAR, its catalytic activity is reduced, and therefore PARG activity helps restore PARP. Petition 870250089799, dated 02 / 10 / 2025, page 9 / 131 2 / 93 to its catalytically active form.

[005] PARG is derived from a single gene with isoforms residing in the nucleus, mitochondria, and cytosol. Another known protein with glycohydrolase activity is ARH3, located in mitochondria. Although primarily known for its direct role in DNA repair, PARG impacts PAR signaling in transcriptional and epigenetic pathways.

[006] Cancer cells can become dependent on a specific DNA repair pathway when other DNA repair mechanisms are not functional. Tumors carrying 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 of BRCA2-deficient cells. However, other tumor mutations can give rise to deficiencies in DNA double-strand repair mechanisms (so-called BRCAness), thus sensitizing tumor cells to PARG inhibition.

[007] Topoisomerases are abundant enzymes, essential for altering DNA topology during DNA replication and transcription, and are classified into two main classes: type I and type II. Topoisomerase inhibitors, as anticancer agents, act specifically on the topoisomerase species mentioned above. For example, topoisomerase II inhibitors include anthracyclines, such as doxorubicin. Topoisomerase inhibitors induce cell death by inhibiting topoisomerase activity, which is generally much more highly expressed in cancerous cells than in normal cells. Topoisomerase inhibitors can also covalently trap topoisomerase in DNA and generate lethal breaks in the DNA strand, leading to cell death. Petition 870250089799, dated 02 / 10 / 2025, page 10 / 131 3 / 93

[008] Despite the many recent advances in cancer therapies, there is still a need for more effective and / or improved treatment for individuals suffering the effects of cancer. This description addresses that need and offers related advantages. SUMMARY

[009] Provided here is a combination comprising a Poly ADP-ribose glycohydrolase (PARG) inhibitor and a topoisomerase inhibitor. The combination is useful for the treatment of a variety of cancers, including solid tumors. In one embodiment, the disease or disorder is an advanced or metastatic solid tumor. The combination is similarly useful for the treatment of any number of PARG-associated diseases. The combination is similarly useful for the treatment of a variety of diseases or disorders in which PARG activity is implicated. The combination is useful for the treatment of a homologous recombinant deficiency (HRD) cancer. The combination is similarly useful for the treatment of a variety of diseases or disorders treatable by topoisomerase inhibition.

[0010] Provided here is a combination product comprising a PARG inhibitor and a topoisomerase inhibitor. The combination product is useful for the treatment of a variety of cancers, including solid tumors. In one embodiment, the disease or disorder is an advanced or metastatic solid tumor. The combination product is similarly useful for the treatment of numerous PARG-associated diseases. The combination product is similarly useful for the treatment of a variety of diseases or disorders in which PARG activity is implicated. The combination product is useful for the treatment of a homologous recombinant deficiency (HRD) cancer. The combination product is similarly useful Petition 870250089799, dated 02 / 10 / 2025, page 11 / 131 4 / 93 for the treatment of a variety of diseases or disorders treatable by inhibiting topoisomerase.

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

[0012] In one embodiment, provided herein is 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.

[0013] In one embodiment, methods provided herein are for treating and / or preventing cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the individual.

[0014] In one embodiment, methods provided herein are for treating and / or preventing cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least one pharmaceutically acceptable vehicle, thereby treating the cancer in the individual.

[0015] In one embodiment, methods are available for treating and / or preventing a recombinant homologous deficiency (HRD) cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the individual.

[0016] In one embodiment, methods are available to treat and / or prevent a recombinant homologous deficiency (HRD) cancer in an individual in need thereof, the methods comprising administering to the individual a combination Petition 870250089799, dated 02 / 10 / 2025, page 12 / 131 5 / 93 comprising a PARG inhibitor and a topoisomerase inhibitor together with at least one pharmaceutically acceptable vehicle, thereby treating cancer in the individual.

[0017] In yet another modality, cancer is characterized by a reduction or absence of gene expression of BRCA1 and / or BRCA2, an absence or mutation of the BRCA1 and / or BRCA2 genes, or a reduced function of the BRCA1 and / or BRCA2 proteins, or a combination thereof.

[0018] In one embodiment, methods provided herein are for treating and / or preventing cancer in an individual in need thereof, the methods comprising administering to the individual 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 cancer in the individual.

[0019] In one embodiment, methods provided herein are for treating and / or preventing a disease or disorder in which PARG activity is implicated in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the disease or disorder in the individual. In one embodiment, the disease or disorder is cancer.

[0020] In one embodiment, methods provided herein are for treating and / or preventing a disease or disorder in which PARG activity is implicated in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, together with at least one pharmaceutically acceptable vehicle, thereby treating the disease or disorder in the individual. Petition 870250089799, dated 02 / 10 / 2025, page 13 / 131 6 / 93 duo. 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 a homologous recombinant deficiency (HRD) cancer.

[0021] In one embodiment, the PARG inhibitor is a compound of Formula I: (Formula I) or a pharmaceutically acceptable salt thereof, wherein the variables of Formula I are defined below.

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

[0023] Certain PARG inhibitors for use in the combination therapy described herein are described in WO2021 / 055744 (PCT / US20 / 51486). The generic and specific compounds described in this application may be used to treat cancer as described herein.

[0024] In another embodiment, the topoisomerase inhibitor is a type II topoisomerase inhibitor (similarly referred to here as Petition 870250089799, dated 02 / 10 / 2025, page 14 / 131 7 / 93 “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, the topoisomerase inhibitor is a type I topoisomerase inhibitor (similarly referred to here as “topoisomerase I inhibitor”).

[0027] In one embodiment, the topoisomerase I inhibitor is topotecan or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 shows an efficacy study evaluating the effects of the combination between Compound A and Doxorubicin (Compound B) in the xenograft model derived from the HR-deficient breast cancer cell line HCC1428.

[0029] FIG. 2 shows an efficacy study evaluating the effects of the combination of Compound A and topotecan (Compound H) on the NCI-H69 small cell lung cancer cell line.

[0030] FIG. 3 shows an efficacy study evaluating the effects of the combination of Compound A and topotecan (Compound H) on the Kuramochi high-grade serous ovarian cancer cell line.

[0031] FIG. 4 shows an efficacy study evaluating the effects of the combination of Compound A and topotecan (Compound H) in the HCC1395 breast cancer model.

[0032] FIG. 5 shows an efficacy study evaluating the effects of the combination of Compound A and Compound J (fam-trastuzumab deruxtecan-nxki) on the NCI-H650 human lung cancer cell line. DETAILED DESCRIPTION

[0033] Provided here is a combination therapy comprising Petition 870250089799, dated 02 / 10 / 2025, page 15 / 131 8 / 93 containing a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof. Combination therapy is useful for the treatment of a variety of cancers, including, for example, ovarian, gastric, breast, lung, cervical, pancreatic, or prostate cancer. In another aspect, combination therapy is useful for the treatment of any number of diseases associated with PARGs.

[0034] The administration of a combination of an inhibitor of PARG and a topoisomerase inhibitor can provide beneficial effects for the treatment of cancer, for example, solid tumors, in an individual. Such an approach – combining or co-administering the two types of agents – can offer uninterrupted treatment to an individual in need during a clinically relevant treatment period. Definitions

[0035] Listed below are the definitions of various terms used herein. These definitions apply to the terms as used throughout this descriptive report and claims, unless otherwise limited in specific cases, individually or as part of a larger group.

[0036] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning commonly understood by someone with ordinary experience in the field. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.

[0037] When used here, the articles “a” and “an” refer to one or more of an (i.e., at least one) grammatical object of the article. As an example, “an element” means one or more of Petition 870250089799, dated 02 / 10 / 2025, p. 16 / 131 9 / 93 an element. Furthermore, the use of the term “including”, as well as other forms such as “include”, “includes” and “included”, is not limiting.

[0038] When used herein, the term “about” will be understood by one skilled in the art and will vary to some extent depending on the context in which it is used. When used herein to refer to a measurable value, such as a quantity, a time duration and the like, the term “about” covers variations of ±20% or ±10%, including ±5%, ±1% and ±0.1% of the specified value, as such variations are appropriate for carrying out the methods described.

[0039] When used in the descriptive report and claims, the term “comprising” may include the modalities “consisting of” and “consisting essentially of”. The terms “comprises”, “includes”, “having”, “has”, “may”, “contains” and variants thereof, as used herein, are intended to be open transition phrases, terms or words that require the presence of the named ingredients / steps and allow the presence of other ingredients / steps.

[0040] It should be noted that ratios, concentrations, quantities, and other numerical data may be expressed here in a range format. It should be understood that such a range format is used for convenience and brevity and, as such, should be interpreted flexibly to include not only the numerical values ​​explicitly cited as the limits of the range, but also to include all individual numerical values ​​or subintervals encompassed by that range, as if each numerical value and subinterval were explicitly cited. Furthermore, the phrase “about 'x' to 'y'” includes “about 'x' to about 'y'”.

[0041] The terms “combination”, “therapeutic combination”, “pharmaceutical combination” or “combination product”, when used herein, refer to a fixed combination in a single form of the Petition 870250089799, dated 02 / 10 / 2025, p. 17 / 131 10 / 93 unit dose, or a non-fixed combination in separate dosage forms, or a kit of components for combined administration, where two or more therapeutic agents can be administered independently, simultaneously or separately at time intervals.

[0042] The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this description. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of active ingredients or in separate formulations (e.g., capsules and / or intravenous formulations) for each active ingredient. Furthermore, such administration similarly encompasses the use of each type of therapeutic agent sequentially or separately, approximately at the same time or at different times. Regardless of whether the active ingredients are administered as a single formulation or in separate formulations, the drugs are administered to the same patient as part of the same course of therapy. In any case, the treatment regimen will provide beneficial effects in the treatment of the conditions or disorders described herein.

[0043] When used herein, the term “treat” or “treatment” refers to the inhibition of a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, condition, or disorder (i.e., halting the further development of the pathology and / or symptomatology) or improving the disease; for example, improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomatology), such as Petition 870250089799, dated 02 / 10 / 2025, page 18 / 131 11 / 93 as a reduction in the severity of the disease.

[0044] When used here, the term “patient”, “individual” or “subject” refers to a human being.

[0045] When used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a non-toxic, yet sufficient, quantity of an agent to provide the desired biological result. This result may be the reduction or relief of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case can be determined by one skilled in the art, using routine experimentation.

[0046] When used herein, the term “pharmaceutically acceptable” refers to a material, such as a vehicle or diluent, that does not negate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting detrimentally with any of the components of the composition in which it is contained.

[0047] When used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the compounds described, in which an original compound is modified by converting an existing acidic or basic portion into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids from basic residues, such as amines; alkaline or organic salts from acidic residues, such as carboxylic acids; and the like. The pharmaceutically acceptable salts described herein include conventional non-toxic salts of the original compound, formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts described and discussed herein may Petition 870250089799, dated 02 / 10 / 2025, page 19 / 131 12 / 93 to be synthesized from the original compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The expression “pharmaceutically acceptable salt” is not limited to a mono- or 1:1 salt. For example, “pharmaceutically acceptable salt” similarly includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0048] When used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound with a pharmaceutically acceptable vehicle. The pharmaceutical composition facilitates the administration of the composition to a patient or individual. There are various techniques for administering a compound in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0049] When used herein, the term “pharmaceutically acceptable vehicle” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid load, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in transporting a compound useful to the patient so that it can perform its intended function. Typically, such constructs are transported from one organ or body part to another organ or body part. Each vehicle must be “acceptable” in the sense of being compatible. Petition 870250089799, dated 02 / 10 / 2025, page 20 / 131 13 / 93 with the other ingredients of the formulation, including the compound described herein, and not harmful to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; Surfactants; alginic acid; pyrogen-free water; isotonic saline solution;Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other compatible non-toxic substances used in pharmaceutical formulations.

[0050] When used herein, “pharmaceutically acceptable vehicle” likewise includes any and all coatings, antibacterial and antifungal agents, absorption retardants and the like that are compatible with the activity of a compound described herein and are physiologically acceptable to the patient. Supplementary active compounds may likewise be incorporated into the compositions. Other additional ingredients that may be included in pharmaceutical compositions are known in the art and described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0051] The term “single formulation”, when used herein, refers to a single vehicle or a vehicle formulated to deliver quantities Petition 870250089799, dated 02 / 10 / 2025, page 21 / 131 14 / 93 therapeutically effective doses of both therapeutic agents to a patient. The single vehicle is designed to deliver a therapeutically effective amount of each of the agents, along with any pharmaceutically acceptable vehicles or excipients. In some embodiments, the vehicle is a tablet, capsule, pill, or patch. In other embodiments, the vehicle is a solution or suspension.

[0052] When used herein, “poly ADP-ribose glycohydrolase inhibitor” or “PARG inhibitor” means an agent that modulates PARG activity.

[0053] When used herein, “topoisomerase inhibitor” refers to an agent that inhibits topoisomerase activity. Examples of topoisomerase inhibitors include, but are not limited to, doxorubicin, etoposide, epirubicin, novobiocin, ciprofloxacin, and teniposide, and pharmaceutically acceptable salts thereof.

[0054] In one embodiment, provided herein is a combination therapy comprising a therapeutically effective amount of a PARG inhibitor and a topoisomerase inhibitor. A “therapeutically effective amount” of a combination of agents (i.e., a PARG inhibitor and a topoisomerase inhibitor) is an amount sufficient to provide an observable improvement relative to the baseline clinically observable signs and symptoms of the disorders treated with the combination. Observable improvements include those that can be visually verified by a clinician and by biological tests, biopsies, and assays.

