Combination therapy comprising a parg inhibitor and a topoisomerase inhibitor for treating cancer

Abstract

Provided herein is a combination of a PARG inhibitor and a topoisomerase inhibitor. Also provided are methods of using such combinations to treat diseases or disorders, for example, cancer.

Description

COMBINATION THERAPY COMPRISING A PARG INHIBITOR AND A TOPOISOMERASE INHIBITOR FOR TREATING CANCERCROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit to U.S. Provisional Application Nos. 63 / 457,312 filed April 05, 2023; 63 / 584,013 filed September 20, 2023; and 63 / 548,513 filed November 14, 2023, each of which is incorporated herein in their entirety and for all purposes.BACKGROUND

[0002] Cancer is caused by uncontrolled and unregulated cellular proliferation. The consequence of this often-rapid proliferation is a high level of oxidative stress within the tumor which damages DNA and leads to a much-increased mutation rate. Tumor cells therefore engage and rely heavily upon DNA damage repair mechanisms.

[0003] Single-strand breaks (SSBs) are the most common type of lesion arising in cells and PARG (Poly ADP -ribose glycohydrolase) together with PARP (poly ADP-ribose polymerase) is involved along with a number of other proteins in single strand break repair (SSBR) and another repair mechanism called base excision repair (BER).

[0004] One of the earliest 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 the repair. The signal initiated by these PAR chains is short-lived as they are rapidly degraded by the enzyme PARG. When PARP is bound to PAR, its catalytic activity is reduced and therefore PARG activity helps to restore PARP to its catalytically active form.

[0005] PARG is derived from a single gene with isoforms that reside in the nucleus, mitochondria and cytosol. Another known protein with glycohydrolase activity' is ARH3 which is localized to the mitochondria. Although known primarily for its direct role in DNA repair, PARG impacts PAR signaling in transcriptional and epigenetic pathways.

[0006] Cancer cells may become reliant upon a specific DNA repair pathway when other mechanisms of DNA repair are non-functional. Tumors carrying mutations in proteins involved in double strand break repair are often more sensitive to PARP inhibitors of SSBR.There is already some evidence that PARG depletion inhibits SSBR and reduces survival of BRCA2-deficient cells. However, other tumor mutations may give rise to deficiencies in double strand DNA repair mechanisms (so-called ‘BRCA-ness”) thereby sensitizing tumor cells to PARG inhibition.

[0007] Topoisomerases are abundant enzy mes essential for changing the topology7of DNA during DNA replication and transcription, and are classified into two major classes: type I and type II. Topoisomerase inhibitors as anticancer agents act specifically upon the above topoisomerase species. For example, topoisomerase II inhibitors include anthracy clines such as doxorubicin. The topoisomerase inhibitors induce cell death by inhibiting the activity7of topoisomerase which is generally expressed much more in cancer cells relative to normal cells. Topoisomerase inhibitors can also covalently trap topoisomerase on DNA and generate lethal DNA strand breaks, leading to cell death.

[0008] Despite many recent advances in cancer therapies, there remains a need for more effective and / or enhanced treatment for those individuals suffering the effects of cancer. The present disclosure addresses this need and provides related advantages.SUMMARY

[0009] Provided herein 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 an embodiment, the disease or disorder is an advanced or metastatic solid tumor. The combination is also useful for the treatment of any number of PARG-associated diseases. The combination is also useful for the treatment of a variety of diseases or disorders in which PARG activity7is implicated. The combination is useful for treating a homologous recombinant deficient (HRD) cancer. The combination is also useful for the treatment of a variety of diseases or disorders treatable by inhibiting topoisomerase.

[0010] Provided herein is a combination product comprising a PARG inhibitor and a topoisomerase inhibitor. The combination product is useful for the treatment of a variety7of cancers, including solid tumors. In an embodiment, the disease or disorder is an advanced or metastatic solid tumor. The combination product is also useful for the treatment of any number of PARG-associated diseases. The combination product is also useful for the treatment of a variety7of diseases or disorders in which PARG activity is implicated. The combination product is useful for the treatment of a homologous recombinant deficient(HRD) cancer. The combination product is also useful for the treatment of a variety of diseases or disorders treatable by inhibiting topoisomerase.

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

[0012] In an 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 an embodiment, provided herein are methods of treating and / or preventing cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0014] In an embodiment, provided herein are methods of treating and or preventing cancer in a subj ect in need thereof, the methods comprising administering to the subj ect a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject.

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

[0016] In an embodiment are methods of treating and / or preventing a homologous recombinant deficient (HRD) cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject.

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

[0018] In an embodiment, provided herein are methods of treating and / or preventing cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a PARGinhibitor and a therapeutically effective amount of a pharmaceutical composition comprising a topoisomerase inhibitor, thereby treating the cancer in the subject.

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

[0020] In an embodiment, provided herein are methods of treating and / or preventing a disease or disorder in which PARG activity is implicated in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, together with at least a pharmaceutically acceptable carrier, thereby treating the disease or disorder in the subject. In an embodiment, the topoisomerase inhibitor is doxorubicin, or a pharmaceutically acceptable salt thereof. In an embodiment, the disease or disorder is cancer. In an embodiment, the cancer is a homologous recombination deficient (HRD) cancer.

[0021] In an 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 of making 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 can be used to treat cancer as described herein.

[0024] In another embodiment, the topoisomerase inhibitor is an inhibitor of type II topoisomerase (also referred herein as “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 an embodiment, the topoisomerase II inhibitor is doxorubicin or a pharmaceutically acceptable salt thereof.

[0026] In another embodiment, the topoisomerase inhibitor is an inhibitor of type I topoisomerase (also referred herein as “topoisomerase I inhibitor”).

[0027] In an 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 assessing combination effects between Compound A and Doxorubicin (Compound B) in the HR deficient breast cancer cell line derived xenograft model HCC1428.

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

[0030] FIG. 3. shows an efficacy study assessing combination effects between Compound A and topotecan (Compound H) in the High-Grade Serous ovarian cancer cell line Kuramochi.

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

[0032] FIG. 5 shows an efficacy study assessing the combination effects between Compound A and Compound J (fam-trastuzumab deruxtecan-nxki) in the Human Lung cancer line NCI-H650.DETAILED DESCRIPTION

[0033] Provided herein is a combination therapy comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof. The 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, the combination therapy is useful for the treatment of any number of PARG-associated diseases.

[0034] Administering a combination of a PARG inhibitor and a topoisomerase inhibitor can provide beneficial effects for treating cancer, e.g., solid tumors, in a subject. Such an approach - combination or co-admini strati on of the two ty pes of agents - may offer an uninterrupted treatment to a subject in need over a clinically relevant treatment period.Definitions

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

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

[0037] As used herein, the articles “a” and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element” means one element or more than one element. Furthermore, use of the term ‘'including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0038] As used herein, the term “about” will be understood by persons of ordinary7skill in the art and will vary7to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term ■‘about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0. 1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0039] As used in the specification and in the claims, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has.” “may.” “contain(s).” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps.

[0040] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x?to about ‘y’”.

[0041] The terms “combination.” “therapeutic combination,” “pharmaceutical combination,” or “combination product” as used herein refer to either a fixed combination in one dosage unit form, or non-fixed combination in separate dosage forms, or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently, at the same time or separately within 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 the present disclosure. Such administration encompasses 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. In addition, such administration also encompasses use of each ty pe of therapeutic agent in a sequential or separate manner, either at approximately 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 treating the conditions or disorders described herein.

[0043] As used herein, the term “treating” or “treatment” refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology7or symptomology of the disease, condition, or disorder (z.e., arresting further development of the pathology7and / or symptomology ) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (z.e., reversing the pathology and / or symptomology7) such as decreasing the severity of the disease.

[0044] As used herein, the term “patient,” “individual,” or “subject” refers to a human.

[0045] As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

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

[0047] As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein a parent compound is modified by converting an existing acid or base moiety7to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts described herein include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts discussed herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The phrase “pharmaceutically acceptable salt” is not limited to a mono, or 1 : 1 , salt. For example, “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton. Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0048] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the composition to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0049] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid fdler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in earn ing or transporting a compound useful to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound disclosed herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar;buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

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

[0051] The term “single formulation” as used herein refers to a single carrier or vehicle formulated to deliver therapeutically effective amounts 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 carriers or excipients. In some embodiments, the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.

[0052] As used herein “Poly ADP-ribose glycohydrolase inhibitor” or “PARG inhibitor” means an agent that modulates the activity of PARG.

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

[0054] In an 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 over the baseline clinically observable signs and symptoms of the disorders treated with the combination. Observable improvements include those that can be visually ascertained by a clinician and biological tests, biopsies, and assays.

[0055] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. Ci-s means one to eight carbons). Alkyl can include any number of carbons, such 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 alky l groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0056] The term '‘Ameliorate” or ‘'amelioration” includes the arrest, prevention, decrease, or improvement in one or more the symptoms, signs, and features of the disease being treated, both temporary7and long-term.

[0057] The term "cycloalky l" refers to a saturated hydrocarbon ring having the indicated number of ring atoms (e.g, C3-6 cycloalkyl). Cycloalkyl is optionally substituted with one, two, or three substituents independently selected from C1-6 alkyl, halo, hydroxy, C1-6 haloalkyl, C 1-6 haloalkoxy, or cyano, unless stated otherwise. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0058] The term "halo" or "halogen," by itself or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0059] The term "haloalkyl," means alkyl, as defined above, that is substituted with 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 alkyl and haloalkyl groups respectively, each as defined herein, that is attached to the remainder of the molecule via an oxygen atom.

[0061] The term "heteroaryl" refers to a 5- to 10-membered aromatic ring that contains from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, 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, furyl, thienyl and the like.

