Piperazine-substituted indazole compounds as PARG inhibitors

Abstract

The present invention provides a compound of formula (I): # imgabs0 # or a pharmaceutically acceptable salt thereof. The compounds provided are potent inhibitors of poly ADP-ribose glycosyl hydrolase (PARG). Additional uses and advantages are also described herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Serial No. 63 / 322,994, filed on March 23, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0003] STATEMENT REGARDING RIGHTS TO INVENTS RESULTING FROM FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0004] not applicable

[0005] Reference to a "Sequence Listing", a table or a computer program listing appendix submitted on a compact disc

[0006] not applicable Background Art

[0007] Cancer is caused by uncontrolled and unregulated cell proliferation. A consequence of this often rapid proliferation is high levels of oxidative stress within the tumor, which damages DNA and leads to a large increase in mutation rates. As a result, tumor cells initiate and become highly dependent on DNA damage repair mechanisms.

[0008] Single-strand breaks (SSBs) are the most common type of damage generated in cells, and PARG (poly ADP-ribose glycosyl hydrolase) together with PARP (poly ADP-ribose polymerase) along with many other proteins are involved in single-strand break repair (SSBR) and another repair mechanism called base excision repair (BER).

[0009] One of the earliest events during single-strand DNA repair is the binding of PARP (poly ADP-ribose polymerase) to the break site and the rapid synthesis of poly ADP-ribose (PAR) on the PARP itself. This molecular structure acts as a signal to recruit other DNA repair proteins, first of all XRCC1, which will continue to repair the break site (Mortusewicz, Fouquerel et al. 2011). The signal initiated by these PAR chains is short-lived because they are rapidly degraded by the enzyme PARG. When PARP is bound to PAR, its catalytic activity is reduced, so PARG activity helps to restore PARP to its catalytically active form (Curtin and Szabo 2013).

[0010] PARG is derived from a single gene with isoforms located in the nucleus, mitochondria, and cytoplasm. Another protein known to have glycosyl hydrolase activity is ARH3, which is localized in mitochondria (Mashimo, Kato et al. 2014). Although PARG is mainly known for its direct role in DNA repair, it also affects PAR signal transduction 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).

[0011] Cancer cells may become dependent on specific DNA repair pathways when other DNA repair mechanisms fail to function. Tumors carrying mutations in proteins involved in double-strand break repair are often more sensitive to PARP inhibitors of SSBR. There is some evidence that PARG loss inhibits SSBR and reduces survival of BRCA2-deficient cells (Fathers, Drayton et al. 2012). However, other tumor mutations may result in defects in double-strand DNA repair mechanisms (so-called “BRCA-ness”), thereby sensitizing tumor cells to PARG inhibition.

[0012] PARG deletion has been studied in a variety of mouse and human model systems. PARG deletion (null) or deletion (depleted) mouse cells show increased sensitivity to experimental and clinical DNA damaging agents. However, since PARG deficiency is not sensitive to all agents (e.g., gemcitabine, camptothecin), this suggests that PARG function is specific in certain DNA damage repair pathways and chemotherapy and radiotherapy (Fujihara, Ogino et al. 2009) (Shirai, Fujimori et al. 2013) (Zhou, Feng et al. 2010) (Zhou, Feng et al. 2011).

[0013] In humans, PARG deficiency sensitizes lung, cervical, and pancreatic cancer cells to γ-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).

[0014] PARP inhibitors are currently undergoing multiple clinical trials, where the concepts of synthetic lethality or chemosensitization are being explored. Clinical resistance to PARP inhibitors has been described (Drost and Jonkers 2014) (Barber, Sandhu et al. 2013), and therefore, there is a need to find other alternative inhibitors that target DNA damage repair mechanisms.

[0015] Although current models suggest that PARG deficiency has PARP-dependent effects on DNA repair, recent studies have shown that this is mechanistically different from PARP inhibition. Unlike PARP deficiency, loss of genotoxic stimulation of PARG results in decreased NAD levels. This leads to lung cancer cell death due to energy failure (Erdelyi, Bai et al. 2009).

[0016] Cell permeable PARG inhibitors are limited to compounds such as tannic acid or gallic tannic acid, which have questionable specificity for PARG and limited bioavailability (Sun, Zhang et al. 2012)(Fathers, Drayton et al. 2012)(Blenn, Wyrsch et al. 2011).

[0017] It is an object of the present invention to provide cell permeable PARG inhibitors. Summary of the invention

[0018] In one aspect, there is provided a compound of formula (I):

[0019]

[0020] or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, there is provided herein a compound of formula (I):

[0022]

[0023] In another aspect, there is provided herein a compound of formula (A):

[0024]

[0025] or a pharmaceutically acceptable salt thereof.

[0026] In another aspect, there is provided herein a compound of formula (A):

[0027]

[0028] In another aspect, provided herein is a compound of formula (B):

[0029]

[0030] or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, provided herein is a compound of formula (B):

[0032]

[0033] In another aspect, there is provided herein a compound of formula (C):

[0034]

[0035] or a pharmaceutically acceptable salt thereof.

[0036] In another aspect, there is provided herein a compound of formula (C):

[0037]

[0038] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), Formula (A), Formula (B) or Formula (C) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0039] In another aspect, the present invention provides a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0040] In another aspect, provided herein is a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in treating cancer. In one embodiment, the cancer is a human cancer.

[0041] In another aspect, provided herein is a compound of Formula (I), Formula (A), Formula (B) or Formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in producing a PARG inhibitory effect.

[0042] In another aspect, provided herein is the use of a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the preparation of a medicament for treating cancer. Suitably, the medicament is used to treat human cancer.

[0043] In another aspect, provided herein is the use of a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the preparation of a medicament for producing a PARG inhibitory effect.

[0044] In another aspect, provided herein is a method for 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) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0045] In another aspect, provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cells with an effective amount of a compound of Formula (I), Formula (A), Formula (B) or Formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0046] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0047] In another aspect, provided herein is a method of treating cancer resistant to one or more platinum drugs 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0048] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has previously received a platinum drug to treat cancer.

[0049] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has previously received a PARP inhibitor to treat cancer.

[0050] On the other hand, the present invention provides a method for identifying PARG activity in a test compound of PARG inhibitory activity, the method comprising (i) contacting the test compound with an isolated PARG enzyme, a biotinylated-PARylated PARP substrate to form a PARG reaction premix; (ii) contacting the PARG reaction premix with a detection antibody and streptavidin-europium to form a PARG reaction mixture; and (iii) measuring the fluorescence intensity of the PARG reaction mixture, wherein the method further comprises performing steps (i)-(iii) using a positive control sample represented by a compound of Formula (I), Formula (A), Formula (B) or Formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition defined herein. In some embodiments, the detection antibody is an anti-His monoclonal antibody-ULight. In some embodiments, streptavidin-europium binds to a biotinylated-PARylated PARP substrate. In some embodiments, fluorescence is measured by providing an excitation wavelength of 317 nM and measuring the emission at 620 nM (streptavidin-europium emission) and 665 nM (ULight emission).

[0051] In another aspect, provided herein are methods of synthesizing a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharmaceutically acceptable salt thereof, as defined herein.

[0052] On the other hand, provided herein is a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, which can be obtained by the synthesis method defined herein or obtained by the synthesis method defined herein or directly obtained by the synthesis method defined herein.

[0053] In another aspect, provided herein are novel intermediates as defined herein, which are suitable for use in any one of the synthetic methods described herein.

[0054] Preferred, suitable and optional features of any particular aspect of the invention are also preferred, suitable and optional features of any other aspect. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 The percent activity of PARPi-resistant MDA-MB-436 cells described in Example 4 is plotted as a function of the logarithmic concentration of Formula A. 50 ” refers to the IC of cells producing PARPi-resistant pro-formula A 50 , and "niraparib-resistant IC 50 ” refers to the IC of formula A after cells develop PARPi resistance 50 .

