Combination therapy comprising PARG inhibitor and topoisomerase inhibitor for treatment of cancer

Abstract

Provided herein are combinations of a PARG inhibitor and a topoisomerase inhibitor. Also provided herein are methods of treating a disease or condition (e.g., cancer) using such combinations.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 457,312, filed April 5, 2023; No. 63 / 584,013, filed September 20, 2023; and No. 63 / 548,513, filed November 14, 2023, each of which is incorporated herein by reference in its entirety and for all purposes. Background Technology

[0002] Cancer is caused by uncontrolled and regulated cell proliferation. This often rapid proliferation results in high levels of oxidative stress within tumors, which damages DNA and leads to a significant increase in mutation rates. Therefore, tumor cells are involved in and heavily dependent on DNA damage repair mechanisms.

[0003] Single-strand breaks (SSBs) are the most common type of lesion produced in cells. PARG (poly-ADP-ribose hydrolase) and PARP (poly-ADP-ribose polymerase), along with many other proteins, are involved in single-strand break repair (SSBR) and other repair mechanisms known as base excision repair (BER).

[0004] One of the earliest events during single-stranded DNA repair is the breakage of PARP (poly-ADP-ribose polymerase) binding and the rapid synthesis of poly-ADP-ribose (PAR) from PARP itself. This molecular structure acts as a signal to recruit other DNA repair proteins to promote repair. The signals initiated by these PAR chains are transient because they are rapidly degraded by the enzyme PARG. When PARP binds to PAR, its catalytic activity decreases, and therefore PARG activity helps to restore PARP to its catalytically active form.

[0005] PARG originates from a single gene of the same type found in the nucleus, mitochondria, and cytosol. Another known protein with glycolytic activity is ARH3, located in the mitochondria. Although known primarily for its direct role in DNA repair, PARG influences PAR signaling in both transcriptional and epigenetic pathways.

[0006] When other mechanisms of DNA repair fail, cancer cells may become dependent on specific DNA repair pathways. Tumors carrying mutations in proteins involved in double-strand break repair are often more sensitive to PARP inhibitors of the SSBR. There is some evidence that PARG depletion inhibits SSBR and reduces the survival of BRCA2-deficient cells. However, other tumor mutations may cause defects in double-strand DNA repair mechanisms (known as "BRCA-ization"), thus making tumor cells sensitive to PARG inhibition.

[0007] Topoisomerases are abundant enzymes essential for altering DNA topology during DNA replication and transcription, and are primarily classified into two classes: type I and type II. Topoisomerase inhibitors, as anticancer agents, specifically target these topoisomerases. For example, topoisomerase II inhibitors include anthracyclines such as doxorubicin. Topoisomerase inhibitors induce cell death by inhibiting topoisomerase activity; topoisomerases are typically expressed in higher amounts in cancer cells compared to normal cells. Topoisomerase inhibitors can also covalently capture topoisomerases on DNA, causing lethal DNA strand breaks and leading to cell death.

[0008] Despite recent advances in cancer treatment, there remains a need for more effective and / or enhanced care for patients affected by cancer. This disclosure addresses this need and offers relevant advantages. Summary of the Invention

[0009] This article provides a combination comprising a poly-ADP-ribose hydrolase (PARG) inhibitor and a topoisomerase inhibitor. This combination is intended for the treatment of various cancers, including solid tumors. In one embodiment, the disease or condition is an advanced or metastatic solid tumor. This combination is also intended for the treatment of any number of PARG-related diseases. This combination is also intended for the treatment of various diseases or conditions involving PARG activity. This combination is intended for the treatment of homologous recombination-deficient (HRD) cancers. This combination is also intended for the treatment of various diseases or conditions treatable by inhibiting topoisomerases.

[0010] This article provides a combination product comprising a PARG inhibitor and a topoisomerase inhibitor. This combination product is intended for the treatment of various cancers, including solid tumors. In one embodiment, the disease or condition is an advanced or metastatic solid tumor. This combination product is also intended for the treatment of any number of PARG-related diseases. This combination product is also intended for the treatment of various diseases or conditions involving PARG activity. This combination product is intended for the treatment of homologous recombination-deficient (HRD) cancers. This combination product is also intended for the treatment of various diseases or conditions treatable by inhibiting topoisomerases.

[0011] In one implementation, this document provides a combination of PARG inhibitors and topoisomerase inhibitors.

[0012] In one embodiment, this document provides a pharmaceutical composition comprising a therapeutically effective amount of a PARG inhibitor, and a second pharmaceutical composition comprising a therapeutically effective amount of a topoisomerase inhibitor.

[0013] In one embodiment, this document provides a method for treating / preventing cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0014] In one embodiment, this document provides a method for treating and / or preventing cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor and a carrier that is at least pharmaceutically acceptable, thereby treating the cancer in the subject.

[0015] One implementation is a method for treating and / or preventing homologous recombination-deficient (HRD) cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0016] One implementation is a method for treating and / or preventing homologous recombination-deficient (HRD) cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor and a carrier that is at least pharmaceutically acceptable, thereby treating the cancer in the subject.

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

[0018] In one embodiment, this document provides a method for treating / preventing cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition containing a PARG inhibitor and a therapeutically effective amount of a pharmaceutical composition containing a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0019] In one embodiment, this document provides a method for treating and / or preventing a disease or condition involving PARG activity in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the disease or condition in the subject. In one embodiment, the disease or condition is cancer.

[0020] In one embodiment, this document provides a method for treating and / or preventing a disease or condition involving PARG activity in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, and at least a pharmaceutically acceptable carrier, thereby treating the disease or condition in the subject. In one embodiment, the topoisomerase inhibitor is doxorubicin, or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or condition is cancer. In one embodiment, the cancer is homologous recombination-deficient (HRD) cancer.

[0021] In one implementation, the PAGR inhibitor is a compound of formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein the variables of Formula I are defined below.

[0022] In another embodiment, the PAGR inhibitor is compound A, which has the following structural formula: Compound A Or its pharmaceutically acceptable salt. A method for preparing compound A is provided in Example 1 of this application.

[0023] Certain PAGR inhibitors used in the combination therapies described herein are described in WO2021 / 055744 (PCT / US20 / 51486), and the general and specific compounds described in this application can be used to treat cancers as described herein.

[0024] In another embodiment, the topoisomerase inhibitor is an inhibitor of type II topoisomerase (also referred to herein as "topoisomerase II inhibitor").

[0025] In yet another embodiment, the topoisomerase II inhibitor is doxorubicin, etoposide, epirubicin, neomycin, ciprofloxacin, or teniposide, or a pharmaceutically acceptable salt thereof. In one embodiment, the topoisomerase II inhibitor is doxorubicin or a pharmaceutically acceptable salt thereof.

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

[0027] In one implementation, the topoisomerase I inhibitor is topotecan or a pharmaceutically acceptable salt thereof. Attached Figure Description

[0028] Figure 1This study demonstrates the effectiveness of evaluating the combined effect of compound A and doxorubicin (compound B) in HCC1428, a xenograft model derived from HR-deficient breast cancer cell lines.

[0029] Figure 2 This study demonstrates the effectiveness of evaluating the combination of compound A and topotecan (compound H) in the small cell lung cancer cell line NCI-H69.

