Sulfonamino indazole compounds as inhibitors of parg

Abstract

Provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. The provided compounds are useful Poly ADP-ribose glycohydrolase (PARG) inhibitors. Additional utilities and advantages are described herein.

Description

PATENT Atorney Docket No.052326-577001WO Client Ref. No.2023-031-B-PCT SULFONAMINO INDAZOLE COMPOUNDS AS INHIBITORS OF PARG CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.63 / 585,942 filed September 27, 2023, which is incorporated herein in its entirety and for al purposes. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] NOT APPLICABLE REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK

[0003] NOT APPLICABLE BACKGROUND

[0004] Cancer is caused by uncontroled and unregulated celular 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 cels therefore engage and rely heavily upon DNA damage repair mechanisms.

[0005] Single-strand breaks (SSBs) are the most common type of lesion arising in cels 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 caled base excision repair (BER).

[0006] 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, initialy XRCC1, which wil then repair the break (Mortusewicz, Fouquerel et al.2011). The signal initiated by these PAR chains is short-lived as they are rapidly degraded by the enzymePARG. When PARP is bound to PAR, its catalytic activity is reduced and therefore PARG activity helps to restore PARP to its catalyticaly active form (Curtin and Szabo 2013).

[0007] 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 (Mashimo, Kato et al.2014). Although, known primarily for its direct role in DNA repair, PARG impacts PAR signaling in splicing, transcriptional and epigenetic pathways (Ji and Tulin 2009) (Le May, Iltis et al.2012) (Dahl, Maturi et al.2014) (Guastafiero, Catizone et al.2013) (Caiafa, Guastafiero et al.2009).

[0008] Cancer cels may become reliant upon a specific DNA repair pathway when other mechanisms of DNA repair are non-functional. Tumors carying 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 cels (Fathers, Drayton et al.2012). However, other tumor mutations may give rise to deficiencies in double strand DNA repair mechanisms (so-caled “BRCA-ness”) thereby sensitizing tumor cels to PARG inhibition.

[0009] PARG depletion has been studied in a number of murine and human model systems. Murine cels that are nul or depleted for PARG display an increased sensitivity to experimental and clinical DNA damaging agents. However, as deficiency in PARG doesn’t sensitize to al agents (e.g. gemcitabine, camptothecin) this suggests a specificity for PARG function with certain pathways of DNA damage repair and chemo- and radiotherapies (Fujihara, Ogino et al. 2009) (Shirai, Fujimori et al.2013) (Zhou, Feng et al.2010) (Zhou, Feng et al.2011).

[0010] In humans, PARG depletion sensitizes lung, cervical and pancreatic cancer cels to ^- iradiation or experimental DNA damaging agents (e.g. hydrogen peroxide, Methylmethanesulfonate) (Ame, Fouquerel et al.2009) (Nakadate, Kodera et al.2013) (Shirai, Poetsch et al.2013).

[0011] PARP inhibitors are currently undergoing multiple clinical trials where the concept of synthetic lethality or chemo-sensitization is being explored. Clinical resistance to PARP inhibitors has already been described (Drost and Jonkers 2014) (Barber, Sandhu et al.2013) andtherefore there is a requirement that alternative inhibitors targeting the DNA damage repair machinery are found.

[0012] Although curent models show that PARG depletion leads to PARP-dependent efects on DNA repair, recent research has shown a mechanistic diferentiation from PARP inhibition. Folowing a genotoxic stimulus depletion of PARG, in contrast to PARP depletion, leads to a drop in NAD levels. This leads to lung cancer cel death as a result of energy failure (Erdelyi, Bai et al.2009).

[0013] Cel permeable PARG inhibitors have been limited to compounds such as Tannic acid or Galotannin which have questionable specificity for PARG and limited bioavailability (Sun, Zhang et al.2012) (Fathers, Drayton et al.2012) (Blenn, Wyrsch et al.2011).

[0014] An object of this disclosure is to provide cel permeable inhibitors of PARG. SUMMARY

[0015] In one aspect, provided herein is a compound of Formula (I): or a pharmaceuticalyR2, R3, R4, and R5 are as described herein.

[0016] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, and one or more pharmaceuticaly acceptable excipients.

[0017] In another aspect, provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0018] In another aspect, provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer. In one embodiment, the cancer is a human cancer.

[0019] In another aspect, provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the production of a PARG inhibitory efect.

[0020] In another aspect, provided herein is the use of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers.

[0021] In another aspect, provided herein is the use of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in the production of a PARG inhibitory efect.

[0022] In another aspect, provided herein is a method of inhibiting PARG in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0023] In another aspect, provided herein is a method of inhibiting cel proliferation in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0024] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0025] In another aspect, provided herein is a method of treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof, said method comprising administering to said patient a therapeuticaly efective amount of a compoundFormula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0026] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been previously treated for cancer with a platin.

[0027] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been previously treated for cancer with a PARP inhibitor.

[0028] In another aspect, provided herein is a method of identifying PARG activity in a test compound of PARG inhibitory activity, said method comprising (i) contacting the test compound with isolated PARG enzyme, a biotinylated-PARylated PARP substrate to form a PARG reaction pre-mixture; (i) contacting the PARG reaction pre-mixture with a detection antibody and streptavidin-europium to form a PARG reaction mixture; and (ii) measuring fluorescence intensity of the PARG reaction mixture, wherein said method further comprises performing steps (i)-(ii) with a positive control sample represented by a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein. In some embodiments, the detection antibody is an anti-His monoclonal antibody-ULight. In some embodimenst the streptavidin-europium binds to the biotinylated-PARylated PARP substrate. In some embodiments fluorescence is measured by providing an excitation wavelength of 317 nM and measuring emissions at 620 nM (streptavidin-europium emission) and 665 nM (ULight emission).

[0029] In another aspect, provided are methods of synthesizing a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, as defined herein.

[0030] In another aspect, provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.

[0031] In another aspect, provided herein are novel intermediates as defined herein which are suitable for use in any one of the synthetic methods as set out herein.

[0032] Preferred, suitable, and optional features of any one particular aspect of the present disclosure are also preferred, suitable, and optional features of any other aspect. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] NOT APPLICABLE DETAILED DESCRIPTION

[0034] Before the present disclosure is further described, it is to be understood that the disclosure is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0035] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaler ranges may independently be included in the smaler ranges, and are also encompassed within the disclosure, patient to any specificaly excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. Unless defined otherwise, al technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skil in the art to which this disclosure belongs.

[0036] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be diferent from the actual publication dates, which may need to be independently confirmed.GENERAL

[0037] Provided herein are compounds of Formula (I), or a pharmaceuticaly acceptable salt thereof, for inhibition of PARG, and pharmaceutical compositions comprising the same. Also provided herein are, for example, methods of treating or preventing a disease, disorder or condition, or a symptom thereof, mediated by inhibition of PARG. DEFINITIONS

[0038] Unless otherwise indicated, the folowing terms are intended to have the meaning set forth below. Other terms are defined elsewhere throughout the specification.

[0039] As used herein “Poly ADP-ribose glycohydrolase inhibitor” or “PARG inhibitor” means an agent that modulates the activity of PARG.

[0040] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0041] 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. C1-8 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 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0042] The term "halo" or "halogen," by itself or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0043] 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.

[0044] The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partialy unsaturated 3 to 10 membered monocyclic or bicyclic ring having from one to four heteroatoms independently selected from N, O, and S and the remaining ring atoms being carbon. Non limiting examples of heterocycloalkyl groups include 3- to 6-membered heterocycloalkyl having one, two, or three heteroatoms independently selected from N, O, and S and the remaining ring atoms being carbon. The bicyclic ring may be fused wherein the two atoms and the bond between them are shared among 2 rings of the bicyclic ring. No ring in the heterocycloalkyl group is aromatic or fuly unsaturated. Partialy unsaturated heterocycloalkyl groups have one or more double or triple bonds in the ring, but heterocycloalkyl group are not aromatic. Non limiting examples of heterocycloalkyl groups include pyrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, and the like. A heterocycloalkyl group can be atached to the remainder of the molecule through a ring carbon or a heteroatom. Non limiting examples of heterocycloalkyl groups include pyridine- 2(H)-one.

[0045] As used herein, a wavy line, " ", that intersects a single, double or triple bond in any chemical structure depicted herein, represent the point atachment of the single, double, or triple bond to the remainder of the molecule. Additionaly, a bond extending to the center of a ring (e.g., a phenyl ring) is meant to indicate atachment at any of the available ring vertices. One of skil in the art wil understand that multiple substituents shown as being atached to a ring wil occupy ring vertices that provide stable compounds and are otherwise stericaly compatible.

[0046] The term "pharmaceuticaly acceptable salts" is meant to include salts of a compound of Formula (I) which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. Base addition salts can be obtained by contacting the neutral form of such compounds with a suficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceuticaly acceptable inorganic bases include aluminum, ammonium, calcium, copper, feric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceuticaly-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclic amines, naturaly-occuring amines and the like, such as arginine, betaine, cafeine, choline, N,N’-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Acid addition salts can be obtained by contacting the neutral form of such compounds with a suficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceuticaly acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as wel as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that alow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound difers from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0047] As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound with a pharmaceuticaly acceptable carier. 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.

[0048] As used herein, the term “pharmaceuticaly acceptable carier” means a pharmaceuticaly acceptable material, composition or carrier, such as a liquid or solid filer, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carying or transporting a compound useful to the patient such that it may perform its intended function. Typicaly, such constructs are caried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carier 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 pharmaceuticaly acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; celulose, and its derivatives, such as sodium carboxymethyl celulose, ethyl celulose and celulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa buter and suppository waxes; oils, such as peanut oil, cotonseed oil, saflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; bufering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate bufer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0049] Certain compounds of Formula (I) possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are al intended to be encompassed within the scope of the present disclosure.

[0050] When a stereochemical depiction is shown, it is meant to refer the compound in which one of the isomers is present and substantialy free of the other isomer. ‘Substantialy free of’ another isomer indicates at least an 80 / 20 ratio of the two isomers, more preferably 90 / 10, or 95 / 5 or more. In some embodiments, one of the isomers wil be present in an amount of at least 99%.

[0051] Formula (I) may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to an amount consisting of 100% of the atomin question. For example, the compounds may incorporate radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C), or non-radioactive isotopes, such as deuterium (2H) or carbon-13 (13C). Such isotopic variations can provide additional utilities to those described elsewhere within this application. For instance, isotopic variants of the compounds of the disclosure may find additional utility, including but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Additionaly, isotopic variants of Formula (I) can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or eficacy during treatment. Al isotopic variations of Formula (I), whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0052] The present disclosure also includes prodrugs of the compound of Formula (I) or a pharmaceuticaly acceptable salt thereof. As used herein, the term “prodrug” refers to compounds that readily undergo chemical changes under physiological conditions to provide a pharmacologicaly active parent compound. The term “prodrug moiety” refers to the chemical moiety of a prodrug that is released under physiological conditions to form the active parent compound. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolicaly hydrolyzed to the carboxylic acid, the active entity. Additionaly, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0053] Certain compounds of Formula (I) can exist in unsolvated forms as wel as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds of Formula (I) may exist in multiple crystaline or amorphous forms. In general, al physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0054] The terms “patient” or “subject” are used interchangeably to refer to a human or a non- human animal (e.g., a mammal). In one embodiment, the patient or subject is a human.

[0055] The terms “administration”, “administer” and the like, as they apply to, for example, a patient, cel, tissue, organ, or biological fluid, refer to contact of, for example, an inhibitor of PARG, a pharmaceutical composition comprising same, or a diagnostic agent to the patient, cel, tissue, organ, or biological fluid. In the context of a cel, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cel, as wel as contact of a reagent to a fluid, where the fluid is in contact with the cel.