[0056] Figure 2The percent activity of PARPi-resistant HCC1428 cells described in Example 4 is plotted as a function of the logarithmic concentration of Formula A. 50 ” refers to the IC of cells producing PARPi-resistant pro-formula A 50 , while "Niraparib-resistant IC 50 ” refers to the IC of formula A after cells develop PARPi resistance 50 .

[0057] Figure 3 The activity of patient-derived cells (PDCs) from ovarian tissue carrying BRCA1 / 2 mutations and cisplatin resistance described in Example 4 was plotted as a function of Formula A concentration.

[0058] Figure 4 : Shown is a patient-derived xenograft (PDX) study using HBCx-34 (Formula A). DETAILED DESCRIPTION

[0059] Before further describing the present invention, it is to be understood that the present invention is not limited to the particular embodiments set forth herein and that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0060] When providing a numerical range, it should be understood that each intermediate value between the upper and lower limits of the range (unless the context clearly indicates otherwise, the intermediate value reaches one-tenth of the unit of the lower limit) and any other intermediate values ​​described or in the described range are included in the present invention. The upper and lower limits of these smaller ranges can be independently included in the smaller ranges, and are also included in the present invention, except for any limits that are definitely beyond the described range. When the described range includes one or both of the limits, the range that exceeds any one or both of those included limits is also included in the present invention. Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as commonly understood by ordinary technicians in the field to which the present invention belongs.

[0061] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0062] Overview

[0063] Provided herein are compounds of formula (I), formula (A), formula (B) or formula (C) or pharmaceutically acceptable salts thereof for inhibiting PARG, and pharmaceutical compositions comprising the same. Also provided herein are methods for treating or preventing a disease, disorder or condition or a symptom thereof, for example by inhibiting PARG.

[0064] Advantageously, the compounds disclosed herein are potent inhibitors of PARG in both cellular 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 combined parameters of the compounds described herein make them ideal compounds for targeting and inhibiting PARG activity.

[0065] definition

[0066] Unless otherwise stated, the following terms are intended to have the meanings set out below. Other terms are defined elsewhere in this specification.

[0067] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional elements. Therefore, this description is intended to serve as an antecedent basis for use of such exclusive terminology as "only," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0068] The term "pharmaceutically acceptable salt" is meant to include salts prepared from compounds of Formula (I), Formula (A), Formula (B) or Formula (C) with relatively nontoxic acids or bases, depending on the particular substituents present 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, permanganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically 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, reduced glucosamine, 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, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, etc.), and salts derived from relatively nontoxic organic acids (e.g., acetic acid, propionic acid, isobutyric acid, malic acid, benzoic acid, succinic acid, sebacic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc.). Also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids (e.g., glucuronic acid or galacturonic acid, etc.) (Berge, SM, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which enables these compounds to be converted into base addition salts or acid addition salts.

[0069] When a stereochemical description is shown, it refers to a compound in which one isomer is present and is substantially free of the other isomer. "Substantially free" of the other isomer means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or higher. In certain embodiments, one of the isomers is present in an amount of at least 99%.

[0070] Formula (I), (A), (B) or (C) may also contain unnatural ratios of atomic isotopes at one or more of the atoms comprising the compound. Unnatural ratios of isotopes may be defined as ranging from the amount found in nature to an amount consisting of 100% of the relevant atoms. For example, a compound may incorporate a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C). Such isotopic variations may provide additional uses to those described elsewhere in this application. For example, isotopic variants of the compounds of the invention may find additional uses, including but not limited to as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of Formula (I), (A), (B) or (C) may have altered pharmacokinetic and pharmacodynamic properties, which may help improve safety, tolerability or effectiveness during treatment. All isotopic variants of Formula (I), (A), (B) or (C), whether radioactive or not, are intended to be included within the scope of the present invention.

[0071] The terms "patient" or "subject" are used interchangeably and refer to a human or a non-human animal (eg, a mammal). In one embodiment, the patient or subject is a human.

[0072] The terms "administration", "administer", etc., when applied to, for example, a patient, cell, tissue, organ or biological fluid, refer to contacting, for example, a PARG inhibitor, a pharmaceutical composition comprising the same, or a diagnostic reagent with a patient, cell, tissue, organ or biological fluid. At the cellular level, administration includes contacting an agent with a cell (e.g., in vitro or ex vivo), as well as contacting an agent with a fluid, wherein the fluid is in contact with a cell.

[0073] The terms "treat", "treating", "treatment" and the like refer to a course of action (e.g., administration of a PARG inhibitor or a pharmaceutical composition comprising the same) initiated after diagnosis, observation of a disease, disorder or condition, or symptoms thereof, to temporarily or permanently eliminate, reduce, inhibit, alleviate or improve at least one potential cause of the disease, disorder or condition in a patient, or at least one symptom associated with the disease, disorder or condition. Thus, treatment includes inhibiting (e.g., preventing the development or further development of a disease, disorder or condition or clinical symptoms associated therewith) active disease.

[0074] As used herein, the term "in need of treatment" refers to a judgment made by a physician or other health care provider that a patient requires or will benefit from treatment. This judgment is based on a variety of factors that are within the physician's or health care provider's area of ​​expertise.

[0075] The terms "prevent", "preventing", "prevention", etc. refer to a course of action (e.g., administration of a PARG inhibitor or a pharmaceutical composition comprising the same) that is initiated in a manner (e.g., before a disease, disorder, condition, or symptom thereof occurs) to temporarily or permanently prevent, stop, inhibit, or reduce the risk of a patient developing a disease, disorder, condition, etc. (e.g., as determined by the absence of clinical symptoms) or delay the onset of the disease, disorder, condition, etc., usually in the context of a patient being susceptible to a particular disease, disorder, or condition. In some cases, these terms also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or other undesirable state.

[0076] As used herein, the term "need for prevention" refers to a judgment made by a physician or other caregiver that a patient needs or will benefit from preventive care. This judgment is based on various factors that fall within the physician's or caregiver's area of ​​expertise.

[0077] The terms "inhibit" and "reduce," or any variants of these terms as they relate to PARG, include any measurable decrease or complete inhibition to achieve a desired result. For example, PARG activity may be reduced by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more compared to normal levels. As used herein, "about" means within ±10% of a given value, preferably ±5%.

[0078] The phrase "therapeutically effective amount" refers to an amount of an agent that, when administered to a patient (whether alone or as part of a pharmaceutical composition, in a single dose or as part of a series of doses), produces any detectable, positive effect on any symptom, aspect or characteristic of a patient's disease, disorder or condition. A therapeutically effective amount can be determined by measuring relevant physiological effects and can be adjusted based on, for example, dosing regimens and diagnostic analysis of the patient's condition. For example, measuring serum levels of a PARG inhibitor (or its metabolites, etc.) at a specific time point after administration can indicate whether a therapeutically effective amount has been used.

[0079] The phrase "platinum drugs" or "platinum-based chemotherapy" refers to a class of chemotherapy drugs containing platinum, which are used to treat cancer. Exemplary platinum drugs include cisplatin, carboplatin, satraplatin, heptaplatin, picoplatin, nedaplatin, triplatin, lipoplatin or oxaliplatin.

[0080] As used herein, "platinum-resistant cancer" or "cancer resistant to one or more platinum drugs" refers to a cancer that does not respond to treatment with a platinum drug. Non-responsiveness can be assessed by continued growth of the tumor when the drug is administered, failure of the tumor to shrink when the drug is administered, or other methods known in the art. Non-responsiveness of a cancer can be determined by clinical observation, diagnosis by a medical professional, experimental testing of isolated cells in a laboratory setting, or by other technical means.

[0081] As used herein, "poly ADP ribose polymerase (PARP) inhibitor" refers to drugs that inhibit PARP activity, including PARP1 and PARP2. Examples of PARP inhibitors include, but are not limited to, niraparib, rucaparib, olaparib, talazoparib, and veliparib.

[0082] As used herein, "cancer resistant to PARP inhibitors" 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 growth of a tumor when the drug is administered, failure of a tumor to shrink when the drug is administered, or other methods known in the art. Non-responsiveness of a cancer can be determined by clinical observation, diagnosis by a medical professional, experimental testing of isolated cells in a laboratory setting, or by other technical means.