[0062] The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially unsaturated 4 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N. O, and S and the remaining ring atom being carbon. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized and one or two ring carbon atoms of the heterocyclic ring may be replaced by -C=(O) group. Non limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine. butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-di oxane, morpholine, thiomorpholine, thiomorpholine- S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, , and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through 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 above, that is substituted with one or two hydroxy. For example, the term "hydroxyCi-4 alkyl" includes hydroxymethyl, 1-, or 2-hydroxy ethyl, 1,2-dihydroxy ethyl, hydroxypropyl, and the like.

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

[0065] As used herein “homologous recombination deficient (HRD) cancer” refers to a cancer that is characterized by a reduction or absence of a functional HR repair pathway. HR deficiency may arise from absence or reduction of one or more HR-associated genes or presence of one or more mutations in one or more HR-associated genes. Examples of HR- associated genes include BRCA1. BRCA2, RAD54, RAD51B. ATM, BARD1, CHK1, CHK2, CDK12, RAD51B, RAD54L, RAD51D, PPP22A, BRIP1, CtIP (CtBP-interacting protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Wemer syndrome , one or more HR-associated genes) Nbs 1 (Nibrin), and genes encoding Fanconi anemia (FA) proteins or FA-like genes e.g,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 disclosure means an immunoglobulin and is a molecule containing an antigen-binding site immunospecifically binding to an antigen. The class of the antibody of the present disclosure may be any of IgG, IgE, IgM, IgD, IgA, and IgY and is preferably IgG. The subclass of the antibody of the present disclosure may be any of IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2 and is preferably IgGl or IgG2. The antibody may be derived from any species, and preferred examples of the species can include humans, rats, mice, and rabbits. When the antibody is derived from other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody of the present disclosure may be a polyclonal antibody or a monoclonal antibody. In an embodiment, the antibody is a monoclonal antibody. The antibody of the present disclosure is capable of targeting tumor cells. Since the antibody of the present disclosure is conjugated with an antitumor compound having antitumor activity via a linker, the antibody preferably possesses one or more of a property of recognizing a tumor cell, a property of binding to a tumor cell, a property of internalizing in a tumor cell, and a property of damaging a tumor cell. In an embodiment, the antibody is a monoclonal antibody that is reactive with a target antigen or epitope of an antigen expressed on a cancer or malignant cell. Techniques for preparing monoclonal antibodies against target antigen are known in the art. Non limiting target antigens are B7-H3. B7-H4. Trop-2, PSMA, folate receptor, EGF receptor (ErbBl), ErbB2, ErbB3, HER-2, tissue factor, CD- 19, VEGF, insulinlike growth factor (ILGF), MUC1 and TA-MUC1.Combination Product

[0067] Provided herein 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 an embodiment, 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. Inanother aspect, the combination product is useful for the treatment of a homologous recombinant deficient (HRD) cancer.

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

[0069] As used herein, the term '‘combination product” includes embodiments in which the PARG inhibitor and topoisomerase inhibitor are formulated together into a single pharmaceutical composition (e.g. tablet or capsule), and alternative embodiments in which each therapeutic agent in the combination is individually formulated into its own pharmaceutical composition and each of the pharmaceutical compositions are administered in the same medical treatment (for example, the same medical treatment of cancer). In this embodiment, each of the pharmaceutical compositions may have the same or different carriers, diluents or excipients. The carrier(s). diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.

[0070] In one embodiment, the combination product comprises first and second pharmaceutical compositions, 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 pharmaceutical compositions are both administered to treat cancer. The first and second pharmaceutical compositions may 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, e.g. one compound may be administered by injection and another compound may be administered orally.PARG inhibitors

[0071] The disclosure provides PARG inhibitors. In an embodiment, the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of cyano, C1-2 alkyl, and Ci-2haloalkyl;Ar is a 5-membered heteroaryl;X2is CH or CF;R2is selected from the group consisting of C1-3 alkyl, C1-3 haloalkyl, hydroxyCi-salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen. CM alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen, C1-6 alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from hydrogen, CM alkyd, hydroxy, CM alkoxy, halo, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

[0072] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1is selected from the group consisting of cyano, C1-2 alkyd, and C1-2 haloalkyl;Ar is a l,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl;X2is CH or CF;R2is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, hydroxyCi- salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen, C alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen, CM alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from CM alkyl, hydrogen, hydroxy. C alkoxy, halo, C 1-6 haloalkyl, and CM haloalkoxy.

[0073] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein X2is CH. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein X2is CF.

[0074] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R1is cyano.

[0075] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R1is methyl.

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

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

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

[0079] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R2is attached to the carbon atom of Ar that is meta to the atom of Ar that is attached to the nitrogen atom of the remainder of the molecule.

[0080] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R2is attached to Ar, as represented by:

[0081] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R2is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano. In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein R2is difluoromethyl.

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

[0083] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Rais hydrogen, C alkyl, C haloalkyl, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen. CM alkyl, or C haloalkyl); and Rband Rcare independently selected from hydrogen, CM alkyl, hydroxy, CM alkoxy, halo, CM haloalkyl, and CM haloalkoxy.

[0084] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Rais hydrogen C alkyl, or CM haloalkyl; and Rband Rcare independently selected from hydrogen, and CM alkyl.

[0085] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Rais hydrogen, CM alkyl, C 1-4 haloalkyl, or -C(O)Rd(where Rdis C alkyl, or C haloalkyl); and Rband Rcare independently selected from hydrogen, CM alkyl, and CM haloalkoxy.

[0086] In some embodiments, the compound, or the pharmaceutically acceptable salt thereof, is the compound of Formula (I), wherein Rais hydrogen; Rband Rcare each independently hydrogen or CM alkyl.

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

[0088] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is Compound Al :Compound Al.

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

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

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

[0092] The disclosure also provides antibody drug conjugates (ADC) comprising an antitumor compound conjugated to an antibody via a linker. In some embodiments, the antibody is a bispecific antibody. In an embodiment, the antitumor compound is a PARG inhibitor. In an embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is a compound of Formula I. In an embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is Compound A. In an embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is Compound Al.

[0093] It should be noted that reference to a PARG inhibitor also includes reference to their pharmaceutically acceptable salts. In other words, “PARG inhibitor” is synonymous with “PARG inhibitor or a pharmaceutically acceptable salt thereof’.Topoisomerase inhibitors

[0094] The disclosure provides topoisomerase inhibitors for use with a PARG inhibitor. A number of agents with topoisomerase inhibitory activity and methods of making the same are known in the art. Each of these is embraced by this disclosure. In an embodiment, the topoisomerase inhibitor is an inhibitor of type I topoisomerase (also referred herein as Topoisomerase 1 inhibitor). In an embodiment, the topoisomerase inhibitor is an inhibitor of type II topoisomerase (also referred herein as Topoisomerase II inhibitor). In an 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.Table 1

[0095] In some cases, the type II topoisomerase inhibitor is selected from the group consisting of the compounds in Table 1. Methods of making and using the compounds in Table 1 are known in the art.

[0096] In an 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 an embodiment, the type II topoisomerase inhibitor is doxorubicin or a pharmaceutically acceptable salt thereof.

[0097] In an embodiment, the type I topoisomerase inhibitor is topotecan (Compound H) having formula:or a pharmaceutically acceptable salt thereof. Methods of making topotecan are known in the art.

[0098] In still 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 also includes reference to their pharmaceutically acceptable salts. In other words, "Topoisomerase inhibitor” is synonymous with “Topoisomerase inhibitor or a pharmaceutically acceptable salt thereof’.

[0100] Reference to the type II topoisomerase inhibitors in Table 1 is intended to include all versions, for example salts including pharmaceutically acceptable salts, polymorphs and solvates. Reference to the type I topoisomerase inhibitors is intended to include all versions, for example salts including pharmaceutically acceptable salts, polymorphs and solvates.

[0101] The disclosure also provides antibody drug conjugates (ADC) comprising at least two antitumor compounds conjugated to an antibody via a linker. In an embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase inhibitor. In an 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 an embodiment, the antitumor compounds are selected from a PARG inhibitor and a topoisomerase inhibitor, wherein the PARG inhibitor is Compound A. In an embodiment, the antitumor compounds are selected from a PARG inhibitor and a Topoisomerase I inhibitor. In an 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 an embodiment, the antitumor compounds are selected from a PARG inhibitor and a Topoisomerase I inhibitor, wherein the PARG inhibitor is Compound A. In an embodiment, the antitumor compounds are selected from a PARG inhibitor and a Topoisomerase II inhibitor. In an 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 an embodiment, the antitumor compounds are selected from a PARG inhibitor and a Topoisomerase II inhibitor, wherein the PARG inhibitor is Compound A.

[0102] The disclosure also provides antibody drug conjugates (ADC) comprising a topoisomerase inhibitor for use with a PARG inhibitor. A number of ADCs comprising a topoisomerase inhibitor and methods of making the same are known in the art. Each of these is embraced by this disclosure. In an embodiment, the ADC comprising the topoisomerase inhibitor is a Type I topoisomerase inhibitor. In still another embodiment, the ADCcomprising the topoisomerase inhibitor is fam-trastuzumab deruxtecan-nxki (Compound J). In still another embodiment, the ADC comprising the topoisomerase inhibitor is AZD8205. In still another embodiment, the ADC comprising the topoisomerase inhibitor is DS- 1062 (also known as datopotamab deruxtecan). In an embodiment, the PARG inhibitor is a compound of Formula (I). In an embodiment, the PARG inhibitor is Compound A.Combinations of PARG inhibitors and topoisomerase inhibitors

[0103] 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 a pharmaceutically acceptable salt thereof, and Compound H or a pharmaceutically acceptable salt thereof.

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

[0105] In another aspect, provided herein is a combination product comprising Compound Al or a pharmaceutically acceptable salt thereof, and Compound B or a pharmaceutically acceptable salt thereof.

[0106] 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.