[0056] The terms “treat”, “treating”, treatment” and the like refer to a course of action (such as administering an inhibitor of PARG or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition aflicting a patient, or at least one of the symptoms associated with a disease, disorder, condition aflicting a patient. Thus, treatment includes inhibiting (e.g., aresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.

[0057] The term “in need of treatment” as used herein refers to a judgment made by a physician or other caregiver that a patient requires or wil benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s or caregiver’s expertise.

[0058] The terms “prevent”, “preventing”, “prevention” and the like refer to a course of action (such as administering a PARG inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a patient’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generaly in the context of a patient predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.

[0059] The term “in need of prevention” as used herein refers to a judgment made by a physician or other caregiver that a patient requires or wil benefit from preventative care. Thisjudgment is made based on a variety of factors that are in the realm of a physician’s or caregiver’s expertise.

[0060] The terms “inhibiting” and “reducing,” or any variation of these terms in relation of PARG, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, reduction of PARG activity compared to normal. About as used herein means within ± 10%, preferably ± 5% of a given value.

[0061] The phrase “therapeuticaly efective amount” refers to the administration of an agent to a patient, either alone or as part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount capable of having any detectable, positive efect on any symptom, aspect, or characteristic of a disease, disorder or condition when administered to the patient. The therapeuticaly efective amount can be ascertained by measuring relevant physiological efects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the patient’s condition, and the like. By way of example, measurement of the serum level of a PARG inhibitor (or, e.g., a metabolite thereof) at a particular time post- administration may be indicative of whether a therapeuticaly effective amount has been used.

[0062] The phrase “platins” or “platinum based-chemotherapeutics” refers to a platinum containing class of chemotherapeutic drug used for treating cancer. Exemplary platins are cisplatin, carboplatin, satraplatin, heptaplatin, picoplatin, nedaplatin, triplatin, lipoplatin, and oxaliplatin.

[0063] As used herein, “platin-resistant cancer” or “cancer resistant to one or more platins” refers to cancers that do not respond to treatment with a platin. Non-responsiveness can be assessed by the continued growth of a tumor when administered the agent, a tumor that does not shrink in size when administered the agent, or other known means in the art. Non- responsiveness of a cancer can be determined through clinical observation, diagnosed as such by a medical professional, experimentaly tested with isolated cels in a laboratory seting, or by another technical means.

[0064] As used herein, “Poly ADP Ribose Polymerase (PARP) inhibitor” refers to an agent that inhibits PARP activity, including PARP1 and PARP2. Examples of PARP inhibitors include, but are not limited to, niraparib, rucaparib, olaparib, talazoparib, and veliparib.

[0065] As used herein, “PARP inhibitor-resistant cancer” or “cancer resistant to one or more PARP inhibitors” refers to cancers that do not respond to treatment with a PARP inhibitor. Non- responsiveness can be assessed by the continued growth of a tumor when administered the agent, a tumor that does not shrink in size when administered the agent, or other known means in the art. Non-responsiveness of a cancer can be determined through clinical observation, diagnosed as such by a medical professional, experimentaly tested with isolated cels in a laboratory seting, or by another technical means.

[0066] As used herein “homologous recombination” refers to the celular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA sequences.

[0067] 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, CHECK1, CHECK2, 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 cels 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner 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.

[0068] The antibodies disclosed in the antibody drug conjugate of the present disclosure means an immunoglobulin and is a molecule containing an antigen-binding site immunospecificaly 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 orIgG2. The antibody may be derived from any species, and prefered 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 wel-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 cels. 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 cel, a property of binding to a tumor cel, a property of internalizing in a tumor cel, and a property of damaging a tumor cel. 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 cel. 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 (ErbB1), ErbB2, ErbB3, HER- 2, tissue factor (TF), CD19, CD22, CD30, CD33, CD79b, CD74, CD138, CD56, CD70, Claudin- 18, folate receptor alpha (FRα), c-Met, Nectin-4, delta-like ligand 3 (DLL3), PTK7, GPNMB, Ley, CA6, CanAng, Av integrin, SLC44A4, CEACAM5, AGS-16, Anti-Cripto, Carbonic Anhydrase 9, Mesotheilin, TENB2, 5T4, VEGF, insulin-like growth factor (ILGF), MUC1 and TA-MUC1. COMPOUNDS

[0069] In some embodiments, the curent disclosure provides compounds of Formula (I): ,wherein X2 is CH, N, or CF;R1 is hydrogen, deuterium, cyano, formyl, -CONH2, -CH2OH, -CH2OC1-2alkyl, C1-2alkyl, C1-2 deuteroalkyl, or C1-2haloalkyl; R2 and R3together with the carbon atom to which they are atached form a 3- or 4- membered heterocyclyl having one (1) heteroatom ring vertex, selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 R2a; each R2a is independently deuterium, C1-4 alkyl, halo, or C1-4 haloalkyl; R4 is hydrogen, C alkyl, C haloalkyl, -C(O) 4a 4a 4b 1-4 1-4 OR, or -C(O)NRR; R4a and R4b are each independently hydrogen or C1-4 alkyl; and R5 is C1-4 alkyl or C1-4 haloalkyl; or a pharmaceuticaly acceptable salt thereof.

[0070] In some embodiments, the curent disclosure provides compounds of Formula (I): , whereinX2 is CH, N, or CF; R1 is hydrogen, deuterium, cyano, formyl, -CONH2, -CH2OH, -CH2OC1-2alkyl, C1-2alkyl, C1-2 deuteroalkyl, or C1-2haloalkyl; R2 and R3together with the carbon atom to which they are atached form a 3- or 4- membered heterocyclyl having one (1) heteroatom ring vertex, selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 5 R2a; each R2a is independently deuterium, C1-4 alkyl, halo, or C1-4 haloalkyl; R4 is hydrogen, C alkyl, C haloa 4a 4a 4b 1-4 1-4 lkyl, -C(O)OR, or -C(O)NRR; R4a and R4b are each independently hydrogen or C1-4 alkyl; and R5 is C1-4 alkyl or C1-4 haloalkyl; or a pharmaceuticaly acceptable salt thereof.

[0071] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) having the structure of Formula (Ia) , or a pharmaceuticaly

[0072] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) having the structure of Formula (Ib) , or a pharmaceuticaly

[0073] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) having the structure of Formula (Ic)Ic), or a pharmaceuticaly acceptab

[0074] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) having the structure of Formula (Ia-1) , or a pharmaceuticaly

[0075] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I) having the structure of Formula (Ia-2) , or a pharmaceuticaly

[0076] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein X2 is CH.

[0077] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein X2 is N.

[0078] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein X2 is CF.

[0079] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is hydrogen, deuterium, cyano, -CH2OH, C1-2alkyl, C1-2 deuteroalkyl, or C1-2haloalkyl.

[0080] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is hydrogen, deuterium, cyano, C1-2 alkyl, C1-2 deuteroalkyl, or C1-2haloalkyl.

[0081] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is hydrogen, methyl, ethyl, trideuteromethyl, cyano, fluoromethyl, difluoromethyl, or hydroxymethyl.

[0082] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is hydrogen, methyl, ethyl, trideuteromethyl, cyano, fluoromethyl, or difluoromethyl.

[0083] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is hydrogen. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is methyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is trideuteromethyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is cyano. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is hydroxymethyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound ofFormula (I), (Ia), (Ib), or (Ic), wherein R1 is fluoromethyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R1 is difluoromethyl.

[0084] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3combine to form a 4- membered heterocyclyl having 1 heteroatom ring vertex, selected from N, O, and S. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3combine to form a 4- membered heterocycloalkyl, and the heterocycloalkyl is oxetanyl which is unsubstituted or substituted with 1 to 4 R2a. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3combine to form an oxetanyl.

[0085] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein the heterocyclyl is unsubstituted. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein the heterocyclyl is substituted with 1 to 4 R2a. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein the heterocyclyl is substituted with 1 to 2 R2a. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein the heterocyclyl is substituted with one (1) R2a.

[0086] With reference to Formula (I), (Ia), (Ib), or (Ic), and any one of embodiments thereof, in some embodiments, R2 and R3combine to form an oxetanyl, which is unsubstituted. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3combine to form an oxetanyl, which is substituted with 1 to 4 R2a. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3 combine to form an oxetanyl, which is substituted with 1 to 2 R2a. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3combine to form an oxetanyl, which is substituted with one R2a.

[0087] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein each R2a is independently deuterium, C1-4 alkyl, or halo. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein each R2a is deuterium. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein each R2a is halo. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein each R2a is C1-4 alkyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein each R2a is methyl.

[0088] With reference to Formula (I), (Ia), (Ib), or (Ic), and any one of embodiments thereof, in some embodiments, R2 and R3combine to form an oxetanyl, which is substituted with 1 to 2 R2a; and each R2a is independently deuterium, C1-4 alkyl, or halo. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3combine to form an oxetanyl, which is substituted with one R2a; and R2a is deuterium, C1-4 alkyl, or halo. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3combine to form an oxetanyl, which is substituted with C1-4 alkyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R2 and R3combine to form an oxetanyl, which is substituted with methyl.

[0089] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R4 is hydrogen. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R4 is C1-4 alkyl.

[0090] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R5 is C1-2 alkyl or C1-2 haloalkyl.

[0091] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R5 is methyl, ethyl, or difluoromethyl.In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R5 is difluoromethyl.

[0092] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R5 is C1-2 haloalkyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein R5 is difluoromethyl.

[0093] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein X2 is CH; R1 is hydrogen, deuterium, cyano, -CHOH, C alkyl, C deuteroalkyl, 2 3 2 1-2 1-2 or C1-2haloalkyl; R and Rtogether with the carbon atom to which they are atached form an oxetanyl, which is unsubstituted or substituted with 1 to 2 R2a; each R2a is independently deuterium or C 4 5 1-4 alkyl; R is hydrogen; and R is C1-4 haloalkyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein X2 is CH; R1 is hydrogen, cyano, C1-2 alkyl, or C1-2haloalkyl; R2 and R3together with the carbon atom to which they are atached form an oxetanyl, which is unsubstituted or substituted with one R2a; R2a is C1-4 alkyl; R4 is hydrogen; and R5 is C1-4 haloalkyl. In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein X2 is CH; R1 is hydrogen, cyano, methyl, fluoromethyl, or difluoromethyl; R2 and R3together with the carbon atom to which they are atached form an oxetanyl, which is unsubstituted or substituted with methyl; R4 is hydrogen; and R5 is difluoromethyl.

[0094] In some embodiments, the compound, or the pharmaceuticaly acceptable salt thereof, is the compound of Formula (I), (Ia), (Ib), or (Ic), wherein the compound is selected from Table 1.Table 1 Example Structure Name N-(3-cyanooxetan-3-yl)-1- )- l)- e 4- )- l)- - 4- )- l)- eExample Structure Name 1-(5-(difluoromethyl)-13,4- H- )- l)- e 4- H-Example Structure Name 7 1-(5-(difluoromethyl)-13,4- )- l)- 4- )- l)- etitumor compound conjugated to an antibody via a linker. In some embodiments, the antibody is a bispecific antibody. A number of ADCs comprising antitumor compounds and methods of making the same are known in the art. Each of these is embraced by this disclosure. 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 a compound in Table 1. BIOLOGICAL ACTIVITY

[0096] The PARG enzyme and cel assays described in accompanying Example section may be used to measure the pharmacological efects of the compounds of the present disclosure.PHARMACEUTICAL COMPOSITIONS

[0097] Also provided are pharmaceutical compositions which comprise a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, in association with a pharmaceuticaly acceptable diluent or carier.