[0083] 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.

[0084] As used herein, "homologous recombination deficient (HRD) cancer" refers to a cancer characterized by reduced or absent function of the HR repair pathway. HR deficiency may result from the absence or reduction of one or more HR-related genes, or the presence of one or more mutations in one or more HR-related genes. Examples of genes associated with HR include BRCA1, BRCA2, RAD54, RAD51B, ATM, BARD1, CHECK1, CHECK2, CDK12, RAD51B, RAD54L, RAD51D, PPP22A, BRIP1, CtIP (CtBP interacting protein), PALB2 (BRCA2 chaperone and localization protein), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Bloom syndrome, one of one or more HR-related genes), Nbs1 (Nibrin), and a gene encoding Fanconi anemia (Fanconi anemia (FA) protein or FA-like genes, such as FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C and XPF.

[0085] Compound

[0086] In one aspect, provided herein is a compound of formula (I)

[0087]

[0088] or a pharmaceutically acceptable salt thereof. In one embodiment, Formula (I) is in free base form.

[0089] In one aspect, provided herein is a compound of formula (A)

[0090]

[0091] or a pharmaceutically acceptable salt thereof. In one embodiment, Formula (A) is in free base form.

[0092] 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.

[0093] In one aspect, provided herein is a compound of formula (B)

[0094]

[0095] or a pharmaceutically acceptable salt thereof. In one embodiment, Formula (B) is in free base form.

[0096] 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.

[0097] In one aspect, provided herein is a compound of formula (C)

[0098]

[0099] or a pharmaceutically acceptable salt thereof. In one embodiment, Formula (C) is in free base form.

[0100] 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.

[0101] Biological Activity

[0102] 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.

[0103] Pharmaceutical composition

[0104] Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0105] The composition can be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., creams, ointments, gels or aqueous or oily solutions or suspensions), administration by inhalation (e.g., fine powders or liquid aerosols), administration by insufflation (e.g., fine powders), or parenteral administration (e.g., sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or suppositories for rectal administration).

[0106] The compositions can be obtained by using conventional pharmaceutical excipients and conventional procedures known in the art. Thus, compositions for oral use may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and / or preservatives.

[0107] An effective amount of a compound of Formula (I), (A), (B) or (C) or a pharmaceutically acceptable salt thereof for use in treatment is an amount sufficient to treat or prevent the proliferative diseases mentioned herein, slow their progression and / or reduce the symptoms associated with the disease.

[0108] The dosage of the compounds of formula (I), (A), (B) or (C) for therapeutic or preventive purposes will vary depending on the nature and severity of the disease, the age and sex of the animal or patient and the route of administration, according to well-known principles in the medical field.

[0109] When a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof is used for therapeutic or preventive purposes, the compound is usually administered so that its total daily dose is in the range of, for example, 0.01 mg / kg to 100 mg / kg body weight. Oral administration may also be suitable, particularly in tablet form.

[0110] In some embodiments, the composition of formula (A) comprises at least 70% of the display isomer. In some embodiments, the composition of formula (A) comprises at least 75% of the display isomer. In some embodiments, the composition of formula (A) comprises at least 80% of the display isomer. In some embodiments, the composition of formula (A) comprises at least 85% of the display isomer. In some embodiments, the composition of formula (A) comprises at least 90% of the display isomer. In some embodiments, the composition of formula (A) comprises at least 95% of the display isomer. In some embodiments, the composition of formula (A) comprises at least 99% of the display isomer.

[0111] In some embodiments, the composition of formula (B) comprises at least 70% of the display isomer. In some embodiments, the composition of formula (B) comprises at least 75% of the display isomer. In some embodiments, the composition of formula (B) comprises at least 80% of the display isomer. In some embodiments, the composition of formula (B) comprises at least 85% of the display isomer. In some embodiments, the composition of formula (B) comprises at least 90% of the display isomer. In some embodiments, the composition of formula (B) comprises at least 95% of the display isomer. In some embodiments, the composition of formula (B) comprises at least 99% of the display isomer.

[0112] In some embodiments, the composition of formula (C) comprises at least 70% of the display isomer. In some embodiments, the composition of formula (C) comprises at least 75% of the display isomer. In some embodiments, the composition of formula (C) comprises at least 80% of the display isomer. In some embodiments, the composition of formula (C) comprises at least 85% of the display isomer. In some embodiments, the composition of formula (C) comprises at least 90% of the display isomer. In some embodiments, the composition of formula (C) comprises at least 95% of the display isomer. In some embodiments, the composition of formula (C) comprises at least 99% of the display isomer.

[0113] Therapeutic uses and applications

[0114] Provided herein are compounds that act as PARG inhibitors.

[0115] The present invention therefore provides a method for inhibiting PARG enzyme activity in vitro or in vivo, which method comprises contacting a cell with an effective amount of a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0116] The present invention also provides a method for treating a disease or condition associated with 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) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. In one embodiment, the disease or condition is an advanced or metastatic solid tumor. In one embodiment, the disease or condition 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 homologous recombination defect (HRD) cancer.

[0117] Provided herein is a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cells with an effective amount of a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition defined herein.

[0118] Provided herein is a method for treating a proliferative disease 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. In one embodiment, the proliferative disease is a solid tumor. In one embodiment, the proliferative disease is a metastatic solid tumor. In one embodiment, the proliferative disease 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 homologous recombination defect (HRD) cancer.

[0119] Provided herein is a method for 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. 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 homologous recombination defective (HRD) cancer.

[0120] Provided herein is a method for treating and / or preventing a patient's homologous recombination deficiency (HRD) cancer, 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. In one embodiment, the patient is identified as needing such treatment. In one embodiment, the homologous recombination deficiency (HRD) cancer is breast cancer, ovarian cancer, gastric cancer, prostate cancer, lung cancer, cervical cancer or pancreatic cancer.

[0121] Provided herein is 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, 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein. 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.

[0122] In one embodiment, the cancer is resistant to a PARP inhibitor. In some embodiments, the cancer resistant to a PARP inhibitor is resistant to any one or more of niraparib, olaparib, rucaparib, talazoparib, veliparib, AZD5305, or AZD9574. In some embodiments, the cancer resistant to a PARP inhibitor is resistant to niraparib. In some embodiments, the cancer resistant to a PARP inhibitor is resistant to olaparib. In some embodiments, the cancer resistant to a PARP inhibitor is ovarian cancer, breast cancer, or pancreatic cancer.

[0123] In one embodiment, the cancer is resistant to platinum drugs. In some embodiments, the cancer resistant to platinum drugs is resistant to any one or more of cisplatin, carboplatin, satraplatin, heptaplatin, picoplatin, nedaplatin, trinuclear platinum, liposomal cisplatin, or oxaliplatin. In some embodiments, the cancer resistant to platinum drugs is resistant to cisplatin. In some embodiments, the cancer resistant to platinum drugs is resistant to carboplatin.

[0124] 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 pharmaceutically 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 method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been diagnosed as resistant to one or more PARP inhibitors.

[0125] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been determined to be resistant to platinum-based chemotherapy. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (A), Formula (B) or Formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, wherein the patient has been diagnosed as resistant to one or more platinum-based chemotherapy.

[0126] Provided herein are compounds of Formula (I), Formula (A), Formula (B) or Formula (C), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for use in therapy.

[0127] Provided herein are compounds of Formula (I), Formula (A), Formula (B) or Formula (C), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for use in treating a proliferative disease.

[0128] Provided herein are compounds of formula (I), formula (A), formula (B) or formula (C) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for use in treating cancer. In a specific embodiment, the cancer is a 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 homologous recombination defect (HRD) cancer.

[0129] Provided herein are compounds of Formula (I), Formula (A), Formula (B) or Formula (C) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for use in inhibiting PARG enzyme activity.

[0130] Provided herein are compounds of Formula (I), Formula (A), Formula (B) or Formula (C) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for use in treating a disease or condition involving PARG activity.

[0131] Provided herein is the use of a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the preparation of a medicament for treating a proliferative disease.