[0055] The term alkyl, alone or as part of another substituent, means, unless otherwise stated, a saturated hydrocarbon radical of linear or branched chain having the designated number of carbon atoms (i.e., C1-8 means from one to eight carbons). Alkyl may include any number of carbon atoms. Petition 870250089799, dated 02 / 10 / 2025, page 22 / 131 15 / 93 nos, as C1-2, C1-3, C1-4, C1-5, C1-6, C1-7, C1-8, C1-9, C1-10, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

[0056] The term “Improve” or “improvement” includes the interruption, prevention, reduction or improvement of one or more symptoms, signs and characteristics of the disease being treated, whether temporary or long-term.

[0057] The term cycloalkyl refers to a saturated hydrocarbon ring having the indicated number of atoms in the ring (e.g., C3-6 cycloalkyl). Cycloalkyl is optionally substituted by one, two, or three substituents independently selected from C1-6 alkyl, halo, hydroxyl, C1-6 haloalkyl, C1-6 haloalkoxyl, or cyano, unless otherwise stated. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

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

[0059] The term haloalkyl means alkyl, as defined above, that is substituted by one to five halo atoms and includes monohaloalkyl and polyhaloalkyl. For example, the term C1-4 haloalkyl includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

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

[0061] The term heteroaryl refers to a 5-membered aromatic group containing one to five heteroatoms selected from Petition 870250089799, dated 02 / 10 / 2025, p. 23 / 131 16 / 93 from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group may be attached to the remainder of the molecule via a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furilla, tienila and similar products.

[0062] The term heterocycloalkyl or heterocyclyl refers to a saturated or partially unsaturated monocyclic or bicyclic ring of 4 to 10 members, having one to four heteroatoms independently selected from N, O, and S, the remaining ring atom being carbon. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized, and one or two carbon atoms of the heterocyclic ring may be replaced by the -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, tetrahydrothiophene, and the like. A heterocycloalkyl group may be attached to the rest of the molecule via a ring carbon or a heteroatom.Non-limiting examples of heterocycloalkyl groups include pyridine-2(H)-one.

[0063] The term hydroxyalkyl means alkyl, as defined Petition 870250089799, dated 02 / 10 / 2025, page 24 / 131 17 / 93 above, which is replaced by one or two hydroxyl groups. For example, the term C1-4 hydroxyalkyl includes hydroxymethyl, 1- or 2-hydroxyethyl, 1,2-dihydroxyethyl, hydroxypropyl and the like.

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

[0065] When used herein, “recombinant homologous deficiency (HRD) cancer” refers to a cancer characterized by a reduction or absence of a functional HR repair pathway. HR deficiency can arise from the absence or reduction of one or more genes associated with HR or from the presence of one or more mutations in one or more genes associated with HR.Examples of genes associated with HR include BRCA1, BRCA2, RAD54, RAD51B, ATM, BARD1, CHK1, CHK2, CDK12, RAD51B, RAD54L, RAD51D, PPP22A, BRIP1, CtIP (CtBP-interacting protein), PALB2 (BRCA2 partner and locator), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ-like protein 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, one or more genes associated with HR), Nbs 1 (Nibrin), and genes encoding Fanconi anemia (FA) proteins or FA-like genes, for example, 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 the present description are immunoglobulins and are molecules containing an antigen-binding site that binds immunospecifically to an antigen. The antibody class of the present description may be any of IgG, IgE, IgM, IgD, IgA, and IgY and is preferably Petition 870250089799, dated 02 / 10 / 2025, p. 25 / 131 18 / 93 Primarily IgG. The antibody subclass of the present description may be any one of IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, and is preferably IgG1 or IgG2. The antibody may be derived from any species, and preferred examples of species may include humans, rats, mice, and rabbits. When the antibody is derived from a species other than human, it is preferably chimerized or humanized using a well-known technique. The antibody of the present description may be a polyclonal antibody or a monoclonal antibody. In one embodiment, the antibody is a monoclonal antibody. The antibody of the present description is capable of targeting tumor cells.Since the antibody of the present description is conjugated with an antitumor compound having antitumor activity through a ligand, the antibody preferentially possesses one or more of the following properties: recognizing a tumor cell, binding to a tumor cell, internalizing into a tumor cell, and damaging a tumor cell. In one embodiment, the antibody is a monoclonal antibody reactive with a target antigen or epitope of an antigen expressed on a cancerous or malignant cell. Techniques for preparing monoclonal antibodies against the target antigen are known in the art. Non-limiting target antigens are 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. Combination Product

[0067] Provided here is a combination product comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof. The combination product is useful for the treatment of a variety of cancers, including solid tumors. In a Petition 870250089799, dated 02 / 10 / 2025, page 26 / 131 In the 19 / 93 modality, the disease or disorder is an advanced or metastatic solid tumor. In another aspect, the combination product is useful for the treatment of any number of PARG-associated diseases. In another aspect, the combination product is useful for the treatment of a disease or disorder in which PARG activity is implicated. In another aspect, the combination product is useful for the treatment of a homologous recombinant deficiency (HRD) cancer.

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

[0069] When used herein, the term “combination product” includes embodiments in which the PARG inhibitor and the topoisomerase inhibitor are formulated together in a single pharmaceutical composition (e.g., tablet or capsule), and alternative embodiments in which each therapeutic agent in the combination is formulated individually in its own pharmaceutical composition and each of the pharmaceutical compositions is administered in the same medical treatment (e.g., the same medical treatment for cancer). In this embodiment, each of the pharmaceutical compositions may have the same or different vehicles, diluents, or excipients. The vehicle(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, pharmaceutically formulatable, and 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 contains a topoisomerase inhibitor (suitably selected from Compounds B, C, D, E, F, G or H, or pharmaceutically acceptable salts thereof), the second pharmaceutical composition contains Compound A (or a pharmaceutically acceptable salt thereof) and the first and second Petition 870250089799, dated 02 / 10 / 2025, page 27 / 131 20 / 93 pharmaceutical compositions are both administered to treat cancer. The first and second pharmaceutical compositions can be administered simultaneously, separately, or sequentially, and in any order. Furthermore, it does not matter if the compounds are administered in the same dosage form; for example, one compound can be administered by injection and another compound can be administered orally. PARG inhibitors

[0071] The description provides PARG inhibitors. In one embodiment, the PARG inhibitor is a compound of Formula I: (Formula I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a heteroaryl group with 5 members; X2 is CH or CF; R2 is selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl and cyano; Ring B is a 5- or 6-membered heterocycloalkyl group substituted by Ra, Rb, and Rc; Rae is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxy or -C(O)Rd (where Rd stands for hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rbe Rcsão selected independently from hydrogen, C1-6 alkyl, hydroxy, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

[0072] In some forms, the compound of Formula (I) or a Petition 870250089799, dated 02 / 10 / 2025, page 28 / 131 21 / 93 pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2 is CH or CF; R2 is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, C1-3 hydroxyalkyl and cyano; Ring B is a 5- or 6-membered heterocycloalkyl group substituted by Ra, Rb, and Rc; Rae is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxy or -C(O)Rd (where Rd stands for hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rbe Rcsão are independently selected from C1-6 alkyl, hydrogen, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C16 haloalkoxy.

[0073] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), where X2 is CH. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), where X2 is CF.

[0074] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R1 is cyan.

[0075] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R1 is methyl.

[0076] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), where Ar is 1,2,4-thiadiazolyl or 1,3,4-thiadiazol-2-yl.

[0077] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), where Ar is 1,2,4-thiadiazolyl or 1,3,4-thiadiazol-2-yl.

[0078] In some forms, the compound, or pharmaceutical salt Petition 870250089799, dated 02 / 10 / 2025, p. 29 / 131 22 / 93 most acceptable of the same, is the compound of Formula (I), wherein Ar is 1,2,4-thiadiazolyl.

[0079] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R2 is bonded to the carbon atom of Ar which is meta to the Ar atom which is bonded to the nitrogen atom of the remainder of the molecule.

[0080] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R2 is bonded to Ar, as represented by: or

[0081] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R2 is methyl, ethyl, difluoromethyl, trifluoromethyl or cyano. In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R2 is difluoromethyl.

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

[0083] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Ra is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd (where R is hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rb and Rc are independently selected from hydrogen, C1-6 alkyl, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

[0084] In some forms, the compound, or pharmaceutical salt Petition 870250089799, dated 02 / 10 / 2025, p. 30 / 131 23 / 93 most acceptable of the same, is the compound of Formula (I), wherein Ra is hydrogen, C1-4 alkyl or C1-4 haloalkyl; and Rb and Rc are independently selected from hydrogen and C1-6 alkyl.

[0085] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Ra is hydrogen, C1-4 alkyl, C1-4 haloalkyl or -C(O)Rd (where R is C1-6 alkyl or C1-6 haloalkyl); and Rb and Rc are independently selected from hydrogen, C1-6 alkyl and C1-6 haloalkoxy.

[0086] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Ra is hydrogen; Rb and Rc are each independently hydrogen or C1-6 alkyl.

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

[0088] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound A1: Compound A1. Petition 870250089799, dated 02 / 10 / 2025, p. 31 / 131 24 / 93

[0089] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound A: F H Compound A or a pharmaceutically acceptable salt thereof.

[0090] In another embodiment, the PARG inhibitor is Compound A: F H Compound A.

[0091] The preparation and activity of certain PARG inhibitors provided herein are described in PCT / US20 / 51486 (WO2021 / 055744), the total contents of which are incorporated herein by reference in their entirety.

[0092] The description similarly provides antibody-drug conjugates (ADCs) comprising an antitumor compound conjugated to an antibody via a ligand. In some embodiments, the antibody is a bispecific antibody. In one embodiment, the antitumor compound is a PARG inhibitor. In another embodiment, the antitumor compound is a PARG inhibitor, wherein the inhibitor of Petition 870250089799, dated 02 / 10 / 2025, page 32 / 131 25 / 93 PARG is a compound of Formula I. In one embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is Compound A. In another embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is Compound A1.

[0093] It should be noted that reference to a PARG inhibitor likewise includes reference to its pharmaceutically acceptable salts. In other words, PARG inhibitor is synonymous with PARG inhibitor or a pharmaceutically acceptable salt thereof. Topoisomerase Inhibitors

[0094] The description provides topoisomerase inhibitors for use with a PARG inhibitor. Several agents with topoisomerase inhibitory activity and methods for their production are known in the art. Each of them is covered by this description. In one embodiment, the topoisomerase inhibitor is a type I topoisomerase inhibitor (similarly referred to herein as Topoisomerase I inhibitor). In one embodiment, the topoisomerase inhibitor is a type II topoisomerase inhibitor (similarly referred to herein as topoisomerase II inhibitor). In one embodiment, the type II topoisomerase inhibitor is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt or hydrate thereof. Petition 870250089799, dated 02 / 10 / 2025, page 33 / 131 26 / 93 derived from the group consisting of the compounds in Table 1. The methods of preparation and use of the compounds 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 a pharmaceutically acceptable salt thereof. In another embodiment, the type II topoisomerase inhibitor is doxorubicin or a pharmaceutically acceptable salt thereof.

[0097] In one embodiment, the type I topoisomerase inhibitor is topotecan (Compound H) having the formula: or a pharmaceutically acceptable salt thereof. Methods of preparing topotecan are known in the art. Petition 870250089799, dated 02 / 10 / 2025, page 34 / 131 27 / 93

[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, belotecan or a pharmaceutically acceptable salt thereof.

[0099] It should be noted that reference to a topoisomerase inhibitor likewise includes reference to pharmaceutically acceptable salts thereof. In other words, “topoisomerase inhibitor” is synonymous with “topoisomerase inhibitor or a pharmaceutically acceptable salt thereof”.

[00100] The reference to type II topoisomerase inhibitors in Table 1 is intended to include all versions, for example, salts, including pharmaceutically acceptable salts, polymorphs and solvates. The reference to type I topoisomerase inhibitors is intended to include all versions, for example, salts, including pharmaceutically acceptable salts, polymorphs and solvates.

[00101] The description in the same form provides antibody-drug conjugates (ADCs) comprising at least two antitumor compounds conjugated to an antibody via a ligand. 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, wherein 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, wherein 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, wherein the PARG inhibitor is a compound of Formula I. In one Petition 870250089799, dated 02 / 10 / 2025, page 35 / 131 In one embodiment, the antitumor compounds are selected from a PARG inhibitor and a Topoisomerase I inhibitor, wherein the PARG inhibitor is Compound A. In another embodiment, the antitumor compounds are selected from a PARG inhibitor and a Topoisomerase II inhibitor. In another embodiment, the antitumor compounds are selected from a PARG inhibitor and a Topoisomerase II inhibitor, wherein the PARG inhibitor is a compound of Formula I. In another embodiment, the antitumor compounds are selected from a PARG inhibitor and a Topoisomerase II inhibitor, wherein the PARG inhibitor is Compound A.

[00102] The description in the same form provides antibody-drug conjugates (ADCs) comprising a topoisomerase inhibitor for use with a PARG inhibitor. Several ADCs comprising a topoisomerase inhibitor and methods for their production are known in the art. Each of them is covered by this description. In one embodiment, the ADC comprising the topoisomerase inhibitor is a Type I topoisomerase inhibitor. In another embodiment, the ADC comprising the topoisomerase inhibitor is fam-trastuzumab deruxtecan-nxki (Compound J). In another embodiment, the ADC comprising the topoisomerase inhibitor is AZD8205. In another embodiment, the ADC comprising the 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. Combinations of PARG inhibitors and topoisomerase inhibitors

[00103] In another aspect, provided herein is a combination product comprising Compound A, or a pharmaceutically acceptable salt thereof, and Compounds B, C, D, E, F or G, or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a combination product comprising Compound A, or Petition 870250089799, dated 02 / 10 / 2025, page 36 / 131 29 / 93 a pharmaceutically acceptable salt thereof, and Compound H, or a pharmaceutically acceptable salt thereof.