[0098] The compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insuflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0099] The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, wel known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0100] An efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof for use in therapy is an amount suficient to treat or prevent a proliferative condition refered to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0101] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) wil naturaly vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to wel-known principles of medicine.

[0102] In using a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof for therapeutic or prophylactic purposes it wil generaly be administered so that a total daily dose in the range, for example, 0.01 mg / kg to 100 mg / kg body weight is received. Oral administration may also be suitable, particularly in tablet form.

[0103] In some embodiments, compositions comprise at least 70 % of the displayed isomer. In some embodiments, compositions comprise at least 75 % of the displayed isomer. In someembodiments, compositions comprise at least 80 % of the displayed isomer. In some embodiments, compositions comprise at least 85 % of the displayed isomer. In some embodiments, compositions comprise at least 90 % of the displayed isomer. In some embodiments, compositions comprise at least 95 % of the displayed isomer. In some embodiments, compositions comprise at least 99 % of the displayed isomer. THERAPEUTIC USES AND APPLICATIONS

[0104] Provided herein are compounds that function as inhibitors of PARG.

[0105] The present disclosure therefore provides a method of inhibiting PARG enzyme activity in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0106] The present disclosure also provides a method of treating a disease or disorder in which PARG activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly effective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein. In an embodiment, the disease or disorder is an advanced or metastatic solid tumor. In an embodiment, the disease or disorder is cancer. In some embodiments, cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial 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. In an embodiment, the cancer is a homologous recombinant deficient (HRD) cancer. In stil another embodiment, the cancer is characterized by microsatelite instability-high (MSI-H). In stil another embodiment, the cancer is characterized by microsatelite stable (MSS).

[0107] Provided herein is a method of inhibiting cel proliferation, in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0108] Provided herein is a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly efectiveamount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein. In an embodiment, the proliferative disorder is a solid tumor. In an embodiment, the proliferative disorder is a metastatic solid tumor. In an embodiment, the proliferative disorder is cancer. In some embodiments, cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial 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. In an embodiment, the cancer is a homologous recombinant deficient (HRD) cancer.

[0109] Provided herein is a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly effective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein. In some embodiments, cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial 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 a homologous recombinant deficient (HRD) cancer. In stil another embodiment, the cancer is characterized by microsatelite instability-high (MSI-H). In stil another embodiment, the cancer is characterized by microsatelite stable (MSS).

[0110] Provided herein is a method of treating and / or preventing a cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is HRD cancer, is ER positive, is optionaly PR positive, and is optionaly HER2 negative. In an embodiment, the cancer is breast cancer or ovarian cancer.

[0111] Provided herein is a method of treating and / or preventing a breast cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the cancer is HRD cancer, is ER positive, is optionaly PR positive, and is optionaly HER2 negative.

[0112] Provided herein is a method of treating and / or preventing a homologous recombinant deficient (HRD) cancer in a patient comprising administering to the patient a therapeuticaly efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein. In an embodiment, the patient is in recognized need of such treatment. In some embodiments, the homologous recombinant deficient (HRD) cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer. In an embodiment, the homologous recombinant deficient (HRD) cancer is breast cancer, ovarian cancer, gastric cancer, prostate cancer, lung cancer, cervical cancer, or pancreatic cancer.

[0113] Provided herein is a method of treating and / or preventing a cancer in a patient, where 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, the method comprising administering to the patient a therapeuticaly effective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein. In some embodiments, the homologous recombinant deficient (HRD) cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial 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.

[0114] In an embodiment, the cancer is PARP inhibitor-resistant. In some embodiments the PARP inhibitor-resistant cancer is resistant to any one or more of niraparib, olaparib, rucaparib, talazoparib, veliparib, AZD5305, or AZD9574. In some embodiments the PARP inhibitor- resistant cancer is resistant to niraparib. In some embodiments the PARP inhibitor-resistant cancer is resistant to olaparib. In some embodiments, the PARP inhibitor-resistant cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer. In some embodiments, the PARP inhibitor-resistant cancer is ovarian cancer, breast cancer, or pancreatic cancer.

[0115] In an embodiment, the cancer is platin-resistant. In some embodiments, the platin- resistant cancer is resistant to any one or more of cisplatin, carboplatin, satraplatin, heptaplatin,picoplatin, nedaplatin, triplatin, lipoplatin, or oxaliplatin. In some embodiments, the platin- resistant cancer is resistant to cisplatin. In some embodiments, the platin-resistant cancer is resistant to carboplatin. In some embodiments, the platin-resistant cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer. In some embodiments, the platin-resistant cancer is ovarian cancer, breast cancer, or pancreatic cancer.

[0116] Provided herein are methods of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly effective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been determined to be resistant to one or more PARP inhibitors. In some embodiments, said methods comprise administering to said patient a therapeuticaly efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein said patient has been diagnosed as resistant to one or more PARP inhibitors.

[0117] Provided herein are methods of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeuticaly effective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been determined to be resistant to platinum based chemotherapeutics. In some embodiments, said methods comprise administering to said patient a therapeuticaly efective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein said patient has been diagnosed as resistant to one or more platinum based chemotherapeutics.

[0118] Provided herein are methods of treating cancer in a subject in need thereof, the method comprising (a) obtaining a biological sample from the subject; (b) determining if the biological sample is i) a homologous recombination deficient (HRD) cancer; i) an ER positive cancer;ii) a PR positive cancer; iv) a HER2 negative cancer; v) a cancer characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, an absence or mutation of BRCA1 and / or BRCA2 genes, a reduced function of BRCA1 and / or BRCA2 proteins, or a combination thereof; vi) microsatelite instability-high (MSI-H), microsatelite instability-low (MSI-L), or microsatelite stable (MSS); or vi) any combination of i) to vi); and (c) administering to the subject a therapeuticaly efective amount of a therapeuticaly effective amount of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein, if the biological sample is i) a homologous recombination deficient (HRD) cancer; i) an ER positive cancer; ii) a PR positive cancer; iv) a HER2 negative cancer; v) a cancer characterized by a reduction or absence of BRCA1 and / or BRCA2 gene expression, the absence or mutation of BRCA1 and / or BRCA2 genes, or reduced function of BRCA1 and / or BRCA2 proteins, or combination thereof; vi) microsatelite instability-high (MSI-H) or microsatelite stable (MSS); or vi) any combination of i) to vi).

[0119] In an embodiment, the biological sample is tissue or blood. In an embodiment, the biological sample is tissue. In an embodiment, the biological sample is blood. In an embodiment, the blood is whole blood. In an embodiment, the blood is blood serum. In an embodiment, the blood is blood plasma.

[0120] It is understood that methods of determining if a biological sample is a homologous recombination deficient (HRD) cancer, an ER positive cancer, a PR positive cancer, a HER2 negative cancer, a cancer characterized by a reduction or absence of BRCA1 and / or BRCA2gene expression, the absence or mutation of BRCA1 and / or BRCA2 genes, or reduced function of BRCA1 and / or BRCA2 proteins, or combination thereof, or a microsatelite instability-high (MSI-H), microsatelite instability-low (MSI-L), or microsatelite stable (MSS) sample are known in the art. It is understood that methods of determining if a biological sample is any one of i) to (vi) as defined and described herein or any combination thereof are known in the art.

[0121] Provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein for use in therapy.

[0122] Provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition.

[0123] Provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer. In a particular embodiment, the cancer is human cancer. In some embodiments, cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial 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. In an embodiment, the cancer is a homologous recombinant deficient (HRD) cancer. In stil another embodiment, the cancer is characterized by microsatelite instability-high (MSI-H). In stil another embodiment, the cancer is characterized by microsatelite stable (MSS).

[0124] Provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the inhibition of PARG enzyme activity.

[0125] Provided herein is a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein for use in the treatment of a disease or disorder in which PARG activity is implicated.

[0126] Provided herein is a use of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a proliferative condition.

[0127] Provided herein is a use of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancers. In some embodiments, cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial 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. In an embodiment, the cancer is a homologous recombinant deficient (HRD) cancer.

[0128] Provided herein is a use of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the inhibition of PARG enzyme activity.

[0129] Provided herein is a use of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which PARG activity is implicated.

[0130] The present disclosure also contemplates the use of the compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein in combination with other therapeuticaly active agents or compounds as described herein in order to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0131] The term “proliferative disorder” and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontroled celular proliferation of excessive or abnormal cels which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant celular proliferation, including but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. Any type of cel may be treated, including but not limited to, lung, colon, breast, ovarian, prostate, gastric, liver, pancreas, brain, and skin. Proliferative disorders also include, for example, advanced or metastatic solid tumors.

[0132] The anti-proliferative efects of a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition as defined herein have particular application in the treatment of human cancers (by virtue of their inhibition of PARG enzyme activity).

[0133] The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cel proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumor from its origin), the inhibition of invasion (the spread of tumor cels into neighboring normal structures), or the promotion of apoptosis (programmed cel death).

[0134] In a particular embodiment of the disclosure, the proliferative condition to be treated is cancer. COMBINATION THERAPY

[0135] The present disclosure contemplates the use of compounds of Formula (I), or a pharmaceuticaly acceptable salt thereof in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents frequently have diferent, complementary mechanisms of action. Such combination therapy may be especialy advantageous by alowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse efects associated with one or more of the agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

[0136] As used herein, “combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a “co-formulation”).

[0137] In certain embodiments, the compounds of Formula (I), or a pharmaceuticaly acceptable salt thereof are administered or applied sequentialy, e.g., where one agent is administered prior to one or more other agents. In other embodiments, the compounds of Formula (I), or a pharmaceuticaly acceptable salt thereof are administered simultaneously, e.g.,where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentialy or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.

[0138] The present disclosure provides methods for treating cancer with a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof and at least one additional therapeutic agent or diagnostic agent.

[0139] A wide variety of therapeutic agents with anti-cancer activity and methods of making the same are known in the art. Each of these is embraced by this disclosure. i) Chemotherapeutic Agents

[0140] In an embodiment, the additional therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents include alkylating agent, microtubule inhibitors, antimetabolites, anti- tumor antibiotics, as wel as corticosteroids.

[0141] In some embodiments, the chemotherapeutic agent is an alkylating agent. In some embodiments, the alkylating agent is altretamine, bendamustine, busulfan, improsulfan, piposulfan, procarbazine, mechlorethamine, carmustine, lomustine, semustine chlorambucil, cyclophosphamide, thiotepa, ifosfamide, dacarbazine, temozolomide, or perfosamide. In some embodiments, the alkylating agent is mechlorethamine. In some embodiments, the alkylating agent is perfosamide.

[0142] In an embodiment, the alkylating agent is a platinum-based chemotherapy agent. In some embodiments, the alkylating agent is carboplatin, cisplatin, oxaliplatin, nedaplatin, saraplatin, lobaplatin, or heptaplatin. In some embodiments, the alkylating agent is carboplatin. In some embodiments, the alkylating agent is cisplatin. In some embodiments, the alkylating agent is saraplatin.

[0143] In some embodiments, the chemotherapeutic agent is a microtubule inhibitor. In an embodiment, the microtubule inhibitor is eribulin, ixabepilone, cabazitaxel, enfortumab, vedotin, trastuzumab emtansine, tirbanibulin. In some embodiments microtuial inhibitors are plantalkaloids. In some embodiments, the plant alkaloid is a taxane (taxol, paclitaxel and docetaxel), a vinca alkaloid (vinblastine, vincristine, vindesine and vinorelbine), colchicine, podophylotoxin, or abraxane (protein-bound paclitaxel). In some embodiments, the chemotherapeutic agent is paclitaxel.