[0030] Figure 3 This study demonstrates the effectiveness of evaluating the combined effect of compound A and topotecan (compound H) in the high-grade serous ovarian cancer cell line Kuramochi.

[0031] Figure 4 This study demonstrates the effectiveness of evaluating the combination effect between compound A and topotecan (compound H) in the breast cancer model HCC1395.

[0032] Figure 5 This study demonstrates the effectiveness of the combination of compound A and compound J (fam-trastuzumab-drutecan-nxki) in the human lung cancer cell line NCI-H650. Detailed Implementation

[0033] This article provides a combination therapy comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. The combination therapy is used to treat a variety of cancers, including, for example, ovarian cancer, gastric cancer, lung cancer, cervical cancer, pancreatic cancer, or prostate cancer. In another aspect, the combination therapy is used to treat any number of PARG-related diseases.

[0034] The combination of PARG inhibitors and topoisomerase inhibitors can provide beneficial therapeutic effects in subjects treating cancer (e.g., solid tumors). Such approaches (combination or co-administration of the two types of agents) can provide uninterrupted treatment to subjects in need during clinically relevant therapy.

[0035] definition The following lists the definitions of various terms used herein. Unless otherwise limited in a particular case, whether used alone or as part of a larger group, these definitions apply to the terms used throughout this specification and claims.

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

[0037] As used herein, the articles “a” and “an” refer to one or more grammatical objects of the article (i.e., at least one). For example, “an element” means one or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” does not constitute a limitation.

[0038] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to measurable values ​​(such as quantity, duration, etc.), the term “about” is intended to cover variations of ±20% or ±10% from a specified value, including ±5%, ±1%, and ±0.1%, as these variations apply to the performance of the disclosed methods.

[0039] As used in the specification and claims, the term "comprising" may include embodiments "consisting of" and "consisting essentially of". As used herein, the terms "comprise(s)", "include(s)", "having", "has", "may", "contain(s)", and variations thereof are intended to be open-ended transitional phrases, terms, or words that require the presence of a specified ingredient / step and allow for the presence of other ingredients / steps.

[0040] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed in range form herein. It should be understood that this range form is used for convenience and brevity, and therefore should be interpreted flexibly, including not only the values ​​explicitly stated as range limits, but also all individual values ​​or subranges covered within that range, as if each value and subrange were explicitly stated. Furthermore, the phrase “about 'x' to 'y'” includes “about 'x' to about 'y'”.

[0041] As used herein, the terms “combination,” “treatment combination,” “drug combination,” or “combination product” refer to a fixed combination in the form of a single dose unit, or a non-fixed combination in a single dosage form, or a kit for combined administration in which two or more therapeutic agents can be administered independently, simultaneously, or at time intervals.

[0042] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the condition or symptom described in this disclosure. Such administration encompasses the combined administration of these therapeutic agents in a substantially simultaneous manner, such as as a single formulation having a fixed proportion of active ingredients or as a separate formulation of each active ingredient (e.g., capsules and / or intravenous formulations). Furthermore, such administration also encompasses the use of each type of therapeutic agent sequentially or separately, at approximately the same time or at different times. Regardless of whether the active ingredient is administered as a single formulation or in a separate formulation, the medication is administered to the same patient as part of the same course of treatment. In any case, the treatment regimen will provide a beneficial effect in treating the condition or symptom described herein.

[0043] As used herein, the terms “treating” or “treatment” refer to suppressing a disease, such as suppressing a disease, condition, or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or symptom (i.e., preventing further development of the pathology and / or symptoms) or improving a disease; such as improving a disease, condition, or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of a disease, condition, or symptom (i.e., reversing the pathology and / or symptoms), such as reducing the severity of the disease.

[0044] As used herein, the terms “patient,” “individual,” or “subject” refer to a person.

[0045] As used herein, the terms "effective amount," "drug-effective amount," and "therapeutic-effective amount" refer to a non-toxic but sufficient amount of a drug to provide the desired biological outcome. This outcome may be a reduction or relief of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In any individual case, a person skilled in the art can determine the appropriate therapeutic amount using routine laboratory methods.

[0046] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic, meaning that the material can be administered to an individual without causing undesirable biological effects or interacting with any component contained in the composition in a harmful manner.

[0047] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; bases or organic salts of acidic residues such as carboxylic acids; etc. Pharmaceutically acceptable salts as described herein include conventionally nontoxic salts of parent compounds, for example, salts formed from nontoxic inorganic or organic acids. The pharmaceutically acceptable salts discussed herein can be synthesized from parent compounds containing basic or acidic moieties using conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The phrase "pharmaceutically acceptable salt" is not limited to single salts or 1:1 salts. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

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

[0049] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspension, diluent, excipient, thickener, solvent, or encapsulating material, relating to carrying or transporting a compound useful to a patient so that it can perform its intended function. Typically, such a structure carries or transports a compound from one organ or part of the body to another. Each carrier must be "acceptable," meaning it is compatible with other components of the formulation, including the compounds disclosed herein, and is harmless to the patient. Examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical preparations.

[0050] As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delay agents that are compatible with the activity of the compounds disclosed herein and are physiologically acceptable to patients. Additional active compounds may also be incorporated into the composition. Other additional ingredients that may be included in pharmaceutical compositions are well known in the art and are described, for example, in Remington's Pharmaceutical Sciences (edited. Genaro, Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0051] As used herein, the term "single formulation" refers to a single carrier or delivery unit formulated to deliver a therapeutically effective amount of two therapeutic agents to a patient. This single delivery unit is designed to deliver a therapeutically effective amount of each agent, along with any pharmaceutically acceptable carrier or excipient. In some embodiments, the delivery unit is a tablet, capsule, pill, or patch. In other embodiments, the delivery unit is a solution or suspension.

[0052] As used herein, “poly-ADP-ribose hydrolase inhibitor” or “PAGRG inhibitor” refers to a drug that modulates PARG activity.

[0053] As used herein, "topoisomerase inhibitor" refers to an agent that inhibits the activity of topoisomerases. Examples of topoisomerase inhibitors include, but are not limited to, doxorubicin, etoposide, epirubicin, neomycin, ciprofloxacin, and teniposide, and their pharmaceutically acceptable salts.

[0054] In one embodiment, this document provides a combination therapy comprising a therapeutically effective amount of a PARG inhibitor and a topoisomerase inhibitor. The “therapeuticly effective amount” of the combination of agents (i.e., a PARG inhibitor and a topoisomerase inhibitor) is an amount sufficient to provide an observable improvement over baseline clinically observable signs and symptoms of the condition treated with the combination. Observable improvements include those that can be visually determined by clinicians and biological tests, tissue biopsies, and assays.

[0055] Unless otherwise stated, the term "alkyl" (either on its own or as part of another substituent) means having a specified number of carbon atoms (i.e., C40, C50, C6 ... 1-8 Alkyl groups refer to saturated straight-chain or branched hydrocarbon groups (one to eight carbon atoms). Alkyl groups can include any number of carbons, such as C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-2 C 1-3 C 1-4 C 1-5 C 1-6 C 1-7 C 1-8 C 1-9 C 1-10 C 2-3 C 2-4 C 2-5 C 2-6 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 and C 5-6 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0056] The term "amelorate" or "amelioration" includes temporarily and permanently stopping, preventing, reducing, or improving one or more symptoms, signs, and characteristics of a disease being treated.