[00104] In another aspect, supplied herein is a combination product comprising Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof.

[00105] In another aspect, supplied herein is a combination product comprising Compound A1, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof.

[00106] In another aspect, provided herein is a combination product comprising Compound A, or a pharmaceutically acceptable salt thereof, and Compound H, or a pharmaceutically acceptable salt thereof.

[00107] In another aspect, supplied herein is a combination product comprising Compound A1, or a pharmaceutically acceptable salt thereof, and Compound H, or a pharmaceutically acceptable salt thereof.

[00108] In another aspect, supplied herein is 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.

[00109] In another aspect, supplied herein is 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.

[00110] Administration of a pharmaceutical combination provided here may result in a beneficial effect, for example, an effect Petition 870250089799, dated 02 / 10 / 2025, page 37 / 131 30 / 93 synergistic therapeutic, for example, with regard to the relief, slowing of progression or inhibition of symptoms, and may likewise result in other surprising beneficial effects, for example, fewer side effects, a better quality of life or a decrease in morbidity, compared to monotherapy applying only one of the pharmaceutically active ingredients used in the combination described. Treatment Methods

[00111] In one embodiment, provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a PARG inhibitor and administering to the individual a therapeutically effective amount of a topoisomerase inhibitor, thereby treating the cancer in the individual.

[00112] In one embodiment, methods provided herein are for treating cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, together with at least one pharmaceutically acceptable vehicle, thereby treating the cancer in the individual.

[00113] In one embodiment, methods provided herein are for treating and / or preventing a recombinant homologous deficient (HRD) cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the individual. In one embodiment, methods provided herein are for treating a recombinant homologous deficient (HRD) cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and Petition 870250089799, dated 02 / 10 / 2025, page 38 / 131 31 / 93 is a topoisomerase inhibitor, thus treating cancer in the individual.

[00114] In one embodiment, methods are provided herein for treating and / or preventing a recombinant homologous deficient (HRD) cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least one pharmaceutically acceptable vehicle, thereby treating and / or preventing the cancer in the individual. In one embodiment, the recombinant homologous deficient cancer is breast cancer.In one embodiment, the cancer with recombinant homolog deficiency is ovarian cancer.

[00115] In one embodiment, methods provided herein are for treating and / or preventing cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing cancer in the individual, wherein the cancer is a homologous recombinant deficiency (HRD) cancer and is estrogen receptor (ER) positive. In another embodiment, methods provided herein are for treating cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating cancer in the individual, wherein the cancer is a Petition 870250089799, dated 02 / 10 / 2025, page 39 / 131 32 / 93 with recombinant homologous deficiency (HRD) and is positive for the Estrogen Receptor (ER).

[00116] In one embodiment, methods provided herein are for treating and / or preventing cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing cancer in the individual, wherein the cancer is a recombinant homologous deficiency (HRD) cancer, is positive for the Estrogen Receptor (ER) and is optionally positive for the Progesterone Receptor (PR). In another embodiment, methods provided herein are for treating cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating cancer in the individual, wherein the cancer is an HRD cancer, is positive for ER and, optionally, positive for the Progesterone Receptor (PR).

[00117] In one embodiment, methods provided herein are for treating and / or preventing cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing cancer in the individual, wherein the cancer is HRD cancer, is ER-positive and optionally negative for human epidermal growth factor receptor 2 (HER2). In another embodiment, methods provided herein are for treating cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating cancer in the individual, wherein the cancer is HRD cancer, is ER-positive and optionally negative Petition 870250089799, dated 02 / 10 / 2025, page 40 / 131 33 / 93 active for human epidermal growth factor receptor 2 (HER2).

[00118] In one embodiment, methods provided herein are for treating and / or preventing cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing cancer in the individual, wherein the cancer is HRD cancer, is ER positive, is optionally PR positive and is optionally HER2 negative. In one embodiment, the cancerous tumor is a breast or ovarian cancer tumor.

[00119] In one embodiment, methods provided herein are for treating and / or preventing breast cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing cancer in the individual, wherein the cancer is HRD cancer, is ER positive, is optionally PR positive and is optionally HER2 negative. In another embodiment, methods provided herein are for treating breast cancer in an individual in need thereof, the methods comprising administering to the individual a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating cancer in the individual, wherein the cancer is HRD cancer, is ER positive, is optionally PR positive and is optionally Petition 870250089799, dated 02 / 10 / 2025, page 41 / 131 34 / 93 te HER2 negative.

[00120] 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, renal cancer, kidney cancer, urothelial cancer, melanoma, liver cancer, bladder cancer, stomach cancer, carcinoma, lymphoma, glioblastoma, sarcoma, leukemia, myeloma, or lymphoid malignancies.

[00121] In another modality, the cancer is characterized by a reduction or absence of gene expression of BRCA1 and / or BRCA2, an absence or mutation of the BRCA1 and / or BRCA2 genes, or a reduced function of the BRCA1 and / or BRCA2 proteins, or a combination thereof.

[00122] In one embodiment, methods provided herein are for treating cancer in an individual in need thereof, the methods comprising administering to the individual 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 cancer in the individual.

[00123] In one embodiment, the use of a combination of a PARG inhibitor and a topoisomerase inhibitor for the manufacture of a medicament 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 medicament is provided. In one embodiment, the topoisomerase inhibitor is Compound Petition 870250089799, dated 02 / 10 / 2025, p. 42 / 131 35 / 93 to H. In one embodiment, the use of a combination of Compound A and Compound H for the manufacture of a medicament is provided. In another 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 medicament is provided.

[00124] In another embodiment, the use of a combination of a PARG inhibitor and a topoisomerase inhibitor is provided 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 is provided for the treatment of cancer. In one embodiment, the use of a combination of Compound A and Compound H is provided for the treatment of cancer. In one embodiment, the use of a combination of Compound A and Compound C, Compound D, Compound E, Compound F, or Compound G is provided for the treatment of cancer.

[00125] In one embodiment, the PARG inhibitor is a compound of Formula I: (Formula I) or a pharmaceutically acceptable salt thereof; wherein the variables are defined above.

[00126] In another embodiment, the PARG inhibitor is Compound A1, or a pharmaceutically acceptable salt thereof.

[00127] In another embodiment, the PARG inhibitor is Compound A, or a pharmaceutically acceptable salt thereof.

[00128] In one embodiment, the topoisomerase inhibitor is selected Petition 870250089799, dated 02 / 10 / 2025, page 43 / 131 36 / 93 derived from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt or hydrate thereof.

[00129] In another embodiment, the topoisomerase inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

[00130] In another embodiment, the topoisomerase inhibitor is the Compound H or a pharmaceutically acceptable salt thereof.

[00131] In another embodiment, the topoisomerase inhibitor is the Compound C, Compound D, Compound E, Compound F, or Compound G, or a pharmaceutically acceptable salt thereof.

[00132] In another aspect, provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the individual a therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof.

[00133] In another aspect, provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the individual a therapeutically effective amount of Compound H or a pharmaceutically acceptable salt thereof.

[00134] In another aspect, provided herein is a method for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the individual a therapeutically effective amount of Compound C, Compound D, Compound E, Compound F, Compound G or a pharmaceutically acceptable salt thereof. Petition 870250089799, dated 02 / 10 / 2025, page 44 / 131 37 / 93

[00135] In another embodiment, a product is provided that includes 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 that includes Compound A and Compound B as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, a product is provided that includes Compound A and Compound H as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, a product is provided that includes 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 medicine.

[00136] In another embodiment, a product is provided that includes a PARG inhibitor and a topoisomerase inhibitor as a combination product for simultaneous, separate, or sequential use in the treatment of cancer in an individual. 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 that includes Compound A and Compound B as a combination product for simultaneous, separate, or sequential use in the treatment of cancer in an individual. In one embodiment, a product is provided that includes Compound A and Compound H as a combination product for simultaneous, separate, or sequential use in the treatment of cancer in an individual. In one embodiment, a product is provided that includes 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 cancer in an individual. Petition 870250089799, dated 02 / 10 / 2025, page 45 / 131 38 / 93

[00137] In yet another modality, the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, and esophageal cancer. In one modality, the cancer is ovarian, gastric, or breast cancer. In one modality, the cancer is lung, cervical, or pancreatic cancer. In one modality, the cancer is prostate cancer.

[00138] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is endometrial cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is non-small cell lung cancer (NSCLC). In one embodiment, the cancer is small cell lung cancer. In one embodiment, the cancer is renal cancer, kidney cancer, urothelial cancer, melanoma, liver cancer, bladder cancer, stomach cancer, carcinoma, lymphoma, glioblastoma, sarcoma, leukemia, myeloma, or lymphoid malignancies.

[00139] In another modality, the cancer is metastatic. In one modality, the disease or disorder is an advanced or metastatic solid tumor.

[00140] In another sense, cancer is a solid malignant tumor.

[00141] In one embodiment, the PARG inhibitor and the topoisomerase inhibitor are in separate dosage forms. In another embodiment, the PARG inhibitor and the topoisomerase inhibitor are in the same dosage form.

[00142] In another embodiment, the treatment comprises the administration of the PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, substantially at the same time. In another embodiment, the treatment comprises the administration of the PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the inhibitor Petition 870250089799, dated 02 / 10 / 2025, page 46 / 131 39 / 93 topoisomerase pain, or a pharmaceutically acceptable salt thereof, at different times.

[00143] In another embodiment, the PARG inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the individual, followed by the administration of the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof. In one embodiment, the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the individual, followed by the administration of the PARG inhibitor, or a pharmaceutically acceptable salt thereof.

[00144] In one embodiment, the PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, are administered orally.

[00145] In one aspect, supplied herein is a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, for use in therapy.

[00146] In one embodiment, the PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, are for use in the treatment of cancer in an individual in need thereof.

[00147] In one embodiment of the methods, the method involves administering a therapeutically effective amount of a combination or composition comprising the compounds provided herein, or pharmaceutically acceptable salts thereof, to an individual (including, but not limited to, a human or animal) in need of treatment (including an individual identified as needy).

[00148] In another modality of the methods, the treatment includes the co-administration of the amount of PARG inhibitor, or a pharmaceutical salt Petition 870250089799, dated 02 / 10 / 2025, page 47 / 131 40 / 93 pharmaceutically acceptable quantity thereof, and quantity of topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof. In one embodiment, the quantity of PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the quantity of topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, are in a single formulation or unit dosage form. In other embodiments, the quantity of PARG inhibitor or a pharmaceutically acceptable salt thereof and the quantity of topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are in separate formulations or unit dosage forms.

[00149] In the previous methods, treatment may include 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 at the same time, or administering an amount of 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 foregoing methods, the amount of PARG inhibitor or a pharmaceutically acceptable salt thereof and / or the amount of topoisomerase inhibitor or a pharmaceutically acceptable salt thereof is administered in dosages that would not be effective when the PARG inhibitor or a pharmaceutically acceptable salt thereof, or the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, were administered alone, but whose amounts are effective in combination.

[00150] In another embodiment of the methods, the treatment includes the co-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 a mode Petition 870250089799, dated 02 / 10 / 2025, page 48 / 131 41 / 93 In embodiments, the quantity of Compound A, or of a pharmaceutically acceptable salt thereof, and the quantity of Compound B, or of a pharmaceutically acceptable salt thereof, are in a single formulation or unit dosage form. In still other embodiments, the quantity of Compound A, or of a pharmaceutically acceptable salt thereof, and the quantity of Compound B, or of a pharmaceutically acceptable salt thereof, are in separate formulations or unit dosage forms.

[00151] In the previous methods, treatment may include administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound B, or a pharmaceutically acceptable salt thereof, substantially at the same time, or administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound B, or a pharmaceutically acceptable salt thereof, at different times. In some embodiments of the previous methods, the amount of Compound A, or a pharmaceutically acceptable salt thereof, and / or the amount of Compound B, or a pharmaceutically acceptable salt thereof, is administered in dosages that would not be effective when one or both, Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt thereof, were administered alone, but whose amounts are effective in combination.

[00152] In another embodiment of the methods, the treatment includes the co-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 amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound H or a pharmaceutically acceptable salt Petition 870250089799, dated 02 / 10 / 2025, page 49 / 131 42 / 93 pharmaceutically acceptable amounts thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound H or a pharmaceutically acceptable salt thereof are in separate formulations or unit dosage forms.

[00153] In the above methods, treatment may include administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound H or a pharmaceutically acceptable salt thereof substantially at the same time or administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound H or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the above methods, the amount of Compound A or a pharmaceutically acceptable salt thereof and / or the amount of Compound H or a pharmaceutically acceptable salt thereof is administered in dosages that would not be effective when either or both Compound A or a pharmaceutically acceptable salt thereof and Compound H or a pharmaceutically acceptable salt thereof were administered alone, but which are effective in combination. Non-Limiting Exemplary Modalities:

[00154] In other categories 1 to 93 below, the present description includes:

[00155] Embodiment 1. In one embodiment, a method is provided for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor and administering to the individual a therapeutically effective amount of a topoisomerase inhibitor. Petition 870250089799, dated 02 / 10 / 2025, page 50 / 131 43 / 93

[00156] Embodiment 1A. In embodiment 1A, a method is provided for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a poly ADP-ribose glycohydrolase (PARG) inhibitor and administering to the individual a therapeutically effective amount of an antibody-drug conjugate (ADC) comprising a topoisomerase inhibitor.