[0144] In some embodiments, the chemotherapeutic agent is an antimetabolite. In an embodiment, the antimetabolite is 5-fluorouracil (5-FU), capecitabine, floxuridine, cytarabine, 5-fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, cytosine arabinoside, 5-azacytidine, gemcitabine, clofarabine, mercaptopurine, thioguanine, azathioprine, pentostatin, erythrohydroxynonyladenine, fludarabine, cladribine decitabine, Azacitidine, vidaza, or methotrexate. In an embodiment, the antimetabolite is cladribine. In an embodiment, the antimetabolite is clofarabine. In an embodiment, the antimetabolite is cytarabine. In an embodiment, the antimetabolite is gemcitabine. In an embodiment, the antimetabolite is floxuridine.

[0145] In some embodiments, the chemotherapeutic agent is an antitumor antibiotic. In some embodiments, the antitumor antibiotic is bleomycin, dactinomycin, or mitomycin. In some embodiments, the antitumor antibiotic is daunorubicin, doxorubicin, doxil, epirubicin, idarubicin, mitoxantrone, or valrubicin.

[0146] In some embodiments, the chemotherapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is prednisone, methylprednisolone, or dexamethasone. i) Cel Cycle Checkpoint Inhibitors

[0147] In an embodiment, the additional therapeutic agent is a cel cycle checkpoint inhibitor. In some embodiments, the cel cycle checkpoint inhibitor is KU60019, AZD0156, Ceralasertib, Camonsertib, VE821, AZD7762, SRA737, Rabusertib, Prexasertib, SCH900776, or Adavosertib. In some embodiments, the cel cycle checkpoint inhibitor is KU60019. In some embodiments, the cel cycle checkpoint inhibitor is AZD0156. In some embodiments, the cel cycle checkpoint inhibitor is ceralasertib. In some embodiments, the cel cycle checkpoint inhibitor is camonsertib. In some embodiments, the cel cycle checkpoint inhibitor is VE821. In some embodiments, the cel cycle checkpoint inhibitor is AZD7762. In some embodiments, the cel cycle checkpoint inhibitor is SRA737. In some embodiments, the cel cycle checkpoint inhibitor is rabusertib. Insome embodiments, the cel cycle checkpoint inhibitor is prexasertib. In some embodiments, the cel cycle checkpoint inhibitor is SCH900776. In some embodiments, the cel cycle checkpoint inhibitor is adavosertib. ii) Immune Checkpoint Inhibitors

[0148] In an embodiment, the additional therapeutic agent is an immune check point inhibitor. In some embodiments, the immune checkpoint inhibitor is a PD-1 / PD-L1 inhibitor, a LAG-3 inhibitor, a CTLA-4 inhibitor, a BTLA inhibitor, a TIM-3 inhibitor, or a TIGIT inhibitor.

[0149] In an embodiment, the PD-1 / PD-L1 inhibitor is a PD-1 inhibitor. In an embodiment, the PD-1 inhibitor is nivolumab, pembrolizumab, cemiplimab, dostarlimab, zimberelimab, retifanlimab, or atezolizumab. In an embodiment, the PD-1 inhibitor is nivolumab. In an embodiment, the PD-1 inhibitor is pembrolizumab. In an embodiment, the PD-1 inhibitor is cemiplimab. In an embodiment, the PD-1 inhibitor is dostarlimab. In an embodiment, the PD-1 inhibitor is zimberelimab. In an embodiment, the PD-1 inhibitor is retifanlimab. In an embodiment, the PD-1 inhibitor is atezolizumab.

[0150] In an embodiment PD-1 / PD-L1 inhibitor is a PD-L1 inhibitor. In an embodiment, the PD-L1 inhibitor is avelumab, atezolizumab, or durvalumab. In an embodiment, the PD-L1 inhibitor is avelumab. In an embodiment, the PD-L1 inhibitor is atezolizumab. In an embodiment, the PD-L1 inhibitor is durvalumab.

[0151] In some embodiments, the immune checkpoint inhibitor is a LAG-3 inhibitor. In some embodiments, the LAG-3 inhibitor is relatlimab.

[0152] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor. In some embodiments, the ipilimumab or tremelimumab

[0153] In some embodiments, the immune checkpoint inhibitor is a BTLA inhibitor.

[0154] In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367 (NCT03099109). In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is sabatolimab, TSR-022 (NCT02817633), MBG453 (NCT02608268), or LY3321367(NCT03099109). In some embodiments, the TIM-3 inhibitor is sabatolimab. In some embodiments, the immune checkpoint inhibitor is a TIM-3 inhibitor. In some embodiments, the TIM-3 inhibitor is TSR-022 (NCT02817633). In some embodiments, the TIM-3 inhibitor is MBG453 (NCT02608268). In some embodiments, the TIM-3 inhibitor is LY3321367 (NCT03099109).

[0155] In some embodiments, the immune checkpoint inhibitor is a TIGIT inhibitor. In some embodiments, the TIGIT inhibitor is tiragolumab, domvanalimab, vibostolimab, etigilimab, M6223, or ociperlimab. In some embodiments, the TIGIT inhibitor is tiragolumab. In some embodiments, the TIGIT inhibitor is domvanalimab. In some embodiments, the TIGIT inhibitor is vibostolimab. In some embodiments, the TIGIT inhibitor is etigilimab. In some embodiments, the TIGIT inhibitor is M6223. In some embodiments, the TIGIT inhibitor is ociperlimab. iv) BCL-2 Inhibitors

[0156] In some embodiments, the additional therapeutic agent is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is venetoclax, navitoclax, oblimersen, obatoclax mesylate, AT-101, subatoclax, maritoclax, gossypol, apogossypol, TW-37, UMI-77, or BDA-366. v) Anti-CD20 therapeutic agents

[0157] In some embodiments, the additional therapeutic agent is an anti-CD20 therapeutic agent. In some embodiments, the anti-CD20 therapeutic agent is rituximab, arzera, gazyva, ibritumomab tiuxetan, obinutuzumab, ofatumumab, riabni, rituxan, ruxience, truxima, zevalin, or tositumomab. vi) Hormonal Therapeutic Agents

[0158] In some embodiments, the additional therapeutic agent is a hormonal therapeutic agent. In some embodiments, the hormonal therapeutic agent is anastrozole, exemestand, letrozole, zoladex, lupon eligard, tamoxifen, raloxifene, goserelin, leuprorelin, fulvestrant, 4- hydroxytamoxifen, trioxifene, keoxifene, onapristone, toremifene; flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, or goserelin. vi) PARP Inhibitors

[0159] In some embodiments, the additional therapeutic agent is a PARP inhibitor. In some embodiments, the PARP inhibitor is niraparib, rucaparib, olaparib, talazoparib, or veliparib. In some embodiments, the PARP inhibitor is niraparib, rucaparib, olaparib, saruparib, talazoparib, or veliparib. vii) MAT2A Inhibitors

[0160] In some embodiments, the additional therapeutic agent is a MAT2A inhibitor. In some embodiments, the MAT2A inhibitor is AG- (Compound 8), or. In some embodiments, the MAT2A(Compound 8). In some embodiments, the MAT2A 8) or a pharmaceuticaly acceptable salt thereof. In someis a compound disclosed in WO2020 / 123395, the content of which is incorporated herein by reference for al purposes. In some embodiments, the MAT2A inhibitor is a compound disclosed in WO2018 / 045071, the content of which is incorporated herein by reference for al purposes. ix) Radiotherapy

[0161] In some embodiments, the additional therapeutic agent is radiation therapy. x) VEGF Inhibitors

[0162] In some embodiments, the additional therapeutic agent is a VEGF inhibitor. In some embodiments, the VEGF inhibitor is Bevacizumab, aflibercept, ranibizumab, sorafenib,dasatinib, sunitinib, nilotinib, pazopanib, pegaptanib, axitinib, lenvatinib, ramucirumab, or regorafenib. xi) Tyrosine Kinase Inhibitors

[0163] In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is afatinib, cetuximab, imatinib, trastuzumab, gefitinib, dacomitinib, osimertinib, neratinib, almonertinib, brigatinib, icotinib, olmutinib, sorafenib, dasatinib, bosutinib, ponatinib, asciminib, sunitinib, erlotinib, nilotinib, lapatinib, tucatinib, pyrotinib, panitumumab, nimotuzumab, necitumumab, mobocertinib, vandetanib, lenvatinib, pazopanib, mubritinib, fostamatinib, calquence, pertuzumab, acalabrutinib, alectinib, cabozantinib, ceritinib, capmatinib, or crizotinib. xi) mTOR Inhibitors

[0164] In some embodiments, the additional therapeutic agent is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is rapamycin, everolimus, sirolimus, or temsirolimus. xii) AKT Inhibitors

[0165] In some embodiments, the additional therapeutic agent is an ATK inhibitor. In some embodiments, the ATK inhibitor is ipatasertib, mk-2206, perifosine, capivasertib, triciribine, or GSK690693. xiv)CDK Inhibitors

[0166] In some embodiments, the additional therapeutic agent is a CDK inhibitor. In some embodiments, the CDK inhibitor is flavopiridol, roscovitine, RO-3306, dinaciclib, milciclib, palbociclib, ribociclib, abemaciclib, BS-181, DRB, meriolin 3, variolin b, meridianin e, nortopsentins, AZD5438, roniciclib, SNS-032, sorafenib, K03861, THZ531, THZ1, E9, SY- 1365, or seliciclib. In some embodiments, the CDK inhibitor is palbociclib, ribociclib, or abemaciclib. xv) PI3K Inhibitors

[0167] In some embodiments, the additional therapeutic agent is a PI3K inhibitor. In some embodiments, the PI3K inhibitor is idelalisib, alpelisib, leniolisib, duvelisib, or copanlisib. xvi)JAK Inhibitors

[0168] In some embodiments, the additional therapeutic agent is a JAK inhibitor. In some embodiments, the JAK inhibitor is tofacitinib, baricitinib, ruxolitinib, upadacitinib, fedratinib, filgotinib, or abrocitinib. xvi) Inhibitors of Cereblon (Ubiquitin Ligase)

[0169] In some embodiments, the additional therapeutic agent is an inhibitor of cereblon. In some embodiments, the inhibitor of cereblon is thalidomide or lenalidomide. xvii) MAPK / ERK Inhibitors

[0170] In some embodiments, the additional therapeutic agent is a MAPK / ERK inhibitor. In some embodiments, the MAPK / ERK inhibitor is vemurafenib, dabrafenib, octreotide, pasireotide, SB590885, GDC0879, LGX818, AZ628, RAF709, binimetinib, L-778, MK2206, pimasertib, rafametinib, salirasib, selumetinib, SML-8-731, tipifarnib, lonafarnib, trametinib, ulixertinib, WX-554, or cobimetinib. xix)Wnt / β-catenin Inhibitors

[0171] In some embodiments, the additional therapeutic agent is a Wnt / β-catenin inhibitor. In some embodiments, the Wnt / β-catenin inhibitor is capmatinib, resibufogenin, or isoquercitrin. xx) Proteosome Inhibitors

[0172] In some embodiments, the additional therapeutic agent is a proteosome inhibitor. In some embodiments, the proteosome inhibitor bortezomib, carfilzomib, or ixazomib. xxi)Histone Deacetylase Inhibitors

[0173] In some embodiments, the additional therapeutic agent is a histone deacetylase inhibitor. In some embodiments, the histone deacetylase inhibitor is vorinostat, romidepsin, panobinostat, or belinostat. xxi) Recombinant IL-2

[0174] In some embodiments, the additional therapeutic agent is a recombinant IL-2. In some embodiments, the recombinant IL-2 is aldesleukin. xxii) RANKL Inhibitors

[0175] In some embodiments, the additional therapeutic agent is a RANKL inhibitor. In some embodiments, the RANKL inhibitor is Denosumab or AS2676293. xxiv) B4GALNT1 Inhibitors