[0057] The term "cycloalkyl" refers to a saturated hydrocarbon ring having a specified number of ring atoms (e.g., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl groups. Unless otherwise stated, cycloalkyl groups may optionally be substituted by one, two, or three independent substituents selected from the following: C 1-6 Alkyl, halogen, hydroxyl, C 1-6 Haloalkyl, C 1-6Halogenated alkoxy or cyano groups. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl groups.

[0058] Unless otherwise stated, the term "halo" or "halogen" (either on its own or as part of another substituent) refers to a fluorine, chlorine, bromine, or iodine atom.

[0059] The term "haloalkyl" refers to an alkyl group as defined above, which is substituted with one to five halogen atoms, and includes both monohaloalkyl and polyhaloalkyl groups. For example, the term "C..." 1-4 "Haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0060] The terms “alkoxy” and “haloalkoxy” refer to alkyl and haloalkyl as defined herein, respectively, which are attached to the rest of the molecule by an oxygen atom.

[0061] The term "heteroaryl" refers to a 5- to 10-membered aromatic ring containing one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule via heteroatoms. Non-limiting examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purine, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazolyl, isobenzofuranyl, isoindolyl, indolazinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothiopheneyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, inzolyl, pteridinyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrroleyl, thiazolyl, furanyl, thiopheneyl, etc.

[0062] The term "heterocyclic alkyl" or "heterocyclic group" refers to a saturated or partially unsaturated 4- to 10-membered monocyclic or bicyclic ring having one to four independent heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized, and one or two ring carbon atoms of the heterocycle may be replaced by a -C=(O) group. Non-limiting examples of heterocyclic alkyl groups include pyrrolidine, imidazoline, pyrazolidine, butyrolactam, valeron, imidazolinone, hydantoin, dioxolane, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrrolidine, thiaran, pyranone, tetrahydrofuran, tetrahydrothiophene, etc. Heterocyclic alkyl groups can be attached to the rest of the molecule via ring carbon atoms or heteroatoms. Non-limiting examples of heterocyclic alkyl groups include pyridin-2(H)-one.

[0063] The term "hydroxyalkyl" refers to an alkyl group as defined above, which is substituted with one or two hydroxyl groups. For example, the term "hydroxyC" 1-4 "Alkyl" includes hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl, 1,2-dihydroxyethyl, hydroxypropyl, etc.

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

[0065] As used herein, “homological recombination-deficient (HRD) cancer” refers to cancer characterized by a reduction or absence of functional HR repair pathways. HR deficiency may be caused by the deletion of one or more HR-related genes or by the presence of one or more mutations in one or more HR-related genes. Examples of HR-related genes include BRCA1, BRCA2, RAD54, RAD51B, ATM, BARD1, CHK1, CHK2, CDK12, RAD51B, RAD54L, RAD51D, PPP22A, BRIP1, Ct1P (CtBP interacting protein), PALB2 (BRCA2 chaperone and locator), XRCC2 (X-ray repair supplementation defect repair in Chinese hamster cells 2), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, one or more HR-related genes), Nbs 1 (Nibrin) and genes encoding the protein of fauni anemia (FA) or FA-like genes, such as FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.

[0066] The antibodies described in the antibody-drug conjugates of this disclosure refer to immunoglobulins, and are molecules containing antigen-binding sites that specifically bind to an antigen. The antibody class of this disclosure can be any of IgG, IgE, IgM, IgD, IgA, and IgY, with IgG being preferred. The antibody subclass of this disclosure can be any of IgG1, IgG2, IgG3, IgG4, IgG1, and IgA2, with IgG1 or IgG2 being preferred. Antibodies can be derived from any species, and preferred examples of species include humans, rats, mice, and rabbits. When antibodies are derived from species other than humans, chimerism or humanization using well-known techniques is preferred. The antibodies of this disclosure can be polyclonal or monoclonal antibodies. In one embodiment, the antibody is a monoclonal antibody. The antibodies of this disclosure are capable of targeting tumor cells. Because the antibodies of this disclosure are conjugated to antitumor compounds with antitumor activity via linkers, the antibodies preferably have one or more of the following properties: recognizing tumor cells, binding to tumor cells, internalizing within tumor cells, and damaging tumor cells. In one embodiment, the antibody is a monoclonal antibody that reacts with a target antigen or an epitope of an antigen expressed on cancer or malignant cells. Techniques for preparing monoclonal antibodies against target antigens are known in the art. Non-restricted target antigens include B7-H3, B7-H4, Trop-2, PSMA, folate receptor, EGF receptor (ErbB1), ErbB2, ErbB3, HER-2, tissue factor, CD-19, VEGF, insulin-like growth factor (ILGF), MUC1, and TA-MUC1.

[0067] Combination products This document provides a combination product comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof, and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. This combination product is intended for the treatment of various cancers, including solid tumors. In one embodiment, the disease or condition is an advanced or metastatic solid tumor. In another aspect, the combination product is intended for the treatment of any number of PARG-related diseases. In yet another aspect, the combination product is intended for the treatment of various diseases or conditions involving PARG activity. In yet another aspect, the combination product is intended for the treatment of homologous recombination-deficient (HRD) cancers.

[0068] In one embodiment, this document provides a combination of a PARG inhibitor and a topoisomerase inhibitor.

[0069] As used herein, the term "combination product" includes embodiments in which a PARG inhibitor and a topoisomerase inhibitor are formulated together as a single pharmaceutical composition (e.g., tablets or capsules), and alternative embodiments in which each therapeutic agent in the combination is formulated separately as its own pharmaceutical composition and each pharmaceutical composition is administered in the same medical context (e.g., the same medical context for cancer). In this embodiment, each pharmaceutical composition may have the same or different carriers, diluents, or excipients. The carrier, diluent, or excipient must be acceptable because it is compatible with the other components of the formulation, capable of being formulated into a pharmaceutical preparation, and harmless to its receptors.

[0070] In one embodiment, the combination product comprises first and second pharmaceutical compositions, wherein the first pharmaceutical composition comprises a topoisomerase inhibitor (suitably selected from compounds B, C, D, E, F, G, or H, or a pharmaceutically acceptable salt thereof), the second pharmaceutical composition comprises compound A (or a pharmaceutically acceptable salt thereof), and both the first and second pharmaceutical compositions are administered to treat cancer. The first and second pharmaceutical compositions may be administered simultaneously, individually, or sequentially, and in any order. Furthermore, it is not important whether the compounds are administered in the same dosage form; for example, one compound may be administered by injection, and another compound may be administered orally.

[0071] PARG inhibitors This disclosure provides PARG inhibitors. In one embodiment, the PAGR inhibitor is a compound of formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is a 5-membered heteroaryl group; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Alkyl, C 1-3 Halogenated alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R)d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Independently selected from hydrogen and C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0072] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, wherein R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazole-yl; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0073] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein X 2 It is CH. In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein X 2 It's CF.

[0074] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R 1 It is a cyano group.

[0075] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R 1 It is a methyl group.

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

[0077] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein Ar is 1,3,4-thiadiazol-2-yl.

