Piperazine-substituted indazole compounds as PARG inhibitors

Abstract

As used herein, a compound of formula (I): The present invention provides JPEG2025512780000038.jpg53128 or a pharma- ceutically acceptable salt thereof. The provided compounds are useful poly(ADP-ribose) glycohydrolase (PARG) inhibitors. Further utilities and advantages are described herein.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 322,994, filed March 23, 2022, which is incorporated by reference in its entirety.

[0002] STATEMENT OF RIGHTS TO INVETIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT N / A

[0003] REFERENCE TO A "SEQUENCE LISTING," TABLE, OR COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISC N / A [Background technology]

[0004] Cancer is caused by uncontrolled and unregulated cell proliferation. This rapid proliferation often results in high levels of oxidative stress within the tumor, which damages DNA and greatly increases the rate of mutations. Therefore, tumor cells engage and are highly dependent on DNA damage repair mechanisms.

[0005] Single-strand breaks (SSBs) are the most common type of damage occurring in cells, and PARG (poly(ADP-ribose) glycohydrolase), together with PARP (poly(ADP-ribose) polymerase), along with several other proteins, are involved in alternative repair mechanisms called single-strand break repair (SSBR) and base excision repair (BER).

[0006] One of the earliest events during single-stranded DNA repair is the binding of PARP (poly(ADP-ribose) polymerase) to the break and the rapid synthesis of poly ADP-ribose (PAR) on itself. This molecular structure serves as a signal to recruit other DNA repair proteins, first XRCC1, which then repairs the break (Mortusewicz, Fouquerel et al. 2011). The signals initiated by these PAR chains are short-lived as they are rapidly degraded by the enzyme PARG. Binding of PAR to PARP reduces its catalytic activity, and thus PARG activity helps restore PARP to its catalytically active form (Curtin and Szabo 2013).

[0007] PARG is derived from a single gene with isoforms present in the nucleus, mitochondria and cytosol. Another known protein with glycohydrolase activity is ARH3, which is localized to mitochondria (Mashimo, Kato et al. 2014). Although primarily known for its direct role in DNA repair, PARG influences PAR signaling in splicing, transcription and epigenetic pathways (Ji and Tulin 2009) (Le May, Iltis et al. 2012) (Dahl, Maturi et al. 2014) (Guastafierro, Catizone et al. 2013) (Caiafa, Guastafierro et al. 2009).

[0008] Cancer cells may become dependent on specific DNA repair pathways when other mechanisms of DNA repair fail. Tumors with mutations in proteins involved in double-strand break repair are often more sensitive to PARP inhibitors of SSBR. There is already some evidence that PARG depletion inhibits SSBR and reduces survival of BRCA2-deficient cells (Fathers, Drayton et al. 2012). However, mutations in other tumors may result in defects in double-strand DNA repair mechanisms (so-called "BRCA-ness"), which may make tumor cells sensitive to PARG inhibition.

[0009] PARG depletion has been studied in many mouse and human model systems. Mouse cells lacking or depleted of PARG show increased sensitivity to experimental and clinical DNA damaging agents. However, PARG deficiency does not result in sensitivity to all agents (e.g. gemcitabine, camptothecin), suggesting specificity of PARG function for certain pathways of DNA repair and chemo- and radiotherapy (Fujihara, Ogino et al. 2009) (Shirai, Fujimori et al. 2013) (Zhou, Feng et al. 2010) (Zhou, Feng et al. 2011).

[0010] In humans, depletion of PARG sensitizes lung, cervical and pancreatic cancer cells to gamma irradiation or experimental DNA damaging agents (e.g., hydrogen peroxide, methyl methanesulfonate) (Ame, Fouquerel et al. 2009) (Nakadate, Kodera et al. 2013) (Shirai, Poetsch et al. 2013).

[0011] PARP inhibitors are currently in multiple clinical trials, exploring the concept of synthetic lethality or chemotherapy sensitization. Clinical resistance to PARP inhibitors has already been described (Drost and Jonkers 2014) (Barber, Sandhu et al. 2013), and therefore there is a need to find alternative inhibitors that target DNA repair mechanisms.

[0012] Current models indicate that PARG depletion leads to PARP-dependent effects on DNA repair, but recent studies have demonstrated mechanistic differences with PARP inhibition. Following genotoxic stimulation, PARG depletion, in contrast to PARP depletion, results in reduced NAD levels. This leads to lung cancer cell death as a result of energy insufficiency (Erdelyi, Bai et al. 2009).

[0013] Cell-permeable PARG inhibitors are limited to compounds such as tannic acid or gallotannins, which have questionable specificity for PARG and low bioavailability (Sun, Zhang et al. 2012) (Fathers, Drayton et al. 2012) (Blenn, Wyrsch et al. 2011).

[0014] It is an object of the present invention to provide cell-permeable inhibitors of PARG. Summary of the Invention

[0015] In one aspect, provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof.

[0016] In another aspect, provided herein is a compound of formula (I) [ka]

[0017] In another aspect, provided herein is a compound of formula (A) [ka] or a pharma- ceutically acceptable salt thereof.

[0018] In another aspect, provided herein is a compound of formula (A) [ka]

[0019] In another aspect, provided herein is a compound of formula (B) [ka] or a pharma- ceutically acceptable salt thereof.

[0020] In another aspect, provided herein is a compound of formula (B) [ka]

[0021] In another aspect, provided herein is a compound of formula (C) [ka] or a pharma- ceutically acceptable salt thereof.

[0022] In another aspect, provided herein is a compound of formula (C) [ka]

[0023] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0024] In another aspect, there is provided herein a compound of formula (I), formula (A), formula (B) or formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0025] In another aspect, there is provided herein a compound of formula (I), formula (A), formula (B) or formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer. In one embodiment, the cancer is a human cancer.

[0026] In another aspect, there is provided herein a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition, as defined herein, for use in producing a PARG inhibitory effect.

[0027] In another aspect, there is provided herein the use of a compound of formula (I), formula (A), formula (B) or formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as de?ned 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 cancer.

[0028] In another aspect, there is provided herein the use of a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for use in producing a PARG inhibitory effect.

[0029] In another aspect, provided herein is a method of inhibiting PARG in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0030] In another aspect, provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0031] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition, as defined herein.

[0032] In another aspect, provided herein is a method of treating cancer resistant to one or more platins or one or more PARP inhibitors in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

[0033] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition, as defined herein, wherein the patient has previously been treated for cancer with a platin.

[0034] In another aspect, provided herein is a method of treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition, as defined herein, wherein the patient has previously been treated for cancer with a PARP inhibitor.

[0035] In another aspect, provided herein is a method for identifying PARG activity of a test compound for PARG inhibitory activity, the method comprising the steps of (i) contacting the test compound with an isolated PARG enzyme, a biotinylated-PARYlated PARP substrate to form a PARG reaction pre-mixture, (ii) contacting the PARG reaction pre-mixture with a detection antibody and streptavidin-europium to form a PARG reaction mixture, and (iii) measuring the fluorescence intensity of the PARG reaction mixture, the method further comprising performing steps (i)-(iii) with a positive control sample represented by a compound of Formula (I), Formula (A), Formula (B), or Formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition. In some embodiments, the detection antibody is an anti-His monoclonal antibody-ULight. In some embodiments, the streptavidin-europium binds to the biotinylated-PARYlated PARP substrate. In some embodiments, fluorescence is measured by irradiating with an excitation wavelength of 317 nM and measuring emissions at 620 nM (streptavidin-europium emission) and 665 nM (ULight emission).

[0036] In another aspect, provided herein is a method of synthesizing a compound of Formula (I), Formula (A), Formula (B), or Formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof.

[0037] In another aspect, provided herein is a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt, obtainable or obtained or directly obtained by a synthetic process as defined herein.

[0038] In another aspect, provided herein are novel intermediates, as defined herein, suitable for use in any one of the synthetic methods described herein.

[0039] Preferred, appropriate, and optional features of any one particular embodiment of the present invention are also preferred, appropriate, and optional features of any other embodiment. [Brief description of the drawings]

[0040] [Figure 1] 1 illustrates the percent viability of PARPi-resistant MDA-MB-436 cells as a function of Log concentration of Formula A described in Example 4. "Parental IC50" refers to the IC50 of Formula A before the cells acquire PARPi resistance, and "Niraparib-resistant IC50" refers to the IC50 of Formula A after the cells acquire PARPi resistance.