[00157] Embodiment 1A1. In embodiment 1A1, a method is provided according to embodiment 1A, wherein the ADC comprises a topoisomerase inhibitor, which is a Type I topoisomerase inhibitor.

[00158] Embodiment 1A2. In embodiment 1A2, a method is provided in accordance with embodiment 1A, wherein the ADC comprising the topoisomerase inhibitor is fam-trastuzumab deruxtecan-nxki.

[00159] Embodiment 1A3. In embodiment 1A3, a method is provided according to embodiment 1A, wherein the ADC comprising the topoisomerase inhibitor is AZD8205.

[00160] Embodiment 1A4. In embodiment 1A4, a method is provided in accordance with embodiment 1A, wherein the ADC comprising the topoisomerase inhibitor is DS-1062 (also known as datopotamab deruxtecan).

[00161] Embodiment 2. In one embodiment, a method is provided for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a poly ADP-ribose glycohydrolase (PARG) inhibitor, wherein the individual is concomitantly receiving a topoisomerase inhibitor.

[00162] Modality 2A. In modality 2A, a method is provided for treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a poly ADP-ribose glycohydrolase inhibitor. Petition 870250089799, dated 02 / 10 / 2025, page 51 / 131 44 / 93 (PARG), in which the individual simultaneously receives an antibody-drug conjugate (ADC) comprising a topoisomerase inhibitor.

[00163] Embodiment 2A1. In embodiment 2A1, a method of embodiment 2A is provided, in which the ADC comprising a topoisomerase inhibitor is an ADC comprising a Type I topoisomerase inhibitor.

[00164] Modality 2A2. In modality 2A2, a method of modality 2A is provided, in which the ADC comprising the topoisomerase inhibitor is fam-trastuzumab deruxtecan-nxki.

[00165] Modality 2A3. In Modality 2A3, a method is provided according to Modality 2A, wherein the ADC comprising the topoisomerase inhibitor is AZD8205.

[00166] Modality 2A4. In Modality 2A4, a method is provided according to Modality 2A, wherein the ADC comprising the topoisomerase inhibitor is DS-1062 (similarly known as datopotamab deruxtecan).

[00167] Embodiment 3. In one embodiment, a method is provided for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor, wherein the individual has received treatment with a topoisomerase inhibitor.

[00168] Modality 3A. In Modality 3A, a method is provided for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor, wherein the individual has received treatment with an antibody-drug conjugate (ADC) comprising a topoisomerase inhibitor. Petition 870250089799, dated 02 / 10 / 2025, page 52 / 131 45 / 93

[00169] Embodiment 3A1. In Embodiment 3A1, a method is provided according to Embodiment 3A, wherein the ADC comprising a topoisomerase inhibitor is an ADC comprising a Type I topoisomerase inhibitor.

[00170] Modality 3A2. In Modality 3A2, a method is provided in accordance with Modality 3A, wherein the ADC comprising the topoisomerase inhibitor is fam-trastuzumab deruxtecan-nxki.

[00171] Modality 3A3. In modality 3A3, a method of modality 3A is provided, in which the ADC comprising the topoisomerase inhibitor is AZD8205.

[00172] Embodiment 3A4. In embodiment 3A4, a method is provided in accordance with embodiment 3A, wherein the ADC comprising the topoisomerase inhibitor is DS-1062 (also known as datopotamab deruxtecan).

[00173] Embodiment 4. In embodiment 4, the method is provided according to any of embodiments 1 to 3, wherein the PARG inhibitor is a compound of Formula I: R24- Air IBJ (Formula I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a heteroaryl group with 5 members; X2 is CH or CF; R2 is selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl and cyano; Ring B is a substituted 5- or 6-membered heterocycloalkyl group. Petition 870250089799, dated 02 / 10 / 2025, page 53 / 131 46 / 93 by Ra, Rbe Rc; Rae is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxy or -C(O)Rd (where Rd stands for hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rbe Rcsão are independently selected from hydrogen, C1-6 alkyl, hydroxy, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

[00174] Modality 5. In modality 5, the method is provided according to modality 4, in which R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2 is CH or CF; R2 is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, C1-3 hydroxyalkyl and cyano; Ring B is a 5- or 6-membered heterocycloalkyl group substituted by Ra, Rb, and Rc; Rae is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxy or -C(O)Rd (where Rd stands for hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rbe Rcsão are independently selected from C1-6 alkyl, hydrogen, hydroxy, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

[00175] Mode 6. In mode 6, the method is provided according to mode 4 or 5, where X2 is CH.

[00176] Mode 7. In mode 7, the method is provided according to mode 4 or 5, where X2 is CF.

[00177] Modality 8. In embodiment 8, the method is provided according to any of embodiments 4 to 7, where R1 is methyl.

[00178] Mode 9. In mode 9, the method is provided according to any of modes 4 to 7, where R1 is cyan.

[00179] Mode 10. In mode 10, the method is provided of Petition 870250089799, dated 02 / 10 / 2025, p. 54 / 131 47 / 93 in accordance with any of the modalities 4 to 9, where Ar is 1,2,4-thiadiazolyl or 1,3,4-thiadiazol-2-yl.

[00180] Embodiment 11. In Embodiment 11, the method is provided according to any of the embodiments 4 to 10, where Ar is 1,3,4-thiadiazol-2-yl.

[00181] Modality 12. In Modality 12, the method is provided according to any of the modalities 4 to 10, where Ar is 1,2,4-thiadiazolyl.

[00182] Modality 13. In Modality 13, the method is provided according to any of the modalities 4 to 12, wherein R2 is bonded to the carbon atom of Ar which is meta to the Ar atom which is bonded to the nitrogen atom of the remainder of the molecule.

[00183] Embodiment 14. In embodiment 14, the method is provided according to any of embodiments 4 to 13, wherein R2 is methyl, ethyl, difluoromethyl, trifluoromethyl, cyano.

[00184] Embodiment 15. In embodiment 15, the method is provided according to any of embodiments 4 to 14, wherein R2 is difluoromethyl.

[00185] Embodiment 16. In embodiment 16, the method is provided 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.

[00186] Embodiment 17. In embodiment 17, the method is provided according to any of embodiments 4 to 16, wherein ring B is piperazinyl.

[00187] Embodiment 18. In embodiment 18, the method is provided according to any one of embodiments 4 to 17, wherein Ra is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd (where R is hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rb and Rc are independently selected from C1-6 alkyl, hydrogen, hydro Petition 870250089799, dated 02 / 10 / 2025, p. 55 / 131 48 / 93 xyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

[00188] Embodiment 19. In Embodiment 19, the method is provided according to any one of embodiments 4 to 17, wherein Ra is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd (where R is hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rb and Rc are independently selected from hydrogen, C1-6 alkyl, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

[00189] Embodiment 20. In Embodiment 20, the method is provided according to any one of embodiments 4 to 17, wherein Ra is hydrogen, C1-4 alkyl or C1-4 haloalkyl; and Rb and Rc are independently selected from hydrogen and C1-6 alkyl.

[00190] Embodiment 21. In embodiment 21, the method is provided according to any one of embodiments 4 to 17, wherein Ra is hydrogen or C1-4 alkyl; and Rb and Rc are independently selected from C1-6 alkyl and hydrogen.

[00191] Embodiment 22. In embodiment 22, the method is provided according to any one of embodiments 4 to 17, wherein Ra is hydrogen; Rb and Rcsion, each independently C1-6 alkyl or hydrogen.

[00192] Embodiment 23. In embodiment 23, the method is provided in accordance with any of embodiments 4 to 22, wherein the PARG inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof.

[00193] Embodiment 24. In embodiment 24, the method is provided in accordance with any of embodiments 4 to 23, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

[00194] Embodiment 25. In Embodiment 25, the method is provided according to any of the embodiments 4 to 24, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. Petition 870250089799, dated 02 / 10 / 2025, p. 56 / 131 49 / 93

[00195] Embodiment 25A. In Embodiment 25A, the method according to embodiment 25 is provided, wherein the topoisomerase I inhibitor is Compound H or a pharmaceutically acceptable salt or hydrate thereof.

[00196] Embodiment 26. In Embodiment 26, the method is provided according to any of the embodiments 4 to 24, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

[00197] Embodiment 27. In Embodiment 27, the method according to Embodiment 26 is provided, 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 a pharmaceutically acceptable salt or hydrate thereof.

[00198] Embodiment 28. In Embodiment 28, the method is provided according to Embodiment 27, wherein the topoisomerase II inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

[00199] Modality 29. In Modality 29, the method is provided according to any of the modalities 1 to 28, wherein the cancer is a homologous recombinant deficiency (HRD) cancer.

[00200] Modality 30. In Modality 30, the method is provided according to any of the modalities 1 to 29, in which the cancer is characterized by a reduction or absence of BRCA1 gene expression, an absence or mutation of the BRCA1 genes, or a reduced function of the BRCA1 proteins.

[00201] Modality 31. In Modality 31, the method is provided according to any of the modalities 1 to 30, in which the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of the BRCA2 genes, or a reduced function of the BRCA2 proteins.

[00202] Modality 32. In Modality 32, the method is provided according to any of the modalities 1 to 31, in which the cancer is Petition 870250089799, dated 02 / 10 / 2025, page 57 / 131 50 / 93 Positive ER.

[00203] Mode 33. In Mode 33, the method is provided according to any of the modes 1 to 32, in which the cancer is PR positive.

[00204] Mode 34. In Mode 34, the method is provided according to any of the modes 1 to 33, in which the cancer is HER2 negative.

[00205] Modality 35. In Modality 35, the method is provided according to any of the modalities 1 to 34, where the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and prostate cancer.

[00206] Modality 35A. In Modality 35A, the method is provided according to any of the modalities 1 to 34, where 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.

[00207] Modality 36. In modality 36, the method is provided according to any of the modalities 1 to 35, where the cancer is breast cancer or ovarian cancer.

[00208] Embodiment 37. In embodiment 37, the method is provided according to any of embodiments 1 to 36, wherein the PARG inhibitor and the topoisomerase inhibitor are in separate dosage forms.

[00209] Modality 38. In modality 38, the method is provided according to any of the modalities 1 to 36, in which the PARG inhibitor and the topoisomerase inhibitor are in the same dosage form.

[00210] Modality 39. In modality 39, a product is provided. Petition 870250089799, dated 02 / 10 / 2025, page 58 / 131 51 / 93 combination comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[00211] Embodiment 40. In embodiment 40, the PARG inhibitor according to embodiment 39 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[00212] Embodiment 41. In embodiment 41, the PARG inhibitor according to embodiment 40 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of embodiments 4 to 22.

[00213] Embodiment 42. In embodiment 42, the PARG inhibitor according to embodiment 39 or 40 is Compound A1 or a pharmaceutically acceptable salt thereof.

[00214] Embodiment 43. In embodiment 43, the PARG inhibitor according to embodiment 39 or 40 is Compound A or a pharmaceutically acceptable salt thereof.

[00215] Modality 44. In Modality 44, the topoisomerase inhibitor according to any of the embodiments 39 to 43 is a type I topoisomerase inhibitor.

[00216] Embodiment 44A. In Embodiment 44A, the topoisomerase inhibitor of Embodiment 44 is Compound H or a pharmaceutically acceptable salt or hydrate thereof.

[00217] Modality 44B. In Modality 44A, the topoisomerase inhibitor of Modality 44 is 10-hydroxycamptothecin, irinotecan and topotecan, hexylresorcinol, exatecan, deruxtecan, belotecan or a pharmaceutically acceptable salt thereof.

[00218] Modality 45. In Modality 45, the topoisomerase inhibitor according to any of the embodiments 39 to 43 is a type II topoisomerase inhibitor.

[00219] Mode 46. In mode 46, the topoisothiazolinone inhibitor Petition 870250089799, dated 02 / 10 / 2025, page 59 / 131 52 / 93 according to embodiment 45 is Compound B, Compound C, Compound D, Compound E, Compound F or Compound G, or a pharmaceutically acceptable salt thereof.

[00220] Embodiment 47. In embodiment 47, the topoisomerase inhibitor according to embodiment 46 is Compound B or a pharmaceutically acceptable salt thereof.

[00221] Embodiment 48. In embodiment 48, a combination product is provided comprising a first 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.

[00222] Embodiment 49. In embodiment 49, the PARG inhibitor of embodiment 48 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[00223] Embodiment 50. In Embodiment 50, the PARG inhibitor according to embodiment 49 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of embodiments 4 to 22.

[00224] Embodiment 51. In Embodiment 51, the PARG inhibitor according to embodiment 48 or 49 is Compound A1, or a pharmaceutically acceptable salt thereof.

[00225] Embodiment 52. In Embodiment 52, the PARG inhibitor according to embodiment 48 or 49 is Compound A, or a pharmaceutically acceptable salt thereof.

[00226] Modality 53. In Modality 53, the topoisomerase inhibitor according to any of the embodiments 48 to 52 is a type I topoisomerase inhibitor.

[00227] Modality 53A. In modality 53A, the topoisomerase inhibitor according to modality 53 is Compound H or a Petition 870250089799, dated 02 / 10 / 2025, page 60 / 131 53 / 93 salt or pharmaceutically acceptable carbohydrate thereof.

[00228] Modality 54. In embodiment 54, the topoisomerase inhibitor according to any of embodiments 48 to 52 is a type II topoisomerase inhibitor.

[00229] Embodiment 55. In embodiment 55, the topoisomerase inhibitor according to embodiment 54 is Compound B, Compound C, Compound D, Compound E, Compound F or Compound G, or a pharmaceutically acceptable salt thereof.