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

[0079] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R 2 A carbon atom attached to Ar is located at a metaposition with the nitrogen atom of the rest of the molecule.

[0080] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R 2 Attached to Ar, it is represented by the following: , or .

[0081] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R 2 It is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano. In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R 2 It is difluoromethyl.

[0082] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein ring B is morpholino, 1,1-dioxothiomorpholino, pyrrolyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazine. In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein ring B is piperazine.

[0083] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein Ra It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Independently selected from hydrogen and C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0084] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R a It is hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; and R b and R c Independently selected from hydrogen and C 1-6 alkyl.

[0085] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -C(O)R d (where R) d It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkoxy groups.

[0086] In some embodiments, the compound or its pharmaceutically acceptable salt is a compound of formula (I), wherein R a It is hydrogen; R b and R c Each is independently either hydrogen or C. 1-6 alkyl.

[0087] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is compound A1: Compound A1 Or its pharmaceutically acceptable salt.

[0088] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is compound A1: Compound A1.

[0089] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is compound A: Compound A Or its pharmaceutically acceptable salt.

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

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

[0092] This disclosure also provides antibody-drug conjugates (ADCs) comprising an antitumor compound conjugated to an antibody via a linker. In some embodiments, the antibody is a bispecific antibody. In one embodiment, the antitumor compound is a PARG inhibitor. In one embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is a compound of formula I. In one embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is compound A. In one embodiment, the antitumor compound is a PARG inhibitor, wherein the PARG inhibitor is compound A1.

[0093] It should be noted that mentioning PARG inhibitors also includes mentioning their pharmaceutically acceptable salts. In other words, "PARG inhibitor" is synonymous with "PARG inhibitor or its pharmaceutically acceptable salt."

[0094] topoisomerase inhibitors This disclosure provides topoisomerase inhibitors for use with PARG inhibitors. Various agents with topoisomerase inhibitory activity and methods for their preparation are known in the art. Each of these is covered in this disclosure. In one embodiment, the topoisomerase inhibitor is an inhibitor of type I topoisomerase (also referred to herein as a topoisomerase I inhibitor). In one embodiment, the topoisomerase inhibitor is a type II topoisomerase inhibitor (also referred to herein as a topoisomerase II inhibitor). In one embodiment, the type II topoisomerase inhibitor is selected from: compounds in Table 1 or their pharmaceutically acceptable salts or hydrates.

[0095] Table 1

[0096] In some cases, type II topoisomerase inhibitors are selected from the compounds listed in Table 1. Methods for preparing and using the compounds in Table 1 are known in the art.

[0097] In one embodiment, the type II topoisomerase inhibitor is selected from: doxorubicin, etoposide, epirubicin, neomycin, ciprofloxacin, and teniposide, or pharmaceutically acceptable salts thereof. In one embodiment, the type II topoisomerase inhibitor is doxorubicin or a pharmaceutically acceptable salt thereof.

[0098] In one embodiment, the type I topoisomerase inhibitor is topotecan (compound H) having the following formula: Or its pharmaceutically acceptable salt. Methods for preparing topotecan are known in the art.

[0099] In yet another embodiment, the type I topoisomerase inhibitor is selected from: 10-hydroxycamptothecin, irinotecan and topotecan, hexylresorcinol, eczetidine, delutec, belotecidine, or pharmaceutically acceptable salts thereof.

[0100] It should be noted that mentioning topoisomerase inhibitors also includes mentioning their pharmaceutically acceptable salts. In other words, "topoisomerase inhibitor" is synonymous with "topoisomerase inhibitor or its pharmaceutically acceptable salt."

[0101] References to type II topoisomerase inhibitors in Table 1 are intended to include all forms, such as salts, including pharmaceutically acceptable salts, polymorphs, and solvates. References to type I topoisomerase inhibitors are intended to include all forms, such as salts, including pharmaceutically acceptable salts, polymorphs, and solvates.

[0102] This disclosure also provides antibody-drug conjugates (ADCs) comprising at least two antitumor compounds conjugated to an antibody via a linker. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase inhibitors. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase inhibitors, wherein the PARG inhibitor is a compound of formula I. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase inhibitors, wherein the PARG inhibitor is compound A. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase I inhibitors. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase I inhibitors, wherein the PARG inhibitor is a compound of formula I. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase I inhibitors, wherein the PARG inhibitor is compound A. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase II inhibitors. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase II inhibitors, wherein the PARG inhibitor is a compound of formula I. In one embodiment, the antitumor compound is selected from PARG inhibitors and topoisomerase II inhibitors, wherein the PARG inhibitor is compound A.

[0103] This disclosure also provides antibody-drug conjugates (ADCs) comprising a topoisomerase inhibitor for use with a PARG inhibitor. Various ADCs comprising topoisomerase inhibitors and methods for their preparation are known in the art. Each of these is covered in this disclosure. In one embodiment, the ADC comprising a topoisomerase inhibitor is a type I topoisomerase inhibitor. In yet another embodiment, the ADC comprising a topoisomerase inhibitor is fam-trastuzumab-drutecan-nxki (compound J). In yet another embodiment, the ADC comprising a topoisomerase inhibitor is AZD8205. In yet another embodiment, the ADC comprising a topoisomerase inhibitor is DS-1062 (also known as datopotamab-drutecan). In one embodiment, the PARG inhibitor is a compound of formula (I). In one embodiment, the PARG inhibitor is compound A.

[0104] Combination of PARG inhibitors and topoisomerase inhibitors In another aspect, this document provides a combination product comprising compound A or a pharmaceutically acceptable salt thereof, and compounds B, C, D, E, F, or G or pharmaceutically acceptable salt thereof. In yet another aspect, this document provides a combination product comprising compound A or a pharmaceutically acceptable salt thereof, and compound H or a pharmaceutically acceptable salt thereof.

[0105] In another aspect, this article provides a combination product comprising compound A or a pharmaceutically acceptable salt thereof, and compound B or a pharmaceutically acceptable salt thereof.

[0106] In another aspect, this article provides a combination product comprising compound A1 or a pharmaceutically acceptable salt thereof, and compound B or a pharmaceutically acceptable salt thereof.

[0107] In another aspect, this article provides a combination product comprising compound A or a pharmaceutically acceptable salt thereof, and compound H or a pharmaceutically acceptable salt thereof.

[0108] In another aspect, this article provides a combination product comprising compound A1 or a pharmaceutically acceptable salt thereof, and compound H or a pharmaceutically acceptable salt thereof.

[0109] In another aspect, this article provides a combination product comprising compound A or a pharmaceutically acceptable salt thereof, and compounds selected from: compound C, compound D, compound E, compound F, and compound G or a pharmaceutically acceptable salt thereof.

[0110] In another aspect, this article provides a combination product comprising compound A1 or a pharmaceutically acceptable salt thereof, and compounds selected from: compound C, compound D, compound E, compound F, and compound G or a pharmaceutically acceptable salt thereof.

[0111] Compared to monotherapy that uses only one of the active pharmaceutical ingredients in a combination of the contents of this disclosure, administration of the pharmaceutical combination provided herein may produce beneficial effects, such as synergistic therapeutic effects, for example, in relieving, delaying the progression of symptoms or suppressing symptoms, and may also produce further surprising beneficial effects, such as fewer side effects, improved quality of life or reduced morbidity.