[0041] [Diagram 2] 1 illustrates the percent viability of PARPi-resistant HCC1428 cells as a function of the Log concentration of Formula A described in Example 4. "Parental IC50" refers to the IC50 of Formula A before the cells acquire PARPi resistance, and "Niraparib-resistant IC50" refers to the IC50 of Formula A after the cells acquire PARPi resistance.

[0042] [Diagram 3] 1 illustrates patient-derived cells (PDCs) from ovarian tissue with BRCA1 / 2 mutations and cisplatin resistance as a function of concentration of Formula A as described in Example 4.

[0043] [Figure 4] FIG. 1 shows a patient-derived xenograft (PDX) study using HBCx-34 (Formula A). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] Before the present invention is further described, it is to be understood that the invention is not limited to particular embodiments described herein, and the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0045] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit between the upper and lower limits of that range, and any other stated or intervening value in the stated range, is encompassed within the invention, unless the context clearly dictates otherwise. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are still encompassed within the invention, subject to any specifically excluded limit in the stated range. Where a 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 otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0046] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed.

[0047] overview Provided herein are compounds of Formula (I), (A), (B), or (C), or pharma- ceutically acceptable salts thereof, for the inhibition of PARG, and pharmaceutical compositions comprising the same. Also provided herein are methods for treating or preventing, for example, a disease, disorder, or condition, or a symptom thereof, mediated by the inhibition of PARG.

[0048] Advantageously, the compounds disclosed herein are potent inhibitors of PARG in both cell and in vitro assays.Kinetic solubility studies also show that these compounds are highly soluble at both pH 2.0 and pH 7.4.Overall, the parameters of the compounds described herein combine to make them ideal compounds for targeting and inhibiting PARG activity.

[0049] definition Unless otherwise indicated, the following terms are intended to have the meanings set forth below. Other terms are defined elsewhere throughout the specification.

[0050] As used herein, the singular forms "a," "an," and "the" include plural references unless the context dictates otherwise. Additionally, it should be noted that the claims may be drafted to exclude any element. Accordingly, this statement is intended to serve as a prerequisite for the use of exclusive terminology such as "solely," "only," and the like in connection with the recitation of claim elements, or for the use of a "negative" limitation.

[0051] The term "pharmaceutically acceptable salts" is meant to include salts of compounds of formula (I), formula (A), formula (B), or formula (C) prepared with relatively non-toxic 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 sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, 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 sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, bisulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain compounds of the invention contain both basic and acidic functional groups, which allows the compounds to be converted into either base or acid addition salts.

[0052] When a stereochemical depiction is given, it is meant to refer to a compound in which one of the isomers is present and is substantially free of the other isomer. "Substantially free" of another isomer indicates that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or greater. In some embodiments, one of the isomers is present in an amount of at least 99%.

[0053] Formula (I), Formula (A), Formula (B), or Formula (C) 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 the amount that constitutes 100% of the atom in question. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C), or for example, deuterium ( 2 H) or carbon-13 ( 13Non-radioactive isotopes such as , , and C) may be incorporated into the compounds of the present invention. Such isotopic variations may provide additional utility to those described elsewhere in this application. For example, isotopic variations of the compounds of the present invention may find additional utility, including but not limited to, as diagnostic and / or imaging reagents or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variations of formula (I), formula (A), formula (B), or formula (C) may have altered pharmacokinetic and pharmacodynamic properties, which may contribute to enhanced safety, tolerability, or efficacy during treatment. All isotopic variations of formula (I), formula (A), formula (B), or formula (C), whether radioactive or not, are intended to be encompassed within the scope of the present invention.

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

[0055] The terms "administration," "administering," and the like, when they are used in reference to, e.g., a patient, a cell, a tissue, an organ, or a biological fluid, refer to the contact of, e.g., an inhibitor of PARG, a pharmaceutical composition comprising same, or a diagnostic agent, to the patient, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact of a reagent with the cell (e.g., in vitro or ex vivo), as well as contact of a reagent with a fluid in contact with the cell.

[0056] The terms "treat," "treating," "treatment," and the like refer to a course of action (such as administration of 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, or the like, to temporarily or permanently eliminate, reduce, inhibit, alleviate, or ameliorate at least one of the underlying causes of, or at least one of the symptoms associated with, the disease, disorder, or condition afflicting a patient. Thus, treatment includes inhibiting an active disease (e.g., preventing the onset or further progression of a disease, disorder, or condition, or clinical symptoms associated therewith).

[0057] As used herein, the term "in need of treatment" refers to a judgment made by a physician or other caregiver that a patient requires or would benefit from treatment. This judgment is made based on a variety of factors that are within the physician's or caregiver's expertise.

[0058] The terms "prevent," "preventing," "prevention," and the like, generally in the context of a patient susceptible to a particular disease, disorder, or condition, refer to a course of action (e.g., administering a PARG inhibitor or a pharmaceutical composition comprising same) that is initiated in such a manner (e.g., prior to the onset of the disease, disorder, condition, or symptoms thereof) to prevent, suppress, inhibit, or reduce, either temporarily or permanently, the patient's risk of developing the disease, disorder, condition, or the like (e.g., as determined by the absence of clinical symptoms) or to delay its onset. In some cases, these terms also refer to slowing the progression of the disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state.

[0059] As used herein, the term "in need of prevention" refers to a judgment made by a physician or other caregiver that a patient needs or would benefit from preventative care. This judgment is made based on a variety of factors that are within the physician's or caregiver's expertise.

[0060] The terms "inhibit" and "reduce" or all variations of these terms with respect to PARG include any measurable reduction or complete inhibition to obtain a desired result. For example, the reduction may be about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more of PARG activity compared to normal. As used herein, "about" means within ±10%, preferably within ±5% of a given value.

[0061] The phrase "therapeutically effective amount" refers to the administration of an agent to a patient, either in a single dose or as part of a series of doses, in an amount that, when administered to a patient, can have any detectable positive effect on any symptom, aspect or characteristic of a disease, disorder or condition. A therapeutically effective amount can be ascertained by measuring the relevant physiological effect, and can be adjusted in conjunction with dosing regimens, diagnostic analysis of the patient's condition, and the like. As an example, measuring serum levels of a PARG inhibitor (or, for example, its metabolites) at a particular time after administration can indicate whether a therapeutically effective amount has been used.

[0062] The phrase "platin" or "platinum-based chemotherapeutic agent" refers to the platinum-containing class of chemotherapeutic agents used to treat 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 a cancer that does not respond to treatment with a platin. Non-responsiveness can be assessed by continued tumor growth when the drug is administered, by a tumor not decreasing in size when the drug is administered, or by other means known in the art. Non-responsiveness of a cancer may be determined through clinical observation, may be so diagnosed by a medical professional, may be experimentally tested using isolated cells in a laboratory setting, or may be determined by another technical means.

[0064] As used herein, "poly(ADP-ribose) polymerase (PARP) inhibitors" refers to agents that inhibit 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 a cancer that does not respond to treatment with a PARP inhibitor. Non-responsiveness can be assessed by continued tumor growth when the drug is administered, by tumors that do not decrease in size when the drug is administered, or by other means known in the art. Non-responsiveness of a cancer can be determined through clinical observation, diagnosed as such by a medical professional, experimentally tested using isolated cells in a laboratory environment, or determined by another technical means.

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

[0067] As used herein, "homologous recombination deficient (HRD) cancer" refers to cancer characterized by a reduction or absence of a functional HR repair pathway. HR deficiency can result from the absence or reduction of one or more HR-associated genes or the 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 cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom's syndrome, RecQ helicase-like), WRN (Werner's syndrome, one or more HR-associated genes), Nbs ...2, BRCA1, BRCA2, RAD54, RAD51B, ATM, BARD1, CHECK1, CHECK2, CDK12, RAD51B, RAD54L, RAD51D, PPP 1 (Nibrin), and genes encoding Fanconi anemia (FA) proteins or FA-like genes, such as FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.