[0107] In another aspect, provided herein is a combination product comprising Compound Al or a pharmaceutically acceptable salt thereof, and Compound H or a pharmaceutically acceptable salt thereof.

[0108] In another aspect, provided 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.

[0109] In another aspect, provided herein is a combination product comprising Compound Al or a pharmaceutically acceptable salt thereof, and a compound selected from the groupconsisting of Compound C, Compound D, Compound E, Compound F, and Compound G, or a pharmaceutically acceptable salt thereof.

[0110] The administration of a pharmaceutical combination provided herein may result in a beneficial effect, e.g. a synergistic therapeutic effect, e.g., with regard to alleviating, delaying progression of or inhibiting the symptoms, and may also result in further surprising beneficial effects, e.g., fewer side-effects, an improved quality of life or a decreased morbidity, compared with a monotherapy applying only one of the pharmaceutically active ingredients used in the combination of the disclosure.Methods of Treatment[OHl] In an embodiment, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a PARG inhibitor and administering to the subject a therapeutically effective amount of a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0112] In an embodiment, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subj ect a combination comprising a PARG inhibitor and a topoisomerase inhibitor, together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject.

[0113] In an embodiment, provided herein are methods of treating and / or preventing a homologous recombinant deficient (HRD) cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the subject. In an embodiment, provided herein are methods of treating a homologous recombinant deficient (HRD) cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0114] In an embodiment, provided herein are methods of treating and / or preventing a homologous recombinant deficient (HRD) cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least a pharmaceutically acceptable carrier, thereby treating and / or preventing the cancer in the subject. In an embodiment, provided herein are methods of treating a homologous recombinant deficient (HRD) cancer in a subject in needthereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject. In an embodiment, the HRD cancer is breast cancer. In an embodiment, the HRD cancer is ovarian cancer.

[0115] In an embodiment, provided herein are methods of treating and / or preventing a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the subject, wherein the cancer is homologous recombinant deficient (HRD) cancer and is Estrogen Receptor (ER) positive. In an embodiment, provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject, wherein the cancer is homologous recombinant deficient (HRD) cancer and is Estrogen Receptor (ER) positive.

[0116] In an embodiment, provided herein are methods of treating and / or preventing a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, and is optionally Progesterone Receptor (PR) positive. In an embodiment, provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, and is optionally Progesterone Receptor (PR) positive.

[0117] In an embodiment, provided herein are methods of treating and / or preventing a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, and is optionally human epidermal grow th factor receptor 2 (HER2) negative. In an embodiment, provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, and is optionally human epidermal growth factor receptor 2 (HER2) negative.

[0118] In an embodiment, provided herein are methods of treating and / or preventing a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, is optionally PR positive, and is optionally HER2 negative. In an embodiment, provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, is optionally PR positive, and is optionally HER2 negative. In an embodiment, the cancer tumor is breast or ovarian cancer tumor.

[0119] In an embodiment, provided herein are methods of treating and / or preventing a breast cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, is optionally PR positive, and is optionally HER2 negative. In an embodiment, provided herein are methods of treating a breast cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, is optionally PR positive, and is optionally HER2 negative.

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

[0121] In still another embodiment, the cancer is characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, an absence or mutation of BRCA1 and / or BRCA2 genes, or a reduced function of BRCA1 and / or BRCA2 proteins, or a combination thereof.

[0122] In an embodiment, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subj ect a therapeutically effective amount of a pharmaceutical composition comprising a PARG inhibitor and a therapeuticallyeffective amount of a pharmaceutical composition comprising a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0123] In an embodiment, 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 Al. In one embodiment, the topoisomerase inhibitor is Compound B. In one embodiment, provided is the use of a combination of Compound A and Compound B for the manufacture of a medicament. In one embodiment, the topoisomerase inhibitor is Compound H. In one embodiment, provided is the use of a combination of Compound A and Compound H for the manufacture of a medicament. In one embodiment, provided is 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.

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

[0125] In an embodiment, the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof; wherein the variables are defined supra.

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

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

[0128] In an embodiment, the topoisomerase inhibitor is selected from the group consisting of the compounds in Table 1, or a pharmaceutically acceptable salt or hydrate thereof.

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

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

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

[0132] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof.

[0133] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound H or a pharmaceutically acceptable salt thereof.

[0134] In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound C, Compound D, Compound E, Compound F, Compound G, or a pharmaceutically acceptable salt thereof.

[0135] In another embodiment, provided is a product including 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, provided is a product including Compound A and Compound B as a combination product for simultaneous,separate, or sequential use in medicine. In one embodiment, provided is a product including Compound A and Compound H as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, provided is a product including 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.

[0136] In another embodiment, provided is a product including a PARG inhibitor and a topoisomerase inhibitor as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, the PARG inhibitor is a compound of Formula I. In one embodiment, the PARG inhibitor is Compound A. In one embodiment, provided is a product including Compound A and Compound B as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, provided is a product including Compound A and Compound H as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, provided is a product including 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 treating cancer in a subject.

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

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

[0139] In still another embodiment, the cancer is metastatic. In an embodiment, the disease or disorder is an advanced or metastatic solid tumor.

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

[0141] In an 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.

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

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

[0144] In an embodiment, the PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, are administered orally.

[0145] In an aspect, provided 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.

[0146] In an 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 a subject in need thereof.

[0147] In an embodiment of the methods, the method involves the administration of a therapeutically effective amount of a combination or composition comprising compounds provided herein, or pharmaceutically acceptable salts thereof, to a subject (including, but not limited to a human or animal) in need of treatment (including a subject identified as in need).

[0148] In another embodiment of the methods, the treatment includes co-administering the amount of the PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the amount of the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of the PARG inhibitor or a pharmaceutically acceptable salt thereofand the amount of topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of PARG inhibitor or a pharmaceutically acceptable salt thereof and the amount of topoisomerase inhibitor or a pharmaceutically acceptable salt thereof are in separate formulations or unit dosage forms.

[0149] In the foregoing methods, the treatment can include administering the amount of a PARG inhibitor or a pharmaceutically acceptable salt thereof and the amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of PARG inhibitor or a pharmaceutically acceptable salt thereof and the 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 at dosages that would not be effective when either of PARG inhibitor or a pharmaceutically acceptable salt thereof, or topoisomerase inhibitor or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

[0150] In another embodiment of the methods, the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound B, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound B or a pharmaceutically acceptable salt 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 B or a pharmaceutically acceptable salt thereof are in separate formulations or unit dosage forms.

[0151] In the foregoing methods, the treatment can 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 at substantially 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 foregoing 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 at dosages that would not be effective when one or both ofCompound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

[0152] In another embodiment of the methods, the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound H, or a pharmaceutically acceptable salt thereof. In an embodiment, 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 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.

[0153] In the foregoing methods, the treatment can 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 at substantially 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 foregoing 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 at dosages that would not be effective when one or both of Compound A or a pharmaceutically acceptable salt thereof and Compound H or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.Non-Limiting Exemplary Embodiments:

[0154] In further embodiments 1 to 93 below, the present disclosure includes:

[0155] Embodiment 1. In an embodiment, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor and administering to the subject a therapeutically effective amount of a topoisomerase inhibitor.

[0156] Embodiment 1 A. In embodiment 1 A, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor and administeringto the subject a therapeutically effective amount of an antibody drug conjugate (ADC) comprising a topoisomerase inhibitor.

[0157] Embodiment 1 Al. In embodiment 1 Al, provided is a method of embodiment 1A. wherein the ADC comprises a topoisomerase inhibitor which is a Type I topoisomerase inhibitor.

[0158] Embodiment 1 A2. In embodiment 1 A2, provided is a method of embodiment 1A, wherein the ADC comprising the topoisomerase inhibitor is fam-trastuzumab deruxtecan- nxki.

[0159] Embodiment 1 A3. In embodiment 1 A3, provided is a method of embodiment 1A. wherein the ADC comprising the topoisomerase inhibitor is AZD8205.

[0160] Embodiment 1 A4. In embodiment 1 A4, provided is a method of embodiment 1A, wherein the ADC comprising the topoisomerase inhibitor is DS-1062 (also known as datopotamab deruxtecan).

[0161] Embodiment 2. In an embodiment, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor, wherein the subject is concurrently receiving a topoisomerase inhibitor.

[0162] Embodiment 2A. In embodiment 2A, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor, wherein the subject is concurrently receiving an antibody drug conjugate (ADC) comprising a topoisomerase inhibitor.

[0163] Embodiment 2A1. In embodiment 2A1, provided is a method of embodiment 2A, wherein the ADC comprising a topoisomerase inhibitor is an ADC comprising a Type I topoisomerase inhibitor.

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

[0165] Embodiment 2 A3. In embodiment 2 A3, provided is a method of embodiment 2A, wherein the ADC comprising the topoisomerase inhibitor is AZD8205.

[0166] Embodiment 2A4. In embodiment 2A4, provided is a method of embodiment 2A, wherein the ADC comprising the topoisomerase inhibitor is DS- 1062 (also known as datopotamab deruxtecan).

[0167] Embodiment 3. In an embodiment, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor, wherein the subject has received treatment with a topoisomerase inhibitor.

[0168] Embodiment 3A. In embodiment 3A, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a Poly ADP-ribose glycohydrolase (PARG) inhibitor, wherein the subject has received treatment with an antibody drug conjugate (ADC) comprising a topoisomerase inhibitor.

[0169] Embodiment 3A1. In embodiment 3A1, provided is a method of embodiment 3A. wherein the ADC comprising a topoisomerase inhibitor is an ADC comprising a Type I topoisomerase inhibitor.

[0170] Embodiment 3A2. In embodiment 3A2, provided is a method of embodiment 3A, wherein the ADC comprising the topoisomerase inhibitor is fam-trastuzumab deruxtecan- nxki.

[0171] Embodiment 3A3. In embodiment 3A3, provided is a method of embodiment 3A. wherein the ADC comprising the topoisomerase inhibitor is AZD8205.