[0176] In some embodiments, the additional therapeutic agent is a B4GALNT1 inhibitor. In some embodiments, the B4GALNT1 inhibitor is Dinutuximab. xxv) SLAMF7 Inhibitors

[0177] In some embodiments, the additional therapeutic agent is a SLAMF7 inhibitor. In some embodiments, the SLAMF7 inhibitor is elotuzumab. xxvi) IDH2 / IDH1 Inhibitors

[0178] In some embodiments, the additional therapeutic agent is a IDH2 / IDH1 inhibitor. In some embodiments, the IDH2 / IDH1 inhibitor is enasidenib, ivosidenib, AGI-6780, AG-221, FT- 2102, IDH305, GSK 321, or BAY1436032. xxvi) BTK Inhibitors

[0179] In some embodiments, the additional therapeutic agent is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, acalabrutinib, zanubrutinib, or pirtobrutinib. xxvii) FLT3 Inhibitors

[0180] In some embodiments, the additional therapeutic agent is a FLT3 inhibitor. In some embodiments, the FLT3 inhibitor is sunitinib, midostaurin, lestaurtinib, KW-2449, crenolanib, or gilteritinib. xxix) PDGFRα Inhibitors

[0181] In some embodiments, the additional therapeutic agent is a PDGFRα inhibitor. In some embodiments, the PDGFRα inhibitor is olaratumab, avapritinib, ayvakit, imatinib, ripretinib, or regorafenib. xxx) Smoothened (Smo) Inhibitors

[0182] In some embodiments, the additional therapeutic agent is a smoothened inhibitor. In some embodiments, the smoothened inhibitor is sonidegib, itraconazole, or glasdegib. xxxi) LHRH antagonists or LHRH agonists

[0183] In some embodiments, the additional therapeutic agent is a LHRH antagonist or LHRH agonist. In some embodiments, the LHRH antagonist or LHRH agonist is goserelin, leuprorelin or buserelin. xxxi) Cel Based Therapy

[0184] In some embodiments, the additional therapeutic agent is a cel based therapy. In some embodiments, the cel based therapy is tumor-infiltrating lymphocyte (TIL) therapy; engineered t cel receptor (TCR) therapy; chimeric antigen receptor (CAR) T cel therapy; Natural Kiler (NK) cel therapy; or sipuleucel-T. xxxii) OX40 Inhibitors

[0185] In some embodiments, the additional therapeutic agent is a OX40 inhibitor. In some embodiments, the OX40 inhibitor is ivuxolimab, cudarolimab, utomilumab, or INBRX-106. xxxiv) 41BB (CD137) Inhibitors

[0186] In some embodiments, the additional therapeutic agent is a 41BB (CD137) inhibitor. In some embodiments, the 41BB (CD137) inhibitor is urelumab. xxxv) VISTA Inhibitors

[0187] In some embodiments, the additional therapeutic agent is a VISTA inhibitor. In some embodiments, the VISTA inhibitor is hmbd-002. xxxvi) CD96 Inhibitors

[0188] In some embodiments, the additional therapeutic agent is a CD96 inhibitor. In some embodiments, the CD96 inhibitor is GSK6097608. xxxvi) TGFβ Inhibitors

[0189] In some embodiments, the additional therapeutic agent is a TGFβ inhibitor. In some embodiments, the TGFβ inhibitor is SAR-439459. xxxvii) CD19 Inhibitors

[0190] In some embodiments, the additional therapeutic agent is a CD19 inhibitor. In some embodiments, the CD19 inhibitor is tafasitamab, loncastuximab tesirine, or blinatumomab. xxxix) CD30 Inhibitors

[0191] In some embodiments, the additional therapeutic agent is a CD30 inhibitor. In some embodiments, the CD30 inhibitor is brentuximab, vedotin, SGN-30, or MDX-060. xl) CD38 Inhibitors

[0192] In some embodiments, the additional therapeutic agent is a CD38 inhibitor. In some embodiments, the CD38 inhibitor is daratumumab, darzalex, isatuximab, or sarclisa. xli) CD39 Inhibitors

[0193] In some embodiments, the additional therapeutic agent is a CD39 inhibitor. In some embodiments, the CD39 inhibitor is pur001, ES002023, TTX-030, IPH5201, or SRF617.xli) CD52 Inhibitors

[0194] In some embodiments, the additional therapeutic agent is a CD52 inhibitor. In some embodiments, the CD52 inhibitor is alemtuzumab. xlii) CD73 Inhibitors

[0195] In some embodiments, the additional therapeutic agent is a CD73 inhibitor. In some embodiments, the CD73 inhibitor is oleclumab, PSB-12379, OP-5244, AB-680, CD73-IN-3, MethADP triammonium, dalutrafusp alfa, BK50164, mupadolimab, uliledlimab, MRS4620, BMS-986179, NZV930, AK119, SYM024, INCA00186, or ORIC-533. xliv) A2AR Inhibitors

[0196] In some embodiments, the additional therapeutic agent is an A2AR inhibitor. In some embodiments, the A2AR inhibitor is istradefyline, vipadenant, CVT-6883, enprofyline, ciforadenant, imaradenant, etrumadenant, NIR178, EOS100850, CS3005, PBF-999, or INCB106385. xlv)A2BR Inhibitors

[0197] In some embodiments, the additional therapeutic agent is an A2BR inhibitor. In some embodiments, the A2BR inhibitor is pbf-1129, QAF805, LAS101057 AB928, ISAM140, or TT- 4. xlvi) IDO1 & TDO2 Inhibitors

[0198] In some embodiments, the additional therapeutic agent is an IDO1 or a TDO2 inhibitor. In some embodiments, the IDO1 or TDO2 inhibitor is Indoximod, Epacadostat, Navoximod, PF- 06840003, BGS-5777, BMS-986205, LW106, IOM2983, RG-70099, LY-3381916, NLG-802, or LPM-3480226. xlvi) Arginase Inhibitors

[0199] In some embodiments, the additional therapeutic agent is an arginase inhibitor. In some embodiments, the arginase inhibitor is numidargistat, pegzilarginase, or INCB001158.xlvii) B7-H3 Inhibitors

[0200] In some embodiments, the additional therapeutic agent is a B7-H3 inhibitor. In some embodiments, the B7-H3 inhibitor is enoblituzumab, I-Omburtamab, DS-7300, or MGC018. xlix) B7-H4 Inhibitors

[0201] In some embodiments, the additional therapeutic agent is a B7-H4 inhibitor. In some embodiments, the B7-H4 inhibitor is mt-1660, FPA150, or AZD8205. l) PRMT5 Inhibitors

[0202] In some embodiments, the additional therapeutic agent is a PRMT5 inhibitor. In some embodiments, the PRMT5 inhibitor is a MTA-cooperative PRMT5 inhibitor. In some embodiments, the PRMT5 inhibitor is a compound having the structure: or a pharmaceuticaly

[0203] In some embodiments, the PRMT5 inhibitor is or a pharmaceuticaly acceptable

[0204] In some embodiments, the PRMT5 inhibitor is:or a pharmaceuticaly acceptable salt

[0205] In an embodiment, the PRMT5 inhibitor is or a pharmaceuticaly

[0206] In an embodiment, the PRMT5 inhibitor is or a pharmaceuticaly

[0207] In an embodiment, the PRMT5 inhibitor is MRTX-1719 or a pharmaceuticaly acceptable salt thereof. In an embodiment, the PRMT5 inhibitor is TNG462 or a pharmaceuticaly acceptable salt thereof. In an embodiment, the PRMT5 inhibitor is TNG908 or a pharmaceuticaly acceptable salt thereof. In an embodiment, the PRMT5 inhibitor is AZD3470 or a pharmaceuticaly acceptable salt thereof.

[0208] Additional PRMT5 inhibitors can include those described in WO2022 / 026892, WO2021 / 086879, WO2021 / 050915, and WO2023 / 036974, the contents of each are incorporated herein by reference in their entirety. li) PTK7 inhibitors

[0209] In some embodiments, the additional therapeutic agent is a PTK7 inhibitor. li) Antibody Drug Conjugates (ADC)

[0210] The disclosure also provides antibody drug conjugates (ADC) comprising one or more antitumor compound conjugated to an antibody via a linker. In some embodiments, the antibody is a bispecific antibody. A number of ADCs comprising antitumor compounds and methods of making the same are known in the art. Each of these is embraced by this disclosure. In an embodiment, the antitumor compound is an additional therapeutic agent disclosed herein. In an embodiment, the antitumor compound is a chemotherapeutic agent disclosed herein.

[0211] 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 at least two antitumor compounds are selected from a PARG inhibitor disclosed herein and one or more additional therapeutic agents disclosed herein. In an embodiment, the at least two antitumor compounds are selected from the additional therapeutic agents disclosed herein. In an embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is a compound of Formula (I).

[0212] The disclosure also provides antibody drug conjugates (ADC) disclosed herein for use with a PARG inhibitor disclosed herein.

[0213] Additional treatment modalities that may be used in combination with a compound of Formula (I), or a pharmaceuticaly acceptable salt thereof disclosed herein include radiotherapy, a monoclonal antibody against a tumor antigen, a T-cel adjuvant, bone marow transplant, or antigen presenting cels (e.g., dendritic cel therapy). DOSING

[0214] The compounds of Formula (I), or a pharmaceuticaly acceptable salt thereof provided herein may be administered to a subject in an amount that is dependent upon, for example, the goal of administration (e.g., the degree of resolution desired); the age, weight, sex, and health and physical condition of the subject to which the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition or symptom thereof. Thedosing regimen may also take into consideration the existence, nature, and extent of any adverse efects associated with the agent(s) being administered.

[0215] An efective dose (ED) is the dose or amount of an agent that produces a therapeutic response or desired efect in some fraction of the subjects taking it. The “median effective dose” or ED50 of an agent is the dose or amount of an agent that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is commonly used as a measure of reasonable expectance of an agent’s effect, it is not necessarily the dose that a clinician might deem appropriate taking into consideration al relevant factors. Thus, in some situations the efective amount is more than the calculated ED50, in other situations the efective amount is less than the calculated ED50, and in stil other situations the efective amount is the same as the calculated ED50. ROUTES OF ADMINISTRATION

[0216] A compound of Formula (I), or a pharmaceuticaly acceptable salt thereof or pharmaceutical compositions comprising this compound may be administered to a patient by any convenient route of administration, whether systemicaly / peripheraly or topicaly (i.e., at the site of desired action).

[0217] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insuflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Some embodiments of the present disclosure contemplate oral administration.

[0218] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pils, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pelets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolizedformulations 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.

[0219] 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 pharmaceuticaly excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose, calcium carbonate, sodium carbonate, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as cornstarch or alginic acid, binding agents such as starch, gelatin, or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc, antioxidants such as ascorbic acid and sodium bisulfate, preservatives such as, benzyl alcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate, emulsifying agents, suspending agents, dispersing agents, solvents, filers, bulking agents, detergents, bufers, vehicles, and / or adjuvants. Additionaly such compositions may contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceuticaly elegant and palatable preparations. For example, a suitable vehicle may be physiological saline solution or citrate bufered saline, possibly supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral bufered saline or saline mixed with serum albumin are further exemplary vehicles. Those skiled in the art wil readily recognize a variety of bufers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical bufers include, but are not limited to, pharmaceuticaly acceptable weak acids, weak bases, or mixtures thereof. As an example, the bufer components can be water soluble materials such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, a Tris bufer, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N- Morpholino)ethanesulfonic acid (MES), 2-(N-Morpholino)ethanesulfonic acid sodium salt, 3-(N- Morpholino)propanesulfonic acid (MOPS), and N-tris[Hydroxymethyl]methyl-3- aminopropanesulfonic acid (TAPS). 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 fororal use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0220] 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, optionaly containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.