[0112] Treatment In one embodiment, this document provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of a PARG inhibitor and administering to the subject a therapeutically effective amount of a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0113] In one embodiment, this document provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor and at least one pharmaceutically acceptable carrier, thereby treating the cancer in the subject.

[0114] In one embodiment, this document provides a method for treating and / or preventing homologous recombination-deficient (HRD) cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the subject. In another embodiment, this document provides a method for treating homologous recombination-deficient (HRD) cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0115] In one embodiment, this document provides a method for treating and / or preventing homologous recombination-deficient (HRD) cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, and at least one pharmaceutically acceptable carrier, thereby treating and / or preventing the cancer in the subject. In one embodiment, this document provides a method for treating homologous recombination-deficient (HRD) cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, and at least one pharmaceutically acceptable carrier, thereby treating the cancer in the subject. In one embodiment, the HRD cancer is breast cancer. In one embodiment, the HRD cancer is ovarian cancer.

[0116] In one embodiment, this document provides a method for treating and / or preventing cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating and / or preventing the cancer in the subject, wherein the cancer is a homologous recombination-deficient (HRD) cancer and is estrogen receptor (ER) positive. In another embodiment, this document provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor, thereby treating the cancer in the subject, wherein the cancer is a homologous recombination-deficient (HRD) cancer and is estrogen receptor (ER) positive.

[0117] In one embodiment, this document provides a method for treating and / or preventing cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent the cancer in the subject, wherein the cancer is HRD cancer, is ER-positive, and optionally is progesterone receptor (PR) positive. In another embodiment, this document provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat the cancer in the subject, wherein the cancer is HRD cancer, is ER-positive, and optionally is progesterone receptor (PR) positive.

[0118] In one embodiment, this document provides a method for treating and / or preventing cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, and optionally is human epidermal growth factor receptor 2 (HER2) negative. In another embodiment, this document provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat the cancer in the subject, wherein the cancer is HRD cancer, is ER positive, and optionally is human epidermal growth factor receptor 2 (HER2) negative.

[0119] In one embodiment, this document provides a method for treating and / or preventing cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent the cancer in the subject, wherein the cancer is HRD cancer, is ER-positive, optionally PR-positive, and optionally HER2-negative. In one embodiment, this document provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat the cancer in the subject, wherein the cancer is HRD cancer, is ER-positive, optionally PR-positive, and optionally HER2-negative. In one embodiment, the cancerous tumor is a breast or ovarian cancerous tumor.

[0120] In one embodiment, this document provides a method for treating and / or preventing breast cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat and / or prevent the cancer in the subject, wherein the cancer is HRD cancer, is ER-positive, optionally PR-positive, and optionally HER2-negative. In another embodiment, this document provides a method for treating breast cancer in a subject with this need, the method comprising administering to the subject a combination comprising a PARG inhibitor and a topoisomerase inhibitor to treat the cancer in the subject, wherein the cancer is HRD cancer, is ER-positive, optionally PR-positive, and optionally HER2-negative.

[0121] In one embodiment, the HRD cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), or prostate cancer. In another embodiment, the HRD cancer is breast cancer or ovarian cancer. In yet another embodiment, the HRD cancer is small cell lung cancer, kidney cancer, renal cancer, urothelial carcinoma, melanoma, liver cancer, bladder cancer, stomach cancer, tumor, lymphoma, glioblastoma, sarcoma, leukemia, myeloma, or a malignant tumor of the lymphatic system.

[0122] In yet another embodiment, the cancer is characterized by reduced or absent expression of the BRCA1 and / or BRCA2 genes, absence or mutation of the BRCA1 and / or BRCA2 genes, or reduced function of the BRCA1 and / or BRCA2 proteins, or a combination thereof.

[0123] In one embodiment, this document provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a PARG inhibitor and a therapeutically effective amount of a pharmaceutical composition comprising a topoisomerase inhibitor, thereby treating the cancer in the subject.

[0124] In one embodiment, the use of a combination of a PARG inhibitor and a topoisomerase inhibitor in the preparation of a medicament is provided. In one embodiment, the PARG inhibitor is compound A. In one embodiment, the PARG inhibitor is compound A1. In one embodiment, the topoisomerase inhibitor is compound B. In one embodiment, the use of a combination of compound A and compound B in the preparation of a medicament is provided. In one embodiment, the topoisomerase inhibitor is compound H. In one embodiment, the use of a combination of compound A and compound H in the preparation of a medicament is provided. In one embodiment, the use of a combination of compound A and compounds C, D, E, F, or G in the preparation of a medicament is provided.

[0125] In another embodiment, the use of a combination of a PARG inhibitor and a topoisomerase inhibitor for treating cancer is provided. In one embodiment, the PARG inhibitor is a compound of formula I. In one embodiment, the PARG inhibitor is compound A. In one embodiment, the use of a combination of compound A and compound B for treating cancer is provided; in another embodiment, the use of a combination of compound A and compound H for treating cancer is provided. In one embodiment, the use of a combination of compound A and compounds C, D, E, F, or G for treating cancer is provided.

[0126] In one embodiment, the PAGR inhibitor is a compound of formula I: (Formula I) Or its pharmaceutically acceptable salt; where the variable is as defined above.

[0127] In another embodiment, the PARG inhibitor is compound A1 or a pharmaceutically acceptable salt thereof.

[0128] In another embodiment, the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0129] In one embodiment, the topoisomerase inhibitor is selected from compounds listed in Table 1 or their pharmaceutically acceptable salts or hydrates.

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

[0131] In another embodiment, the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0132] In another embodiment, the topoisomerase inhibitor is compound C, compound D, compound E, compound F, or compound G, or a pharmaceutically acceptable salt thereof.

[0133] In another aspect, this article provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of compound B or a pharmaceutically acceptable salt thereof.

[0134] In another aspect, this article provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of compound H or a pharmaceutically acceptable salt thereof.

[0135] In yet another aspect, this article provides a method for treating cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of compound C, compound D, compound E, compound F, compound G or a pharmaceutically acceptable salt thereof.

[0136] In another embodiment, a product is provided comprising a PARG inhibitor and a topoisomerase inhibitor as a combination product for simultaneous, single, or sequential use in a pharmaceutical product. In one embodiment, the PARG inhibitor is a compound of formula I. In one embodiment, the PARG inhibitor is compound A. In one embodiment, a product is provided comprising compound A and compound B as a combination product for simultaneous, single, or sequential use in a pharmaceutical product. In one embodiment, a product is provided comprising compound A and compound H as a combination product for simultaneous, single, or sequential use in a pharmaceutical product. In one embodiment, a product is provided comprising compound A and compounds C, D, E, F, or G as a combination product for simultaneous, single, or sequential use in a pharmaceutical product.

[0137] In another embodiment, a product is provided comprising a PARG inhibitor and a topoisomerase inhibitor as a combination product for simultaneous, individual, or sequential treatment of cancer in a subject. In one embodiment, the PARG inhibitor is a compound of formula I. In one embodiment, the PARG inhibitor is compound A. In one embodiment, a product is provided comprising compound A and compound B as a combination product for simultaneous, individual, or sequential treatment of cancer in a subject. In one embodiment, a product is provided comprising compound A and compound H as a combination product for simultaneous, individual, or sequential treatment of cancer in a subject. In one embodiment, a product is provided comprising compound A and compounds C, D, E, F, or G as a combination product for simultaneous, individual, or sequential treatment of cancer in a subject.