[0172] Embodiment 3A4. In embodiment 3A4, provided is a method of embodiment 3A, wherein the ADC comprising the topoisomerase inhibitor is DS- 1062 (also known as datopotamab deruxtecan).

[0173] Embodiment 4. In embodiment 4, provided is the method of any one of embodiments 1 to 3, wherein the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of cyano, C1-2 alkyl, and Ci.2haloalkyl;Ar is a 5-membered heteroaryl;X2is CH or CF;R2is selected from the group consisting of C1-3 alkyl, C 1-3 haloalkyl, hydroxyCi-salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen, C1-4 alkyl, C 1-4 haloalky 1, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen, C1-6 alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from hydrogen, C1-6 alkyd, hydroxy, C1-6 alkoxy, halo, Ci-6 haloalkyl, and C1-6 haloalkoxy.

[0174] Embodiment 5. In embodiment 5, provided is the method of embodiment 4, whereinR1is selected from the group consisting of cyano, C1-2 alkyl, and Ci-2haloalkyl;Ar is a l,3,4-thiadiazol-2-yl or 1,2.4-thiadiazolyl;X2is CH or CF;R2is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, hydroxyCi- salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen. C1-4 alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen, C1-6 alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from C1-6 alkyl, hydrogen, hydroxy, C1-6 alkoxy, halo, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

[0175] Embodiment 6. In embodiment 6, provided is the method of embodiment 4 or5, wherein X2is CH.

[0176] Embodiment 7. In embodiment 7, provided is the method of embodiment 4 or5, wherein X2is CF.

[0177] Embodiment 8. In embodiment 8, provided is the method of any one of embodiments 4 to 7, wherein R1is methyl.

[0178] Embodiment 9. In embodiment 9, provided is the method of any one of embodiments 4 to 7, wherein R1is cyano.

[0179] Embodiment 10. In embodiment 10, provided is the method of any one of embodiments 4 to 9, wherein Ar is 1,2,4-thiadiazolyl or l,3,4-thiadiazol-2-yl.

[0180] Embodiment 11. In embodiment 11, provided is the method of any one of embodiments 4 to 10, wherein Ar is l,3,4-thiadiazol-2-yl.

[0181] Embodiment 12. In embodiment 12, provided is the method of any one of embodiments 4 to 10, wherein Ar is 1.2,4-thiadiazolyl.

[0182] Embodiment 13. In embodiment 13, provided is the method of any one of embodiments 4 to 12, wherein R2is attached to the carbon atom of Ar that is meta to the atom of Ar that is attached to the nitrogen atom of the remainder of the molecule.

[0183] Embodiment 14. In embodiment 14, provided is the method of any one of embodiments 4 to 13, wherein R2is methyl, ethyl, difluoromethyl, trifluoromethyl, cyano

[0184] Embodiment 15. In embodiment 15, provided is the method of any one of embodiments 4 to 14, wherein R2is difluoromethyl.

[0185] Embodiment 16. In embodiment 16, provided is the method of any one of embodiments 4 to 15, wherein ring B is morpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, piperidinyl, 6-oxo-l,6-dihydropyridinyl, or piperazinyl.

[0186] Embodiment 17. In embodiment 17, provided is the method of any one of embodiments 4 to 16, wherein ring B is piperazinyl.

[0187] Embodiment 18. In embodiment 18, provided is the method of any one of embodiments 4 to 17, wherein Rais hydrogen, Ci-4 alkyl, Cw haloalkyl. halo, hydroxy, or - C(O)Rd(where Rdis hydrogen, Ci-6 alky l, or Ci-6 haloalkyl); and Rband Rcare independently selected from Ci-6 alkyl , hydrogen, hydroxy, Ci-6 alkoxy, halo, Ci-6 haloalkyl, and Ci-6 haloalkoxy.

[0188] Embodiment 19. In embodiment 19, provided is the method of any one of embodiments 4 to 17, wherein Rais hydrogen, Ci-4 alkyl, Ci-4 haloalkyl, halo, hydroxy, or - C(O)Rd(where Rdis hydrogen, Ci-6 alky l, or Ci-6 haloalkyl); and Rband Rcare independently selected from hydrogen, Ci-6 alkyl, hydroxy, Ci-6 alkoxy, halo, Ci-6 haloalkyl, and Ci-6 haloalkoxy.

[0189] Embodiment 20. In embodiment 20, provided is the method of any one of embodiments 4 to 17, wherein Rais hydrogen. Ci-4 alkyl, or C 1-4 haloalky 1; and Rband Rcare independently selected from hydrogen and Ci -6 alkyl.

[0190] Embodiment 21. In embodiment 21, provided is the method of any one of embodiments 4 to 17, wherein Rais hydrogen or C1-4 alky l; and Rband Rcare independently selected from C1-6 alkyl and hydrogen.

[0191] Embodiment 22. In embodiment 22, provided is the method of any one of embodiments 4 to 17, wherein Rais hydrogen; Rband Rcare each independently C1-6 alkyl or hydrogen.

[0192] Embodiment 23. In embodiment 23, provided is the method of any one of embodiments 4 to 22, wherein the PARG inhibitor is Compound Al or a pharmaceutically acceptable salt thereof.

[0193] Embodiment 24. In embodiment 24, provided is the method of any one of embodiments 4 to 23, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

[0194] Embodiment 25. In embodiment 25, provided is the method of any one of embodiments 4 to 24, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

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

[0196] Embodiment 26. In embodiment 26, provided is the method of any one of embodiments 4 to 24, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

[0197] Embodiment 27. In embodiment 27, provided is the method of embodiment 26, wherein the topoisomerase II inhibitor is selected from the group consisting of Compound B, Compound C, Compound D. Compound E, Compound F. and Compound G, or a pharmaceutically acceptable salt or hydrate thereof.

[0198] Embodiment 28. In embodiment 28, provided is the method of embodiment 27, wherein the topoisomerase II inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

[0199] Embodiment 29. In embodiment 29, provided is the method of any one of embodiments 1 to 28, wherein the cancer is a homologous recombination deficient (HRD) cancer.

[0200] Embodiment 30. In embodiment 30, provided is the method of any one of embodiments 1 to 29, wherein the cancer is characterized by a reduction or absence of BRCA1 gene expression, an absence or mutation of BRCA1 genes, or a reduced function of BRCA1 proteins.

[0201] Embodiment 31. In embodiment 31, provided is the method of any one of embodiments 1 to 30, wherein the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of BRCA2 genes, or a reduced function of BRCA2 proteins.

[0202] Embodiment 32. In embodiment 32, provided is the method of any one of embodiments 1 to 31 , wherein the cancer is ER positive.

[0203] Embodiment 33. In embodiment , provided is the method of any one of embodiments 1 to 32, wherein the cancer is PR positive

[0204] Embodiment 34. In embodiment 34, provided is the method of any one of embodiments 1 to 33, wherein the cancer is HER2 negative.

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

[0206] Embodiment 35A. In embodiment 35A, provided is the method of any one of embodiments 1 to 34, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer.

[0207] Embodiment 36. In embodiment 36, provided is the method of any one of embodiments 1 to 35, wherein the cancer is breast cancer or ovarian cancer.

[0208] Embodiment 37. In embodiment 37, provided is the method of any one of embodiments 1 to 36, wherein the PARG inhibitor and the topoisomerase inhibitor are in separate dosage forms.

[0209] Embodiment 38. In embodiment 38, provided is the method of any one of embodiments 1 to 36, wherein the PARG inhibitor and the topoisomerase inhibitor are in the same dosage form.

[0210] Embodiment 39. In embodiment 39, provided is a combination product comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

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

[0212] Embodiment 41. In embodiment 41, the PARG inhibitor of embodiment 40 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 4-22.

[0213] Embodiment 42. In embodiment 42, the PARG inhibitor of embodiment 39 or 40 is Compound Al or a pharmaceutically acceptable salt thereof.

[0214] Embodiment 43. In embodiment 43, the PARG inhibitor of embodiment 39 or 40 is Compound A or a pharmaceutically acceptable salt thereof.

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

[0216] Embodiment 44A. In embodiment 44A, the topoisomerase inhibitor of embodiment 44 is Compound H or a pharmaceutically acceptable salt or hydrate thereof.

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

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

[0219] Embodiment 46. In embodiment 46, the topoisomerase inhibitor of embodiment45 is Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G, or a pharmaceutically acceptable salt thereof.

[0220] Embodiment 47. In embodiment 47, the topoisomerase inhibitor of embodiment46 is Compound B or a pharmaceutically acceptable salt thereof.

[0221] Embodiment 48. In embodiment 48, provided 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.

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

[0223] Embodiment 50. In embodiment 50, the PARG inhibitor of embodiment 49 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 4-22.

[0224] Embodiment 51. In embodiment 51 , the PARG inhibitor of embodiment 48 or 49 is Compound Al, or a pharmaceutically acceptable salt thereof.

[0225] Embodiment 52. In embodiment 52, the PARG inhibitor of embodiment 48 or 49 is Compound A, or a pharmaceutically acceptable salt thereof.

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

[0227] Embodiment 53A. In embodiment 53A, the topoisomerase inhibitor of embodiment 53 is Compound H or a pharmaceutically acceptable salt or hydrate thereof.

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

[0229] Embodiment 55. In embodiment 55, the topoisomerase inhibitor of embodiment54 is Compound B, Compound C. Compound D, Compound E. Compound F, or Compound G, or a pharmaceutically acceptable salt thereof.

[0230] Embodiment 56. In embodiment 56, the topoisomerase inhibitor of embodiment55 is Compound B or a pharmaceutically acceptable salt thereof.

[0231] Embodiment 57. In embodiment 57, provided 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

[0232] Embodiment 57 A. In embodiment 57A, provided 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

[0233] Embodiment 58. In embodiment 58, provided is a PARG inhibitor for use in treating cancer, wherein the PARG inhibitor is to be administered simultaneously or sequentially with a topoisomerase inhibitor.