[0132] Provided herein is the use of a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the preparation of a medicament for treating cancer. Suitably, the medicament is used to treat 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 homologous recombination defect (HRD) cancer.

[0133] Provided herein is the use of a compound of formula (I), formula (A), formula (B) or formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition defined herein, in the preparation of a medicament for inhibiting PARG enzyme activity.

[0134] Provided herein is the use of a compound of Formula (I), Formula (A), Formula (B) or Formula (C) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in the preparation of a medicament for treating a disease or condition involving PARG activity.

[0135] The present disclosure also contemplates the use of a compound of Formula (I), Formula (A), Formula (B) or Formula (C), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, in combination with other therapeutically active agents or compounds described herein to treat the diseases, disorders and conditions contemplated by the present disclosure.

[0136] The terms "proliferative disease" and "proliferative disorder" are used interchangeably herein and refer to unwanted or uncontrolled cell proliferation (e.g., neoplastic or proliferative growth) of excess or abnormal cells, whether in vitro or in vivo, which is undesirable. Examples of proliferative diseases include, but are not limited to, precancerous and malignant cell proliferation, including, but not limited to, malignancies and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative diseases (e.g., proliferative diseases 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 cells. Proliferative diseases also include, for example, advanced or metastatic solid tumors.

[0137] The anti-proliferative effects of the compounds of formula (I), (A), (B) or (C) or their pharmaceutically acceptable salts, or pharmaceutical compositions defined herein have particular application in the treatment of human cancers (through their inhibitory effect on PARG enzyme activity).

[0138] Anticancer effects may occur through one or more mechanisms, including but not limited to modulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of a tumor from its original site), inhibition of invasion (spread of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).

[0139] In a specific embodiment of the invention, the proliferative disease to be treated is cancer.

[0140] Route of administration

[0141] A compound of formula (I), formula (A), formula (B) or formula (C), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, may be administered to a patient by any convenient route of administration, whether systemically / peripherally or locally (i.e., at the target site of action).

[0142] Administration routes include, but are not limited to: oral (e.g., by swallowing); buccal; sublingual; transdermal (including, for example, by patch, dressing, etc.); transmucosal (including, for example, by patch, dressing, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, such as by aerosol, such as by mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal suppository); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal injection; by implanting a reservoir or sustained release agent, such as subcutaneous or intramuscular implantation. Some embodiments of the present invention contemplate oral administration.

[0143] Implementation

[0144] Embodiment 1. A compound of formula (I):

[0145]

[0146] or a pharmaceutically acceptable salt thereof.

[0147] Embodiment 2. The compound according to embodiment 1, which is represented by formula (A):

[0148]

[0149] or a pharmaceutically acceptable salt thereof.

[0150] Embodiment 3. A compound according to Embodiment 1 in free base form. Embodiment 3A. A compound according to Embodiment 2 in free base form.

[0151] Embodiment 4. A compound according to Embodiment 2 or 3A which is at least 90% free of other isomers.

[0152] Embodiment 5. A compound according to Embodiment 2 or 3A which is at least 95% free of other isomers.

[0153] Embodiment 6. A compound according to Embodiment 2 or 3A which is at least 99% free of other isomers.

[0154] Embodiment 7. The compound according to Embodiment 1, which is represented by formula (B):

[0155]

[0156] or a pharmaceutically acceptable salt thereof.

[0157] Embodiment 8. The compound according to embodiment 7, which is in free base form.

[0158] Embodiment 9. The compound according to embodiment 7 or 8 which is at least 90% free from other isomers.

[0159] Embodiment 10. The compound according to embodiment 7 or 8 which is at least 95% free from other isomers.

[0160] Embodiment 11. A compound according to embodiment 7 or 8 which is at least 99% free of other isomers.

[0161] Embodiment 12. The compound according to Embodiment 1, which is represented by formula (C):

[0162]

[0163] or a pharmaceutically acceptable salt thereof.

[0164] Embodiment 13. The compound according to embodiment 12, which is in free base form.

[0165] Embodiment 14. A compound according to embodiment 12 or 13 which is at least 90% free of other isomers.

[0166] Embodiment 15. The compound according to embodiment 12 or 13 which is at least 95% free from other isomers.

[0167] Embodiment 16. The compound according to embodiment 12 or 13 which is at least 99% free of other isomers.

[0168] Embodiment 17. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0169] Embodiment 18. A method of treating a disease or condition involving PARG activity in a patient, the method comprising administering to the patient an effective amount of a compound according to any one of Embodiments 1 to 16, or a pharmaceutically 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 condition is cancer. Embodiment 18B. The method according to Embodiment 18, wherein the disease or condition 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.

[0170] Embodiment 19. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 17.

[0171] 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.

[0172] Embodiment 21. A compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 17, for use in therapy.

[0173] Embodiment 22. The compound according to Embodiment 21, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the treatment is treatment of cancer.

[0174] Embodiment 23. A compound or a pharmaceutically acceptable salt or a pharmaceutical composition according to Embodiment 22, wherein the cancer is ovarian cancer, gastric cancer, or breast cancer. Embodiment 23A. A compound or a pharmaceutically acceptable salt or a pharmaceutical composition according to Embodiment 22, wherein the cancer is lung cancer, cervical cancer, or pancreatic cancer. Embodiment 23B. A compound or a pharmaceutically acceptable salt or a 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.

[0175] Embodiment 24. Use of a compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 17, in the preparation of a medicament for treatment.

[0176] Embodiment 25. The use according to embodiment 24, wherein the treatment is the treatment of cancer.

[0177] 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.

[0178] Embodiment 27. A method of inhibiting PARG in vivo, the method comprising administering to the patient an effective amount of a compound according to any one of Embodiments 1 to 16 or a pharmaceutically 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 being in need of such treatment.

[0179] Embodiment 28. A method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 17. Embodiment 28A. A method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a sample with an effective amount of a compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 17.

[0180] Embodiment 29. A method of treating a cancer that is resistant to 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 any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 17. Embodiment 29A. The method of Embodiment 29, wherein the patient is identified as being in need of such treatment. Embodiment 29B. The method of Embodiment 29, wherein the patient is determined to be resistant to one or more PARP inhibitors. Embodiment 29C. The method of Embodiment 29, wherein the patient is diagnosed as being resistant to one or more PARP inhibitors. Embodiment 29D. The method of any one of Embodiments 29, 29A, 29B, or 29C, wherein the one or more PARP inhibitors are talazoparib, olaparib, veliparib, rucaparib, niraparib, AZD5303, AZD9574, or a pharmaceutically acceptable salt thereof.

[0181] Embodiment 30. The method of any one of Embodiments 29, 29A, 29B, 29C, or 29D, wherein the cancer is ovarian cancer, gastric cancer, or breast cancer. Embodiment 30A. The method of any one of Embodiments 29, 29A, 29B, 29C, or 29D, wherein the cancer is lung cancer, cervical cancer, or pancreatic cancer. Embodiment 30B. The method of any one of Embodiments 29, 29A, 29B, 29C, or 29D, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

[0182] Embodiment 31. A method of treating a cancer that is resistant to one or more platinum drugs in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound according to any one of Embodiments 1 to 16, or a pharmaceutically 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 platinum drugs. Embodiment 31C. The method according to Embodiment 31, wherein the patient is diagnosed as being resistant to one or more platinum drugs. Embodiment 31D. The method according to any one of Embodiments 31, 31A, 31B, or 31C, wherein the one or more platinum drugs comprise cisplatin, carboplatin, sitraplatin, heptaplatin, picoplatin, nedaplatin, trinuclear platinum, liposomal cisplatin, or oxaliplatin, or a pharmaceutically acceptable salt thereof.

[0183] Embodiment 32. The method of Embodiment 31, 31A, 31B, 31C, or 31D, wherein the cancer is ovarian cancer, gastric cancer, or breast cancer. Embodiment 32A. The method of Embodiment 31, 31A, 31B, 31C, or 31D, wherein the cancer is lung cancer, cervical cancer, or pancreatic cancer. Embodiment 32B. The method of any of Embodiments 31, 31A, 31B, 31C, or 31D, wherein the cancer is breast cancer, ovarian cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, or pancreatic cancer.