[0221] In one embodiment, it may be administered via injection. NON-LIMITING EXEMPLARY EMBODIMENTS

[0222] Embodiment 1. A compound of Formula (I): , whereinX2 is CH, N, or CF; R1 is hydrogen, deuterium, cyano, formyl, -CONH2, -CH2OH, -CH2OC1-2alkyl, C1-2alkyl, C1-2 deuteroalkyl, or C1-2haloalkyl; R2 and R3together with the carbon atom to which they are atached form a 3- or 4- membered heterocyclyl having one (1) heteroatom ring vertex, selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 R2a; each R2a is independently deuterium, C1-4 alkyl, halo, or C1-4 haloalkyl; R4 is hydrogen, C alkyl, C haloalkyl 4a 4a 4b 1-4 1-4 , -C(O)OR, or -C(O)NRR; R4a and R4b are each independently hydrogen or C1-4 alkyl; and R5 is C1-4 alkyl or C1-4 haloalkyl; or a pharmaceuticaly acceptable salt thereof.

[0223] Embodiment 2. The compound of embodiment 1, having Formula (Ia) , or a pharmaceuticaly

[0224] Embodiment 3. The compound of embodiment 1, having Formula (Ib) , or a pharmaceuticaly

[0225] Embodiment 4. The compound of embodiment 1, having Formula (Ic) , or a pharmaceuticaly

[0226] Embodiment 5. The compound of any one of embodiments 1 to 4, or a pharmaceuticaly acceptable salt thereof, wherein X2 is CH.

[0227] Embodiment 6. The compound of any one of embodiments 1 to 4, or a pharmaceuticaly acceptable salt thereof, wherein X2 is N.

[0228] Embodiment 7. The compound of any one of embodiments 1 to 4, or a pharmaceuticaly acceptable salt thereof, wherein X2 is CF.

[0229] Embodiment 8. The compound of any one of embodiments 1 to 7, or a pharmaceuticaly acceptable salt thereof, wherein R1 is hydrogen, methyl, ethyl, trideuteromethyl, cyano, fluoromethyl, difluoromethyl, or hydroxymethyl.

[0230] Embodiment 9. The compound of any one of embodiments 1 to 8, or a pharmaceuticaly acceptable salt thereof, wherein R1 is hydrogen, methyl, ethyl, trideuteromethyl, cyano, fluoromethyl, or difluoromethyl.

[0231] Embodiment 10. The compound of any one of embodiments 1 to 9, or a pharmaceuticaly acceptable salt thereof, wherein R1 is hydrogen.

[0232] Embodiment 11. The compound of any one of embodiments 1 to 9, wherein R1 is methyl.

[0233] Embodiment 12. The compound of any one of embodiments 1 to 9, or a pharmaceuticaly acceptable salt thereof, wherein R1 is trideuteromethyl.

[0234] Embodiment 13. The compound of any one of embodiments 1 to 9, or a pharmaceuticaly acceptable salt thereof, wherein R1 is cyano.

[0235] Embodiment 14. The compound of any one of embodiments 1 to 9, or a pharmaceuticaly acceptable salt thereof, wherein R1 is fluoromethyl.

[0236] Embodiment 15. The compound of any one of embodiments 1 to 9, or a pharmaceuticaly acceptable salt thereof, wherein R1 is difluoromethyl.

[0237] Embodiment 16. The compound of any one of embodiments 1 to 8, or a pharmaceuticaly acceptable salt thereof, wherein R1 is hydroxymethyl.

[0238] Embodiment 17. The compound of any one of embodiments 1 to 16, or a pharmaceuticaly acceptable salt thereof, wherein R2 and R3combine to form a 4- membered heterocyclyl having one (1) heteroatom ring vertex, selected from N, O, and S.

[0239] Embodiment 18. The compound of any one of embodiments 1 to 17, or a pharmaceuticaly acceptable salt thereof, wherein R2 and R3combine to form a 4- membered heterocycloalkyl, and the heterocycloalkyl is oxetanyl which is unsubstituted or substituted with 1 to 4 R2a.

[0240] Embodiment 19. The compound of any one of embodiments 1 to 18, or a pharmaceuticaly acceptable salt thereof, wherein the heterocyclyl is unsubstituted.

[0241] Embodiment 20. The compound of any one of embodiments 1 to 18, or a pharmaceuticaly acceptable salt thereof, wherein the heterocyclyl is substituted with 1 to 3 R2a.

[0242] Embodiment 21. The compound of any one of embodiments 1 to 18, or a pharmaceuticaly acceptable salt thereof, wherein the heterocyclyl is substituted with 1 to 2 R2a.

[0243] Embodiment 22. The compound of any one of embodiments 1 to 18 and 20 to 21, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is independently deuterium, C1-4 alkyl, or halo.

[0244] Embodiment 23. The compound of any one of embodiments 1 to 18 and 20 to 22, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is deuterium.

[0245] Embodiment 24. The compound of any one of embodiments 1 to 18 and 20 to 22, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is halo.

[0246] Embodiment 25. The compound of any one of embodiments 1 to 18 and 20 to 22, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is C1-4 alkyl.

[0247] Embodiment 26. The compound of any one of embodiments 1 to 18, 20 to 22, and 25, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is methyl.

[0248] Embodiment 27. The compound of any one of embodiments 1 to 26, or a pharmaceuticaly acceptable salt thereof, wherein R4 is hydrogen.

[0249] Embodiment 28. The compound of any one of embodiments 1 to 26, or a pharmaceuticaly acceptable salt thereof, wherein R4 is C1-4 alkyl.

[0250] Embodiment 29. The compound of any one of embodiments 1 to 28, or a pharmaceuticaly acceptable salt thereof, wherein R5 is C1-2 alkyl or C1-2 haloalkyl.

[0251] Embodiment 30. The compound of any one of embodiments 1 to 29, or a pharmaceuticaly acceptable salt thereof, wherein R5 is methyl, ethyl, or difluoromethyl.

[0252] Embodiment 31. The compound of any one of embodiments 1 to 28, or a pharmaceuticaly acceptable salt thereof, wherein R5 is C1-2 haloalkyl.

[0253] Embodiment 32. The compound of any one of embodiments 1 to 31, or a pharmaceuticaly acceptable salt thereof, wherein R5 is difluoromethyl.

[0254] Embodiment 33. The compound of embodiment 1, or a pharmaceuticaly acceptable salt thereof, wherein the compound is selected from Table 1.

[0255] Embodiment 34. A pharmaceutical composition comprising a compound, or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, and a pharmaceuticaly acceptable excipient.

[0256] Embodiment 35. A method of treating a disease or disorder in which PARG activity is implicated in a patient, said method comprising administering to said patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34.

[0257] Embodiment 36. The method of embodiment 35, wherein the patient is in recognized need of such treatment.

[0258] Embodiment 37. A method of treating a cancer in a patient in need thereof, said method comprising administering to said patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34.

[0259] Embodiment 38. The method of embodiment 37, wherein said cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer.

[0260] Embodiment 39. A compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33 or a pharmaceutical composition of embodiment 34, for use in therapy.

[0261] Embodiment 40. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition according to embodiment 39, wherein said therapy is the treatment of a cancer.

[0262] Embodiment 41. The compound or the pharmaceuticaly acceptable salt thereof or the pharmaceutical composition according to embodiment 40, wherein said cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer.

[0263] Embodiment 42. Use of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34 in the manufacture of a medicament for therapy.

[0264] Embodiment 43. The use of embodiment 42, wherein said therapy is the treatment of a cancer.

[0265] Embodiment 44. The use of embodiment 43, wherein said cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer.

[0266] Embodiment 45. A method of inhibiting PARG in vivo in a patient, said method comprising administering to said patient an efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34.

[0267] Embodiment 46. A method of inhibiting cel proliferation, in vitro or in vivo, said method comprising contacting a cel with an efective amount of a compound or apharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34.

[0268] Embodiment 47. A method of treating a cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof, said method comprising administering to said patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34.

[0269] Embodiment 48. A method of treating and / or preventing a homologous recombinant deficient (HRD) cancer in a patient comprising administering to the patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34.

[0270] Embodiment 49. The method of embodiment 48, wherein the patient is in recognized need of such treatment.

[0271] Embodiment 50. A method of treating and / or preventing a cancer in a patient, 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, the method comprising administering to the patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of embodiments 1 to 33, or a pharmaceutical composition of embodiment 34.

[0272] Embodiment 51. The method of embodiment 50, wherein the patient is in recognized need of such treatment.

[0273] Embodiment 52. A PARG inhibitor for use in the treatment of cancer, wherein the PARG inhibitor is a compound of any one of embodiments 1 to 33, or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

[0274] Embodiment 53. Use of a PARG inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the PARG inhibitor is a compound of any one of embodiments 1 to 33, or a pharmaceuticaly acceptable salt thereof, or a pharmaceutical composition of embodiment 34.

[0275] Embodiment 54. The use of embodiment 52 or 53, wherein said cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer. EXAMPLES

[0276] The folowing examples are put forth so as to provide those of ordinary skil in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure, nor are they intended to represent that the experiments below were performed or that they are al of the experiments that may be performed. It is to be understood that exemplary descriptions writen in the present tense were not necessarily performed, but rather that the descriptions can be performed to generate data and the like of a nature described therein. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.), but some experimental erors and deviations should be accounted for. Synthesis Examples General procedure for preparation of compounds 1 to 8 Intermediate 1 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-sulfonic acidStep 1: Preparation of 4-(benzylthio)-2,6-difluorobenzaldehyde:

[0277] To a stired solution of 4-bromo-2,6-difluorobenzaldehyde (100 g, 452 mmol) in 1,4- dioxane (600 mL) was added phenylmethanethiol (61.8 g, 498 mmol), DIPEA (154 mL, 905 mmol), xantphos (2.88 g, 4.98 mmol), Pd2(dba)3 (2.07 g, 2.26 mmol) at room temperature. The reaction mixture was stired at 50 °C for 3 h. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (2 x 600 mL). The combined organic layers were washed with aqueous 1 M HCl (500 mL), brine solution (500 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was stired with petroleum ether (500 mL), filtered, washed with petroleum ether and dried under vacuum to aford 4-(benzylthio)-2,6-difluorobenzaldehyde (98 g, 82% yield) as a brown solid. MS ESI calculated for C14H10F2OS[M+H]+ 265.04, found 265.06. Step 2: Preparation of 4-(benzylthio)-2,6-difluorobenzaldehyde oxime:

[0278] To ag, 379 mmol) in CH3CN (400 mL) was added hydroxylamine hydrochloride (26.3 g, 379 mmol), and triethylamine (58 mL, 417 mmol) at room temperature. The reaction mixture was stired at 60 °C for 3 h. The reaction mixture was quenched with water (500 mL) and stired for 2 h at room temperature. The precipitate colected by filtration to aford 4-(benzylthio)-2,6- difluorobenzaldehyde oxime (90 g, 85% yield) as an of-white solid. MS ESI calculated for C14H11F2NOS[M+H]+ 280.05, found 280.12. Step 3: Preparation of 6-(benzylthio)-4-fluoro-1H-indazole:

[0279] To a stired solution of 4-(benzylthio)-2,6-difluorobenzaldehyde oxime (100 g, 360 mmol) in DME (300 mL) was added hydrazine hydrate (35 wt% in water, 300 mL) at room temperature. The reaction mixture was stired at 70 °C for 48 h. The reaction mixture was cooled to room temperature, quenched with water (800 mL) and stired at room temperature for 2 h. The precipitate was colected by filtration and washed with water (100 mL) and dried under vacuum to aford 6-(benzylthio)-4-fluoro-1H-indazole (75.0 g, 80.8% yield) as an of-white solid. MS ESI calculated for C H FNS[M+ + 14 11 2 H] 259.06, found 259.14. Step 4: Preparation of 4-fluoro-1H-indazole-6-sulfonic acid:

[0280] a - g, mmol) in CH3CN (500 mL) was added AcOH (11.0 mL, 194 mmol) and water (50 mL) at room temperature. Then, to the reaction mixture was added 1,3-dichloro-5,5-dimethylimidazolidine- 2,4-dione (114 g, 581 mmol) at 0oC. The reaction mixture was stired at 0 °C for 1 h. The reaction mixture was diluted with water (300 mL) at 0 °C and then stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure until a precipitate is observed, then CH3CN (500 mL) was added at room temperature. The precipitate was colected by filtration, washed with CH3CN and dried under vacuum to aford 4-fluoro-1H-indazole-6-sulfonic acid (68.5 g, 83.7% yield) as a purple solid. MS ESI calculated for C + 7H5FN2O3S[M+H] 217.00, found 217.06. Step 5: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6- sulfonic acid:

[0281] To a s g, 231 mmol) in NMP (1500 mL) was added K3PO4 (147 g, 694 mmol), 2-bromo-5-(difluoromethyl)-1,3,4- thiadiazole (50.8 g, 236 mmol) at room temperature. The reaction mixture was stired at 50 °C for 50 h. The reaction mixture was quenched with water (1500 mL) and stirred for 2 h at room temperature. The precipitate was colected by filtration and washed with water. The precipitate was then suspended in CH3CN (300 mL) and water (300 mL) and stired at 70 °C until clear solution appeared. The mixture was cooled to room temp while stiring, then further cooled with an ice bath stiring overnight. The precipitate was colected by filtration and dried under vacuum to aford 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-sulfonic acid (26 g, 32% yield) as a pale pink solid. MS ESI calculated for C + 10H5F3N4O3S2[M-H] 348.98, found 348.90.

[0282] 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.84 (s, 1H), 8.59 (d, J = 1.2 Hz, 1H), 7.61 (t, J = 1H), 7.38-7.41 (m, 1H). Scheme 2 - Example 4- - (difluoromethyl)oxetan-3-yl)-4-fluoro-1H-indazole-6-sulfonamide:

[0283] ro-1H- indazole-6-sulfonic acid (0.5 g, 1.427 mmol) in DCM (5 mL) were added oxalyl chloride (0.306 mL, 3.568 mmol) and catalytic DMF (0.011 mL, 0.143 mmol) at 0 °C, and the reaction mixture was stired at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, the solid thus obtained was dissolved in acetonitrile (5 mL), and subsequently to it was added 3-(difluoromethyl)oxetan-3-amine (0.211 g, 1.713 mmol) dissolved in pyridine (2.5 mL) and the reaction mixture was stired at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer separated, washed with brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100-200) and eluted with 5% MeOH in DCM. Pure fractions were concentrated under reduced pressure to aford 11-(5-(difluoromethyl)-1,3,4-thiadiazol-2- yl)-N-(3-(difluoromethyl)oxetan-3-yl)-4-fluoro-1H-indazole-6-sulfonamide (0.25 g, yield: 38.46%) as a brown solid. MS ESI calculated for C + 14H10F5N5O3S2[M+H] 456.02, found 456.29. Step 2: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3- (difluoromethyl)oxetan-3-yl)-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-1H-indazole-6- sulfonamide:

[0284] To a stired solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3- (difluoromethyl)oxetan-3-yl)-4-fluoro-1H-indazole-6-sulfonamide (0.1 g, 0.220 mmol) and (2S,6S)-2,6-dimethylpiperazine (0.050 g, 0.439 mmol) in DMSO (5 mL) was added DIPEA (0.5 mL, 1.098 mmol) at room temperature, and the reaction mixture was stired at 130 °C for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was separated, washed with brine solution (100 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by Prep HPLC. Purification conditions: COLUMN: CHROMASOL C18 (21.1 x 250 mm, 5 mm, BUFFER A: 10 mM ABC, BUFFER B: ACETONITRILE, MOBILE PHASE CONDITIONS (% OF B): 0 / 40,2 / 40,12 / 55,16 / 55,16.01 / 98,20 / 98,20.01 / 40,23 / 410, FLOW: 16 mL, ANL-MCL5-PREP-021, SOLUBILITY: ACN, Fraction Volume: 150 mL. The pure fractions were concentrated and lyophilized to aford 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(difluoromethyl)oxetan- 3-yl)-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-1H-indazole-6-sulfonamide (80 mg, 66%) as a yelow solid. MS ESI calculated for C20H23F4N7O3S2[M+H]+ 550.13, found 550.29.

[0285] 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.77 (s, 1H), 8.41 (s, 1H), 7.59 (t, J = 53.2 Hz, 1H), 7.16 (s, 1H), 6.27 (t, J = 55.2 Hz, 1H), 4.53-4.58 (m, 4H), 3.40-3.42 (m, 2H), 3.37-3.39 (m, 2H), 3.10-3.14 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H). Example 1 Synthesis of N-(3-cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(3S,5S)- 3,5-dimethylpiperazin-1-yl)-1H-indazole-6-sulfonamide:

[0286] Example 1 was synth ple 4 above, using commercialy available amine 3-aminooxetane-3-carbonitrile hydrochloride instead in step 1 to aford N-(3- cyanooxetan-3-yl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5S)-3,5- dimethylpiperazin-1-yl)-1H-indazole-6-sulfonamide (1.0 mg, 0.8% yield) as a yelow solid. MS mass calculated for [M+1]+ Chemical Formula: (C + 20H23F2N8O3S2) requires m / z 525.1, MS found m / z 525.2;1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.37 (s, 1H), 8.18 (s, 1H), 7.60 (t, J = 53.1 Hz, 1H), 7.10 (d, J = 1.3 Hz, 1H), 4.72 (d, J = 6.4 Hz, 2H), 4.63 (dd, J = 6.5, 3.2 Hz, 2H), 3.56 – 3.26 (m, 4H), 3.12 (dd, J = 12.1, 6.3 Hz, 2H), 1.27 (s, 3H), 1.25 (s, 3H). Example 2 Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(3S,5S)-3,5-dimethylpiperazin-1- yl)-N-(3-(fluoromethyl)oxetan-3-yl)-1H-indazole-6-sulfonamide:

[0287] Example 2 was4 above, using commercialy available amine 3-(fluoromethyl)oxetan-3-amine hydrochloride instead in step 1 to aford 1-(5- (difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3- (fluoromethyl)oxetan-3-yl)-1H-indazole-6-sulfonamide (75.0 mg, 60.8% yield). LC / ESI-MSanalysis gave 100.0% purity, [M+H]+ = 531.6.1H NMR (400 MHz, DMSO) δ 8.80 (d, J = 0.8 Hz, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.61 (t, J = 53.1 Hz, 2H), 7.16 (d, J = 1.4 Hz, 1H), 4.68 (s, 1H), 4.57 (q, J = 3.5 Hz, 3H), 4.36 (dd, J = 6.5, 1.6 Hz, 2H), 3.43 (td, J = 11.8, 9.9, 4.6 Hz, 5H), 3.23 – 3.09 (m, 3H), 1.23 (d, J = 6.2 Hz, 6H), 1.05 (d, J = 6.6 Hz, 1H). Example 3 Synthesis of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(3S,5S)-3,5-dimethylpiperazin-1- yl)-N-(3-methyloxetan-3-yl)-1H-indazole-6-sulfonamide:

[0288] Example 3 was4 above, using commercialy available amine 3-Methyloxetan-3-amine hydrochloride instead in step 1 to aford 1-(5- (difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-(3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(3- methyloxetan-3-yl)-1H-indazole-6-sulfonamide (3.5 g, yield: 47.64%) as a yelow solid. MS ESI calculated for CH FNOS [M+H]+ 1 20 252 7 32 514.15, found 514.29.H NMR (400MHz, DMSO-d6): δ 8.74 (s, 1H), 8.38 (s, 1H), 7.55 (t, J = 53.0 Hz, 1H), 7.12 (s, 1H), 4.58 (t, J = 5.8 Hz, 2H), 4.14 (t, J = 6.0 Hz, 2H), 3.38 (dd, J = 11.6 Hz, 2.4 Hz, 2H), 3.27-3.31 (m, 2H), 3.09-3.13 (m, 2H), 1.44 (s, 3H), 1.18 (d, J = 6.4 Hz, 6H).

[0289] Examples 5 to 8 can be synthesized using the procedures described herein as wel as those generaly available in the art.Biological Examples Example 1 Inhibition of PARG enzymatic assay (TR-FRET) Enzymatic EC50 Assay

[0290] 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 ful inhibition of enzymatic activity. Materials: Enzyme: • PARG o hPARG: 250 pM, 1-976, His-tagged, Proteos, 2.0 mg / mL (17.9 µM) o Substrate: 30 nM o Test Compound / Enzyme Pre-incubation time: 1 hr o Enzyme / Substrate Reaction time: 10 minutes Substrate: hPARP1, His6-TEV tagged, 1.2 mg / mL (10.3 µM) Detection Antibody: anti-His monoclonal antibody-ULight, Perkin Elmer catalog # TRF0134-M Streptavidin-Europium: Perkin Elmer catalog # AD0062 Assay Bufer: 50mM Tris-HCL pH 7.4, 50mM KCL, 3mM EDTA, 0.4mM EGTA, 1mM DTT, 0.01% Tween 20, 0.01% BSA Temperature: 23℃ Total reaction volume: 20 µL Controls: • 0% inhibition: DMSO • 100% inhibiton: No enzyme Enzyme reaction and Detection:1. Transfer 200 nL of 100x compound or DMSO to the appropriate wels of a 384 wel white polystyrene microtitre plate (Corning Catalog#3574). 2. Transfer 10 uL of 2x final concentration of enzyme in assay bufer or assay bufer alone to the appropriate wels. 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 al test wels. 6. Incubate the plate at room temperature for 10 minutes 7. Transfer 10 uL of 3x mixture of 42 nM detection antibody and 2.25 nM streptavidin- europium in 50mM Tris-HCL pH 7.4 to al test wels. 8. Incubate the plate at room temperature for 1 hour. 9. Read the plate on a plate reader (Envision) Excitation: 317 nM Emission: 620 nM Emission: 665 nM Data Analysis:

[0291] EC50values were calculated in Colaborative Drug Discovery vault (CDD). Curves were fited by CDD as response (%) vs compound concentration (uM) using a 4-parameter inhibition model using Formula 1.