[0068] compound In one aspect, the present invention provides a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof. In one embodiment, formula (I) is in the form of a free base.

[0069] In one aspect, the present invention provides a compound of formula (A): [ka] or a pharma- ceutically acceptable salt thereof. In one embodiment, Formula (A) is in the form of a free base.

[0070] In some embodiments, Formula (A) is at least 70% free of other isomers. In some embodiments, Formula (A) is at least 75% free of other isomers. In some embodiments, Formula (A) is at least 80% free of other isomers. In some embodiments, Formula (A) is at least 85% free of other isomers. In some embodiments, Formula (A) is at least 90% free of other isomers. In some embodiments, Formula (A) is at least 95% free of other isomers. In some embodiments, Formula (A) is at least 99% free of other isomers.

[0071] In one aspect, the present invention provides a compound of formula (B): [ka] or a pharma- ceutically acceptable salt thereof. In one embodiment, Formula (B) is in the form of a free base.

[0072] In some embodiments, Formula (B) is at least 70% free of other isomers. In some embodiments, Formula (B) is at least 75% free of other isomers. In some embodiments, Formula (B) is at least 80% free of other isomers. In some embodiments, Formula (B) is at least 85% free of other isomers. In some embodiments, Formula (B) is at least 90% free of other isomers. In some embodiments, Formula (B) is at least 95% free of other isomers. In some embodiments, Formula (B) is at least 99% free of other isomers.

[0073] In one aspect, the present invention provides a compound of formula (C): [ka] or a pharma- ceutically acceptable salt thereof. In one embodiment, Formula (C) is in the form of a free base.

[0074] In some embodiments, Formula (C) is at least 70% free of other isomers. In some embodiments, Formula (C) is at least 75% free of other isomers. In some embodiments, Formula (C) is at least 80% free of other isomers. In some embodiments, Formula (C) is at least 85% free of other isomers. In some embodiments, Formula (C) is at least 90% free of other isomers. In some embodiments, Formula (C) is at least 95% free of other isomers. In some embodiments, Formula (C) is at least 99% free of other isomers.

[0075] biological activity The PARG enzyme and cellular assays described in the accompanying Examples section can be used to measure the pharmacological effects of the compounds of the invention.

[0076] Pharmaceutical Compositions Also provided is a pharmaceutical composition comprising a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharma- ceutically acceptable salt thereof, in association with a pharma- ceutically acceptable diluent or carrier.

[0077] The compositions of the present disclosure may be in a form suitable for oral use (e.g., as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by insufflation (e.g., as a finely divided powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0078] The compositions can be obtained by conventional procedures using conventional pharmaceutical additives known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0079] An effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the proliferative conditions referred to herein.

[0080] The magnitude of a dose of a compound of Formula (I), Formula (A), Formula (B), or Formula (C) for therapeutic or prophylactic purposes will, of course, vary with the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration, in accordance with well-known principles of medicine.

[0081] When using a compound of formula (I), formula (A), formula (B) or formula (C), or a pharma- ceutically acceptable salt thereof, for therapeutic or prophylactic purposes, it is generally administered so that a total daily dose is taken, for example, in the range of 0.01 mg / kg body weight to 100 mg / kg body weight. Oral administration may also be appropriate, particularly in tablet form.

[0082] In some embodiments, the composition of Formula (A) comprises at least 70% of the indicated isomer. In some embodiments, the composition of Formula (A) comprises at least 75% of the indicated isomer. In some embodiments, the composition of Formula (A) comprises at least 80% of the indicated isomer. In some embodiments, the composition of Formula (A) comprises at least 85% of the indicated isomer. In some embodiments, the composition of Formula (A) comprises at least 90% of the indicated isomer. In some embodiments, the composition of Formula (A) comprises at least 95% of the indicated isomer. In some embodiments, the composition of Formula (A) comprises at least 99% of the indicated isomer.

[0083] In some embodiments, the composition of Formula (B) comprises at least 70% of the indicated isomer. In some embodiments, the composition of Formula (B) comprises at least 75% of the indicated isomer. In some embodiments, the composition of Formula (B) comprises at least 80% of the indicated isomer. In some embodiments, the composition of Formula (B) comprises at least 85% of the indicated isomer. In some embodiments, the composition of Formula (B) comprises at least 90% of the indicated isomer. In some embodiments, the composition of Formula (B) comprises at least 95% of the indicated isomer. In some embodiments, the composition of Formula (B) comprises at least 99% of the indicated isomer.

[0084] In some embodiments, the composition of Formula (C) comprises at least 70% of the indicated isomer. In some embodiments, the composition of Formula (C) comprises at least 75% of the indicated isomer. In some embodiments, the composition of Formula (C) comprises at least 80% of the indicated isomer. In some embodiments, the composition of Formula (C) comprises at least 85% of the indicated isomer. In some embodiments, the composition of Formula (C) comprises at least 90% of the indicated isomer. In some embodiments, the composition of Formula (C) comprises at least 95% of the indicated isomer. In some embodiments, the composition of Formula (C) comprises at least 99% of the indicated isomer.

[0085] Therapeutic Uses and Applications Provided herein are compounds that function as inhibitors of PARG.

[0086] Thus, the present invention provides a method for inhibiting PARG enzyme activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0087] The present invention also provides a method of treating a disease or disorder involving PARG activity in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition. In one embodiment, the disease or disorder is an advanced or metastatic solid tumor. In one embodiment, the disease or disorder is cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is a homologous recombination deficient (HRD) cancer.

[0088] Provided herein are methods of inhibiting cell proliferation in vitro or in vivo, the methods comprising contacting a cell with an effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0089] Provided herein is a method of treating a proliferative disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition. In one embodiment, the proliferative disorder is a solid tumor. In one embodiment, the proliferative disorder is a metastatic solid tumor. In one embodiment, the proliferative disorder is cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is a homologous recombination deficient (HRD) cancer.

[0090] Provided herein is a method of treating cancer in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is a homologous recombination deficient (HRD) cancer.

[0091] Provided herein is a method of treating and / or preventing a homologous recombination deficient (HRD) cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the patient is identified as being in need of such treatment. In one embodiment, the homologous recombination deficient (HRD) cancer is breast cancer, ovarian cancer, gastric cancer, prostate cancer, lung cancer, cervical cancer, or pancreatic cancer.

[0092] Provided herein is a method of treating and / or preventing cancer in a patient, the cancer being characterized by reduced or absent expression of BRCA1 and / or BRCA2 genes, absent or mutated BRCA1 and / or BRCA2 genes, or reduced function of BRCA1 and / or BRCA2 proteins, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I), formula (A), formula (B), or formula (C) as defined herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer.

[0093] In one 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 cancer, breast cancer, or pancreatic cancer.

[0094] In one 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.

[0095] Provided herein are methods of treating cancer in a patient in need of such treatment, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically 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, the methods comprise administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been diagnosed as resistant to one or more PARP inhibitors.

[0096] Provided herein are methods of treating cancer in a patient in need of such treatment, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been determined to be resistant to a platinum-based chemotherapeutic agent. In some embodiments, the methods comprise administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been diagnosed as resistant to one or more platinum-based chemotherapeutic agents.

[0097] Provided herein is a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0098] Provided herein is a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.

[0099] Provided herein is a compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition, as de?ned herein, for use in the treatment of cancer. In certain embodiments, the cancer is a human cancer. In one embodiment, the cancer is ovarian, gastric, or breast cancer. In one embodiment, the cancer is lung, cervical, or pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is a homologous recombination de?cient (HRD) cancer.

[0100] Provided herein is a compound of formula (I), formula (A), formula (B) or formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in inhibiting PARG enzyme activity.

[0101] Provided herein is a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharma- ceutically 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.

[0102] There is provided herein the use of a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment of a proliferative condition.

[0103] Provided herein is the use of a compound of formula (I), formula (A), formula (B) or formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as de?ned herein, in the manufacture of a medicament for the treatment of cancer. Suitably, the medicament is for use in the treatment of human cancer. In one embodiment, the cancer is ovarian cancer, gastric cancer, or breast cancer. In one embodiment, the cancer is lung cancer, cervical cancer, or pancreatic cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is a homologous recombination de?cient (HRD) cancer.