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

[0235] 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 one of embodiments 4-22.

[0236] Embodiment 61. In embodiment 61, the PARG inhibitor of embodiment 58 or 59 is Compound Al, or a pharmaceutically acceptable salt thereof.

[0237] Embodiment 62. In embodiment 62, the PARG inhibitor of embodiment 58 or 59 is Compound A, or a pharmaceutically acceptable salt thereof

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

[0239] Embodiment 63A. In embodiment 63 A, the topoisomerase inhibitor of embodiment 63 is Compound H or a pharmaceutically acceptable salt or hydrate thereof.

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

[0241] Embodiment 65. In embodiment 65, the topoisomerase inhibitor of embodiment64 is Compound B, Compound C, Compound D, Compound E, Compound F, or Compound G, or a pharmaceutically acceptable salt thereof.

[0242] Embodiment 66. In embodiment 66, the topoisomerase inhibitor of embodiment65 is Compound B or a pharmaceutically acceptable salt thereof.

[0243] Embodiment 67. In embodiment 67, provided is a PARG inhibitor for use in treating 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 B or a pharmaceutically acceptable salt thereof.

[0244] Embodiment 67A. In embodiment 67A, provided is a PARG inhibitor for use in treating 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.

[0245] Embodiment 68. In embodiment 68, provided is the use of any one of embodiments 58 to 67. wherein the cancer is a homologous recombination deficient (HRD) cancer.

[0246] Embodiment 69. In embodiment 69, provided is the use of any one of embodiments 58 to 68, wherein 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.

[0247] Embodiment 70. In embodiment 70, provided is the use of any one of embodiments 58 to 69, wherein 9the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of BRCA2 genes, or a reduced function of BRCA2 proteins.

[0248] Embodiment 71. In embodiment 71, provided is the use of any one of embodiments 58 to 70. wherein the cancer is ER positive.

[0249] Embodiment 72. In embodiment 72, provided is the use of any one of embodiments 58 to 71, wherein the cancer is PR positive.

[0250] Embodiment 73. In embodiment 73, provided is the use of any one of embodiments 58 to 72, wherein the cancer is HER2 negative.

[0251] Embodiment 74. In embodiment 74, provided is the use of any one of embodiments 58 to 73. wherein the cancer is breast cancer, ovarian cancer, endometrialcancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and prostate cancer.

[0252] Embodiment 74A. In embodiment 74A, provided is the use of any one of embodiments 58 to 73, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer.

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

[0254] Embodiment 76. In embodiment 76, provided is a use of a PARG inhibitor in the manufacture of a medicament for treating cancer, wherein the PARG inhibitor is to be administered simultaneously or sequentially with a topoisomerase inhibitor.

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

[0256] 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 one of embodiments 4-22.

[0257] Embodiment 79. In embodiment 79, the PARG inhibitor of embodiment 76 or 77 is Compound Al, or a pharmaceutically acceptable salt thereof.

[0258] Embodiment 80. In embodiment 80, the PARG inhibitor of embodiment 76 or 77 is Compound A, or a pharmaceutically acceptable salt thereof.

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

[0260] Embodiment 81A. In embodiment 81A, the topoisomerase inhibitor of embodiment 81 is Compound H or a pharmaceutically acceptable salt or hy drate thereof.

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

[0262] 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.

[0263] Embodiment 84. In embodiment 84, the topoisomerase inhibitor of embodiment 83 is Compound B or a pharmaceutically acceptable salt thereof.

[0264] Embodiment 85. In embodiment 85, provided is a use of a PARG inhibitor in the manufacture of a medicament for treating 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 B or a pharmaceutically acceptable salt thereof.

[0265] Embodiment 85A. In embodiment 85A, provided is a use of a PARG inhibitor in the manufacture of a medicament for treating 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.

[0266] Embodiment 86. In embodiment 86, provided is the use of any one of embodiments 76 to 85A, wherein the cancer is a homologous recombination deficient (HRD) cancer.

[0267] Embodiment 87. In embodiment 87, provided is the use of any one of embodiments 76 to 86, wherein the cancer is characterized by a reduction or absence of BRCA1 gene expression, an absence or mutation of BRCA1 genes, or a reduced function of BRCA1 proteins.

[0268] Embodiment 88. In embodiment 88, provided is the use of any one of embodiments 76 to 87, wherein the cancer is characterized by a reduction or absence of BRCA2 gene expression, an absence or mutation of BRCA2 genes, or a reduced function of BRCA2 proteins.

[0269] Embodiment 89. In embodiment 89, provided is the use of any one of embodiments 76 to 88, wherein the cancer is ER positive.

[0270] Embodiment 90. In embodiment 90, provided is the use of any one of embodiments 76 to 89, wherein the cancer is PR positive.

[0271] Embodiment 91. In embodiment 91, provided is the use of any one of embodiments 76 to 90. wherein the cancer is IIER2 negative.

[0272] Embodiment 92. In embodiment 92, provided is the use of any one of embodiments 76 to 91. wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and prostate cancer.

[0273] Embodiment 92A. In embodiment 92A, provided is the use of any one of embodiments 76 to 91, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, gastric cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer.

[0274] Embodiment 93. In embodiment 93, provided is the use of any one of embodiments 76 to 92, wherein the cancer is breast cancer or ovarian cancer.

[0275] For the embodiments above, when reference is made to previous embodiments, the reference will include those embodiments having lettered notations or combinations. For example, reference to embodiments 1-3 will include embodiments 1, 1A. 1A1, 1A2, 1A3, 1A4, 2, 2A, 2A1, 2A2, 2A3, 2A4, 3, 3A, 3A1, 3A2, 3A3 and 3A4.Additional Non-Limiting Exemplary Embodiments:

[0276] Embodiment 1. In embodiment 1 , provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a P ARG inhibitor and administering to the subject a therapeutically effective amount of a topoisomerase inhibitor, wherein the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of cyano, C1-2 alkyl, and Ci-2haloalkyl:Ar is a l,3,4-thiadiazol-2-yl or 1,2.4-thiadiazolyl;X2is CH or CF;R2is selected from the group consisting of C1-3 haloalkyl, C1-3 alky l, hydroxyCi-salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen, C1-4 alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen, C1-6 alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from C 1-6 alkyl, hydrogen, hydroxy, C1-6 alkoxy, halo, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

[0277] Embodiment 2. In embodiment 2, provided is the method of embodiment 1, wherein X2is CH.

[0278] Embodiment 3. In embodiment 3, provided is the method of embodiment 1 or2, wherein R1is methy l.

[0279] Embodiment 4. In embodiment 4, provided is the method of embodiment 1 or2, wherein R1is cyano.

[0280] Embodiment s. In embodiment 5. provided is the method of any one of embodiments 1 to 4, wherein Ar is l,3,4-thiadiazol-2-yl.

[0281] Embodiment 6. In embodiment 6, provided is the method of any one of embodiments 1 to 5, wherein R2is attached to the carbon atom of Ar that is meta to the atom of Ar that is attached to the nitrogen atom of the remainder of the molecule.

[0282] Embodiment 7. In embodiment 7, provided is the method of any one of embodiments 1 to 6, wherein R2is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano.

[0283] Embodiment 8. In embodiment 8, provided is the method of any one of embodiments 1 to 7, wherein R2is difluoromethyl.

[0284] Embodiment 9. In embodiment 9, provided is the method of any one of embodiments 1 to 8, wherein ring B is morpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, piperidinyl, 6-oxo- 1.6-dihydropyridinyl. or piperazinyl.

[0285] Embodiment 10. In embodiment 10, provided is the method of any one of embodiments 1 to 9, wherein ring B is piperazinyl.

[0286] Embodiment 11. In embodiment 11, provided is the method of any one of embodiments 1 to 10, wherein Rais hydrogen, C1-4 alkyl, C 1-4 haloalkyl, halo, hydroxy, or - C(O)Rd(where Rdis hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl); and Rband Rcare independentlyselected from Ci-6 alkyl , hydrogen, hydroxy, Ci-6 alkoxy, halo, Ci-ehaloalkyl, and Ci-6 haloalkoxy.

[0287] Embodiment 12. In embodiment 12, provided is the method of any one of embodiments 1 to 11, wherein Rais hydrogen Ci-4 alkyl, or Ci.4haloalkyl; and Rband Rcare independently selected from Ci-6 alkyl and hydrogen.

[0288] Embodiment 13. In embodiment 13, provided is the method of any one of embodiments 1 to 12, wherein Rais hydrogen; Rband Rcare each independently Ci-6 alkyl or hydrogen.

[0289] Embodiment 14. In embodiment 14, provided is the method of any one of embodiments 1 to 13, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.Embodiment 15. In embodiment 15, provided is the method of any one of claims 1 to 14, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

[0290] Embodiment 16. In embodiment 16, provided is the method of any one of embodiments 1 to 15, wherein the topoisomerase inhibitor is selected from the group consisting of Compound B, Compound C, Compound D, Compound E, Compound F, and Compound G, or a pharmaceutically acceptable salt or hy drate thereof.

[0291] Embodiment 17. In embodiment 17, provided is the method of any one of embodiments 1 to 16, wherein the topoisomerase inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

[0292] Embodiment 18. In embodiment 18, provided is the method of any one of embodiments 1 to 14, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0293] Embodiments 19. In embodiment 19, provided is the method of any one of embodiments 1 to 14, wherein the topoisomerase inhibitor is Compound H or a pharmaceutically acceptable salt thereof.

[0294] Embodiment 20. In embodiment 20, provided is the method of any one of embodiments 1 to 19, wherein the cancer is a homologous recombination deficient (HRD) cancer.