[0138] In yet another embodiment, the cancer is selected from: breast cancer, stomach cancer, ovarian cancer, and esophageal cancer. In one embodiment, the cancer is ovarian cancer, stomach 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.

[0139] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is endometrial cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is non-small cell lung cancer (NSCLC). In one embodiment, the cancer is small cell lung cancer. In one embodiment, the cancer is kidney cancer, renal cancer, urothelial carcinoma, melanoma, liver cancer, bladder cancer, stomach cancer, tumor, lymphoma, glioblastoma, sarcoma, leukemia, myeloma, or a malignant tumor of the lymphatic system.

[0140] In yet another embodiment, the cancer is metastatic. In one embodiment, the disease or condition is an advanced or metastatic solid tumor.

[0141] In yet another embodiment, the cancer is a solid malignant tumor.

[0142] In one embodiment, the PARG inhibitor and the topoisomerase inhibitor are in separate dosage forms. In another embodiment, the PARG inhibitor and the topoisomerase inhibitor are in the same dosage form.

[0143] In another embodiment, the treatment comprises substantially simultaneous administration of the PARG inhibitor or a pharmaceutically acceptable salt thereof and the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. In yet another embodiment, the treatment comprises administration of the PARG inhibitor or a pharmaceutically acceptable salt thereof and the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof at different times.

[0144] In yet another embodiment, the subject is given the PARG inhibitor or a pharmaceutically acceptable salt thereof, followed by the administration of the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. In one embodiment, the subject is given the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, followed by the administration of the PARG inhibitor or a pharmaceutically acceptable salt thereof.

[0145] In one embodiment, the PARG inhibitor or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, are administered orally.

[0146] In one aspect, this article provides PARG inhibitors or pharmaceutically acceptable salts thereof, and topoisomerase inhibitors or pharmaceutically acceptable salts thereof, for use in therapy.

[0147] In one embodiment, the PARG inhibitor or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, are used for the treatment of cancer in subjects in need of such treatment.

[0148] In one embodiment of the method, the method involves administering a therapeutically effective amount of a combination or composition comprising the compounds provided herein or pharmaceutically acceptable salts thereof to a subject (including, but not limited to, a human or animal) who requires treatment (including a subject identified as needing treatment).

[0149] In another embodiment of the method, the treatment comprises co-administering the amount of the PARG inhibitor or its pharmaceutically acceptable salt and the amount of the topoisomerase inhibitor or its pharmaceutically acceptable salt. In one embodiment, the amount of the PARG inhibitor or its pharmaceutically acceptable salt and the amount of the topoisomerase inhibitor or its pharmaceutically acceptable salt are in a single formulation or unit dosage form. In still other embodiments, the amount of the PARG inhibitor or its pharmaceutically acceptable salt and the amount of the topoisomerase inhibitor or its pharmaceutically acceptable salt are in a single formulation or unit dosage form.

[0150] In the foregoing method, the treatment may include substantially simultaneous administration of the amount of PARG inhibitor or its pharmaceutically acceptable salt and the amount of topoisomerase inhibitor or its pharmaceutically acceptable salt, or administration of the amount of PARG inhibitor or its pharmaceutically acceptable salt and the amount of topoisomerase inhibitor or its pharmaceutically acceptable salt at different times. In some embodiments of the foregoing method, the amount of PARG inhibitor or its pharmaceutically acceptable salt and / or the amount of topoisomerase inhibitor or its pharmaceutically acceptable salt may be administered at doses that would be ineffective when either PARG inhibitor or its pharmaceutically acceptable salt or topoisomerase inhibitor or its pharmaceutically acceptable salt is administered alone, but the combination of these amounts is effective.

[0151] In another embodiment of the method, the treatment includes co-administering an amount of compound A or a pharmaceutically acceptable salt thereof, and an amount of compound B or a pharmaceutically acceptable salt thereof. In one embodiment, the amount of compound A or a pharmaceutically acceptable salt thereof and the amount of compound B or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of compound A or a pharmaceutically acceptable salt thereof and the amount of compound B or a pharmaceutically acceptable salt thereof are in a separate formulation or unit dosage form.

[0152] In the aforementioned method, the treatment may include substantially simultaneous administration of the amount of compound A or its pharmaceutically acceptable salt and the amount of compound B or its pharmaceutically acceptable salt, or administration of the amount of compound A or its pharmaceutically acceptable salt and the amount of compound B or its pharmaceutically acceptable salt at different times. In some embodiments of the aforementioned method, the amount of compound A or its pharmaceutically acceptable salt and / or the amount of compound B or its pharmaceutically acceptable salt may be administered at doses that would be ineffective when administered alone, but the combination of these amounts is effective.

[0153] In another embodiment of the method, the treatment includes co-administering the amount of compound A or its pharmaceutically acceptable salt, and the amount of compound H or its pharmaceutically acceptable salt. In one embodiment, the amount of compound A or its pharmaceutically acceptable salt and the amount of compound H or its pharmaceutically acceptable salt are in a single formulation or unit dosage form. In still other embodiments, the amount of compound A or its pharmaceutically acceptable salt and the amount of compound H or its pharmaceutically acceptable salt are in a separate formulation or unit dosage form.

[0154] In the aforementioned method, the treatment may include substantially simultaneous administration of the amount of compound A or its pharmaceutically acceptable salt and the amount of compound H or its pharmaceutically acceptable salt, or administration of the amount of compound A or its pharmaceutically acceptable salt and the amount of compound H or its pharmaceutically acceptable salt at different times. In some embodiments of the aforementioned method, the amount of compound A or its pharmaceutically acceptable salt and / or the amount of compound H or its pharmaceutically acceptable salt may be ineffective when administered at doses that would be ineffective when administered alone as one or both of compound A or its pharmaceutically acceptable salt and compound H or its pharmaceutically acceptable salt, but the combination of these amounts is effective.

[0155] Non-limiting exemplary implementation: In the following further embodiments 1 to 93, the present disclosure includes: Implementation 1. In one implementation, a method of treating cancer in a subject with this need is provided, the method comprising administering to the subject a therapeutically effective amount of a poly-ADP-ribose hydrolase (PARG) inhibitor and administering to the subject a therapeutically effective amount of a topoisomerase inhibitor.

[0156] Implementation 1A. In Implementation 1A, a method for treating cancer in a subject with this need is provided, the method comprising administering to the subject a therapeutically effective amount of a poly-ADP-ribose hydrolase (PARG) inhibitor and administering to the subject a therapeutically effective amount of an antibody-drug conjugate (ADC) containing a topoisomerase inhibitor.

[0157] Embodiment 1A1. In Embodiment 1A1, a method according to Embodiment 1A is provided, wherein the ADC comprises a topoisomerase inhibitor, which is a type I topoisomerase inhibitor.

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

[0159] Embodiment 1A3. In Embodiment 1A3, a method according to Embodiment 1A is provided, wherein the ADC containing the topoisomerase inhibitor is AZD8205.