[0104] Provided herein is the use of a compound of formula (I), formula (A), formula (B) or formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for the inhibition of PARG enzyme activity.

[0105] Provided herein is the use of a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharma- ceutically 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.

[0106] The present disclosure also contemplates the use of compounds of Formula (I), Formula (A), Formula (B), or Formula (C), or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions as de?ned herein, in combination With other therapeutically active agents or compounds described herein, for the treatment of diseases, disorders, and conditions contemplated by the present disclosure.

[0107] The terms "proliferative disorder" and "proliferative condition" are used interchangeably herein and relate to undesired or uncontrolled cell proliferation, such as undesired excess or abnormal cells, whether in vitro or in vivo, such as neoplastic or hyperplastic proliferation. Examples of proliferative conditions include, but are not limited to, pre-malignant and malignant cell proliferation, including, but not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Any type of cell can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, stomach, liver, pancreas, brain, and skin. Proliferative disorders also include, for example, progressive or metastatic solid tumors.

[0108] The anti-proliferative effects of the compounds of formula (I), formula (A), formula (B) or formula (C) as defined herein, or pharma- ceutically acceptable salts or pharmaceutical compositions thereof, have particular application in the treatment of human cancers (by their inhibition of PARG enzymatic activity).

[0109] The anti-cancer effect may occur through one or more mechanisms, including, but not limited to, modulating cell proliferation, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of a tumor from its primary site), inhibiting invasion (the spread of tumor cells into adjacent normal structures), or promoting apoptosis (programmed cell death).

[0110] In certain embodiments of the invention, the proliferative condition being treated is cancer.

[0111] Route of administration A compound of Formula (I), Formula (A), Formula (B), or Formula (C), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, may be administered to a patient by any convenient route of administration, whether systemic / peripheral or local (i.e., to the desired site of action).

[0112] Routes of administration include, but are not limited to, oral (e.g., by ingestion), buccal, sublingual, transdermal (including, e.g., by patches, plasters, etc.), transmucosal (including, e.g., by patches, plasters, etc.), intranasal (e.g., by nasal spray), intraocular (e.g., by eye drops), pulmonary (e.g., via aerosol, e.g., through the mouth or nose, e.g., by inhalation or insufflation therapy), rectal (e.g., by suppository or enema), intravaginal (e.g., by pessary), by injection, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal, and parenterally, e.g., by implantation of a depot or reservoir subcutaneously or intramuscularly. Some embodiments of the invention contemplate oral administration.

[0113] Embodiment Embodiment 1. Compound of Formula (I) [ka] or a pharma- ceutically acceptable salt thereof.

[0114] Embodiment 2. The compound according to embodiment 1, represented by formula (A) [ka] or a pharma- ceutically acceptable salt thereof.

[0115] Embodiment 3. The compound of embodiment 1, in the form of a free base.Embodiment 3A. The compound of embodiment 2, in the form of a free base.

[0116] Embodiment 4. A compound according to embodiment 2 or 3A, which is at least 90% free of other isomers.

[0117] Embodiment 5. A compound according to embodiment 2 or 3A, which is at least 95% free of other isomers.

[0118] Embodiment 6. A compound according to embodiment 2 or 3A, which is at least 99% free of other isomers.

[0119] Embodiment 7. The compound according to embodiment 1, represented by formula (B): [ka] or a pharma- ceutically acceptable salt thereof.

[0120] Embodiment 8. The compound of embodiment 7, in the form of a free base.

[0121] Embodiment 9. A compound according to embodiment 7 or 8, which is at least 90% free of other isomers.

[0122] Embodiment 10. A compound according to embodiment 7 or 8, which is at least 95% free of other isomers.

[0123] Embodiment 11. A compound according to embodiment 7 or 8, which is at least 99% free of other isomers.

[0124] Embodiment 12. The compound according to embodiment 1, represented by formula (C): [ka] or a pharma- ceutically acceptable salt thereof.

[0125] Embodiment 13. The compound of embodiment 12, in the form of a free base.

[0126] Embodiment 14. A compound according to embodiment 12 or 13, which is at least 90% free of other isomers.

[0127] Embodiment 15. A compound according to embodiment 12 or 13, which is at least 95% free of other isomers.

[0128] Embodiment 16. A compound according to embodiment 12 or 13, which is at least 99% free of other isomers.

[0129] Embodiment 17. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0130] Embodiment 18. A method for treating a disease or disorder involving PARG activity in a patient, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17.Embodiment 18A. The method according to embodiment 18, wherein the patient is identified as being in need of such treatment and the disease or disorder is cancer.Embodiment 18B. The method according to embodiment 18, wherein the disease or disorder is cancer.Embodiment 18B. The method according to embodiment 18A or 18B, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

[0131] Embodiment 19. A method for treating cancer in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17.

[0132] Embodiment 20. The method of embodiment 19, wherein the cancer is ovarian cancer, gastric cancer, or breast cancer.Embodiment 20A. The method of embodiment 19, wherein the cancer is lung cancer, cervical cancer, or pancreatic cancer.Embodiment 20B. The method of embodiment 19, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

[0133] Embodiment 21. A compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17, for use in therapy.

[0134] Embodiment 22. The compound or a pharma- ceutically acceptable salt thereof, or pharmaceutical composition of embodiment 21, wherein the treatment is treatment of cancer.

[0135] Embodiment 23. The compound or its pharmaceutically acceptable salt or pharmaceutical composition according to embodiment 22, wherein the cancer is ovarian cancer, gastric cancer, or breast cancer.Embodiment 23A. The compound or its pharmaceutically acceptable salt or pharmaceutical composition according to embodiment 22, wherein the cancer is lung cancer, cervical cancer, or pancreatic cancer.Embodiment 23B. The compound or its pharmaceutically acceptable salt or pharmaceutical composition according to embodiment 22, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

[0136] Embodiment 24. Use of a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17, in the manufacture of a medicament for use in therapy.

[0137] Embodiment 25. The use according to embodiment 24, wherein the treatment is treatment of cancer.

[0138] Embodiment 26. The use according to embodiment 25, wherein the cancer is ovarian cancer, gastric cancer or breast cancer.Embodiment 26A. The use according to embodiment 25, wherein the cancer is lung cancer, cervical cancer or pancreatic cancer.Embodiment 26B. The use according to embodiment 25, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer or pancreatic cancer.

[0139] Embodiment 27. A method of inhibiting PARG in vivo, comprising administering to a patient an effective amount of a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17. Embodiment 27A. The method according to embodiment 27, wherein the patient is identified as in need of such treatment.

[0140] Embodiment 28. A method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17.Embodiment 28A. A method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a sample with an effective amount of a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17.

[0141] Embodiment 29. A method of treating cancer resistant to one or more PARP inhibitors in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1-16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17.Embodiment 29A. The method according to embodiment 29, wherein the patient is identified as being in need of such treatment.Embodiment 29B. The method according to embodiment 29, wherein the patient is determined to be resistant to one or more PARP inhibitors.Embodiment 29C. The method according to embodiment 29, wherein the patient is diagnosed as being resistant to one or more PARP inhibitors.Embodiment 29D. The method according to any one of embodiments 29, 29A, 29B, and 29C, wherein the one or more PARP inhibitors are talazoparib, olaparib, veliparib, rucaparib, niraparib, AZD5303, AZD9574, or a pharma- ceutically acceptable salt thereof.

[0142] Embodiment 30. The method according to any one of embodiments 29, 29A, 29B, 29C, and 29D, wherein the cancer is ovarian cancer, gastric cancer, or breast cancer.Embodiment 30A. The method according to any one of embodiments 29, 29A, 29B, 29C, and 29D, wherein the cancer is lung cancer, cervical cancer, or pancreatic cancer.Embodiment 30B. The method according to any one of embodiments 29, 29A, 29B, 29C, and 29D, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

[0143] Embodiment 31. A method of treating cancer resistant to one or more platins in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to any one of embodiments 1-16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17.Embodiment 31A. The method according to embodiment 31, wherein the patient is identified as being in need of such treatment.Embodiment 31B. The method according to embodiment 31, wherein the patient is determined to be resistant to one or more platins.Embodiment 31C. The method according to embodiment 31, wherein the patient is diagnosed as being resistant to one or more platins.Embodiment 31D. The method according to any one of embodiments 31, 31A, 31B and 31C, wherein the one or more platins are cisplatin, carboplatin, satraplatin, heptaplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or oxaliplatin, or a pharma- ceutically acceptable salt thereof.