[0184] Embodiment 33. A method of treating and / or preventing homologous recombination deficient (HRD) cancer, comprising administering to a patient a therapeutically effective amount of a compound according to any one of Embodiments 1 to 16 or a pharmaceutically 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 being in need of such treatment.

[0185] 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.

[0186] Embodiment 35. A method of treating and / or preventing cancer in a patient, wherein the cancer is characterized by reduced or absent expression of BRCA1 and / or BRCA2 genes, a deletion or mutation of BRCA1 and / or BRCA2 genes, or reduced BRCA1 and / or BRCA2 protein function, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of Embodiments 1 to 16, or a pharmaceutically 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 being in need of such treatment.

[0187] 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 36B. The method of Embodiment 35 or 35A, wherein the HRD cancer is lung cancer, cervical cancer, or pancreatic cancer.

[0188] 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 17.

[0189] Embodiment 38. Use of a PARG inhibitor in the preparation of a medicament for treating cancer, wherein the PARG inhibitor is a compound according to any one of Embodiments 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment 17.

[0190] It should be understood that when an embodiment is dependent upon, for example, embodiments 1 to 4, it is dependent upon embodiments 1, 2, 3, 3A, and 4. Thus, when multiple dependencies are listed, all embodiments within the scope of the listing are included (including embodiments ending in "A", "B" or other letters).

[0191] Example

[0192] 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 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 were performed or that they are all experiments that could be performed. It should be understood that the exemplary descriptions written in the present tense need not be performed, but rather the descriptions may be performed to generate data of the properties described therein, etc. Every effort has been made to ensure accuracy of the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations may exist.

[0193] Synthesis Example

[0194] Example 1: Preparation of compound of formula (A)

[0195]

[0196] Step 1: Preparation of 2,6-difluoro-4-iodobenzaldehyde

[0197]

[0198] To a stirred solution of 1,3-difluoro-5-iodobenzene (Compound 1) (50 g, 208.3 mmol, Oakwood Chemical, CAS 2265-91-0, catalog #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 the complete reaction of the starting material, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2×300 mL), the combined organic phases were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give an oily crude product. The crude product was purified by column chromatography using silica gel (100-200) and eluted with a 20% EtOAc / n-hexane gradient. The product was eluted with a 30% EtOAc / n-hexane gradient. The purified fractions were concentrated under reduced pressure to obtain 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).

[0199] Step 2: Preparation of 4-fluoro-6-iodo-1H-indazole

[0200]

[0201] 2,6-difluoro-4-iodobenzaldehyde (Compound 2) (5 g, 18.6 mmol) was added to 1,4-difluorobenzaldehyde at RT. To the stirred solution in 2-nitropropane (110 mL) was added hydrazine hydrate (18.6 mL, 373.1 mmol), and the resulting mixture was stirred at 100 ° C for 24 h. The reaction mixture was concentrated under reduced pressure and ice water (100 mL) was added. The mixture was stirred for 30 min, during which time a solid precipitated. After filtering the mixture. The solid was washed with water (100 mL) and n-pentane (50 mL) and dried in vacuo to obtain the product 4-fluoro-6-iodo-1H-indazole (compound 3) (2.3 g) as a solid. MS ESI C7H4FIN2[M+H] + Calculated value: 262.94., Measured value: 262.99. 1 H NMR (CDCl3, 400MHz): 10.12 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.15 (dd, J = 9Hz, 1H).

[0202] Step 3: Preparation of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4-thiadiazole

[0203]

[0204] 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 reaction progress was monitored by TLC. The reaction mixture was quenched with ice water (50 mL) and stirred for 30 min, during which time solids precipitated. The mixture was filtered. The collected solid was washed with water (100 mL) and then n-pentane (100 mL), and dried in vacuo to give the product 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 H4F3IN4S[M+H] + Calculated value: 396.92., Measured value: 396.91. 1 H NMR (CDCl3, 500MHz): 8.87 (s, 1H), 8.29 (s, 1H), 7.40 (dd, J = 17Hz, 1H), 7.0 (t, J = 53.5Hz, 1H).

[0205] Step 4: Preparation of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)thiobenzoate

[0206]

[0207] To a stirred solution of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazole-1-yl)-1,3,4-thiadiazole (Compound 5) (100 mg, 0.25 mmol) in toluene (1 mL) degassed for 5 min at room temperature, CuI (5 mg, 0.025 mmol), 1,10-phenanthroline (11 mg, 0.05 mmol) and potassium thiobenzoate (67 mg, 0.378 mmol) were added. The resulting mixture was stirred at 100 ° C for 16 h. The reaction progress was monitored by LCMS. The crude mixture was purified by column chromatography with silica gel (100-200) and eluted with a 10% EtOAc / n-hexane gradient. 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)thiobenzoate (Compound 6) (55 mg) as a solid. MS ESIC 17 H9F3N4OS2[M+H] + Calculated value 407.02., measured value 407.01. 1 H NMR (CDCl3, 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).

[0208] Step 5: Preparation of N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-sulfonamide

[0209]

[0210] To a stirred solution of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)thiobenzoate (Compound 6) (500 mg, 1.23 mmol) in acetonitrile (10 mL) was added BnMe3NCl (682 mg, 3.69 mmol) and TCCA (trichloroisocyanuric acid) (370 mg, 1.59 mmol) in acetonitrile (40 mL) at 0°C. The reaction mixture was stirred for 20 min. A solution of 1-methylcyclopropane-1-amine (1.71 g, 7.38 mmol, Combi-Blocks, CAS22936-83-0, catalog # QH-3639) in pyridine (2.5 mL) and cesium carbonate (198 mg, 0.61 mmol) were then added to the reaction mixture at 0°C and stirred at room temperature for 2 h. The reaction progress was monitored by LCMS. LCMS showed that the starting material (S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-yl)thiobenzoate) (Compound 6) was completely consumed. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography with silica gel (100-200) eluting with a 5% to 50% EtOAc / n-hexane gradient. The product was eluted with a 20% EtOAc / n-hexane gradient. 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). MS ESI C 14 H9F3N6O2S2[M+H] + Calculated value 404.04., measured value 404.18. 1 H NMR (CDCl3, 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).

[0211] Step 6: Preparation of tert-butyl (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate

[0212]

[0213] 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 (2 mL) was added tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (85 mg, 0.39 mmol, BLD Pharmatech, CAS 574007-66-2, Catalog # BD233798) and DIPEA (N,N-diisopropylethylamine) (0.1 mL, 0.59 mmol) and the reaction mixture was stirred at 130° C. for 2 h. The reaction mixture was quenched with ice water (20 mL) and stirred for 30 min. The obtained solid was filtered, washed with water (10 mL), dried in vacuo, and purified by column chromatography on silica gel (100-200) with a gradient elution of 50% EtOAc / n-hexane. The purified fractions were concentrated under reduced pressure to give (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (Compound 8) (110 mg, yield: 92%) as a solid. MS ESI C 25 H 33 F2N7O4S2[M+H] + Calculated value 598.20, measured value 598.26.

[0214] 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)

[0215]

[0216] To a stirred solution of tert-butyl (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate (Compound 8) (100 mg, 0.16 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.07 mL, 0.98 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and purified by Prep HPLC (Prep HPLC conditions: mobile phase—10 mM ammonium bicarbonate in H2O: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: soluble; fraction volume: 100 mL) to obtain 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) (18 mg, yield: 21%) as a solid. MS ESIC 20 H 25 F2N7O2S2[M+H] + Calculated value 498.15, measured value 498.34. 1 H NMR (DMSO-d6, 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(brdd,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).

[0217] Example 2: Preparation of compound of formula (B)

[0218]

[0219]

[0220] Step 1: Preparation of tert-butyl (2R,6R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylate

[0221] 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)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (Compound 9) (0.266 g, 1.239 mmol, Pharmablock, CAS 574007-62-8, Product Model: 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): n-hexane; mobile phase (B): EtOAc; column: silica gel (40 g); method: gradient). The purified fraction was concentrated under reduced pressure to obtain tert-butyl (2R,6R)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-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 F2N7O4S2[MH] + Calculated value 596.20, measured value 596.62.