[0160] Implementation 1A4. In Implementation 1A4, a method according to Implementation 1A is provided, wherein the ADC containing the topoisomerase inhibitor is DS-1062 (also known as datopotamab).

[0161] Implementation 2. In one implementation, a method of treating cancer in a subject with this need is provided, the method comprising administering to the subject a therapeutically effective amount of a poly-ADP-ribose hydrolase (PARG) inhibitor, wherein the subject simultaneously receives a topoisomerase inhibitor.

[0162] Implementation Method 2A. In Implementation Method 2A, a method for treating cancer in a subject with this need is provided, the method comprising administering to the subject a therapeutically effective amount of a poly-ADP-ribose hydrolase (PARG) inhibitor, wherein the subject simultaneously receives an antibody-drug conjugate (ADC) comprising a topoisomerase inhibitor.

[0163] Embodiment 2A1. In Embodiment 2A1, a method according to Embodiment 2A is provided, wherein the ADC containing the topoisomerase inhibitor is an ADC containing a type I topoisomerase inhibitor.

[0164] Implementation 2A2. In Implementation 2A2, a method according to Implementation 2A is provided, wherein the ADC comprising a topoisomerase inhibitor is fam-trastuzumab-drutecan-nxki.

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

[0166] Implementation 2A4. In Implementation 2A4, a method according to Implementation 2A is provided, wherein the ADC containing the topoisomerase inhibitor is DS-1062 (also known as datopotamab).

[0167] Implementation 3. In one implementation, a method of treating cancer in a subject with this need is provided, the method comprising administering to the subject a therapeutically effective amount of a poly-ADP-ribose hydrolase (PARG) inhibitor, wherein the subject has received topoisomerase inhibitor treatment.

[0168] Implementation Method 3A. In Implementation Method 3A, a method for treating cancer in a subject with this need is provided, the method comprising administering to the subject a therapeutically effective amount of a poly-ADP-ribose hydrolase (PARG) inhibitor, wherein the subject has received treatment with an antibody-drug conjugate (ADC) comprising a topoisomerase inhibitor.

[0169] Embodiment 3A1. In Embodiment 3A1, a method according to Embodiment 3A is provided, wherein the ADC containing the topoisomerase inhibitor is an ADC containing a type I topoisomerase inhibitor.

[0170] Implementation 3A2. In Implementation 3A2, a method according to Implementation 3A is provided, wherein the ADC comprising a topoisomerase inhibitor is fam-trastuzumab-drutecan-nxki.

[0171] Implementation 3A3. In Implementation 3A3, a method according to Implementation 3A is provided, wherein the ADC containing the topoisomerase inhibitor is AZD8205.

[0172] Implementation 3A4. In Implementation 3A4, a method according to Implementation 3A is provided, wherein the ADC containing the topoisomerase inhibitor is DS-1062 (also known as datopotamab).

[0173] Embodiment 4. In Embodiment 4, a method according to any one of Embodiments 1 to 3 is provided, wherein the PAGR inhibitor is a compound of Formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is a 5-membered heteroaryl group; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Alkyl, C 1-3 Halogenated alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Independently selected from hydrogen and C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0174] Implementation Method 5. In Implementation Method 5, a method according to Implementation Method 4 is provided, wherein... R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazole-yl; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0175] Implementation 6. In implementation 6, a method according to implementation 4 or 5 is provided, wherein X 2 It is CH.

[0176] Implementation 7. In implementation 7, a method according to implementation 4 or 5 is provided, wherein X 2 It's CF.

[0177] Implementation Method 8. In Implementation Method 8, a method according to any one of Implementation Methods 4 to 7 is provided, wherein R 1 It is a methyl group.

[0178] Implementation 9. In implementation 9, a method according to any one of implementations 4 to 7 is provided, wherein R 1 It is a cyano group.

[0179] Embodiment 10. In Embodiment 10, a method according to any one of Embodiments 4 to 9 is provided, wherein Ar is 1,2,4-thiadiazolyl or 1,3,4-thiadiazol-2-yl.

[0180] Implementation 11. In implementation 11, a method according to any one of implementations 4 to 10 is provided, wherein Ar is 1,3,4-thiadiazol-2-yl.

[0181] Embodiment 12. In Embodiment 12, a method according to any one of Embodiments 4 to 10 is provided, wherein Ar is 1,2,4-thiadiazolyl.

[0182] Implementation 13. In implementation 13, a method according to any one of implementations 4 to 12 is provided, wherein R 2 A carbon atom attached to Ar is located at a metaposition with the nitrogen atom of the rest of the molecule.

[0183] Implementation 14. In implementation 14, a method according to any one of implementations 4 to 13 is provided, wherein R 2 It is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano.

[0184] Implementation 15. In implementation 15, a method according to any one of implementations 4 to 14 is provided, wherein R 2 It is difluoromethyl.

[0185] Embodiment 16. In Embodiment 16, a method according to any one of Embodiments 4 to 15 is provided, wherein ring B is morpholino, 1,1-dioxothiomorpholino, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazine.

[0186] Embodiment 17. In Embodiment 17, a method according to any one of Embodiments 4 to 16 is provided, wherein ring B is piperazine group.

[0187] Implementation 18. In implementation 18, a method according to any one of implementations 4 to 17 is provided, wherein R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0188] Implementation 19. In implementation 19, a method according to any one of implementations 4 to 17 is provided, wherein R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Independently selected from hydrogen and C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0189] Implementation 20. In implementation 20, a method according to any one of implementations 4 to 17 is provided, wherein R a It is hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; and R b and R c Independently selected from hydrogen and C 1-6 alkyl.

[0190] Implementation 21. In implementation 21, a method according to any one of implementations 4 to 17 is provided, wherein R a Is it hydrogen or C? 1-4 Alkyl groups; and R b and R c Selected independently from C 1-6 Alkyl groups and hydrogen.

[0191] Implementation 22. In implementation 22, a method according to any one of implementations 4 to 17 is provided, wherein R a It is hydrogen; R b and R c Each is C independently 1-6 Alkyl or hydrogen.

[0192] Embodiment 23. In Embodiment 23, a method according to any one of Embodiments 4 to 22 is provided, wherein the PARG inhibitor is compound A1 or a pharmaceutically acceptable salt thereof.

[0193] Embodiment 24. In Embodiment 24, a method according to any one of Embodiments 4 to 23 is provided, wherein the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof.

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

[0195] Embodiment 25A. In Embodiment 25A, a method according to Embodiment 25 is provided, wherein the topoisomerase I inhibitor is compound H or its pharmaceutically acceptable salt or hydrate.

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

[0197] Implementation Method 27. In Implementation Method 27, a method according to Implementation Method 26 is provided, wherein the topoisomerase II inhibitor is selected from: compound B, compound C, compound D, compound E, compound F and compound G or their pharmaceutically acceptable salts or hydrates.

[0198] Implementation 28. In Implementation 28, a method according to Implementation 27 is provided, wherein the topoisomerase II inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0199] Implementation 29. In implementation 29, a method according to any one of implementations 1 to 28 is provided, wherein the cancer is homologous recombination defective (HRD) cancer.