[0144] Embodiment 32. The method according to embodiment 31, 31A, 31B, 31B, and 31D, wherein the cancer is ovarian cancer, gastric cancer, or breast cancer.Embodiment 32A. The method according to embodiment 31, 31A, 31B, 31C, and 31D, wherein the cancer is lung cancer, cervical cancer, or pancreatic cancer.Embodiment 31B. The method according to any one of embodiments 31, 31A, 31B, 31C, and 31D, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

[0145] Embodiment 33. A method for treating and / or preventing homologous recombination deficient (HRD) cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17. Embodiment 33A. The method according to embodiment 33, wherein the patient is identified as in need of such treatment.

[0146] Embodiment 34. The method of embodiment 33 or 33A, wherein the HRD cancer is breast cancer, ovarian cancer, gastric cancer, prostate cancer, or pancreatic cancer.Embodiment 34A. The method of embodiment 33 or 33A, wherein the HRD cancer is breast cancer, ovarian cancer, or gastric cancer.Embodiment 34B. The method of embodiment 33 or 33A, wherein the HRD cancer is lung cancer, cervical cancer, or pancreatic cancer.

[0147] Embodiment 35. A method for treating and / or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent expression of BRCA1 and / or BRCA2 genes, absence or mutation of BRCA1 and / or BRCA2 genes, or reduced function of BRCA1 and / or BRCA2 proteins, comprising administering to the patient a therapeutically effective amount of a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17.Embodiment 35A. The method according to embodiment 35, wherein the patient is identified as in need of such treatment.

[0148] Embodiment 36. The method of embodiment 35 or 35A, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, prostate cancer, or pancreatic cancer.Embodiment 36A. The method of embodiment 35 or 35A, wherein the HRD cancer is breast cancer, ovarian cancer, or gastric cancer.Embodiment 34B. The method of embodiment 35 or 35A, wherein the HRD cancer is lung cancer, cervical cancer, or pancreatic cancer.

[0149] Embodiment 37. A PARG inhibitor for use in the treatment of cancer, wherein the PARG inhibitor is a compound according to any one of embodiments 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 17.

[0150] Embodiment 38. Use of a PARG inhibitor in the manufacture of a medicament for treating cancer, wherein the PARG inhibitor is a compound according to any one of claims 1 to 16 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17.

[0151] If an embodiment relies, for example, on embodiments 1-4, it is understood to rely on embodiments 1, 2, 3, 3A, and 4. Thus, when multiple reliances are listed, all embodiments within the listed range are included (including embodiments ending with "A," "B," or any other letter). EXAMPLES

[0152] The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments have been performed or that they are all that may be performed. It is understood that the exemplary descriptions written in the present tense have not necessarily been performed, but rather, the descriptions may be performed to generate data of the nature described therein, etc. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0153] Synthesis Examples Example 1: Preparation of Compounds of Formula (A) [ka] Step 1: Preparation of 2,6-difluoro-4-iodobenzaldehyde [ka] To a stirred solution of 1,3-difluoro-5-iodobenzene (compound 1) (50 g, 208.3 mmol, Oakwood Chemical, CAS2265-91-0, catalog number 024566) in THF (500 mL) was added LDA (80 mL, 625.0 mmol) and DMF (48.3 mL, 625 mmol) at -78 °C and stirred at -78 °C for 2 h. After complete consumption of the starting material, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2x300 mL), the combined organic phase was washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product as an oil. The crude material was purified by column chromatography on silica gel (100-200) eluting with a gradient of 20% EtOAc / Hexanes. The product was eluted with a gradient of 30% EtOAc / Hexanes. The purified fraction was concentrated under reduced pressure to give 2,6-difluoro-4-iodobenzaldehyde (compound 2) (23 g) as a solid. 1 H NMR (500 MHz, chloroform-d) δ: 10.29 (s, 1H), 7.37-7.46 (m, 2H).

[0154] Step 2: Preparation of 4-fluoro-6-iodo-1H-indazole [ka] To a stirred solution of 2,6-difluoro-4-iodobenzaldehyde (compound 2) (5 g, 18.6 mmol) in 1,4-dioxane (110 mL) was added hydrazine hydrate (18.6 mL, 373.1 mmol) at room temperature, and the resulting mixture was stirred at 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and ice-cold water (100 mL) was added. The mixture was stirred for 30 minutes, during which time a solid precipitated. The mixture was filtered. The solid was washed with water (100 mL), n-pentane (50 mL) and dried under vacuum to give the product 4-fluoro-6-iodo-1H-indazole (compound 3) (2.3 g) as a solid. MS ESI:C 7 H 4 FIN 2 [M+H] +Calculated value: 262.94, actual value: 262.99. 1 H NMR (CDCl 3 ,400MHz):10.12(s,1H),8.10(s,1H),7.70(s,1H),7.15(dd,J=9Hz,1H).

[0155] Step 3: Preparation of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4-thiadiazole [ka] To a stirred solution of 4-fluoro-6-iodo-1H-indazole (compound 3) (5 g, 19.0 mmol) in DMF (50 mL) was added cesium carbonate (18.6 g, 57.24 mmol) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (compound 4) (3.8 g, 18.1 mmol, Enamine Stock Building Blocks, CAS1340313-49-6, catalog number EN300-108825). The resulting mixture was stirred at 60° C. for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (50 mL) and stirred for 30 min during which time a solid precipitated. The mixture was filtered. The collected solid was washed with water (100 mL), followed by n-pentane (100 mL) and dried under vacuum to give 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4-thiadiazole (compound 5) (4.2 g) as a solid. MS ESI:C 10 H 4 F 3 IN 4 S[M+H] + Calculated value: 396.92, actual value: 396.91. 1 H NMR (CDCl 3 ,500MHz):8.87(s,1H),8.29(s,1H),7.40(dd,J=17Hz,1H),7.0(t,J=53.5Hz,1H).

[0156] Step 4: Preparation of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)benzothioate [ka] To a stirred solution of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4-thiadiazole (compound 5) (100 mg, 0.25 mmol) in toluene (1 mL) that had been degassed for 5 min, CuI (5 mg, 0.025 mmol), 1,10-phenanthroline (phen) (11 mg, 0.05 mmol), and potassium thiobenzoate (67 mg, 0.378 mmol) were added at room temperature. The resulting mixture was stirred at 100 °C for 16 h. The progress of the reaction was monitored by LCMS. The crude mixture was purified by column chromatography on silica gel (100-200) eluting with a gradient of 10% EtOAc / hexanes. The purified fractions were collected and concentrated under reduced pressure to give S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)benzothioate (compound 6) (55 mg) as a solid. MS ESI:C 17 H 9 F 3 N 4 OS 2 [M+H] + Calculated value: 407.02, actual value: 407.01. 1 H NMR (CDCl 3 ,400MHz):8.68(s,1H),8.39(s,1H),8.03(d,J=7.6Hz,2H),7.64(t,J=7.2Hz,1H),7.53(t,J=7.6Hz,2H),7.27(s,1H),6.99(t,J=53.2Hz,1H).

[0157] Step 5: Preparation of N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-sulfonamide [ka] To a solution of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)benzothioate (compound 6) (500 mg, 1.23 mmol) in acetonitrile (10 mL) was added BnMe 3 A solution of NCl (682 mg, 3.69 mmol) and TCCA (trichloroisocyanuric acid) (370 mg, 1.59 mmol) in acetonitrile (40 mL) was added at 0° C. The reaction mixture was stirred for 20 min. Then, a solution of 1-methylcyclopropan-1-amine (1.71 g, 7.38 mmol, Combi-Blocks, CAS22936-83-0, Cat. No. QH-3639) in pyridine (2.5 mL) and cesium carbonate (198 mg, 0.61 mmol) was added to the reaction mixture at 0° C. and stirred at room temperature for 2 h. The progress of the reaction was monitored by LCMS. LCMS showed complete consumption of the starting material (S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)benzothioate) (compound 6). The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (100-200) eluting with a gradient of 5-50% EtOAc / Hexanes. The product was eluted with 20% EtOAc / Hexanes. The purified fractions were collected and concentrated under reduced pressure to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound 7) (90 mg) as a solid. MS ESI:C 14 H 9 F 3 N 6 O 2 S 2 [M+H] + Calculated value: 404.04, actual value: 404.18. 1 H NMR (CDCl 3,400MHz):9.00(s,1H),8.80(s,1H),8.54(s,1H),7.63(t,J=48.8Hz,2H),1.10(s,3H),0.65(s,2H),0.44(s,2H).