[0222] 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)

[0223] To a stirred solution of (2R,6R)-tert-butyl 4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminosulfonyl)-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 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 light yellow solid. MS ESI C 20 H 25 F2N7O2S2[M+H] + Calculated value 498.15, measured value 498.30. 1 H NMR (400MHz, DMSO-d6): 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).

[0224] Example 3: Preparation of compound of formula (C)

[0225]

[0226] 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))

[0227]

[0228] 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, CAS21655-48-1, Catalog No.: OR-0130) in NMP (120 mL) was stirred at 50 ° C for 18 h under N2 protection. The reaction mixture was cooled to RT (25 ° C) and combined with another batch of reaction mixture using 1.0 g of Compound 7. Water (260 mL) was slowly added to the combined reaction mixture below 25 ° C and stirred for 2 h. The reaction mixture was filtered and the solid was washed with water (26 mL) to obtain 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 F2N7O2S2[M+H] + Calculated value 498.15, measured value 498.04. 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 8.89 (d, J = 0.7Hz, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 7.59 (t, J = 53.2Hz, 1H), 7.12 (d, J = 1.2Hz, 1H), 3.66 (br d,J=10.0Hz,2H),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).

[0229] Biological Examples

[0230] Example 1: PARG enzyme inhibition assay (TR-FRET)

[0231] Enzyme EC 50 test

[0232] In a microtiter plate, PARG enzyme is incubated with compound or solvent (DMSO) and biotinylated PARylated PARP-1 substrate. After adding detection antibody and streptavidin-Europium and continuing incubation, the fluorescence intensity of the plate is read. The low control (DMSO) has a low fluorescence intensity, representing no inhibition of enzyme activity, while the high control (no enzyme) has a high fluorescence intensity, representing complete inhibition of enzyme activity.

[0233] Material:

[0234] Enzymes:

[0235] ·PARG

[0236] οhPARG: 250pM, 1-976, His-tagged, Proteos, 2.0mg / mL (17.9μM)

[0237] οSubstrate: 30nM

[0238] oTest compound / enzyme pre-incubation time: 1 hr

[0239] ο Enzyme / substrate reaction time: 10 min Substrate: hPARP1, His6-TEV labeled, 1.2 mg / mL (10.3 μM)

[0240] Detection Antibody: Anti-His Monoclonal Antibody - ULight, Perkin Elmer Catalog #TRF0134-M

[0241] Streptavidin-Europium: Perkin Elmer Catalog #AD0062

[0242] Assay buffer: 50 mM Tris-HCL pH 7.4, 50 mM KCL, 3 mM EDTA, 0.4 mM EGTA, 1 mM DTT, 0.01% Tween 20, 0.01% BSA

[0243] Temperature: 23℃

[0244] Total reaction volume: 20 μL

[0245] Comparison:

[0246] 0% inhibition: DMSO

[0247] 100% inhibition: no enzyme

[0248] Enzyme reaction and detection:

[0249] 1. Transfer 200 nL of 100X compound or DMSO to the appropriate wells of a 384-well white polystyrene microtiter plate (Corning Catalog #3574).

[0250] 2. Transfer 10 μL of 2× final concentration of enzyme in assay buffer or assay buffer alone to the appropriate wells.

[0251] 3. Centrifuge the plate at 1000 rpm for 30 seconds.

[0252] 4. Incubate the plate at room temperature for 1 hour.

[0253] 5. Add 10 μL of 2× substrate solution in assay buffer to all test wells.

[0254] 6. Incubate at room temperature for 10 minutes.

[0255] 7. Transfer 10 μL of a mixture of 3×42 nM detection antibody and 2.25 nM streptavidin-europium in 50 mM Tris-HCL solution (pH 7.4) to all test wells.

[0256] 8. Incubate the plate at room temperature for 1 hour.

[0257] 9. Read on a plate reader (Envision).

[0258] Excitation wavelength: 317nm

[0259] Emission wavelength: 620nm

[0260] Emission wavelength: 665nm

[0261] Data Analysis:

[0262] Calculating EC in Collaborative Drug Discovery Vault (CDD) 50 The curves were fitted by CDD based on the relationship between response (%) and compound concentration (μM) by a 4-parameter inhibition model using Equation 1.

[0263] Formula 1:

[0264] Fit=(A+((BA) / (1+((C / x)^D))))

[0265] Res = (y-fit)

[0266] Table 1 below provides the TR-FRET EC of formula (A), formula (B), formula (C) and some comparative compounds. 50 value.

[0267] Example 2

[0268] Cell viability assay

[0269] The ability of the compounds disclosed herein to inhibit PARG was determined in two cell lines: RMUGS-NucLight Red and SNU601-NucLight Red. RMUGS-NucLight Red and SNU601-NucLight Red cells were grown using The cell lines were generated by stably transducing parental cells (RMUGS-JCRB Cell Bank, catalog number: IFO50320; SNU601-Korean Cell Line Bank, catalog number: 00601) with NucLight Red lentivirus (Sartorius, catalog number: 4476). The experimental procedures for these two cell lines are described below.

[0270] SNU601-NucLight Red:

[0271] The cells were seeded at 200 cells / well in a 384-well black plate with a transparent flat bottom. The plates were imaged using the S3 Live Cell Analysis System and the number of live cells per well (Day 0) was counted. Test compounds were added using a Tecan digital dispenser to generate a 9-point dose curve with a 3-fold dilution gradient and a maximum concentration of 10 μM. All treatments were performed in triplicate. After 7 days of incubation, the cells were plated using The S3 system images the plate and counts the number of viable cells per well (Day 7). For each well in the plate, the number of viable cells on Day 7 is normalized to the number of cells on Day 0 (Day 7 / Day 0). The average of the DMSO-treated wells in the plate is calculated. All data points are normalized to the DMSO average. The % control for each sample is compared to the DMSO-treated control sample. EC is calculated in Collaborative Drug Discoveryvault (CDD) 50 The curve was fitted by CDD based on the relationship between control % and log [compound concentration] using a four-parameter inhibition model (Levenberg-Marquardt algorithm):

[0272] Fit=(A+((BA) / (1+((C / x)^D))))

[0273] Res = (y-fit)

[0274] When a clear biphasic behavior was observed from the resulting data, the EC of the major response component was calculated in GraphPad Prism software using the following formula: 50 :

[0275] Span=Top-Bottom

[0276] Section1=Span*Frac / (1+10^((LogEC50_1–X)*nH1))

[0277] Section2=Span*(1–Frac) / (1+10^((LogEC50_2–X)*nH2))

[0278] Y=Bottom+Section1+Section2

[0279] Frac = the fraction of more efficient reactions from the top (100) to the bottom (0) of the normalized curve

[0280] EC 50_1 , E.C. 50_2 = EC of response curves 1 and 2 for each part 50

[0281] nH1, nH2 = Normalized Hill slopes of response curves 1 and 2 of each section

[0282] X = log(concentration)

[0283] RMUGS - NucLight Red:

[0284] The cells were seeded at 1000 cells / well in a 96-well black plate with a transparent flat bottom. The plates were imaged using the S3 Live Cell Analysis System and the number of live cells per well (Day 0) was counted. Test compounds were added using a Tecan digital dispenser to generate a 9-point dose curve with a 3-fold dilution gradient and a maximum concentration of 10 μM. All treatments were performed in duplicate. After 7 days of incubation, the cells were plated using The S3 system images the plate and counts the number of viable cells per well (Day 7). For each well in the plate, the number of viable cells on Day 7 is normalized to the number of viable cells on Day 0 (Day 7 / Day 0). The average of the DMSO-treated wells in the plate is calculated. All data points are normalized to the DMSO average. The % control for each sample is compared to the DMSO-treated control sample. EC is calculated in Collaborative Drug Discoveryvault (CDD) 50 The curve was fitted by CDD based on the relationship between control % and log [compound concentration] using a four-parameter inhibition model (Levenberg-Marquardt algorithm):

[0285] Fit=(A+((BA) / (1+((C / x)^D))))

[0286] Res = (y-fit)

[0287] Table 1 below provides the results of Formula (A), Formula (B), Formula (C) and some comparative compounds in SNU601-NucLight Red and RMUGS-NucLight Red.