[00230] Embodiment 56. In embodiment 56, the topoisomerase inhibitor according to embodiment 55 is Compound B or a pharmaceutically acceptable salt thereof.

[00231] Embodiment 57. In embodiment 57, a combination product is supplied 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.

[00232] Embodiment 57A. In embodiment 57A, a combination product is supplied 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.

[00233] Modality 58. In embodiment 58, a PARG inhibitor is provided for use in the treatment of cancer, wherein the PARG inhibitor must be administered simultaneously or sequentially with a topoisomerase inhibitor.

[00234] Modality 59. In modality 59, the PARG inhibitor of Petition 870250089799, dated 02 / 10 / 2025, page 61 / 131 54 / 93 modality 58 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[00235] Embodiment 60. In embodiment 60, the PARG inhibitor of embodiment 59 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of embodiments 4 to 22.

[00236] Embodiment 61. In embodiment 61, the PARG inhibitor of embodiment 58 or 59 is Compound A1, or a pharmaceutically acceptable salt thereof.

[00237] Embodiment 62. In embodiment 62, the PARG inhibitor of embodiment 58 or 59 is Compound A, or a pharmaceutically acceptable salt thereof.

[00238] Modality 63. In embodiment 63, the topoisomerase inhibitor according to any of embodiments 58 to 62 is a type I topoisomerase inhibitor.

[00239] Embodiment 63A. In embodiment 63A, the topoisomerase inhibitor according to embodiment 63 is Compound H or a pharmaceutically acceptable salt or hydrate thereof.

[00240] Modality 64. In embodiment 64, the topoisomerase inhibitor according to any of embodiments 58 to 62 is a type II topoisomerase inhibitor.

[00241] Embodiment 65. In embodiment 65, the topoisomerase inhibitor according to embodiment 64 is Compound B, Compound C, Compound D, Compound E, Compound F or Compound G, or a pharmaceutically acceptable salt thereof.

[00242] Embodiment 66. In embodiment 66, the topoisomerase inhibitor according to embodiment 65 is Compound B or a pharmaceutically acceptable salt thereof.

[00243] Modality 67. In modality 67, a PARG inhibitor is provided for use in the treatment of cancer, wherein the inhibitor of Petition 870250089799, dated 02 / 10 / 2025, page 62 / 131 55 / 93 PARG should be administered simultaneously 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.

[00244] Embodiment 67A. In embodiment 67A, a PARG inhibitor is provided for use in the treatment of cancer, wherein the PARG inhibitor is to be administered simultaneously 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.

[00245] Modality 68. In modality 68, the use of any of the modalities 58 to 67 is provided, where the cancer is a homologous recombinant deficiency (HRD) cancer.

[00246] Modality 69. In modality 69, the use of any of the modalities 58 to 68 is provided, in which the cancer is characterized by a reduction or absence of BRCA1 gene expression, an absence or mutation of BRCA1, or a reduced function of BRCA1 proteins.

[00247] Modality 70. In Modality 70, the use of any of the modalities 58 to 69 is provided, in which the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of the BRCA2 genes, or a reduced function of the BRCA2 proteins.

[00248] Mode 71. In Mode 71, the use of any of the modes 58 to 70 is provided, where the cancer is ER positive.

[00249] Mode 72. In Mode 72, the use of any of the modes 58 to 71 is provided, in which the cancer is PR positive. Petition 870250089799, dated 02 / 10 / 2025, page 63 / 131 56 / 93 vol.

[00250] Mode 73. In Mode 73, the use of any of the modes 58 to 72 is provided, in which the cancer is HER2 negative.

[00251] Modality 74. In modality 74, the use of any of the modalities 58 to 73 is provided, where the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and prostate cancer.

[00252] Modality 74A. In modality 74A, the use of any of the modalities 58 to 73 is provided, where 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.

[00253] Modality 75. In modality 75, the use of any of the modalities 58 to 74 is provided, where the cancer is breast cancer or ovarian cancer.

[00254] Embodiment 76. In embodiment 76, the use of a PARG inhibitor in the manufacture of a cancer treatment drug is provided, wherein the PARG inhibitor must be administered simultaneously or sequentially with a topoisomerase inhibitor.

[00255] Embodiment 77. In embodiment 77, the PARG inhibitor of embodiment 76 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[00256] Embodiment 78. In embodiment 78, the PARG inhibitor of embodiment 77 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined in any of embodiments 4 to 22.

[00257] Modality 79. In embodiment 79, the PARG inhibitor of embodiment 76 or 77 is Compound A1, or a pharmaceutically available salt. Petition 870250089799, dated 02 / 10 / 2025, page 64 / 131 57 / 93 acceptable of the same.

[00258] Embodiment 80. In Embodiment 80, the PARG inhibitor according to embodiment 76 or 77 is Compound A, or a pharmaceutically acceptable salt thereof.

[00259] Modality 81. In Modality 81, the topoisomerase inhibitor according to any of the embodiments 76 to 80 is a type I topoisomerase inhibitor.

[00260] Embodiment 81A. In Embodiment 81A, the topoisomerase inhibitor of Embodiment 81 is Compound H or a pharmaceutically acceptable salt or hydrate thereof.

[00261] Modality 82. In Modality 82, the topoisomerase inhibitor according to any of the embodiments 76 to 80 is a type II topoisomerase inhibitor.

[00262] Embodiment 83. In Embodiment 83, the topoisomerase inhibitor of Embodiment 82 is Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G, or a pharmaceutically acceptable salt thereof.

[00263] Embodiment 84. In embodiment 84, the topoisomerase inhibitor of embodiment 83 is Compound B or a pharmaceutically acceptable salt thereof.

[00264] Embodiment 85. In embodiment 85, a use of a PARG inhibitor is provided in the manufacture of a cancer treatment drug, wherein the PARG inhibitor is to be administered simultaneously 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.

[00265] Embodiment 85A. In embodiment 85A, a use of a PARG inhibitor is provided in the manufacture of a cancer treatment drug, wherein the PARG inhibitor must be administered Petition 870250089799, dated 02 / 10 / 2025, page 65 / 131 58 / 93 simultaneously 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.

[00266] Modality 86. In modality 86, the use of any of the modalities 76 to 85A is provided, where the cancer is a homologous recombinant deficiency (HRD) cancer.

[00267] Modality 87. In modality 87, the use of any of the modalities 76 to 86 is provided, in which the cancer is characterized by a reduction or absence of BRCA1 gene expression, an absence or mutation of the BRCA1 genes, or a reduced function of the BRCA1 proteins.

[00268] Modality 88. In Modality 88, the use of any of the modalities 76 to 87 is provided, in which the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of the BRCA2 genes, or a reduced function of the BRCA2 proteins.

[00269] Mode 89. In Mode 89, the use of any of the modes 76 to 88 is provided, where the cancer is ER positive.

[00270] Mode 90. In Mode 90, the use of any of the modes 76 to 89 is provided, in which the cancer is PR positive.

[00271] Mode 91. In Mode 91, the use of any of the modes 76 to 90 is provided, in which the cancer is HER2 negative.

[00272] Modality 92. In modality 92, the use of any of the modalities 76 to 91 is provided, where the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer. Petition 870250089799, dated 02 / 10 / 2025, page 66 / 131 59 / 93 (NSCLC) and prostate cancer.

[00273] Modality 92A. In modality 92A, the use of any of the modalities 76 to 91 is provided, where 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.

[00274] Modality 93. In modality 93, the use of any of the modalities 76 to 92 is provided, where the cancer is breast cancer or ovarian cancer.

[00275] For the above modalities, when reference is made to previous modalities, the reference will include those modalities having letter notations or combinations. For example, the reference to modalities 1 to 3 will include modalities 1, 1A, 1A1, 1A2, 1A3, 1A4, 2, 2A, 2A1, 2A2, 2A3, 2A4, 3, 3A, 3A1, 3A2, 3A3 and 3A4. Additional Non-Limiting Exemplary Modalities:

[00276] Embodiment 1. In embodiment 1, a method is provided for treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a PARG inhibitor and administering to the individual a therapeutically effective amount of a topoisomerase inhibitor, wherein the PARG inhibitor is a compound of Formula I: r24- Air IBJ (Formula I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Petition 870250089799, dated 02 / 10 / 2025, page 67 / 131 60 / 93 Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2 is CH or CF; R2 is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, C1-3 hydroxyalkyl and cyano; Ring B is a 5- or 6-membered heterocycloalkyl group substituted by Ra, Rb, and Rc; Rae is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd (where Rd stands for hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rbe Rcsão are independently selected from C1-6 alkyl, hydrogen, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C16 haloalkoxy.

[00277] Modality 2. In modality 2, the method is provided according to modality 1, where X2 is CH.

[00278] Modality 3. In modality 3, the method is provided according to modality 1 or 2, where R1 is methyl.

[00279] Mode 4. In mode 4, the method is provided according to mode 1 or 2, where R1 is cyan.

[00280] Modality 5. In embodiment 5, the method is provided according to any of embodiments 1 to 4, wherein Ar is 1,3,4-thiadiazol-2-yl.

[00281] Modality 6. In embodiment 6, the method is provided according to any of embodiments 1 to 5, wherein R2 is bonded to the carbon atom of Ar which is meta to the Ar atom which is bonded to the nitrogen atom of the remainder of the molecule.

[00282] Embodiment 7. In embodiment 7, the method is provided according to any one of embodiments 1 to 6, wherein R2 is methyl, ethyl, difluoromethyl, trifluoromethyl or cyano.

[00283] Embodiment 8. In embodiment 8, the method is provided according to any of embodiments 1 to 7, where R2 is difluoromethyl. Petition 870250089799, dated 02 / 10 / 2025, p. 68 / 131 61 / 93

[00284] Embodiment 9. In embodiment 9, the method is provided 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.

[00285] Embodiment 10. In embodiment 10, the method is provided according to any of embodiments 1 to 9, wherein ring B is piperazinyl.

[00286] Embodiment 11. In Embodiment 11, the method is provided according to any one of embodiments 1 to 10, wherein Ra is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd (where R is hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rb and Rc are independently selected from C1-6 alkyl, hydrogen, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

[00287] Embodiment 12. In Embodiment 12, the method is provided according to any one of embodiments 1 to 11, wherein Ra is hydrogen, C1-4 alkyl or C1-4 haloalkyl; and Rb and Rc are independently selected from C1-6 alkyl and hydrogen.

[00288] Embodiment 13. In embodiment 13, the method is provided according to any of embodiments 1 to 12, wherein Ra is hydrogen; Rb and Rcsion, each independently, C1-6 alkyl or hydrogen.

[00289] Embodiment 14. In embodiment 14, the method is provided in accordance with any of embodiments 1 to 13, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

[00290] Embodiment 15. In embodiment 15, the method is provided according to any one of claims 1 to 14, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

[00291] Modality 16. In Modality 16, the method is provided according to any of the modalities 1 to 15, where the inhibitor Petition 870250089799, dated 02 / 10 / 2025, p. 69 / 131 62 / 93 of topoisomerase is selected from the group consisting of Compound B, Compound C, Compound D, Compound E, Compound F and Compound G, or a pharmaceutically acceptable salt or hydrate thereof.

[00292] Embodiment 17. In Embodiment 17, the method is provided according to any of the embodiments 1 to 16, wherein the topoisomerase inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

[00293] Embodiment 18. In Embodiment 18, the method is provided according to any of the embodiments 1 to 14, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[00294] Embodiments 19. In embodiment 19, the method is provided according to any of embodiments 1 to 14, wherein the topoisomerase inhibitor is Compound H or a pharmaceutically acceptable salt thereof.

[00295] Modality 20. In modality 20, the method is provided according to any of the modalities 1 to 19, wherein the cancer is a homologous recombinant deficiency (HRD) cancer.

[00296] Modality 21. In modality 21, the method is provided according to any of the modalities 1 to 20, in which the cancer is characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, an absence or mutation of the BRCA1 and / or BRCA2 genes, or a reduced function of the BRCA1 and / or BRCA2 proteins.

[00297] Modality 22. In modality 22, the method is provided according to any of the modalities 1 to 21, where the cancer is breast cancer, lung cancer, or ovarian cancer.

[00298] Modality 23. In embodiment 23, the method is provided according to any of embodiments 1 to 22, wherein the PARG inhibitor and the topoisomerase inhibitor are in dosage forms. Petition 870250089799, dated 02 / 10 / 2025, page 70 / 131 63 / 93 separated.

[00299] Modality 24. In embodiment 24, the method is provided according to any of the embodiments 1 to 22, in which the PARG inhibitor and the topoisomerase inhibitor are in the same dosage form.

[00300] Embodiment 25. In embodiment 25, a combination is provided comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[00301] Modality 26. In embodiment 26, the combination of embodiment 25 is provided, wherein the PARG inhibitor is a compound of Formula I: (Formula I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2 is CH or CF; R2 is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, C1-3 hydroxyalkyl and cyano; Ring B is a 5- or 6-membered heterocycloalkyl group substituted with Ra, Rb, and Rc; Rae is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd (where Rd stands for hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rbe Rcsão are independently selected from C1-6 alkyl, hydrogen, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C1 Petition 870250089799, dated 02 / 10 / 2025, page 71 / 131 64 / 93 haloalkoxy.

[00302] Embodiment 27. In embodiment 27, the combination of embodiment 25 or 26 is provided, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

[00303] Modality 28. In modality 28, the combination of any of the modalities 25 to 27 is provided, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[00304] Embodiment 29. In embodiment 29, a combination of any of embodiments 25 to 28 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 a pharmaceutically acceptable salt thereof.

[00305] Embodiment 30. In embodiment 30, a combination of any of embodiments 25 to 29 is provided, 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.