[0158] Step 6: Preparation of tert-butyl (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate [ka] To a stirred solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound 7) (80 mg, 0.19 mmol) in DMSO (dimethyl sulfoxide) (2 mL), (2S,6S)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (85 mg, 0.39 mmol, BLD Pharmatech, CAS574007-66-2, catalog number BD233798) and DIPEA (N,N-diisopropylethylamine) (0.1 mL, 0.59 mmol) were added, and the reaction mixture was stirred at 130° C. for 2 hours. The reaction mixture was quenched with ice-cold water (20 mL) and stirred for 30 minutes. The resulting solid was filtered, washed with water (10 mL), dried under vacuum, and purified by column chromatography on silica gel (100-200) eluted with a gradient of 50% EtOAc / hexanes, and the purified fractions were concentrated under reduced pressure to give tert-butyl (2S,6S-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate (compound 8) (110 mg, yield: 92%) as a solid. MS ESI: C 25 H 33 F 2 N 7 O 4 S 2[M+H] + Calculated value: 598.20, actual value: 598.26.

[0159] Step 7: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (Formula A) [ka] To a stirred solution of (2S,6S-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate (compound 8) (100 mg, 0.16 mmol) in DCM (3 mL), trifluoroacetic acid (0.07 mL, 0.98 mmol) was added at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (preparative HPLC conditions: mobile phase -H 2 Purification by 10 mM ammonium bicarbonate in O:MeCN, column-Inertsil ODS (20X250) mm, 5u, flow rate-18 ml / min, gradient method-0 / 50, 9.5 / 82, 9.55 / 99, 11.5 / 99, 11.55 / 50, 14.5 / 50, solubility: yes, fraction volume: 100 mL) to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1 H-indazole-6-sulfonamide (Formula A) (18 mg, yield: 21%) as a solid. MS ESI: C 20 H 25 F 2 N 7 O 2 S 2 [M+H] + Calculated value: 498.15, actual value: 498.34. 1 H NMR (DMSO-d 6,400MHz):δ(ppm)8.75(s,1H),8.40(s,1H),8.31(s,1H),7.59(t,J=52.8Hz,1H),7.10(d,J=1.0Hz,1H),3.37(br dd,J=11.5,2.9Hz,2H),3.22-3.30(m,2H),3.08(br dd,J=11.7,6.1Hz,2H),1.17(d,J=6.4Hz,6H),1.08(s,3H),0.58-0.76(m,2H),0.29-0.49(m,2H).

[0160] Example 2: Preparation of Compounds of Formula (B) [ka] Step 1: Preparation of tert-butyl (2R,6R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate To a stirred solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound 7) (0.25 g, 0.62 mmol) in DMSO (2 mL) was added DIPEA (0.31 mL, 1.859 mmol) and (2R,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (compound 9) (0.266 g, 1.239 mmol) (Pharmablock, CAS574007-62-8, product number PB05909) at room temperature. The reaction mixture was stirred at 110° C. for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by flash chromatography (Conditions: Mobile phase (A): Hexane, Mobile phase (B): EtOAc, Column: Silica gel (40 g), Method: Gradient). Pure fractions were concentrated under reduced pressure to give tert-butyl (2R,6R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate (compound 10) (0.21 g, yield: 57%) as an off-white solid. MS ESI: C 25 H 33 F 2 N 7 O 4 S 2 [MH] + Calculated value: 596.20, actual value: 596.62.

[0161] Step 2: Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (Formula B) To a stirred solution of (2R,6R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate (compound 10) (0.2 g, 0.335 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.1 mL, 1.338 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3R,5R)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (Formula B) (130 mg, yield: 89.2%) as a pale yellow solid. MS ESI:C 20 H 25 F 2 N 7 O 2 S 2 [M+H] + Calculated value: 498.15, actual value: 498.30. 1 H NMR (400MHz, DMSO-d 6 ):δ(ppm)8.75(s,1H),8.40(s,1H),8.31(s,1H),7.60(t,J=53.0Hz,1H),7.11(s,1H),3.30-3. 42(m,4H),3.05-3.15(m,2H),1.15-1.28(m,7H),1.07(s,3H),0.60-0.70(m,2H),0.38(s,2H).

[0162] Example 3: Preparation of Compounds of Formula (C) [ka] Preparation of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (Formula C) [ka] A solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound 7) (12.0 g, 29.7 mmol) and cis-2,6-dimethylpiperazine (compound 11) (8.49 g, 74.4 mmol) (Combi-Blocks, CAS 21655-48-1, catalog number OR-0130) in NMP (120 mL) was added to 100 mL of N 2 The mixture was stirred under protection at 50° C. for 18 hours. The reaction mixture was cooled to room temperature (25° C.) and combined with another batch of reaction mixture using 1.0 g of compound 7. Water (260 mL) was added slowly to the combined reaction mixture below 25° C. and stirred for 2 hours. The reaction mixture was filtered and the solid was washed with water (26 mL) to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (Formula C) (15.6 g) as a light yellow solid. MS ESI: C 20 H 25 F 2 N 7 O 2 S 2 [M+H] + Calculated value: 498.15, actual value: 498.04. 1 H NMR (DMSO-d 6 ,400MHz)δppm:8.89(d,J=0.7Hz,1H),8.42(s,1H),8.31(s,1H),7.59(d,J=53.2Hz,1H),7.12(d,J=1.2Hz,1H),3.66(br d,J=10.0Hz,1H),2.94-3.11(m,2H),2.43-2.49(m,2H),2.23-2.30(m,1H),1.07(d,J=5.4Hz,9H),0.61-0.71(m,2H),0.35-0.44(m,2H).

[0163] Biological Examples Example 1 Enzyme assay of PARG inhibition (TR-FRET) enzyme EC 50 Assay PARG enzyme was incubated with compound or vehicle (DMSO) and biotinylated-PARylated PARP-1 substrate in a microtiter plate. Detection antibody and streptavidin-europium were added and incubated, and the fluorescence intensity of the plate was read. The low control (DMSO) with low fluorescence intensity represents no inhibition of enzyme activity, and the high control (no enzyme) with high fluorescence intensity represents complete inhibition of enzyme activity. material: enzyme: ●PARG ○hPARG: 250pM, 1-976, His-tagged, Proteos, 2.0mg / mL (17.9μM) ○Substrate: 30nM Preincubation time of test compound / enzyme: 1 hour Enzyme / substrate reaction time: 10 minutes Substrate: hPARP1, His6-TEV tagged, 1.2mg / mL (10.3μM) Detection antibody: Anti-His monoclonal antibody-ULight, PerkinElmer, Cat. No. TRF0134-M Streptavidin-Europium: PerkinElmer, Catalog No. AD0062 Assay buffer: 50mM Tris-HCL pH7.4, 50mM KCL, 3mM EDTA, 0.4mM EGTA, 1mM DTT, 0.01%Tween20, 0.01%BSA Temperature: 23℃ Total reaction volume: 20 μL Control: ●0% inhibition: DMSO ●100% inhibition: no enzyme Enzyme reaction and detection: 1. Transfer 200 nL of 100x compound or DMSO to appropriate wells of a 384-well white polystyrene microtiter plate (Corning, Cat. No. 3574). 2. Transfer 10 μL of 2x final concentration of enzyme in assay buffer or assay buffer alone to appropriate wells. 3. Centrifuge the plate at 1000 rpm for 30 seconds. 4. Incubate the plate at room temperature for 1 minute. 5. Add 10 μL of 2x substrate in assay buffer to all test wells. 6. Incubate the plate at room temperature for 10 minutes. 7. Add 10 μL of a 3× mixture of 42 nM detection antibody and 2.25 nM streptavidin-europium in 50 mM Tris-HCL, pH 7.4 to all test wells. 8. Incubate the plate at room temperature for 1 minute. 9. Read the plate on a plate reader (Envision). Excitation: 317nM Emission: 620nM Emission: 665nM

[0164] Data Analysis: EC 50 Values ​​were calculated in the Collaborative Drug Discovery vault (CDD). Curve fitting was performed by CDD as response (%) versus compound concentration (μM) using a four-parameter inhibition model using Equation 1.