[0295] Embodiment 21. In embodiment 21, provided is the method of any one of embodiments 1 to 20, wherein the cancer is characterized by a reduction or absence ofBRCA1 and / or BRCA2 gene expression, an absence or mutation of BRCA1 and / or BRCA2 genes, or a reduced function of BRCA1 and / or BRCA2 proteins.

[0296] Embodiment 22. In embodiment 22, provided is the method of any one of embodiments 1 to 21, wherein the cancer is breast cancer, lung cancer, or ovarian cancer.

[0297] Embodiment 23 In embodiment 23, provided is the method of any one of embodiments 1 to 22, wherein the PARG inhibitor and the topoisomerase inhibitor are in separate dosage forms.

[0298] Embodiment 24. In embodiment 24, provided is the method of any one of embodiments 1 to 22, wherein the PARG inhibitor and the topoisomerase inhibitor are in the same dosage form.

[0299] Embodiment 25. In embodiment 25, provided is a combination comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof.

[0300] Embodiment 26. In embodiment 26, provided is the combination of embodiment 25, wherein the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of cyano, C1-2 alkyl, and Ci.2haloalkyl;Ar is a l,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl;X2is CH or CF;R2is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, hydroxyCi-salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen, C1-4 alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen, C1-6 alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from Ci-6 alkyl, hydrogen, hydroxy, Ci-6 alkoxy, halo, Ci-e haloalkyl, and Ci-6 haloalkoxy.

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

[0302] Embodiment 28. In embodiment 28, provided is the combination of any one of embodiments 25 to 27, wherein the topoisomerase inhibitor is ty pe II topoisomerase inhibitor.

[0303] Embodiment 29. In embodiment 29, provided is the combination of any one of embodiments 25 to 28. wherein the topoisomerase inhibitor is selected from the group consisting of a compound B, compound C, compound D, compound E, compound F, and compound G, or a pharmaceutically acceptable salt thereof.

[0304] Embodiment 30. In embodiment 30, provided is the combination of any one of embodiments 25 to 29. wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

[0305] Embodiment 31. In embodiment 31, provided is the combination of any one of embodiments 25 to 27, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0306] Embodiment 32. In embodiment 32, provided is the combination of any one of embodiments 25 to 27. wherein the topoisomerase inhibitor is Compound H or a pharmaceutically acceptable salt thereof.

[0307] Embodiment 33. In embodiment 33, provided is a PARG inhibitor for use in treating cancer, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor.

[0308] Embodiment 34. In embodiment 34, provided is the use of embodiment 33, wherein the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of cyano, C1-2 alkyl, and Ci.2haloalkyl;Ar is a l,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl;X2is CH or CF;R2is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, hydroxyCi-salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen, C1-4 alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen, C1-6 alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from C1-6 alkyl, hydrogen, hydroxy, C1-6 alkoxy, halo, C1-6 haloalkyl, and C1-6 haloalkoxy.

[0309] Embodiment 35. In embodiment 35, provided is the use of embodiments 33 or 34, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

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

[0311] Embodiment 37. In embodiment 37, provided is the use of any one of embodiments 33 to 36, wherein the topoisomerase inhibitor is selected from the group consisting of Compound B, Compound C, Compound D, Compound E. Compound F, and Compound G, or a pharmaceutically acceptable salt thereof.

[0312] Embodiment 38. In embodiment 38, provided is the use of any one of embodiments 33 to 37, wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

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

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

[0315] Embodiment 41. In embodiment 41, provided is use of a PARG inhibitor in the manufacture of a medicament for treating cancer, wherein the PARG inhibitor is to be administered simultaneously or sequentially with a topoisomerase inhibitor.

[0316] Embodiment 42. In embodiment 42, provided is the use of embodiment 41, wherein the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of cyano, C1-2 alkyl, and Ci-2haloalkyl;Ar is a l,3,4-thiadiazol-2-yl or 1,2.4-thiadiazolyl;X2is CH or CF;R2is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, hydroxyCi-?alkyl, and cyano; ring B is 5- or 6-membered heterocy cloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen. C1-4 alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd(where Rdis hydrogen, C1-6 alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from C1-6 alkyl, hydrogen, hydroxy, C1-6 alkoxy, halo, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

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

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

[0319] Embodiment 45. In embodiment 45, provided is the use of any one of embodiments 41 to 44, 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.

[0320] Embodiment 46. In embodiment 46, provided is the use of any one of embodiments 41 to 45. wherein the PARG inhibitor is Compound A or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

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

[0322] Embodiment 48. In embodiment 48, provided is the use of any one of embodiments 41 to 43, wherein the topoisomerase inhibitor is Compound H or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 49. In embodiment 49, provided is the use of any one of embodiments 33 to 48, wherein the cancer is a homologous recombination deficient (HRD) cancer.

[0324] Embodiment 50. In embodiment 50, provided is the use of any one of embodiments 33 to 49, wherein the cancer is characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, an absence or mutation of BRCA1 and / or BRCA2 genes, or a reduced function of BRCA1 and / or BRCA2 proteins.

[0325] Embodiment 51. In embodiment 51 , provided is the use of any one of embodiments 33 to 50, wherein the cancer is breast cancer, lung cancer, or ovarian cancer.Pharmaceutical Compositions

[0326] In an 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.

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

[0328] In another aspect, provided herein 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.

[0329] In an embodiment, the PARG inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt thereof; wherein the variables are defined supra.

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

[0331] In another embodiment, the topoisomerase inhibitor is selected from the group consisting of the compounds in Table 1 or a pharmaceutically acceptable salt or hydrate thereof.

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

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

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

[0335] In yet another aspect, provided 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 compositioncomprising a therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof.

[0336] In yet another aspect, provided 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.

[0337] In still another aspect, provided 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.

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

[0339] 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.

[0340] 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

[0341] In another aspect, provided herein is a pharmaceutical composition or pharmaceutical combination comprising the compounds disclosed herein, together with a pharmaceutically acceptable carrier.

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

[0343] Administration of the combination includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurrently but separately, or administration of the individual agents of the combination sequentially by any suitable route. The dosage of the individual agents of the combination may require more frequent administration of one of the agent(s) as compared to the other agent(s) in the combination. Therefore, to permit appropriate dosing, packaged pharmaceutical products may contain one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the combination of agents, but not the other agent(s) of the combination.

[0344] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0345] In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

[0346] A medical doctor, e.g, physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0347] In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to betreated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a disclosed compound for the treatment of pain, a depressive disorder, or drug addiction in a patient.

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

[0349] The optimum ratios, individual and combined dosages, and concentrations of the drug compounds that yield efficacy without toxicity are based on the kinetics of the active ingredients' availability to target sites.

[0350] Routes of administration of any of the compositions discussed herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g.. trans- and penvaginally), (intra)nasal and (trans)rectal). intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

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

[0352] For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gel caps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceuticallyexcipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0353] For parenteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.

[0354] In one embodiment, in particular when the topoisomerase inhibitor is doxorubicin, it may be administered via injection, in some embodiments. In one embodiment, doxorubicin is administered by capsule. In another embodiment, doxorubicin is administered intravenously.Kits

[0355] In an aspect, the present disclosure provides a kit for treating cancer comprising a PARG inhibitor, or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

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

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

[0358] In additional embodiments, pharmaceutical kits are provided. The kit includes a sealed container approved for the storage of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions. In some embodiments, the sealed container minimizes the contact of air with the ingredients, e g. an airless bottle. Inother embodiments, the sealed container is a sealed tube. An instruction for the use of the composition and the information about the composition are to be included in the kit.

[0359] In a particular embodiment, the compounds of the combination can be dosed on the same schedule, whether by administering a single formulation or unit dosage form containing all of the compounds of the combination, or by administering separate formulations or unit dosage forms of the compounds of the combination. However, some of the compounds used in the combination may be administered more frequently than once per day, or with different frequencies that other compounds in the combination. Therefore, in one embodiment, the kit contains a formulation or unit dosage form containing all of the compounds in the combination of compounds, and an additional formulation or unit dosage form that includes one of the compounds in the combination of agents, with no additional active compound, in a container, with instructions for administering the dosage forms on a fixed schedule.

[0360] The kits provided herein include prescribing information, for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.

[0361] In all of the foregoing the combination of compounds of the disclosure can be administered alone, as mixtures, or with additional active agents.

[0362] A kit provided herein can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing). A kit can contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s). including mechanism(s) of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.).

[0363] Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. Labels or inserts can include manufacturer information such as lot numbers and expiration dates. The label or packaging insert can be. e.g., 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 ampule, syringe or vial).

[0364] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto.