[00306] Embodiment 31. In embodiment 31, the combination of any of embodiments 25 to 27 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[00307] Embodiment 32. In embodiment 32, a combination of any of embodiments 25 to 27 is provided, wherein the topoisomerase inhibitor is Compound H or a pharmaceutically acceptable salt thereof.

[00308] Embodiment 33. In embodiment 33, a PARG inhibitor is provided for use in the treatment of cancer, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor.

[00309] Modality 34. In modality 34, the use of modality 33 is provided, in which the PARG inhibitor is a compound of the FórmuPetição 870250089799, dated 02 / 10 / 2025, page 72 / 131 65 / 93 la I: (Formula I) or a pharmaceutically acceptable salt thereof, where: R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2 is CH or CF; R2 is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, C1-3 hydroxyalkyl and cyano; Ring B is a 5- or 6-membered heterocycloalkyl group substituted by Ra, Rb, and Rc; Rae is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxy or -C(O)Rd (where Rd stands for hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rbe Rcsão are independently selected from C1-6 alkyl, hydrogen, hydroxy, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

[00310] Embodiment 35. In embodiment 35, the use of embodiments 33 or 34 is provided, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

[00311] Modality 36. In Modality 36, the use of any of the embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[00312] Modality 37. In Modality 37, the use of any of the embodiments 33 to 36 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, Petition 870250089799, dated 02 / 10 / 2025, page 73 / 131 66 / 93 or a pharmaceutically acceptable salt thereof.

[00313] Embodiment 38. In Embodiment 38, the use of any of the embodiments 33 to 37 is provided, 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.

[00314] Modality 39. In embodiment 39, the use of any of the embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[00315] Embodiment 40. In embodiment 40, the use of any of embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is Compound H or a pharmaceutically acceptable salt thereof.

[00316] Embodiment 41. In embodiment 41, the use of a PARG inhibitor in the manufacture of a cancer treatment drug is provided, wherein the PARG inhibitor must be administered simultaneously or sequentially with a topoisomerase inhibitor.

[00317] Modality 42. In embodiment 42, the use of embodiment 41 is provided, in which the PARG inhibitor is a compound of Formula I: (Formula I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2 is CH or CF; Petition 870250089799, dated 02 / 10 / 2025, p. 74 / 131 67 / 93 R2 is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, C1-3 hydroxyalkyl and cyano; Ring B is a 5- or 6-membered heterocycloalkyl group substituted with Ra, Rb, and Rc; Rae is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd (where Rd stands for hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rbe Rcsão are independently selected from C1-6 alkyl, hydrogen, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C16 haloalkoxy.

[00318] Embodiment 43. In embodiment 43, the use of embodiment 41 or 42 is provided, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

[00319] Modality 44. In modality 44, the use of any of the modalities 41 to 43 is provided, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[00320] Embodiment 45. In embodiment 45, the use of any 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 a pharmaceutically acceptable salt thereof.

[00321] Embodiment 46. In embodiment 46, the use of any of the embodiments Examples 41 to 45 is provided, 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.

[00322] Modality 47. In Modality 47, the use of any of the embodiments 41 to 43 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[00323] Modality 48. In Modality 48, the use of any of the modalities 41 to 43 is provided, in which the topoiso inhibitor Petition 870250089799, dated 02 / 10 / 2025, p. 75 / 131 68 / 93 merase is Compound H or a pharmaceutically acceptable salt thereof.

[00324] Modality 49. In Modality 49, the use of any of the modalities 33 to 48 is provided, where the cancer is a homologous recombinant deficiency (HRD) cancer.

[00325] Modality 50. In Modality 50, the use of any of modalities 33 to 49 is provided, in which the cancer is characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, an absence or mutation of the BRCA1 and / or BRCA2 genes, or a reduced function of the BRCA1 and / or BRCA2 proteins.

[00326] Modality 51. In Modality 51, the use of any of the modalities 33 to 50 is provided, where the cancer is breast cancer, lung cancer, or ovarian cancer. Pharmaceutical Compositions

[00327] In one aspect, provided herein is 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.

[00328] In one embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a PARG inhibitor is provided, and a second pharmaceutical composition comprising a therapeutically effective amount of a topoisomerase inhibitor is provided.

[00329] In another aspect, provided here is a combination product comprising a first 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. Petition 870250089799, dated 02 / 10 / 2025, page 76 / 131 69 / 93

[00330] In one embodiment, the PARG inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein the variables are defined above.

[00331] 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.

[00332] In another embodiment, the topoisomerase inhibitor is selected from the group consisting of the compounds in Table 1 or a pharmaceutically acceptable salt or hydrate thereof.

[00333] In another embodiment, the topoisomerase inhibitor is topotecan (Compound H) or a pharmaceutically acceptable salt or hydrate thereof.

[00334] In another embodiment, the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

[00335] 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 Petition 870250089799, dated 02 / 10 / 2025, page 77 / 131 70 / 93 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.

[00336] In yet another aspect, supplied herein is 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 B or a pharmaceutically acceptable salt thereof.

[00337] In yet another aspect, supplied herein is 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 H or a pharmaceutically acceptable salt thereof.

[00338] In yet another aspect, supplied herein is 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.

[00339] In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective substance, an amount of Compound A or a pharmaceutically acceptable salt thereof; Compound B or a pharmaceutically acceptable salt thereof. Petition 870250089799, dated 02 / 10 / 2025, page 78 / 131 71 / 93 mo; and a pharmaceutically acceptable vehicle.

[00340] In another aspect, provided herein is 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.

[00341] In yet another aspect, provided herein is 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. Administration / Dosage / Formulations

[00342] In another aspect, provided here is a pharmaceutical composition or pharmaceutical combination comprising the compounds described herein, together with a pharmaceutically acceptable carrier.

[00343] In one embodiment of the combination product, the PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, are in the same formulation. In another embodiment of the combination product, the PARG inhibitor and a topoisomerase inhibitor are in separate formulations. In yet another embodiment of this embodiment, the formulations are for simultaneous or sequential administration.

[00344] Administration of the combination includes administration of the combination in a single formulation or unit dose form, administration of the individual agents of the combination concomitantly but separately, or administration of the individual agents of the combination sequentially by any suitable routine. Petition 870250089799, dated 02 / 10 / 2025, page 79 / 131 72 / 93 of the dosage of the individual agents in the combination may require more frequent administration of one of the agents compared to the other agents in the combination. Therefore, to allow for proper dosing, packaged pharmaceutical products may contain one or more dosage forms containing the combination of agents and one or more dosage forms containing one of the agents in the combination but not the other agent(s) in the combination.

[00345] The current dosage levels of the active ingredients in pharmaceutical compositions may be varied in order to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a specific patient, composition and route of administration, without being toxic to the patient.

[00346] In particular, the dosage level selected will depend on a variety of factors, including the activity of the specific compound employed, the time of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical field.

[00347] A physician, for example, a general practitioner or veterinarian skilled in the art, can easily determine and prescribe the effective amount of the pharmaceutical composition needed. For example, the physician or veterinarian could begin administering the pharmaceutical composition to dose the described compound at levels lower than those needed to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[00348] In specific embodiments, it is particularly advantageous to formulate the compound in dosage unit form to facilitate administration and dosage uniformity. The dosage unit form, when used herein, refers to physically discrete units. Petition 870250089799, dated 02 / 10 / 2025, page 80 / 131 73 / 93 suitable unit dosages for the patients to be treated; each unit containing a predetermined amount of the described compound, calculated to produce the desired therapeutic effect in association with the necessary pharmaceutical vehicle. The dosage unit forms are dictated by and directly dependent on (a) unique characteristics of the described compound and the specific therapeutic effect to be achieved, and (b) limitations inherent in the composition / formulation technique of such described compound for the treatment of pain, depressive disorder, or chemical dependency in a patient.

[00349] In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In another embodiment, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a described compound and a pharmaceutically acceptable carrier.

[00350] The ideal ratios, individual and combined dosages, and concentrations of drug compounds that produce efficacy without toxicity are based on the kinetics of the availability of the active ingredients to the target sites.

[00351] The administration routes according to any of the compositions discussed herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds may be formulated for administration by any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., trans and perivaginal), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical. In one embodiment, the preferred administration route is oral. Petition 870250089799, dated 02 / 10 / 2025, p. 81 / 131 74 / 93

[00352] Suitable compositions and dosage forms include, for example, tablets, capsules, coated tablets, pills, gel capsules, trochos, dispersions, suspensions, solutions, syrups, granules, spheres, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that formulations and compositions are not limited to the specific formulations and compositions described herein.

[00353] For oral application, particularly suitable are tablets, coated tablets, liquids, drops, suppositories or capsules, coated tablets and gel capsules. Compositions intended for oral use may be prepared according to any method known in the art and 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, an inert diluent, such as lactose; granulating and disintegrating agents, such as corn starch; binding agents, such as starch; and lubricating agents, such as magnesium stearate. Tablets may be coated or uncoated, by means of known techniques, for greater elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert diluent.

[00354] For parenteral administration, the compounds described 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 an oily or aqueous vehicle, optionally containing Petition 870250089799, dated 02 / 10 / 2025, page 82 / 131 75 / 93 Other formulation agents, such as suspending, stabilizing or dispersing agents, may be used.

[00355] In one embodiment, particularly when the topoisomerase inhibitor is doxorubicin, it can be administered by injection, in some embodiments. In one embodiment, doxorubicin is administered by capsule. In another embodiment, doxorubicin is administered intravenously. Kits

[00356] In one aspect, the present description provides a cancer treatment kit comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[00357] In certain embodiments, the kit comprises a pharmaceutical product comprising a pharmaceutical composition comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle or diluent; and a pharmaceutical composition comprising a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle or diluent.

[00358] 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 vehicle or diluent.

[00359] In additional embodiments, pharmaceutical kits are provided. The kit includes a sealed container approved for the storage of pharmaceutical compositions, the container containing one of the pharmaceutical compositions described above. In some embodiments, the sealed container minimizes contact of air with the ingredients, for example, an airless vial. In other embodiments, the container seals Petition 870250089799, dated 02 / 10 / 2025, page 83 / 131 76 / 93 is a sealed tube. Instructions for use and information about the composition should be included in the kit.

[00360] In one embodiment, the compounds in the combination may be dosed in the same regimen, either by administering a single formulation or unit dose form containing all the compounds in the combination, or by administering separate formulations or unit dose forms of the compounds in the combination. However, some of the compounds used in the combination may be administered more frequently than once a day, or at different frequencies than other compounds in the combination. Therefore, in one embodiment, the kit contains a formulation or unit dose form containing all the compounds in the compound combination, and an additional formulation or unit dose form that includes one of the compounds in the agent combination, without any additional active compound, in a container, with instructions for administering the dosage forms in a fixed regimen.

[00361] The kits provided here include prescribing information, for example, for a patient or healthcare professional, or as a label on a packaged pharmaceutical formulation. Prescribing information may include, for example, efficacy, dosage and administration, contraindications, and information on adverse reactions relating to the pharmaceutical formulation.

[00362] In all the above items, the combination of compounds described may be administered alone, as mixtures, or with additional active agents.

[00363] A kit supplied here may be designed for the conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing). A kit may contain a label or leaflet, including identifying information for the components contained therein and instructions for use (e.g., parameters). Petition 870250089799, dated 02 / 10 / 2025, page 84 / 131 77 / 93 dosage guidelines, clinical pharmacology of the active ingredient(s), including mechanism(s) of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.).

[00364] Each component of the kit can be packaged in an individual container, and all containers can be in a single package. Labels or package inserts may include manufacturer information, such as batch numbers and expiry dates. The label or package insert may, for example, be integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampoule, syringe, or vial).

[00365] Those skilled in the art will recognize or be able to verify, using only routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents have been considered within the scope of this description and covered by the appended claims.

[00366] It should be understood that, whenever values ​​and ranges are provided herein, all values ​​and ranges covered by those values ​​and ranges shall be covered by the scope of this description. Furthermore, all values ​​that fall within those ranges, as well as the upper or lower limits of a range of values, are likewise contemplated by this application.

[00367] The following examples further illustrate aspects of the present description. However, they do not in any way constitute a limitation of the teachings of the present description, as mentioned. EXAMPLES

[00368] The compounds and methods described here are further illustrated by the following examples, which should not be interpreted as additional limitations. The practice of the present description employs Petition 870250089799, dated 02 / 10 / 2025, page 85 / 131 78 / 93 unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture and molecular biology, which are within the technical competence. Example 1 Preparation of Compound A F (Compound A) Step 1: Preparation of 2,6-difluoro-4-benzobenzaldehyde

[00369] To a stirred solution of 1,3-difluoro-5-iodobenzene (Compound 1) (50 g, 208.3 mmol, Oakwood Chemical, CAS 2265-91-0, catalog no. 024566) in THF (500 mL), LDA (80 mL, 625.0 mmol) and DMF (48.3 mL, 625 mmol) were added at -78 °C and stirred at -78 °C for 2 h. After complete consumption of the starting material, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 x 300 mL), the combined organic phases were 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 material was purified by column chromatography using silica gel (100-200) and eluted with 20% EtOAc / Hexane as a gradient. The product was eluted with a 30% EtOAc / Hexane gradient. The purified fractions were concentrated under reduced pressure to provide 2,6-difluoro-4-iodobenzaldehyde (Compound 2). Petition 870250089799, dated 02 / 10 / 2025, page 86 / 131 79 / 93 (23 g) as a solid.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-jndazol Step 2 N2m4H20 1,4-dioKano 10« °C, 24 h

[00370] 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 h. The reaction mixture was concentrated under reduced pressure and ice-cold water (100 mL) was added. The mixture was stirred for 30 min, during which time the solid precipitated. The mixture was filtered. The solid was washed with water (100 mL), n-pentane (50 mL) and dried under vacuum to give the product 4-fluoro-6-iodo-1H-indazole (Compound 3) (2.3 g) as a solid. MS ESI calculated for C7H4FIN2 [M+H]+262.94, found 262.99.1H NMR (CDCh, 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-1-hindazol-1-yl)-1,3,4-thiadiazole

[00371] To a stirred solution of A 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) Petition 870250089799, dated 02 / 10 / 2025, p. 87 / 131 80 / 93 1,3,4-thiadiazole (Compound 4) (3.8 g, 18.1 mmol, Enamine Stock Building Blocks, CAS 1340313-49-6, catalog no. EN300-108825). The resulting mixture was stirred at 60 °C for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (50 mL) and stirred for 30 min, during which time the solid precipitated. The mixture was filtered. The collected solid was washed with water (100 mL), followed by n-pentane (100 mL) and dried under vacuum to give 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4-thiadiazole (Compound 5) (4.2 g) as a solid. MS ESI calculated for C10H4F3IN4S [M+H]+396.92, found 396.91.1H NMR (CDCI3, 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-tjadjazol-2-j1)4-fluoro-1H-indazol-6-yl)benzothioate Step 4 OI (10 % Em mail ptien (2£% em mal) kísccpnn.5 eq}. 100 C.