[0288] Example 3

[0289] Kinetic solubility determination in PBS pH 2.0 and pH 7.4

[0290] Kinetic solubility test

[0291] Material

[0292] Enzymes:

[0293] The control compound diclofenac sodium (batch number BCBW9128) was purchased from Sigma Chemical Co.

[0294] 1.5mL glass flat bottom vial (BioTech Solutions)

[0295] Molded PTFE / SIL plugs (BioTech Solutions)

[0296] PTFE-coated stirring rod (V&P Scientific)

[0297] MultiScreen HTS HV (0.45 μm) 96-well plate (Millipore, MSHVN4510 or MSHVN4550)

[0298] ·Eppendorf Thermomixer Comfort

[0299] Vacuum manifold ORVMN96

[0300] PBS (pH 2.0 and pH 7.4) prepared in the laboratory

[0301] Comparison:

[0302] Diclofenac sodium (lot #BCBW9128), Sigma Chemical Co.

[0303] Kinetic solubility experimental steps:

[0304] 1. Preparation of stock solutions: Prepare stock solutions of the test compound and control compound diclofenac sodium in DMSO at concentrations of 30 mM and 10 mM, respectively.

[0305] 2. Solubility determination steps: 10 μL of the stock solution (30 mM) of the test compound was placed in order in the respective appropriate 96-well plate racks, and 20 μL of DMSO and 970 μL of pH 2.0 or pH 7.4 PBS were added to the vials of each uncapped solubility sample plate; 30 μL of the stock solution (10 mM) of the control compound was placed in order in the respective appropriate 96-well plate racks, and 970 μL of pH 2.0 or pH 7.4 PBS was added to the vials of each uncapped solubility sample plate. The experiment was repeated in two times. A stirring bar was added to each vial and sealed with a molded PTFE / silicone plug. Then, the solubility sample plate was transferred to an Eppendorf Thermomixer Comfort plate shaker and shaken at 1100 RPM at 25°C for 24 hours. After 24 hours, the stopper was removed, the stirring bar was removed using a large magnet, and the sample in the solubility sample plate was transferred to a filter plate. All samples were filtered using a vacuum manifold. Take a 10 μL aliquot from the filtrate and add 990 μL of a mixture of H2O and acetonitrile (1:1 volume ratio). Transfer 200 μL of the dilution to a new 96-well plate for LC-MS / MS analysis. Adjust the dilution factor based on the solubility value and LC-MS signal response.

[0306] 3. Prepare 3μM standard solution (STD): Transfer 15μL or 5μL from the 10mM or 30mM DMSO STD plate to the remaining empty plate, then add 485μL or 495μL DMSO to prepare a 300μM STD. Transfer 5μL from the 300μM DMSO STD plate to the remaining empty plate, add 495μL of a mixture of H2O and acetonitrile (1:1 by volume) to prepare a final concentration of 3μM STD. Transfer 200μL of the dilution to a new 96-well plate for LC-MS / MS analysis. Adjust the standard sample concentration based on the LC-MS signal response.

[0307] 4. Sample analysis step: Place the plate into the well plate autosampler. Evaluate the samples by LC-MS / MS analysis.

[0308] Table 1 below provides the solubility values ​​of Formula (A), Formula (B), Formula (C) and some comparative compounds:

[0309] Table 1

[0310]

[0311]

[0312]

[0313]

[0314] Data Description: Geometric mean (complete data set); *n<3 ("n" is the number of runs) Example 4

[0315] PARG inhibition in PARP inhibitor-resistant and platinum-resistant cell lines Materials and methods

[0316] Generation of cell lines with acquired resistance to PARP inhibitors (PARPi)

[0317] Two cell lines were used to generate PARPi-resistant cell lines: HCC1428 and MDA-MB-436. All cell lines were cultured in the manufacturer's recommended medium at 37°C and 5% CO2. To generate resistant cell lines, niraparib (PARP inhibitor) was added to each cell line at IC50 concentration and gradually increased to IC90 concentration in small increments over 3-4 months until the cell line adapted, developed resistance, and began to proliferate in the presence of high doses of niraparib. These cell lines were used Figure 1 and Figure 2 Research published in.

[0318] Cell proliferation assay

[0319] A panel of cell lines that exhibit intrinsic resistance to PARP inhibitors (as shown in Table 2) were identified, and the effect of formula (A) was determined using a cell proliferation assay in two acquired resistance cell lines (PARPi-resistant cell lines: HCC1428 and MDA-MB-436). In the proliferation assay, cell lines were plated into 96-well plates (Corning #3904) at a density of 1000 cells / well. Compounds dissolved in DMSO were added using a TECAN liquid dispenser to generate a 9-point dose curve with 3-fold dilutions and a starting maximum concentration of 10 μM. After 5 population doublings, cells were treated with 5 μM Vybrant DyeCycle Green (Life Technologies #V35004) and incubated for 60 min. They were then incubated with DMSO and compound-treated wells were imaged on the S3 system to determine the number of nuclei. Counts were normalized to DMSO-treated wells and the IC was determined using the standard four-parameter dose-response equation in GraphPad Prism software. 50 value.

[0320] Patient-derived cells tested in cell viability assays

[0321] Patient-derived cells (PDCs) were derived from ovarian tissue of patients with BRCA1 / 2 mutations and cisplatin resistance. These cells were derived from solid tumor specimens obtained after surgery / resection and cultured in 2-D in selective medium. For each PDC, when the required number of cells for the assay was reached, cells were dissociated using TrypLE and counted. Draq7 dye was added to cells before plating to identify dead cells. Cells were plated into 96-well plates (Greiner #655090) and incubated at 37°C and 5% CO2 for 16-24h. Formula (A) was dispensed using a Tecan HP D300 digital dispenser with a 9-point dose curve and 3-fold serial dilutions, with a starting concentration of 30μM. After 7 days of incubation with compounds, cells were fixed with 2% formaldehyde and stained with Hoechst. Plates were scanned using Nexcelom Celigo high-throughput screening and analyzed for total cell number by Hoechst labeling and cell death using Draq7 fluorescence. For all PDCs, cell nuclei counts were normalized to DMSO-treated wells and the IC was determined using a standard four-parameter dose-response equation in GraphPad Prism software. 50 .like Figure 3 The cells generated were used in the present study.

[0322] result:

[0323] PARPi intrinsically and acquired resistant cell lines are sensitive to formula A

[0324] The antiproliferative effect of PARG inhibition on a panel of cancer cell lines with intrinsic resistance to PARP inhibitors was tested using Formula A. A variety of cell lines carrying BRCA1 / 2 loss-of-function mutations and resistant to niraparib showed sensitivity to Formula A (Table 2). In addition, two breast cancer cell lines with acquired PARPi resistance, MDA-MB-436 and HCC1428, were also tested in the proliferation assay. In MDA-MB-436, Formula A was 9 times more potent in the niraparib-resistant cell line (11.8 nM) than in the parental cell line (103 nM) ( Figure 1 ). The HCC1428 PARPi-resistant cell line maintained sensitivity to Formula A, IC 50 8nM( Figure 2 Formula A was also tested in an ovarian patient-derived cell (PDC) model with BRCA1 mutation and cisplatin resistance. Formula A had an antiproliferative effect on this cell line, with IC 50 The value is 260nM ( Figure 3 ).

[0325] Table 2

[0326]

[0327]

[0328] Example 5

[0329] Patient-Derived Xenograft (PDX) Research

[0330] Female AthymicNude-Foxn1 mice with HBCx-34 tumors growing to a volume of 108 to 288 mm3 were randomly assigned to the groups listed in Table 3. nu Mice were randomly divided into two treatment groups, 8 in each group, and tumor-bearing mice received drinking water containing diluted estrogen (β-estradiol, 8.5 mg / L) from the date 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.