[0365] It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

[0366] The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings of the present disclosure as set forth.EXAMPLES

[0367] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art.Example 1Preparation of Compound A(Compound A)Step 1: Preparation of 2,6-difluoro-4-iodobenzaldehyde

[0368] To a stirred solution of l,3-difluoro-5-iodobenzene (Compound 1) (50 g. 208.3mmol, Oakwood Chemical, CAS 2265-91-0, catalogue #024566) in THF (500 mL) was added LDA (80 mL, 625.0 mmol) and DMF (48.3 mL, 625mmol) at -78°C and stirred at - 78 °C for 2 h. After complete consumption of 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 brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to get 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 gradient of 30% EtOAc / Hexane. The purified fractions were concentrated under reduced pressure to afford 2,6-difluoro-4-iodobenzaldehyde (Compound 2) (23 g) as a solid. 'H NMR (500MHz, CHLOROFORM-d) 5: 10.29 (s, 1H), 7.37-7.46 (m, 2H).Step 2: Preparation of 4-fluoro-6-iodo-lH-indazoleN2H4 H2O

[0369] To a stirred solution of 2,6-difluoro-4-iodobenzaldehyde (Compound 2) (5 g, 18.6 mmol) in 1,4 dioxane (110 mL) was added hydrazine hydrate (18.6 mL, 373.1 mmol) at RT 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 solid was precipitated out. The mixture was filtered. The solid was washed with water (100 mL), w-pentane (50 mL), and dried under vacuum to afford product 4-fluoro-6-iodo-lH-indazole (Compound 3) (2.3 g) as a solid. MS ESI calculated for C7H4FIN2 [M+H]+262.94., found 262.99. *H NMR (CDCh, 400 MHz): 10.12 (s, 1 H), 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-lH-indazol-l-yl)-l,3,4- thiadiazole

[0370] To a stirred solution of 4-fluoro-6-iodo-lH-indazole (Compound 3) (5 g, 19.0 mmol) in DMF (50 mL) was added cesium carbonate (18.6 g, 57.24 mmol) and 2-bromo-5- (difluoromethyl)-l,3,4-thiadiazole (Compound 4) (3.8 g, 18.1 mmol, Enamine Stock Building Blocks. CAS 1340313-49-6. catalogue #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 solid precipitated out. The mixture was filtered. The solid collected was washed with water (100 mL) followed by / 7-pentane (100 mL), and dried under vacuum to afford 2- (difluoromethyl)-5-(4-fluoro-6-iodo-lH-indazol-l-yl)-l,3,4-thiadiazole (Compound 5) (4.2 g) as a solid. MS ESI calculated for C10H4F3IN4S [M+H]+396.92., found 396.91. 'H NMR (CDCh, 500 MHz): 8.87 (s, 1 H), 8.29 (s, 1H), 7.40 (dd, J= 17 Hz, 1H), 7.0 (t, J= 53.5 Hz, 1H).Step 4: Preparation of S-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-fluoro-lH- indazol-6-yI) benzothioate

[0371] To a stirred solution of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-lH-indazol-l-yl)- 1,3,4-thiadiazole (Compound 5) (100 mg, 0.25 mmol) in toluene (1 mL) degassed for 5 min,was added Cui (5 mg, 0.025 mmol), 1,10-phenanthroline (phen) (11 mg, 0.05 mmol), and potassium thiobenzoate (67 mg, 0.378mmol) at RT. 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 afford S-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-fluoro-lH- indazol-6-yl) benzothioate (Compound 6) (55 mg) as a solid. MS ESI calculated for C17H9F3N4OS2 [M+H]+407.02., found 407.01. 'H NMR (CDCI3, 400 MHz): 8.68 (s, 1 H), 8.39 (s, 1H), 8.03 (d, J= 7.6 Hz, 2H), 7.64 (t, J= 7.2 Hz, 1H), 7.53 (t, J= 7.6 Hz, 2H), 7.27 (s, 1H). 6.99 (t. J= 53.2 Hz, 1H).Step 5: Preparation of N-(l -cy anocyclop ropy 1)-1 -(5-(difhioromethy 1)-1, 3, 4-thiadiazol-2- yl)-4-fluoro-lH-indazole-6-sulfonamide1. TCCA, BnMe3NCI

[0372] To a stirred solution of S-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-fluoro-lH- indazol-6-yl) benzothioate (Compound 6) (500 mg, 1.23 mmol) in acetonitrile (10 mL) at 0 °C were added a solution of BnMesNCl (682 mg, 3.69 mmol), and TCCA (trichloroisocyanuricacid) (370 mg 1.59 mmol) in acetonitrile (40 mL). The reaction mixture was stirred for 20 min. Then a solution of 1-methyl cyclopropane- 1 -amine (1.71 g. 7.38 mmol, Combi-Blocks, CAS 22936-83-0, catalogue QH-3639) in pyridine (2.5 mL) and cesium carbonate (198 mg, 0.61 mmol) were added to the reaction mixture at 0 °C and stirred at RT for 2 h. The progress of the reaction was monitored by LCMS. LCMS showed complete consumption of starting material (S-(l-(5-(difluoromethyl)-1.3,4-thiadiazol-2-yl)-4- fluoro-lH-indazol-6-yl) benzothioate) (Compound 6). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x30 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous sodium sulphate, filtered and the filterate was concentrated under reduced pressure to obtain crude product. The crude productwas purified by column chromatography using silica gel (100-200) and eluted with 5 to 50% EtOAc / hexane as a gradient. The product was eluted at 20% EtOAc / hexane. The purified fractions were collected and concentrated under reduced pressure to afford l-(5- (difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-fluoro-N-(l-methylcyclopropyl)-lH-indazole-6- sulfonamide (Compound 7) (90 mg) as a solid. MS ESI calculated for C14H9F3N6O2S2 [M+H]+404.04., found 404.18. *H NMR (CDCI3, 400 MHz): 9.00 (s. 1 H), 8.80 (s, 1H), 8.54 (s, 1H). 7.63 (t. J= 48.8 Hz, 2H). 1.10 (s, 3 H), 0.65 (s, 2 H), 0.44 (s, 2H).Step 6: Preparation of tert-butyl (2S,6S)-4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)- 6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l- carboxylate

[0373] To a stirred solution of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-fluoro-N-(l- methylcyclopropyl)-lH-indazole-6-sulfonamide (Compound 7) (80 mg, 0.19 mmol) in DMSO (dimethyl sulfoxide) (2 mL) were added tert-butyl (2S,6S)-2,6-dimethylpiperazine-l- carboxylate (85 mg, 0.39 mmol, BLD Pharmatech, CAS 574007-66-2, catalogue BD233798) and DIPEA (N,N-diisopropyl ethylamine) (0.1 mL, 0.59 mmol) and 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 obtained solid was filtered, washed with water (10 mL), dried under vacuum and purified by column chromatography over silica gel (100-200) and eluted with 50% EtOAc / hexane as a gradient, purified fractions concentrated under reduced pressure to afford tert-butyl (2.S'.65')-4-( l -(5-(difluoromethyl)- l .3.4-thiadiazol-2-yl)-6-(N-(l - methylcyclopropyl) sulfamoyl)-lH-indazol-4-yl)-2,6-dimethylpiperazine-l-carboxylate (Compound 8) (110 mg, yield: 92%) as a solid. MS ESI calculated for C25H33F2N7O4S2 [M+H]+598.20, found 598.26.Step 7: Preparation of l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-((3S,5S)-3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (Compound A)

[0374] To a stirred solution of / e / -butyl (2S, 65)-4-(l-(5-(difluoromethyl)-l,3,4-thiadiazol- 2-yl)-6-(N-(l-methylcyclopropyl)sulfamoyl)-lH-indazol-4-yl)-2,6-dimethyl piperazine-1- carboxylate (Compound 8) (100 mg, 0.16mmol) in DCM (3 mL) was added trifluoroacetic acid (0.07 mL, 0.98 mmol) at 00C and reaction mixture was stirred at RT for 12 h. The reaction mixture was concentrated under reduced pressure, purified by Prep HPLC purification (Prep 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 afford l-(5-(difluoromethyl)-l,3,4-thiadiazol-2-yl)-4-((3<S',5S -3,5- dimethylpiperazin-l-yl)-N-(l-methylcyclopropyl)-lH-indazole-6-sulfonamide (Compound A) (18 mg, yield: 21%) as a solid. MS ESI calculated for C20H25F2N7O2S2 [M+H]+498.15, found 498.34. 'H NMR (DMSO-d6, 400 MHz): 5 (ppm) 8.75 (s, 1H), 8.40 (s, 1H), 8.31 (s, 1H), 7.59 (t, J= 52.8 Hz, 1H), 7.10 (d, J= 1.0 Hz, 1H), 3.37 (br dd, J= 11.5, 2.9 Hz. 2H), 3.22-3.30 (m, 2H), 3.08 (br dd, J= 11.7. 6.1 Hz, 2H), 1.17 (d. J= 6.4 Hz. 6H), 1.08 (s. 3H), 0.58-0.76 (m, 2H), 0.29-0.49 (m, 2H).Example 2Efficacy study assessing combination effects between Compound A and doxorubicin (Compound B) in the HR deficient breast cancer cell line derived xenograft model HCC1428

[0375] The combination effect between Compound A and doxorubicin was assessed using a cell line derived xenograft (CDX) model of the breast cancer line HCC1428 harboring 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 mm3was achieved as described in Table 2, with a study treatment duration of 35 days. For this xenograft, supplemental estradiol benzoate injections (40 pg / 20 pl / mouse) were administered subcutaneously twice a week, starting one week prior to cell implantation and continuing through to the end of treatment.

[0376] Compound A was administered at 30 mg / kg and 100 mg / kg once daily (QD), leading to a tumor growth inhibition (TGI) of 63.2% and 102.5% respectively, and doxorubicin administered intravenously at 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 1 10% for the groups administered 30 mg / kg and 100 mg / kg of Compound A, respectively, with 50% of animal in the combination group administered Compound A at 100 mg / kg achieving complete regressions. Statistically significant differences in TGI between single agent and combination groups were observed with both the 30 mg / kg and 100 mg / kg doses of Compound A, highlighting the enhanced anti -tumor effect of this combination (Table 3 and Figure 1 (FIG. 1)). Although no mortalities were noted within 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.Table 3: CDX HCC1428 treated with Compound A and / or doxorubicinExample 3Efficacy study assessing combination effects between Compound A and topotecan (Compound H) in the small cell lung cancer cell line NCI-H69

[0377] The combination effect between Compound A and topotecan was assessed using a cell line derived xenograft (CDX) model of the small cell lung cancer line NCI-H69 harboring 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 mm3was achieved. The study consisted of six treatment arms containing ten mice per group with a duration of 42 days on treatment. TGI was calculated on Day 21 when the vehicle group was terminated as the maximum allowable tumor burden was reached.

[0378] Compound A was administered at 100 mg / kg, leading to a TGI of 53%, and topotecan administered at 0.25 mg / kg and 1 mg / kg produced TGI values of 79% and 80% respectively (see Table 4 for dose schedule). Both doses of topotecan showed a combination effect with the 0.25 mg / kg dose having a TGI of 79%, and 1 mg / kg a TGI of 105% with 7 out of 10 animals showing complete regressions by 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.Example 4Efficacy study assessing combination effects between Compound A and topotecan (Compound H) in the High-Grade Serous ovarian cancer cell line Kuramochi.