[00372] To a stirred solution of 2-(difluoromethyl)-5-(4-fluoro-6iodo-1H-indazol-1-yl)-1,3,4-thiadiazole (Compound 5) (100 mg, 0.25 mmol) in toluene (1 mL) degassed for 5 min, Cul (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 h. The progress of the reaction was monitored by LCMS. The crude mixture was purified by column chromatography using silica gel (100-200) and eluted with 10% EtOAc / hexane as a gradient. The purified fractions were collected and concentrated under reduced pressure to provide S-(1-(5(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)benzothioate (Compound 6) (55 mg) as a solid. The calculated MS ESI for C17H9F3N4OS2 [M+H]+ was 407.02, and the value found was 407.01. Petition 870250089799, dated 02 / 10 / 2025, page 88 / 131 81 / 931H NMR (CDCb, 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), 7.7, 2.7 (t, H6), J 1H), 6.99 (t, J = 53.2 Hz, 1H). Stage 5: Preparation of N-(1-cyanocyclopropjl)-1-(5-(djfluorometjl)1,3,4-thiadiazol-2-yl)-4-fluoro-1 H-indazol-6-sulfonamide TCCA. BnM*3NCi Stage 5 PyridiTia,Cs;CO; ACN, RT. 2 Γι

[00373] To a stirred solution of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)benzothioate (Compound 6) (500 mg, 1.23 mmol) in acetonitrile (10 mL) at 0 °C, a solution of BnMesNCI (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 min. Next, a solution of 1-methylcyclopropane-1-amine (1.71 g, 7.38 mmol, Combi-Blocks, CAS 2293683-0, catalog no. QH-3639) in pyridine (2.5 mL) and cesium carbonate (198 mg, 0.61 mmol) was added to the reaction mixture at 0 °C and stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. LCMS showed complete consumption of the starting material (S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)benzothioate) (Compound 6). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 30 mL).The combined organic layer was washed with brine 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 with 5 to 50% EtOAc / hexane as a gradient. The product was eluted to 20%. Petition 870250089799, dated 02 / 10 / 2025, page 89 / 131 82 / 93 of EtOAc / hexane. The purified fractions were collected and concentrated under reduced pressure to provide 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazol-6-sulfonamide (Compound 7) (90 mg) as a solid. MS ESI calculated for C14H9F3N6O2S2 [M+H]+404.04., found 404.18.1H NMR (CDCh, 400 MHz): 9.00 (s, 1H), 8.80 (s, 1H), 8.54 (s, 1H), 7.63 (t, J= 48.8 Hz, 2H), 1.10 (s, 3H), 0.65 (s, 2H), 0.44 (s, 2H). Step 6: Preparation of tert-butyl (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate THE

[00374] To a stirred solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazol-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 no. BD233798) and DIPEA (N,N-diisopropyl ethylamine) (0.1 mL, 0.59 mmol) was added and the reaction mixture was stirred at 130 °C for 2 h. The reaction mixture was quenched with ice-cold water (20 mL) and stirred for 30 min. The resulting solid was filtered, washed with water (10 mL), dried under vacuum, and purified by column chromatography on silica gel (100-200) and eluted with 50% EtOAc / hexane as a gradient. The purified fractions were concentrated under reduced pressure to provide (2S,6S)-4-(1(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)Petição 870250089799, dated 02 / 10 / 2025, page 90 / 131 83 / 93 H-indazol-4-yl)-2,6-dimethylpiperazine-1-tert-butylcarboxylate (Compound 8) (110 mg, yield: 92%) as a solid. MS ESI calculated for C25H33F2N7O4S2 [M+HJ+ 598.20, found 598.26. Step 7: Preparation of 1-(5-(difluoromethyl)-1,3,4-tjadjazol-2-yl)-4((3S,5S)-3,5-dimethylpiperazine-1-yl)-N-(1-methylcyclopropyl)-1H-indazol-6-sulfonamide (Compound A) TFA, DCM TA, 1211 Step 7

[00375] To a stirred solution of (2S,6S)-4-(1-(5-(difluoromethyl)1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-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) at 0 °C was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, purified by preparative HPLC purification (preparative HPLC conditions: MOBILE PHASE - 10 mM ammonium bicarbonate in H2O: MeCN COLUMN - Inertsil ODS (20X250) mm 5u Flow-18ml / 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 provide 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazol-6-sulfonamide (Compound A) (18 mg, Yield: 21%) as a solid.MS ESI calculated for C20H25F2N7O2S2 [M+H]+498.15, found 498.34.1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.75 (s, 1H), 8.40 (s,. Petition 870250089799, dated 02 / 10 / 2025, pp. 91 / 131 84 / 93 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 evaluating the effects of the combination of Compound A and doxorubicin (Compound B) in a xenograft model derived from the HR-deficient breast cancer cell line HCC1428.

[00376] The effect of the combination of Compound A and doxorubicin was evaluated using a xenograft model derived from the HCC1428 breast cancer cell line carrying a BRCA2 mutation. For this study, cells were expanded in RPMI with 10% fetal bovine serum and implanted into BALB / c Nude mice. Animals were randomized into treatment arms once a mean tumor volume of approximately 180 mm3 was reached, as described in Table 2, with a study treatment duration of 35 days. For this xenograft, supplemental estradiol benzoate injections (40 pg / 20 μL / mouse) were administered subcutaneously twice weekly, beginning one week before cell implantation and continuing until the end of treatment.

[00377] Compound A was administered at doses of 30 mg / kg and 100 mg / kg once daily (QD), resulting in tumor growth inhibition (TGI) of 63.2% and 102.5%, respectively, and doxorubicin administered intravenously at doses of 5 mg / kg once weekly for 5 weeks produced a TGI of 57%. Administration of the combination resulted in a more robust and sustained response, with a TGI of 85% and 110% for the groups administered with 30 mg / kg and 100 mg / kg of Compound A, respectively, with Petition 870250089799, dated 02 / 10 / 2025, p. 92 / 131 85 / 93 50% of the animals in the combination group administered with 100 mg / kg of Compound A achieved complete regressions. Statistically significant differences in GI tract activity between the single-agent and combination groups were observed with both the 30 mg / kg and 100 mg / kg doses of Compound A, highlighting the enhanced antitumor effect of this combination (Table 3 and Figure 1 (FIG. 1)). Although no mortality was observed in this study, body weight losses of >10% were observed in the high-dose combination group. Table 2: Study groups for CDX HCC1428 treated with Compound A and / or doxorubicin. Treatment Group Dosage Regimen Dose Volume (ml / kg) 1 Vehicle 1: 0.5% methylcellulose (400 cPs) + 0.5% Tween 80 in distilled water po, QD x 35 10 2 USP saline solution of vehicle salt iv, QW x 5 for 35 days - 3 Compound A 30 mg / kg, po, QD x 35 10 4 Compound A 100 mg / kg, po, QD x 35 10 5 Doxorubicin 5 mg / kg iv, QW x 5 for 35 days 10 6 Doxorubicin + Compound A iv, 5 mg / kg QW x 5 for 35 days + 30 mg / kg QD x 35 days 10 7 Doxorubicin + Compound A 5 mg / kg QW x 5 for 35 days + 100 mg / kg QD x 35 days 10 Petition 870250089799, dated 02 / 10 / 2025, pp. 93 / 131 86 / 93 Table 3: CDX HCC1428 treated with Compound A and / or doxorubicin Compound A Dose (mg / kg) Doxorubicin Dose (mg / kg) % of GI Tract p-value, all groups vs. single agent Compound A p-value, all groups vs. single agent doxorubicin Full regression 30 0 63 NA ns 0 / 8 100 0 102 NA P < 0.0001 0 / 8 0 5 57 NA NA 0 / 8 30 5 82 P < 0.0001 P < 0.0001 0 / 8 100 5 110 P < 0.001 P < 0.0001 4 / 8 Example 3 Efficacy study evaluating the effects of the combination of Compound A and topotecan (Compound H) on the NCI-H69 small cell lung cancer cell line.

[00378] The effect of the combination of Compound A and topotecan was evaluated using a cell line-derived xenograft (CDX) model of the NCI-H69 small cell lung cancer cell line, containing an ATM variant of unknown significance. For this study, NCI-H69 cells were expanded in RPMI with 10% fetal bovine serum and implanted into NOD SCID mice. Animals were randomized into different treatment arms once a mean tumor volume of approximately 100-150 mm3 was reached. The study consisted of six treatment arms containing ten mice per group, lasting 42 days on treatment. TGI was calculated on Day 21, when the vehicle group was terminated, once the maximum allowable tumor burden was reached.

[00379] Compound A was administered at 100 mg / kg, resulting in a GI tract clearance of 53%, and topotecan administered at 0.25 mg / kg and 1 mg / kg produced GI tract clearance values ​​of 79% and 80%, respectively (see Table 4 for the dosing regimen). Both doses of topotecan presented. Petition 870250089799, dated 02 / 10 / 2025, pp. 94 / 131 87 / 93 showed a combined effect, with the 0.25 mg / kg dose showing a GI reduction of 79% and the 1 mg / kg dose showing a GI reduction of 105%, with 7 of 10 animals showing complete regression on Day 42. These results highlight the robust anticancer efficacy of Compound A in combination with the topoisomerase I inhibitor topotecan (see Figure 2 (FIG. 2)). Table 4: Study groups for CDX NCI-H69 treated with Compound A and / or topotecan. Treatment Group Dosage Regimen Dose Volume (ml / kg) 1 Vehicle 1: 0.5% methylcellulose (400 cPs) + 0.5% Tween 80 in distilled water, po, QD 10 2 Topotecan 0.25 mg / kg ip, 5 days on 16 days off 10 3 Topotecan 1 mg / kg ip, 3 days on 4 days off 10 4 Compound A 100 mg / kg, po, QD 10 5 Topotecan + Compound A 0.25 mg / kg ip, 5 days on 16 days off + 100 mg / kg, po, QD 10 6 Topotecan + Compound A 1 mg / kg ip, 3 days on 4 days off + 100 mg / kg, po, QD 10 Example 4 Efficacy study evaluating the effects of the combination of Compound A and topotecan (Compound H) on the Kuramochi high-grade serous ovarian cancer cell line.

[00380] The effect of the combination between Compound A and topotecan was evaluated using a cell line-derived xenograft (CDX) model from the Kuramochi high-grade serous ovarian cancer cell line, which has a BRCA2 mutation (without sentience). Petition 870250089799, dated 02 / 10 / 2025, pp. 95 / 131 88 / 93 do). For this study, Kuramochi cells were expanded in RPMI with 10% fetal bovine serum and implanted into NOD SCID mice. Animals were randomized into different treatment arms when a mean tumor volume of approximately 100-150 mm3 was reached. The study consisted of four treatment arms containing six to eight mice per group, with a treatment duration of 63 days. TGI was calculated on Day 41, when the vehicle group was terminated, as the maximum allowable tumor burden was reached.