[0331] Table 3: HBCx-34 tumor model study groups

[0332] Group deal with Dosage regimen Dose volume (mL / kg) 1 Carrier po, QD×45 10 2 Formula A 100 mg / kg, po, QD × 45 10

[0333] During the experiment, tumors were measured and mice were weighed twice a week. The following formula was used to estimate tumor volume (mm3): tumor volume (TV) = a×b2 / 2, where "a" and "b" are the long and short diameters of the tumor, respectively. Tumor growth inhibition (TGI, an indicator of antitumor activity) was calculated using the following formula by TV: TGI%: (1-{T / T0 / Ct / C0} / 1-{C0 / Ct})×100, where Tt = median volume of tumors in the treatment group at time t; T0 = median volume of tumors in the treatment group at time 0; Ct = median volume of tumors in the control group at time t and C0 = median volume of tumors in the control group at time 0. Formula A administered at 100 mg / kg produced a strong and statistically significant antitumor response, with partial tumor regression achieved in all mice. A summary of the results is shown in Table 4 ( Figure 4 ). Tumor regression refers to the tumor volume being less than the initial volume at D0.

[0334] Table 4: Tumor growth inhibition compared to vehicle group at day 45

[0335]

[0336] References

[0337] [1]Ame,J.C.,E.Fouquerel,L.R.Gauthier,D.Biard,F.D.Boussin,F.Dantzer,G.de Murcia and V.Schreiber(2009)."Radiation-induced mitotic catastrophe inPARG-deficient cells."J Cell Sci 122(Pt 12):1990-2002.

[0338] [2]Barber,L.J.,S.Sandhu,L.Chen,J.Campbell,I.Kozarewa,K.Fenwick,I.Assiotis,D.N.Rodrigues,J.S.Reis Filho,V.Moreno,J.Mateo,L.R.Molife,J.DeBono,S.Kaye,C.J.Lord and A.Ashworth(2013)."Secondary mutations in BRCA2associated with clinical resistance to a PARP inhibitor."J Pathol 229(3):422-429.

[0339] [3]Blenn,C.,P.Wyrsch and F.R.Althaus(2011)."The ups and downs oftannins as inhibitors of poly(ADP-ribose)glycohydrolase."Molecules 16(2):1854-1877.

[0340] [4]Caiafa,P.,T.Guastafierro and M.Zampieri(2009)."Epigenetics:poly(ADP-ribosyl)ation of PARP-1regulates genomic methylation patterns."FASEB J23(3):672-678.

[0341] [5]Curtin,N.J.and C.Szabo(2013)."Therapeutic applications of PARPinhibitors:anticancer therapy and beyond."Mol Aspects Med 34(6):1217-1256.

[0342] [6]Dahl,M.,V.Maturi,P.Lonn,P.Papoutsoglou,A.Zieba,M.Vanlandewijck,L.P.van der Heide,Y.Watanabe,O.Soderberg,M.O.Hottiger,C.H.Heldin andA.Moustakas(2014)."Fine-tuning of Smad protein function by poly(ADP-ribose)polymerases and poly(ADP-ribose)glycohydrolase during transforming growthfactor beta signaling."PLoS One 9(8):e103651.

[0343] [7]Drost,R.and J.Jonkers(2014)."Opportunities and hurdles in thetreatment of BRCA1-related breast cancer."Oncogene 33(29):3753-3763.

[0344] [8]Erdelyi,K.,P.Bai,I.Kovacs,E.Szabo,G.Mocsar,A.Kakuk,C.Szabo,P.Gergely and L.Virag(2009)."Dual role of poly(ADP-ribose)glycohydrolase inthe regulation of cell death in oxidatively stressed A549 cells."FASEB J 23(10):3553-3563.

[0345] [9]Fathers,C.,R.M.Drayton,S.Solovieva and H.E.Bryant(2012)."Inhibition of poly(ADP-ribose)glycohydrolase(PARG)specifically kills BRCA2-deficient tumor cells."Cell Cycle 11(5):990-997.

[0346]

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

[0347]

[11] Frizzell,K.M.,M.J.Gamble,J.G.Berrocal,T.Zhang,R.Krishnakumar,Y.Cen,A.A.Sauve and W.L.Kraus(2009)."Global analysis of transcriptionalregulation by poly(ADP-ribose)polymerase-1 and poly(ADP-ribose)glycohydrolasein MCF-7 human breast cancer cells."J Biol Chem 284(49):33926-33938.

[0348]

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

[0349]

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

[0350]

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

[0351]

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

[0352]

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

[0353]

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

[0354]

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

[19] Shirai,H.,H.Fujimori,A.Gunji,D.Maeda,T.Hirai,A.R.Poetsch,H.Harada,T.Yoshida,K.Sasai,R.Okayasu andM.Masutani(2013)."Parg deficiency confers radio-sensitization throughenhanced cell death in mouse ES cells exposed to various forms of ionizingradiation."Biochem Biophys Res Commun 435(1):100-106.

[0355]

[20] Shirai,H.,A.R.Poetsch,A.Gunji,D.Maeda,H.Fujimori,H.Fujihara,T.Yoshida,H.Ogino and M.Masutani(2013)."PARG dysfunction enhances DNA doublestrand break formation in S-phase after alkylation DNA damage and augmentsdifferent cell death pathways."Cell Death Dis 4:e656.

[0356]

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

[0357]

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

[0358]

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

[0359]

[24] Milbury CA,Creeden J,Yip WK,Smith DL,Pattani V,Maxwell K,SawchynB,Gjoerup O,Meng W,Skoletsky J,Concepcion AD,Tang Y,Bai X,Dewal N,Ma P,BaileyST,Thornton J,Pavlick DC,Frampton GN,Lieber D,White J,Burns C,Vietz C(2022) “Clinical and analytical validation of CDx, a comprehensivegenomic profiling assay for solid tumors." PLOS ONE 17(3):e0264138. https: / / doi.org / 10.1371 / journal.pone.0264138

[0360] Although the above invention has been described in some detail by way of illustration and example for a clear understanding, those skilled in the art will recognize that certain changes and modifications may be made within the scope of the appended claims. In addition, each reference provided herein is incorporated herein by reference in its entirety, and its effect is equivalent to incorporating each reference by reference into this document individually. If there is a conflict between the present application and the reference provided herein, the present application shall prevail.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, which is represented by formula (A): or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, which is in free base form.

4. The compound according to claim 2, which is in free base form.

5. A compound according to any one of claims 2 or 4 which is at least 90% free from other isomers.

6. A compound according to any one of claims 2 or 4 which is at least 95% free from other isomers.

7. The compound according to any one of claims 2 or 4, which is at least 99% free from other isomers.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. A method of treating a disease or condition involving PARG activity in a patient, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8.

10. The method of claim 9, wherein the patient is identified as being in need of such treatment.

11. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8.

12. The method of claim 11, wherein the cancer is ovarian cancer, gastric cancer, or breast cancer.

13. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for use in therapy.

14. The compound or pharmaceutically acceptable salt or pharmaceutical composition according to claim 13, wherein the treatment is the treatment of cancer.

15. The compound or pharmaceutically acceptable salt or pharmaceutical composition according to claim 14, wherein the cancer is ovarian cancer, gastric cancer or breast cancer.

16. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, in the preparation of a medicament for treatment.

17. Use according to claim 16, wherein the treatment is the treatment of cancer.

18. The use according to claim 17, wherein the cancer is ovarian cancer, gastric cancer or breast cancer.

19. A method of inhibiting PARG in vivo in a patient, the method comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8.

20. A method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8.

21. A method of treating cancer resistant to one or more platinum drugs 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 according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8.

22. 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 claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8.

23. The method of claim 22, wherein the patient is identified as being in need of such treatment.

24. 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, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8.

25. The method of claim 24, wherein the patient is identified as being in need of such treatment. 26 . A PARG inhibitor for use in cancer treatment, wherein the PARG inhibitor is a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 .

27. Use of a PARG inhibitor in the preparation of a medicament for treating cancer, wherein the PARG inhibitor is a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8.

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