[0292] Formula 1: Fit = (A+(B-A) / (1+((C / x)^D))) Res = (y-fit)

[0293] The TR-FRET EC50values for Compounds disclosed herein are provided in Table 2, below. TR-FRET **** <= 0.1 ^M, 0.1 ^M < *** <= 0.3 ^M, 0.3 ^M < ** <= 1 ^M, 1 ^M < * < 10 ^MTable 2 Example TR-FRET Example TR-FRET Example TR-FRET Example TR-FRETEC50 (µM) EC50 (µM) EC50 (µM) EC50 (µM) 1 **** 2 **** 3 **** 4 ***References [1] Ame, J. C., E. Fouquerel, L. R. Gauthier, D. Biard, F. D. Boussin, F. Dantzer, G. de Murcia and V. Schreiber (2009). "Radiation-induced mitotic catastrophe in PARG-deficient cels." J Cel Sci 122(Pt 12): 1990-2002. [2] Barber, L. J., S. Sandhu, L. Chen, J. Campbel, I. Kozarewa, K. Fenwick, I. Assiotis, D. N. Rodrigues, J. S. Reis Filho, V. Moreno, J. Mateo, L. R. Molife, J. De Bono, S. Kaye, C. J. Lord and A. Ashworth (2013). "Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor." J Pathol 229(3): 422-429. [3] Blenn, C., P. Wyrsch and F. R. Althaus (2011). "The ups and downs of tannins as inhibitors of poly(ADP-ribose)glycohydrolase." Molecules 16(2): 1854-1877. [4] Caiafa, P., T. Guastafiero and M. Zampieri (2009). "Epigenetics: poly(ADP- ribosyl)ation of PARP-1 regulates genomic methylation paterns." FASEB J 23(3): 672-678. [5] Curtin, N. J. and C. Szabo (2013). "Therapeutic applications of PARP inhibitors: anticancer therapy and beyond." Mol Aspects Med 34(6): 1217-1256. [6] Dahl, M., V. Maturi, P. Lonn, P. Papoutsoglou, A. Zieba, M. Vanlandewijck, L. P. van der Heide, Y. Watanabe, O. Soderberg, M. O. Hotiger, C. H. Heldin and A. Moustakas (2014). "Fine-tuning of Smad protein function by poly(ADP-ribose) polymerases and poly(ADP-ribose) glycohydrolase during transforming growth factor beta signaling." PLoS One 9(8): e103651. [7[ Drost, R. and J. Jonkers (2014). "Opportunities and hurdles in the treatment of BRCA1- related breast cancer." Oncogene 33(29): 3753-3763. [8] Erdelyi, K., P. Bai, I. Kovacs, E. Szabo, G. Mocsar, A. Kakuk, C. Szabo, P. Gergely and L. Virag (2009). "Dual role of poly(ADP-ribose) glycohydrolase in the regulation of cel death in oxidatively stressed A549 cels." FASEB J 23(10): 3553-3563. [9] Fathers, C., R. M. Drayton, S. Solovieva and H. E. Bryant (2012). "Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specificaly kils BRCA2-deficient tumor cels." Cel Cycle 11(5): 990-997.

[0010] Fisher, A. E., H. Hochegger, S. Takeda and K. W. Caldecot (2007). "Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase." Mol Cel Biol 27(15): 5597-5605.

[0011] Frizzel, K. M., M. J. Gamble, J. G. Berocal, T. Zhang, R. Krishnakumar, Y. Cen, A. A. Sauve and W. L. Kraus (2009). "Global analysis of transcriptional regulation by poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in MCF-7 human breast cancer cels." J Biol Chem 284(49): 33926-33938.

[0012] Fujihara, H., H. Ogino, D. Maeda, H. Shirai, T. Nozaki, N. Kamada, K. Jishage, S. Tanuma, T. Takato, T. Ochiya, T. Sugimura and M. Masutani (2009). "Poly(ADP-ribose) Glycohydrolase deficiency sensitizes mouse ES cels to DNA damaging agents." Cur Cancer Drug Targets 9(8): 953-962.

[0013] Guastafiero, T., A. Catizone, R. Calabrese, M. Zampieri, O. Martela, M. G. Bacalini, A. Reale, M. Di Girolamo, M. Miccheli, D. Farrar, E. Klenova, F. Ciccarone and P. Caiafa (2013). "ADP-ribose polymer depletion leads to nuclear Ctcf re-localization and chromatin rearrangement(1)." Biochem J 449(3): 623-630.

[0014] Ji, Y. and A. V. Tulin (2009). "Poly(ADP-ribosyl)ation of heterogeneous nuclear ribonucleoproteins modulates splicing." Nucleic Acids Res 37(11): 3501-3513.

[0015] Le May, N., I. Iltis, J. C. Ame, A. Zhovmer, D. Biard, J. M. Egly, V. Schreiber and F. Coin (2012). "Poly (ADP-ribose) glycohydrolase regulates retinoic acid receptor-mediated gene expression." Mol Cel 48(5): 785-798.

[0016] Mashimo, M., J. Kato and J. Moss (2014). "Structure and function of the ARH family of ADP-ribosyl-acceptor hydrolases." DNA Repair (Amst).

[0017] Mortusewicz, O., E. Fouquerel, J. C. Ame, H. Leonhardt and V. Schreiber (2011). "PARG is recruited to DNA damage sites through poly(ADP-ribose)- and PCNA-dependent mechanisms." Nucleic Acids Res 39(12): 5045-5056.

[0018] Nakadate, Y., Y. Kodera, Y. Kitamura, T. Tachibana, T. Tamura and F. Koizumi (2013). "Silencing of poly(ADP-ribose) glycohydrolase sensitizes lung cancer cels to radiation through the abrogation of DNA damage checkpoint." Biochem Biophys Res Commun 441(4): 793-798.

[0019] Shirai, H., H. Fujimori, A. Gunji, D. Maeda, T. Hirai, A. R. Poetsch, H. Harada, T. Yoshida, K. Sasai, R. Okayasu and M. Masutani (2013). "Parg deficiency confers radio-sensitization through enhanced cel death in mouse ES cels exposed to various forms of ionizing radiation." Biochem Biophys Res Commun 435(1): 100-106.

[0020] Shirai, H., A. R. Poetsch, A. Gunji, D. Maeda, H. Fujimori, H. Fujihara, T. Yoshida, H. Ogino and M. Masutani (2013). "PARG dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments diferent cel death pathways." Cel Death Dis 4: e656.

[0021] Sun, Y., T. Zhang, B. Wang, H. Li and P. Li (2012). "Tannic acid, an inhibitor of poly(ADP-ribose) glycohydrolase, sensitizes ovarian carcinoma cels to cisplatin." Anticancer Drugs 23(9): 979-990.

[0022] Zhou, Y., X. Feng and D. W. Koh (2010). "Enhanced DNA accessibility and increased DNA damage induced by the absence of poly(ADP-ribose) hydrolysis." Biochemistry 49(34): 7360-7366.

[0023] Zhou, Y., X. Feng and D. W. Koh (2011). "Synergistic cytotoxicity of N-methyl-N'- nitro-N-nitrosoguanidine and absence of poly(ADP-ribose) glycohydrolase involves chromatin decondensation." Int J Oncol 39(1): 121-127.

[0024] Milbury CA, Creeden J, Yip WK, Smith DL, Patani V, Maxwel K, Sawchyn B, Gjoerup O, Meng W, Skoletsky J, Concepcion AD, Tang Y, Bai X, Dewal N, Ma P, Bailey ST, Thornton J, Pavlick DC, Frampton GN, Lieber D, White J, Burns C, Vietz C (2022) “Clinical and analytical validation of FoundationOne®CDx, a comprehensive genomic profiling assay for solid tumors.” PLOS ONE 17(3): e0264138. htps: / doi.org / 10.1371 / journal.pone.0264138

[0294] Although the foregoing disclosure has been described in some detail by way of ilustration and example for purposes of clarity of understanding, one of skil in the art wil appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individualy incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shal dominate.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I): , whereinX2 is CH, N, or CF; R1 is hydrogen, deuterium, cyano, formyl, -CONH2, -CH2OH, -CH2OC1-2alkyl, C1-2alkyl, C1-2 deuteroalkyl, or C1-2haloalkyl; R2 and R3together with the carbon atom to which they are atached form a 3- or 4- membered heterocyclyl having one (1) heteroatom ring vertex, selected from N, O, and S, wherein the heterocyclyl is unsubstituted or substituted with 1 to 4 R2a; each R2a is independently deuterium, C1-4 alkyl, halo, or C1-4 haloalkyl; R4 is hydrogen, C 4a 4a 4b 1-4 alkyl, C1-4 haloalkyl, -C(O)OR, or -C(O)NRR; R4a and R4b are each independently hydrogen or C1-4 alkyl; and R5 is C1-4 alkyl or C1-4 haloalkyl; or a pharmaceuticaly acceptable salt thereof.

2. The compound of claim 1, having Formula (Ia) ,or a pharmaceuticaly acceptable salt thereof.

3. The compound of claim 1, having Formula (Ib) or (Ic): , or a4. The compound of any one of claims 1 to 3, or a pharmaceuticaly acceptable salt thereof, wherein X2 is CH.

5. The compound of any one of claims 1 to 4, or a pharmaceuticaly acceptable salt thereof, wherein R1 is hydrogen, methyl, ethyl, trideuteromethyl, cyano, fluoromethyl, difluoromethyl, or hydroxymethyl.

6. The compound of any one of claims 1 to 4, or a pharmaceuticaly acceptable salt thereof, wherein R1 is hydrogen.

7. The compound of any one of claims 1 to 4, or a pharmaceuticaly acceptable salt thereof, wherein R1 is methyl.

8. The compound of any one of claims 1 to 4, or a pharmaceuticaly acceptable salt thereof, wherein R1 is trideuteromethyl.

9. The compound of any one of claims 1 to 4, or a pharmaceuticaly acceptable salt thereof, wherein R1 is cyano.

10. The compound of any one of claims 1 to 4, wherein R1 is fluoromethyl .

11. The compound of any one of claims 1 to 4, wherein R1 is difluoromethyl.

12. The compound of any one of claims 1 to 10, or a pharmaceuticaly acceptable salt thereof, wherein R2 and R3combine to form a 4- membered heterocyclyl having one heteroatom ring vertex, selected from N, O, and S.

13. The compound of any one of claims 1 to 12, or a pharmaceuticaly acceptable salt thereof, wherein R2 and R3combine to form a 4- membered heterocycloalkyl, and the heterocycloalkyl is oxetanyl which is unsubstituted or substituted with 1 to 4 R2a.

14. The compound of any one of claims 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein the heterocyclyl is unsubstituted.

15. The compound of any one of claims 1 to 13, or a pharmaceuticaly acceptable salt thereof, wherein the heterocyclyl is substituted with 1 to 2 R2a.

16. The compound of any one of claims 1 to 13 and 15, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is independently deuterium, C1-4 alkyl, or halo.

17. The compound of any one of claims 1 to 13 and 15, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is deuterium.

18. The compound of any one of claims 1 to 13 and 15, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is C1-4 alkyl.

19. The compound of any one of claims 1 to 13, 15, and 18, or a pharmaceuticaly acceptable salt thereof, wherein each R2a is methyl.

20. The compound of any one of claims 1 to 19, or a pharmaceuticaly acceptable salt thereof, wherein R4 is hydrogen.

21. The compound of any one of claims 1 to 20, or a pharmaceuticaly acceptable salt thereof, wherein R5 is C1-2 haloalkyl.

22. The compound of any one of claims 1 to 20, or a pharmaceuticaly acceptable salt thereof, wherein R5 is difluoromethyl.

23. The compound of any one of claims 1 to 22, having Formula (Ia-1), wherein , or a pharmaceuticaly24. The compound of any one of claims 1 to 22, having Formula (Ia-2), wherein , or a pharmaceuticaly25. The compound of claim 1, wherein the compound is selected from the group consisting of:, 526. A pharmaceutical composition comprising a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 25, and a pharmaceuticaly acceptable excipient.

27. A method of treating a cancer in a patient in need thereof, said method comprising administering to said patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 25, or a pharmaceutical composition of claim 26.

28. A method of treating and / or preventing a homologous recombinant deficient (HRD) cancer in a patient in need thereof, the method comprising administering to the patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 25, or a pharmaceutical composition of claim 26.

29. A method of treating and / or preventing a cancer in a patient in need thereof, where 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, the method comprising administering to the patient a therapeuticaly efective amount of a compound or a pharmaceuticaly acceptable salt thereof of any one of claims 1 to 25, or a pharmaceutical composition of claim 26.

30. The method of any one of claims 27 to 29, wherein said cancer is ovarian, gastric, breast cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, colorectal cancer, head and neck cancer, or endometrial cancer.

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