[00381] Compound A was administered at a dose of 100 mg / kg, resulting in a TGI of 103%, and topotecan administered at a dose of 1 mg / kg produced a TGI value of 77% (see Table 5 for the dosing regimen). The combined arm showed a TGI of 108%, with 6 of 6 animals showing complete regression on Day 52. ​​These results highlight the robust anticancer efficacy of Compound A in combination with the topoisomerase I inhibitor, topotecan (Figure 3, (FIG. 3)). Table 5: Study groups for CDX Kuramochi treated with Compound A and / or topotecan. Treatment Group Dosage Regimen Dose Volume (ml / kg) 1 Vehicle 1: 0.5% methylcellulose (400 cPs) + 0.5% Tween 80 in distilled water, po, QD 10 2 Topotecan 1 mg / kg ip, 3 days on 4 days off 10 3 Compound A 100 mg / kg, po, QD 10 4 Topotecan + Compound A 1 mg / kg ip, 3 days on 4 days off + 100 mg / kg, po, QD 10 Petition 870250089799, dated 02 / 10 / 2025, pp. 96 / 131 89 / 93 Example 5 Inhibition of the PARG enzyme assay (TR-FRET) EC50 enzymatic assay

[00382] The PARG enzyme was incubated with the compound or vehicle (DMSO) and the biotinylated-PARylated PARP-1 substrate in a microtiter plate. After the addition of the detection antibody and streptavidin-europium, and subsequent incubation, the plate was subjected to fluorescence intensity reading. The low control (DMSO) with low fluorescence intensity does not represent inhibition of enzymatic activity, while the high control (without enzyme) with high fluorescence intensity represents total inhibition of enzymatic activity. Materials: Enzyme: PARG or hPARG: 250 pM, 1-976, His-labeled, Proteos, 2.0 mg / mL (17.9 μM) or Substrate: 30 nM or Test Compound / Enzyme Pre-incubation time: 1 hour Enzyme / substrate reaction time: 10 minutes Substrate: hPARP1, labeled with His6-TEV, 1.2 mg / mL (10.3 μM) Detection antibody: anti-His-ULight monoclonal antibody, Perkin Elmer catalog no. TRF0134-M Streptavidin-Europium: Perkin Elmer catalog no. 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 °C Total reaction volume: 20 μL Controls: • 0% inhibition: DMSO Petition 870250089799, dated 02 / 10 / 2025, p. 97 / 131 90 / 93 • 100% inhibition: No enzyme Enzymatic reaction and detection: 1. Transfer 200 nL of 100x compound or DMSO into the appropriate wells of a white polystyrene microtiter plate with 384 wells (Corning Catalog No. 3574). 2. Transfer 10 pL of a final 2x concentration of the enzyme in assay buffer or assay buffer alone to the appropriate wells. 3. Spin the plate at 1000 rpm for 30 seconds. 4. Incubate the plate at room temperature for 1 hour. 5. Transfer 10 pL of 2x substrate in test buffer to all test cavities. 6. Incubate the plate at room temperature for 10 minutes. 7. Transfer 10 pL of a 3x mixture of 42 nM detection antibody and 2.25 nM streptavidin-europium in 50 mM Tris-HCl pH 7.4 to all test wells. 8. Incubate the plate at room temperature for 1 hour. 9. Read the license plate using a license plate reader (Envision). Excitation: 317 nM Emission: 620 nM Emission: 665 nM Data Analysis:

[00383] EC50 values ​​were calculated in the Collaborative Drug Discovery Vault (CDD). Curves were fitted by CDD as response (%) vs compound concentration (pM) using a 4-parameter inhibition model using Formula 1.

[00384] Formula 1: A. Adjust = (A+((BA) / (1+((C / x)AD)))) B. Res = (y-adjustment) Petition 870250089799, dated 02 / 10 / 2025, pp. 98 / 131 91 / 93

[00385] The EC50 value of TR-FRET for Compound A is given in Table 6 below.

[00386] TR-FRET: **** <= 0.1 μΜ Table 6. Results of the TR-FRET Test for Compounds of Formula (I). TR-FRET EC50 Compound (µM) Compound A **** Example 6 Efficacy study evaluating the effects of the combination of Compound A and topotecan (Compound H) in the HCC1395 breast cancer model.

[00387] The effect of the combination of Compound A and topotecan was evaluated using a xenograft model (XG) derived from the HCC1395 breast cancer cell line (BCCM) with BRCA1 and 2 mutations. For this study, HCC1395 cells were expanded in RPMI with 10% fetal bovine serum and implanted into NOG mice. Animals were randomized into different treatment arms when a mean tumor volume of approximately 100-150 mm3 was reached. The study consisted of four treatment arms containing eight mice per group, with a treatment duration of 35 days. TGI was calculated on Day 35.

[00388] Compound A was administered at a dose of 100 mg / kg, resulting in a TGI of 56%, and topotecan administered at a dose of 1 mg / kg produced a TGI value of 98% (see Table 7 for the dosing regimen). The combined arm showed a TGI of 102%. These results highlight the robust anticancer efficacy of Compound A in combination with the topoisomerase I inhibitor, topotecan (Figure 4, (FIG. 4)). Petition 870250089799, dated 02 / 10 / 2025, pp. 99 / 131 92 / 93 Table 7: Study groups for CDX HCC1395 treated with Compound A and / or topotecan. Treatment Group Dosage Regimen Dose Volume (ml / kg) 1 Vehicle 1: 0.5% methylcellulose (400 cPs) + 0.5% Tween 80 in distilled water, po, QD 10 2 Topotecan 1 mg / kg ip, 3 days on 4 days off 10 3 Compound A 100 mg / kg, po, QD 10 4 Topotecan + Compound A 1 mg / kg ip, 3 days on 4 days off + 100 mg / kg, po, QD 10 FIG. 4 Example 7 Efficacy study evaluating the effects of the combination of Compound A and Compound J (fam-trastuzumab deruxtecan-nxki) on the NCI-H650 human lung cancer cell line.

[00389] The effect of the combination of Compound A and Compound J (fam-trastuzumab deruxtecan-nxki) was evaluated using a cell line-derived xenograft (CDX) model of the NCI-H650 non-small lung cancer cell line. For this study, NCI-H650 cells were expanded in RPMI with 10% fetal bovine serum and implanted into BALB / c Nude mice. Animals were randomized into different treatment arms when a mean tumor volume of approximately 100-150 mm3 was reached. The study consisted of four treatment arms containing eight mice per group, with a treatment duration of 26 days.

[00390] Compound A was administered at a dose of 100 mg / kg, resulting in a GI tract regression of 5%, and Compound J, with a single dose of 10 mg / kg, produced a GI tract regression value of 100%, with 3 of 8 animals achieving complete regression (see Table 8 for the dosing regimen). The combined arm showed a GI tract regression of 106%, with 6 of 8 Petition 870250089799, dated 02 / 10 / 2025, pp. 100 / 131 93 / 93 animals showed complete regression on day 26. These results highlight the robust anticancer efficacy of Compound A in combination with Compound J (Figure 5). Table 8: Study groups for CDX NCI-H650 treated with Compound A and / or Compound J. Treatment Group Dosage Regimen Dose Volume (ml / kg) 1 5% Glucose Injection IV, QD 10 2 Compound J 10 mg / kg IV, single dose D1 10 3 Compound A 100 mg / kg PO, QD 10 4 Topotecan + Compound A 10 mg / kg IV, single dose D1 + 100 mg / kg PO, QD 10

[00391] Particular embodiments of this description are described herein, including the best known mode for carrying out the description. After reading the foregoing description, variations of the described embodiments may become apparent to those skilled in the art, and it is expected that such skilled practitioners may employ such variations as appropriate. In this manner, it is intended that the description be practiced differently from that specifically described herein, and that the description include all modifications and equivalents of the subject matter set forth in the appended claims, as permitted by applicable law. Furthermore, any combination of the elements described above, in all possible variations thereof, is encompassed by the description, unless otherwise stated herein or clearly contradicted by the context.

[00392] All patent applications, patents and printed publications cited herein are incorporated herein by reference in their entirety, except for any definitions, disclaimers or disclaimers of the subject matter, and except to the extent that the incorporated material is inconsistent with the description expressed herein, in which case the language in this description shall prevail.

[00393] Other modalities are included in the following claims. Petition 870250089799, dated 02 / 10 / 2025, pp. 101 / 131

Claims

1 / 7 CLAIMS 1. A method for treating cancer in an individual in need thereof, characterized in that it comprises administering to the individual a therapeutically effective amount of a PARG inhibitor and administering to the individual a therapeutically effective amount of a topoisomerase inhibitor, wherein the PARG inhibitor is a compound of Formula I: r24-Ar (BJ (Formula I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2 is CH or CF; R2 is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, C1-3 hydroxyalkyl and cyano; ring B is a 5- or 6-membered heterocycloalkyl substituted by Ra, Rb and Rc; Ra is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxy or -C(O)Rd, wherein Rd is hydrogen, C1-6 alkyl or C1-6 haloalkyl);Rb and Rc are independently selected from C1-6 alkyl, hydrogen, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl, and C16 haloalkoxy.

2. Method according to claim 1, characterized in that X2 is CH.

3. Method according to claim 1 or 2, characterized in that R1 is methyl. Petition 870250089799, dated 10 / 02 / 2025, p. 102 / 131 2 / 7 4. Method according to claim 1 or 2, characterized in that R1 is cyan.

5. Method according to any one of claims 1 to 4, characterized in that Ar is 1,3,4-thiadiazol-2-yl.

6. A method according to any one of claims 1 to 5, characterized in that R2 is bonded to the carbon atom of Ar which is meta to the Ar atom which is bonded to the nitrogen atom of the remainder of the molecule.

7. Method according to any one of claims 1 to 6, characterized in that R2 is methyl, ethyl, difluoromethyl, trifluoromethyl or cyano.

8. Method according to any one of claims 1 to 7, characterized in that R2 is difluoromethyl.

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

10. A method according to any one of claims 1 to 9, characterized in that ring B is piperazinyl.

11. Method, according to any one of claims 1 to 10, characterized in that Ra is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd, wherein Rd is hydrogen, C1-6 alkyl or C1-6 haloalkyl); and Rb and Rc are independently selected from C1-6 alkyl, hydrogen, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C1-6 haloalkoxy.

12. Method according to any one of claims 1 to 11, characterized in that Ra is hydrogen, C1-4 alkyl or C1-4 haloalkyl; and Rb and Rc are independently selected from C1-6 alkyl and hydrogen.

13. Method according to any of claims 1 to 12, characterized in that Ra is hydrogen; Rb and Rc are each independently C1-6 alkyl or hydrogen.

14. Method according to any one of claims 1 to 13, characterized in that the PARG inhibitor is Compound A: FH Compound A or a pharmaceutically acceptable salt thereof.

15. Method according to any one of claims 1 to 14, characterized in that the topoisomerase inhibitor is a topoisomerase II inhibitor.

16. A method according to any one of claims 1 to 15, characterized in that the topoisomerase inhibitor is selected from the group consisting of Compound B, Compound C, Compound D, Compound E, Compound F and Compound G, or a pharmaceutically acceptable salt or hydrate thereof.

17. Method according to any one of claims 1 to 16, characterized in that the topoisomerase inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

18. Method according to any one of claims 1 to 14, characterized in that the topoisomerase inhibitor is a topoisomerase I inhibitor.

19. Method according to any one of claims 1 to 14, characterized in that the topoisomerase inhibitor is Compound H or a pharmaceutically acceptable salt thereof.

20. Method according to any one of claims 1 to 14, characterized in that the topoisomerase inhibitor is 10-hydroxycamptothecin and topotecan, hexylresorcinol, exatecan, deruxtecan or belotecan.

21. A method according to any one of claims 1 to 20, characterized in that the cancer is a homologous recombinant deficiency (HRD) cancer.

22. A method according to any one of claims 1 to 20, characterized in that the cancer is particularized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, an absence or mutation of the BRCA1 and / or BRCA2 genes, or a reduced function of the BRCA1 and / or BRCA2 proteins.

23. A method, according to any one of claims 1 to 20, characterized in that the cancer is breast cancer, lung cancer, or ovarian cancer.

24. A method, according to any one of claims 1 to 21, characterized in that 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. Method according to any one of claims 1 to 24, characterized in that the PARG inhibitor and the topoisomerase inhibitor are in separate dosage forms.

26. Method, according to any one of claims 1 to 24, characterized in that the PARG inhibitor and the topoisomerase inhibitor are in the same dosage form.

27. PARG inhibitor for use in cancer treatment, characterized in that the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor. Petition 870250089799, dated 10 / 02 / 2025, pp. 105 / 131 5 / 7 28. Use of a PARG inhibitor in the manufacture of a drug for the treatment of cancer, characterized in that the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor.

29. Use according to claim 27 or 28, characterized in that the PARG inhibitor is a compound of Formula I: (Formula I) or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of cyano, C1-2 alkyl and C1-2 haloalkyl; Ar is a 1,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl; X2 is CH or CF; R2 is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, C1-3 hydroxyalkyl and cyano; ring B is a 5- or 6-membered heterocycloalkyl substituted with Ra, Rb and Rc; Ra is hydrogen, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl or -C(O)Rd, wherein Rd is hydrogen, C1-6 alkyl or C1-6 haloalkyl); Rb and Rc are independently selected from C1-6 alkyl, hydrogen, hydroxyl, C1-6 alkoxy, halo, C1-6 haloalkyl and C16 haloalkoxy.

30. Use in accordance with any of claims 27 to 29, characterized in that the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

31. Use in accordance with any of claims 27 to 30, characterized in that the topoisomerase inhibitor is a type II topoisomerase inhibitor.

32. Use in accordance with any one of claims 27 to 31, characterized in that the topoisomerase inhibitor is selected from the group consisting of Compound B, Compound C, Compound D, Compound E, Compound F and Compound G, or a pharmaceutically acceptable salt thereof.

33. Use in accordance with any one of claims 27 to 32, characterized in that 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. Use in accordance with any one of claims 27 to 30, characterized in that the topoisomerase inhibitor is a topoisomerase I inhibitor.

35. Use in accordance with any one of claims 27 to 30 and 34, characterized in that the topoisomerase inhibitor is Compound H or a pharmaceutically acceptable salt thereof.

36. Use in accordance with any of claims 27 to 35, characterized in that the cancer is a homologous recombinant deficiency (HRD) cancer.

37. Use in accordance with any of claims 27 to 36, characterized in that the cancer is particularized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, an absence or mutation of the BRCA1 and / or BRCA2 genes, or a reduced function of the BRCA1 and / or BRCA2 proteins.

38. Use in accordance with any one of claims 27 to 37, characterized in that the cancer is breast cancer, lung cancer, or ovarian cancer.

39. Use in accordance with any of claims 27 to 37, characterized in that 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. (Petition 870250089799, dated 10 / 02 / 2025, p. 107 / 131 7 / 7)

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