[0165] Formula 1: Fit=(A+((BA) / (1+((C / x)^D)))) Res=(y-fit)

[0166] TR-FRET EC of Formula (A), Formula (B), Formula (C), and selected comparison agents 50 The values ​​are shown in Table 1 below.

[0167] Example 2 Cell viability assay The PARG inhibitory ability of the compounds disclosed herein was determined in two cell lines: RMUGS-NucLight Red and SNU601-NucLight Red. RMUGS-NucLight Red and SNU601-NucLight Red cells were generated by stably transducing parental cells (RMUGS-JCRB Cell Bank, Catalog No.: IFO50320; SNU601-Korean Cell Line Bank, Catalog No.: 00601) with Incucyte® NucLight Red lentivirus (Sartorius, Catalog No.: 4476). The protocols followed for both cell lines are described below.

[0168] SNU601-NucLight Red: Cells were seeded at 200 cells / well in clear flat-bottom 384-well black plates. After 24 hours, the plates were imaged using an Incucyte® S3 Live-Cell Analysis system and the number of viable cells in each well (day 0) was counted. Test compounds were then added by a Tecan digital dispenser to generate a 9-point dose curve with 3-fold dilutions and a top concentration of 10 uM. All treatments were performed in triplicate. After 7 days of incubation, the plates were imaged using an Incucyte® S3 system and the number of viable cells per well (day 7) was counted. For each well on the plate, the number of viable cells on day 7 was normalized to the number of cells on day 0 (day 7 / day 0). The average value of the DMSO-treated wells in the plate was calculated. All data points were normalized to the average DMSO data. The % of control for each sample was compared to the DMSO-treated control sample. EC 50 Values ​​were calculated in the Collaborative Drug Discovery vault (CDD). Curve fitting was performed by CDD using a four-parameter inhibition model (Levenberg-Marquardt algorithm) as % of control versus log[compound concentration]. Fit=(A+((BA) / (1+((C / x)^D)))) Res=(y-fit) If clear biphasic behavior is observed in the data obtained, EC 50 was calculated in GraphPad Prism Software for the main part of the response using the following formula: Span=Top-Bottom Section1=Span * Frac / (1+10^((LogEC 50_1 -X) * nH1)) Section 2=Span * (1-Frac) / (1+10^((LogEC 50_2 -X) * nH2)) Y=Bottom+Section1+Section2 Frac = fraction of stronger responses between the top (100) and bottom (0) of the normalized curve EC 50_1 , E.C. 50_2 = EC of each response curve 1 and 2 in each part 50 nH1, nH2 = normalized Hill slopes of response curves 1 and 2, respectively, in each section X=log(concentration)

[0169] RMUGS-NucLight Red: Cells were seeded at 1000 cells / well in a clear, flat-bottomed, 96-well black plate. After 24 hours, the plates were imaged using an Incucyte® S3 Live-Cell Analysis system and the number of viable cells in each well (day 0) was counted. Test compounds were then added by a Tecan digital dispenser to generate a 9-point dose curve with 3-fold dilutions and a top concentration of 10 uM. All treatments were performed in duplicate. After 7 days of incubation, the plates were imaged using an Incucyte® S3 system and the number of viable cells per well (day 7) was counted. For each well on the plate, the number of viable cells on day 7 was normalized to the number of cells on day 0 (day 7 / day 0). The average value of the DMSO-treated wells in the plate was calculated. All data points were normalized to the average DMSO data. The % of control for each sample was compared to the DMSO-treated control sample. EC 50 Values ​​were calculated in the Collaborative Drug Discovery vault (CDD). Curve fitting was performed by CDD using a four-parameter inhibition model (Levenberg-Marquardt algorithm) as % of control versus log [compound concentration]. Fit=(A+((BA) / (1+((C / x)^D)))) Res=(y-fit)

[0170] The results for Formula (A), Formula (B), Formula (C), and selected comparators SNU601-NucLight Red and RMUGS-NucLight Red are shown in Table 1 below. Example 3 Kinetic solubility measurements in PBS at pH 2.0 and pH 7.4 Kinetic solubility assay material: enzyme: The control compound diclofenac sodium (LOT#BCBW9128) was purchased from Sigma Chemical Co. 1.5mL glass flat-bottom vial (BioTech Solutions) Molded PTFE / SIL plugs (BioTech Solutions) ·PTFE-filled stirring bar (V&P Scientific) ·MultiScreenHTS HV (0.45μm) 96-well plate (Millipore, MSHVN4510 or MSHVN4550) Eppendorf Thermomixer Comfort · Vacuum manifold ORVMN96. PBS of pH 2.0 and pH 7.4 were prepared in our laboratory. Control: Diclofenac sodium (LOT#BCBW9128), Sigma Chemical Kinetic Solubility Protocol: 1. Preparation of Stock Solutions Stock solutions of diclofenac sodium test and control compounds were prepared in DMSO at concentrations of 30 mM and 10 mM, respectively. 2. Solubility Measurement Procedure. 10 μL of test compound stock solution (30 mM) was placed in sequence into their appropriate 96-well rack, 20 μL of DMSO and 970 μL of pH 2.0 or pH 7.4 PBS were added to each vial of the capless solubility sample plate, 30 μL of control compound stock solution (10 mM) was placed in sequence into their appropriate 96-well rack, and 970 μL of pH 2.0 or pH 7.4 PBS was added to each vial of the capless solubility sample plate. Assays were performed in n=2. One stir bar was placed into each vial and sealed with a molded PTFE / silicone plug. The solubility sample plate was then transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 25° C., 1100 RPM for 24 hours. At the end of the 24 hours, the plugs were removed, the stir bars were removed using a large magnet, and the samples were transferred from the solubility sample plate to a filter plate. All samples were filtered using a vacuum manifold. A 10 μL aliquot was taken from the filtrate followed by the addition of 990 μL of a mixture of HO and acetonitrile (1:1 v / v). 200 μL of the dilution was transferred to a new 96-well plate for LC-MS / MS analysis. The dilution factor was varied depending on the solubility value and LC-MS signal response. Preparation of 3.3 μM standards (STD). From the 10 mM or 30 mM DMSO STD plate, 15 μL or 5 μL was transferred to the remaining blank plate, then 485 μL or 495 μL of DMSO was added to the plate to obtain a STD concentration of 300 μM. From the 300 μM DMSO standard plate, 5 μL was transferred to the remaining blank plate, then 495 μL of a mixture of H2O and acetonitrile (1:1 v / v) was added to the plate to obtain a final STD concentration of 3 μM. 200 μL of the dilutions were transferred to a new 96-well plate for LC-MS / MS analysis. The concentration of the standards was varied depending on the LC-MS signal response. 4. Sample analysis procedure. The plate was placed in a well plate autosampler. The samples were evaluated by LC-MS / MS analysis.

[0171] The solubility values ​​of Formula (A), Formula (B), Formula (C), and selected comparative agents are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0172] Data legend: Geometric mean (all data sets), * n<3 (where "n" is the number of experiments)

[0173] Example 4 PARG inhibition in PARP inhibitor-resistant and platin-resistant cell lines Materials and Methods: Generation of PARP inhibitor (PARPi) resistant cell lines Two cell lines were used to generate PARPi-resistant lines, HCC1428 and MDA-MB-436. All cell lines were cultured at 37°C, 5% CO2 in media according to the manufacturer's recommendations. To generate resistant cell lines, an IC50 concentration of the PARP inhibitor Niraparib was added to each cell line and gradually increased to IC90 over a period of 3-4 months until the cell lines adapted, developed resistance, and began to proliferate in the presence of high doses of Niraparib. The cell lines were used in the studies disclosed in Figures 1 and 2.