[0379] The combination effect between Compound A and topotecan was assessed using a cell line derived xenograft (CDX) model of the High-Grade Serous ovarian cancer cell lineKuramochi which harbors a BRCA2 mutation (nonsense). 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 once a mean tumor volume of approximately 100-150 mm3was achieved. The study consisted of four treatment arms containing six to eight mice per group, with a duration of 63 days on treatment. TGI was calculated on Day 41 when the vehicle group was terminated as the maximum allowable tumor burden was reached.

[0380] Compound A was administered at 100 mg / kg, leading to a TGI of 103%, and topotecan administered at 1 mg / kg produced TGI value of 77% (see Table 5 for dose schedule). The combination arm a TGI of 108% with 6 out of 6 animals showing complete regressions by 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.Example 5 Inhibition of PARG enzymatic assay (TR-FRET)Enzymatic ECso Assay

[0381] PARG enzyme was incubated with compound or vehicle (DMSO) and the biotinylated-PARylated PARP-1 substrate in a microtiter plate. After adding detection antibody and streptavidin-europium. and then incubating, the plate was read for fluorescence intensity. The low control (DMSO) with low fluorescence intensity represents no inhibition of enzymatic activity, while the high control (no enzyme) with high fluorescence intensity represents full inhibition of enzymatic activity.Materials:Enzy me: PARG o hPARG: 250 pM, 1-976, His-tagged, Proteos, 2.0 mg / mL (17.9 pM) o Substrate: 30 nM o Test Compound / Enzyme Pre-incubation time: 1 hr o Enzyme / Substrate Reaction time: 10 minutesSubstrate: hPARPl, His6-TEV tagged, 1.2 mg / mL (10.3 pM)Detection Antibody: anti -His monoclonal antibody -ULight, Perkin Elmer catalog # TRF0134-MStreptavidin-Europium: Perkin Elmer catalog # AD0062Assay Buffer: 50mM Tris-HCL pH 7.4, 50mM KCL, 3mM EDTA, 0.4mM EGTA, ImM DTT, 0.01% Tween 20, 0.01% BSATemperature: 23 °CTotal reaction volume: 20 pL Controls:• 0% inhibition: DMSO• 100% inhibiton: No enzymeEnzyme reaction and Detection:1. Transfer 200nL of lOOx compound or DMSO to the appropriate wells of a 384 well white polystyrene microtitre plate (Coming Catalog#3574).2. Transfer 10 uL of 2x final concentration of enzyme in assay buffer or assay buffer alone to the appropriate wells.3. Centrifuge the plate at 1000 rpm for 30 seconds.4. Incubate the plate at room temperature for 1 hour.5. Transfer 10 uL of 2x substrate in assay buffer to all test wells.6. Incubate the plate at room temperature for 10 minutes7. Transfer 10 uL of 3x mixture of 42nM detection antibody and 2.25nM streptavidineuropium in 50mM Tris-HCL pH 7.4 to all test wells.8. Incubate the plate at room temperature for 1 hour.9. Read the plate on a plate reader (Envision)Excitation: 317nMEmission: 620nMEmission: 665nMData Analysis:

[0382] EC50 values were calculated in Collaborative Drug Discovery vault (CDD). Curves were fitted by CDD as response (%) vs compound concentration (uM) using a 4-parameter inhibition model using Formula 1.

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

[0384] The TR-FRET EC50 value for Compound A is provided in Table 6, below.

[0385] TR-FRET: **** <= 0.1 pMTable 6. TR-FRET Assay Results for Compounds of Formula (I).Example 6Efficacy study assessing combination effects between Compound A and topotecan (Compound H) in the Breast cancer model HCC1395

[0386] The combination effect between Compound A and topotecan was assessed using a cell line derived xenograft (CDX) model of the breast cancer (TMBC) HCC1395 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 once a mean tumor volume of approximately 100-150 mm3was achieved. The study consisted of four treatment arms containing eight mice per group, with a duration of 35 days on treatment. TGI was calculated on Day 35

[0387] Compound A was administered at 100 mg / kg, leading to a TGI of 56%, and topotecan administered at 1 mg / kg produced TGI value of 98% (see Table 7 for dose schedule). The combination arm a TGI of 102% These results highlight the robust anti cancer efficacy of Compound A in combination with the topoisomerase I inhibitor topotecan (Figure 4, (FIG. 4)).Table 7: Study groups for CDX HCC1395 treated with Compound A and / or topotecan.FIG. 4Example 7Efficacy study assessing combination effects between Compound A and Compound J (fam-trastuzumab deruxtecan-nxki) in the Human Lung cancer line NCI-H650

[0388] The combination effect between Compound A and Compound J (fam-trastuzumab deruxtecan-nxki) was assessed using a cell line derived xenograft (CDX) model of the Non small Lung cancer line NCI-H650. 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 once a mean tumor volume of approximately 100- 150 mm3was achieved. The study consisted of four treatment arms containing eight mice per group, with a duration of 26 days on treatment.

[0389] Compound A was administered at 100 mg / kg, leading to a TGI of 5%, and Compound J with a single dose of 10 mg / kg produced TGI value of 100% with3 out of 8 animals achiving complete regression (see Table 8 for dose schedule). The combination arm had a TGI of 106% with 6 out of 8 animals showing complete regressions by Day 26. These results highlight the robust anticancer efficacy of Compound A in combination with Compound J (Figure 5, (FIG. 5)).Table 8: Study groups for CDX NCI-H650 treated with Compound A and / or Compound J.

[0390] Particular embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Upon reading the foregoing, description, variations of the disclosed embodiments may become apparent to individuals working in the art, and it is expected that those skilled artisans may employ such variations as appropriate. Accordingly, it is intended that the disclosure be practiced otherwise than as specifically described herein, and that the disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[0391] All patent applications, patents, and printed publications cited herein are incorporated herein by reference in their entireties, except for any definitions, subject matter disclaimers or disavowals, and except to the extent that the incorporated material is inconsistent with the express disclosure herein, in which case the language in this disclosure controls.

[0392] Other embodiments are within the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a PARG inhibitor and administering to the subject a therapeutically effective amount of a topoisomerase inhibitor, wherein the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of cyano, C1-2 alkyl, and Ci-2haloalkyl;Ar is a l,3,4-thiadiazol-2-yl or 1,2,4-thiadiazolyl;X2is CH or CF;R2is selected from the group consisting of C1-3 haloalkyl, C1-3 alkyl, hydroxyCi-salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen, C1-4 alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd, wherein Rdis hydrogen, C1-6 alkyl, or Ci-6 haloalkyl); andRband Rcare independently selected from C1-6 alkyl, hydrogen, hydroxy, C1-6 alkoxy, halo, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

2. The method of claim 1, wherein X2is CH.

3. The method of claim 1 or 2, wherein R1is methyl.

4. The method of claim 1 or 2, wherein R1is cyano.

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

6. The method of any one of claims 1 to 5, wherein R2is attached to the carbon atom of Ar that is meta to the atom of Ar that is attached to the nitrogen atom of the remainder of the molecule.

7. The method of any one of claims 1 to 6, wherein R2is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano.

8. The method of any one of claims 1 to 7, wherein R2is difluoromethyl.

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

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

11. The method of any one of claims 1 to 10. wherein Rais hydrogen. Ci-4 alkyl, C 1-4 haloalky 1, halo, hydroxy, or -C(O)Rd, wherein Rdis hydrogen, Ci-6 alkyl, or Ci-6 haloalkyl); and Rband Rcare independently selected from Ci-6 alkyl , hydrogen, hydroxy, Ci- 6 alkoxy, halo, Ci-6 haloalkyl, and Ci-6 haloalkoxy.

12. The method of any one of claims 1 to 11, wherein Rais hydrogen, C1-4 alkyl, or C 1-4 haloalkyl; and Rband Rcare independently selected from C 1-6 alkyl and hydrogen.

13. The method of any one of claims 1 to 12, wherein Rais hydrogen; Rband Rcare each independently C1-6 alkyl or hydrogen.

14. The method of any one of claims 1 to 13. wherein the PARG inhibitor is Compound A:Compound A or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

22. The method of any one of claims 1 to 20, wherein the cancer is characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, anabsence or mutation of BRCA1 and / or BRCA2 genes, or a reduced function of BRCA1 and / or BRCA2 proteins.

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

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

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

26. The method of any one of claims 1 to 24. w herein the PARC inhibitor and the topoisomerase inhibitor are in the same dosage form.

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

28. Use of a PARG inhibitor in the manufacture of a medicament for treating cancer, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor.

29. The use according to claim 27 or 28, wherein the PARG inhibitor is a compound of Formula I:(Formula I) or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of cyano, C1-2 alkyl, and Ci-2haloalkyl:Ar is a l,3,4-thiadiazol-2-yl or 1,2.4-thiadiazolyl;X2is CH or CF;R2is selected from the group consisting of C1-3 haloalkyl, C1-3 alky l, hydroxyCi-salkyl, and cyano; ring B is 5- or 6-membered heterocycloalkyl substituted with Ra, Rb, and Rc;Rais hydrogen, CM alkyl, C 1-4 haloalkyl, halo, hydroxy, or -C(O)Rd, wherein Rdis hydrogen, C1-6 alkyl, or C 1-6 haloalkyl); andRband Rcare independently selected from C 1-6 alkyl, hydrogen, hydroxy, C1-6 alkoxy, halo, C 1-6 haloalkyl, and C 1-6 haloalkoxy.

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

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

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

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

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

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

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

37. The use according to any one of claims 27 to 36, wherein the cancer is characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, an absence or mutation of BRCA1 and / or BRCA2 genes, or a reduced function of BRCA1 and / or BRCA2 proteins.

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

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

Images