[0174] Cell proliferation assay A panel of cell lines (disclosed in Table 2) exhibiting natural resistance to PARP inhibitors was identified and the effect of Formula A was tested using a cell proliferation assay with two acquired resistance cell lines (PARPi resistant lines: HCC1428 and MDA-MB-436). For the proliferation assay, cell lines were seeded at a density of 1000 cells / well in 96-well plates (Corning #3904). Compounds dissolved in DMSO were added using a TECAN liquid dispenser to generate a 9-point dose curve with a starting top concentration of 10 μM in 3-fold dilutions. After 5 population doublings, cell lines were treated with 5 μM Vybrant DyeCycle Green (Life Technologies #V35004) and incubated for 60 minutes. DMSO and compound treated wells were then imaged using an Incucyte® S3 system to measure nuclei counts. Counts were normalized to DMSO-treated wells and IC50s were determined using a standard four-parameter dose-response equation in GraphPad Prism Software.

[0175] Patient-derived cells tested in cell viability assays Patient-derived cells (PDCs) were identified from ovarian tissue with BRCA1 / 2 mutations and cisplatin resistance. These cells were processed from solid tumor samples received after surgery / resection and cultured in 2D in selective medium. For each PDC, cells were detached and counted using TrypLE after reaching the cell number required for the assay. Draq7 dye was added to cells before plating to identify dead cells. Cells were plated in 96-well plates (Greiner #655090) and incubated at 37°C, 5% CO2 for 16-24 hours. Formula (A) was dispensed in a 9-point dose curve of 3-fold dilutions starting at 30uM using a Tecan HP D300 digital dispenser. After 7 days of incubation with compounds, cells were fixed with 2% formaldehyde and stained with Hoechst. Plates were scanned using Nexcelom Celigo high content screening and analyzed for total cell number using Hoechst labeling and cell death using Draq7 fluorescence. For all PDCs, nuclear counts were normalized to DMSO-treated wells and IC50s were determined using a standard 4-parameter dose-response equation in GraphPad Prism Software. The generated cells were used in the study disclosed in Figure 3.

[0176] result: PAPRi natural and acquired resistance cell lines are sensitive to formula A The antiproliferative effect of PARG inhibition on a panel of cancer cell lines with natural resistance to PARP inhibitors was tested using Formula A. Several cell lines with loss-of-function mutations in BRCA1 / 2 and resistance to niraparib showed sensitivity to Formula A (Table 2). Two breast cancer cell lines that have acquired resistance to PARPi, MDA-MB-436 and HCC1428, were also tested in the proliferation assay. In MDA-MB-436, Formula A was 9-fold more potent in the niraparib-resistant cell line (11.8 nM) compared to the parental cell line (103 nM) (Figure 1). The HCC1428 PARPi-resistant cell line retained sensitivity to Formula A with an IC50 of 8 nM (Figure 2). Formula A was also tested in an ovarian patient-derived cell (PDC) model with BRCA1 mutations and cisplatin resistance. Formula A had an antiproliferative effect on the cell line with an IC50 of 260 nM (Figure 3). [Table 2]

[0177] Example 5 Patient-derived xenograft (PDX) research 108~288mm 3 Athymic Foxn1 females with established and growing HBCx-34 tumors nu Mice are randomized into two treatment groups of 8 mice each according to the groups listed in Table 3, and tumor-bearing mice receive estrogen (β-estradiol, 8.5 mg / l) diluted in drinking water from the day of tumor implantation until the end of the study. In Table 3, the abbreviation "po" refers to oral administration and the abbreviation "QD" refers to once-daily administration. [Table 3]

[0178] Tumors were measured and mice were weighed twice a week during the experiment. Tumor volume (mm 3) was estimated using the formula: Tumor Volume (TV) = a × b2 / 2, where "a" and "b" were the long and short diameters of the tumor, respectively. The TV was used to calculate tumor growth inhibition (TGI, an index of antitumor activity) using the formula TGI%: (1-{T / T0 / Ct / C0} / 1-{C0 / Ct}) × 100, where Tt = median treated tumor volume at time t, T0 = median treated tumor volume at time 0, Ct = median control tumor volume at time t, and C0 = median control tumor volume at time 0. Formula A administered at 100 mg / kg produced a robust and statistically significant antitumor response, with partial regression in all mice. A summary of the results is shown in Table 4 (Figure 4). Tumor regression represents a tumor volume smaller than the initial tumor volume at D0. [Table 4]

[0179] Although the above invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will appreciate that certain changes and modifications may be practiced that are within the scope of the appended claims. Additionally, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of any inconsistency between this application and the references provided herein, this application shall control.

Claims

1. A compound represented by the following structure: 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. The following structure 【Chemistry 2】 A compound represented by the formula:

3. A compound represented by the following structure: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof.

4. The following structure 【Chemistry 4】 A compound represented by the formula:

5. A compound represented by the following structure: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof.

6. The following structure: 【Chemistry 6】 A compound represented by the formula:

7. A compound represented by the following structure: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof.

8. The following structure: 【Chemistry 8】 A compound represented by the formula:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. Formula (A) 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. The following structure: 【Chemistry 10】 A pharmaceutical composition comprising a compound represented by the formula (I): and a pharmaceutically acceptable excipient.

12. A pharmaceutical composition for use in therapy, comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition for use in the treatment of cancer, comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

14. An in vitro method for inhibiting cell proliferation, comprising contacting a cell with an effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

15. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use in treating cancer that is resistant to one or more platins or one or more PARP inhibitors.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for use in treating and / or preventing homologous recombination deficient (HRD) cancer.

17. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for use in the treatment and / or prevention of cancer, wherein the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 gene, absent or mutated BRCA1 and / or BRCA2 gene, or reduced function of the BRCA1 and / or BRCA2 protein.

18. The pharmaceutical composition of claim 13, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

19. The cancer of claim 19, wherein: (i) cancer that is resistant to one or more platins or one or more PARP inhibitors; (ii) homologous recombination deficient (HRD) cancer; and (iii) cancer characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, absence or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins; 19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is selected from:

20. The pharmaceutical composition of claim 13, wherein the cancer is colon cancer, liver cancer, brain cancer, or skin cancer.

21. The cancer of claim 20, wherein: (i) cancer that is resistant to one or more platins or one or more PARP inhibitors; (ii) homologous recombination deficient (HRD) cancer; and (iii) cancer characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, absence or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins; 21. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is selected from:

22. A pharmaceutical composition for use in therapy, comprising: Formula (A) 【Chemistry 11】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. 1. A pharmaceutical composition for use in the treatment of cancer, comprising: Formula (A) 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

24. 1. A pharmaceutical composition for use in the treatment of cancer that is resistant to one or more platins or one or more PARP inhibitors, comprising: Formula (A) 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. A pharmaceutical composition for use in the treatment and / or prevention of homologous recombination deficient (HRD) cancer, comprising: Formula (A) 【Chemistry 14】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

26. A pharmaceutical composition for use in the treatment and / or prevention of cancer, comprising: Formula (A) 【Chemistry 15】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 gene, absence or mutation of the BRCA1 and / or BRCA2 gene, or reduced function of the BRCA1 and / or BRCA2 protein; The pharmaceutical composition.

27. 24. The pharmaceutical composition of claim 23, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

28. The cancer of claim 27, wherein the cancer is: (i) cancer that is resistant to one or more platins or one or more PARP inhibitors; (ii) homologous recombination deficient (HRD) cancer; and (iii) cancer characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, absence or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins; 28. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition is selected from:

29. 24. The pharmaceutical composition of claim 23, wherein the cancer is colon cancer, liver cancer, brain cancer, or skin cancer.

30. The cancer of claim 30, wherein the cancer is: (i) cancer that is resistant to one or more platins or one or more PARP inhibitors; (ii) homologous recombination deficient (HRD) cancer; and (iii) cancer characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, absence or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins; 30. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition is selected from:

31. The compound has the following structure: 【Chemistry 16】 The pharmaceutical composition according to any one of claims 22 to 30, wherein the compound is represented by the formula:

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