[0200] Implementation 30. In implementation 30, a method according to any one of implementations 1 to 29 is provided, wherein the cancer is characterized by a reduction or absence of BRCA1 gene expression, a deletion or mutation of the BRCA1 gene, or a reduction in the function of the BRCA1 protein.

[0201] Implementation 31. In implementation 31, a method according to any one of implementations 1 to 30 is provided, wherein the cancer is characterized by a reduction or absence of BRCA2 gene expression, a deletion or mutation of the BRCA2 gene, or a reduction in the function of the BRCA2 protein.

[0202] Implementation 32. In implementation 32, a method according to any one of implementations 1 to 31 is provided, wherein the cancer is ER positive.

[0203] Implementation 33. In implementation 33, a method according to any one of implementations 1 to 32 is provided, wherein the cancer is PR positive.

[0204] Implementation 34. In implementation 34, a method according to any one of implementations 1 to 33 is provided, wherein the cancer is HER2 negative.

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

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

[0207] Implementation 36. In implementation 36, a method according to any one of implementations 1 to 35 is provided, wherein the cancer is breast cancer or ovarian cancer.

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

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

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

[0211] Implementation 40. In implementation 40, the PARG inhibitor according to implementation 39 is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0212] Implementation 41. In implementation 41, the PARG inhibitor according to implementation 40 is a compound of formula (I) as defined in any one of implementations 4-22 or a pharmaceutically acceptable salt thereof.

[0213] Implementation Method 42. In Implementation Method 42, the PARG inhibitor according to Implementation Method 39 or 40 is compound A1 or a pharmaceutically acceptable salt thereof.

[0214] Implementation 43. In implementation 43, the PARG inhibitor according to implementation 39 or 40 is compound A or a pharmaceutically acceptable salt thereof.

[0215] Implementation 44. In implementation 44, the topoisomerase inhibitor according to any one of implementations 39 to 43 is a type I topoisomerase inhibitor.

[0216] Implementation Method 44A. In Implementation Method 44A, the topoisomerase inhibitor according to Implementation Method 44 is compound H or its pharmaceutically acceptable salt or hydrate.

[0217] Implementation Method 44B. In Implementation Method 44A, the topoisomerase inhibitor according to Implementation Method 44 is 10-hydroxycamptothecin, irinotecan and topotecan, hexylresorcinol, eczemacon, delutec, belotecone, or a pharmaceutically acceptable salt thereof.

[0218] Implementation 45. In implementation 45, the topoisomerase inhibitor according to any one of implementations 39 to 43 is a type II topoisomerase inhibitor.

[0219] Implementation Method 46. In Implementation Method 46, the topoisomerase inhibitor according to Implementation Method 45 is compound B, compound C, compound D, compound E, compound F or compound G or a pharmaceutically acceptable salt thereof.

[0220] Implementation Method 47. In Implementation Method 47, the topoisomerase inhibitor according to Implementation Method 46 is compound B or a pharmaceutically acceptable salt thereof.

[0221] Embodiment 48. In Embodiment 48, a combination product is provided, comprising a first pharmaceutical composition containing a therapeutically effective amount of a PARG inhibitor and a second pharmaceutical composition containing a therapeutically effective amount of a topoisomerase inhibitor.

[0222] Implementation 49. In implementation 49, the PARG inhibitor according to implementation 48 is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0223] Implementation 50. In Implementation 50, the PARG inhibitor according to Implementation 49 is a compound of formula (I) as defined in any one of Implementations 4-22 or a pharmaceutically acceptable salt thereof.

[0224] Implementation 51. In implementation 51, the PARG inhibitor according to implementation 48 or 49 is compound A1 or a pharmaceutically acceptable salt thereof.

[0225] Implementation 52. In implementation 52, the PARG inhibitor according to implementation 48 or 49 is compound A or a pharmaceutically acceptable salt thereof.

[0226] Implementation 53. In implementation 53, the topoisomerase inhibitor according to any one of implementations 48 to 52 is a type I topoisomerase inhibitor.

[0227] Implementation 53A. In Implementation 53A, the topoisomerase inhibitor according to Implementation 53 is compound H or its pharmaceutically acceptable salt or hydrate.

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

[0229] Implementation 55. In implementation 55, the topoisomerase inhibitor according to implementation 54 is compound B, compound C, compound D, compound E, compound F or compound G or a pharmaceutically acceptable salt thereof.

[0230] Implementation 56. In implementation 56, the topoisomerase inhibitor according to implementation 55 is compound B or a pharmaceutically acceptable salt thereof.

[0231] Embodiment 57. In Embodiment 57, a combination product is provided comprising a first pharmaceutical composition containing a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition containing a therapeutically effective amount of compound B or a pharmaceutically acceptable salt thereof.

[0232] Embodiment 57A. In Embodiment 57A, a combination product is provided comprising a first pharmaceutical composition containing a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition containing a therapeutically effective amount of compound H or a pharmaceutically acceptable salt thereof.

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

[0234] Implementation 59. In implementation 59, the PARG inhibitor according to implementation 58 is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0235] Implementation 60. In Implementation 60, the PARG inhibitor according to Implementation 59 is a compound of formula (I) as defined in any one of Implementations 4-22 or a pharmaceutically acceptable salt thereof.

[0236] Implementation Method 61. In Implementation Method 61, the PARG inhibitor according to Implementation Method 58 or 59 is compound A1 or a pharmaceutically acceptable salt thereof.

[0237] Implementation Method 62. In Implementation Method 62, the PARG inhibitor according to Implementation Method 58 or 59 is compound A or a pharmaceutically acceptable salt thereof.

[0238] Implementation 63. In Implementation 63, the topoisomerase inhibitor according to any one of Implementations 58 to 62 is a type I topoisomerase inhibitor.

[0239] Implementation Method 63A. In Implementation Method 63A, the topoisomerase inhibitor according to Implementation Method 63 is compound H or its pharmaceutically acceptable salt or hydrate.

[0240] Implementation 64. In Implementation 64, the topoisomerase inhibitor according to any one of Implementations 58 to 62 is a type II topoisomerase inhibitor.

[0241] Implementation Method 65. In Implementation Method 65, the topoisomerase inhibitor according to Implementation Method 64 is compound B, compound C, compound D, compound E, compound F or compound G or a pharmaceutically acceptable salt thereof.

[0242] Implementation Method 66. In Implementation Method 66, the topoisomerase inhibitor according to Implementation Method 65 is compound B or a pharmaceutically acceptable salt thereof.

[0243] Embodiment 67. In Embodiment 67, a PARG inhibitor for treating cancer is provided, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor; wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof; and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0244] Embodiment 67A. In Embodiment 67A, a PARG inhibitor for treating cancer is provided, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor; wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof; and the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0245] Implementation 68. In implementation 68, the use according to any one of implementations 58 to 67 is provided, wherein the cancer is homologous recombination defective (HRD) cancer.

[0246] Embodiment 69. In Embodiment 69, an application according to any one of Embodiments 58 to 68 is provided, wherein the cancer is characterized by a reduction or absence of BRCA1 gene expression, a deletion or mutation of the BRCA1 gene, or a reduction in the function of the BRCA1 protein.

[0247] Embodiment 70. In Embodiment 70, the use according to any one of Embodiments 58 to 69 is provided, wherein the cancer is characterized by reduced or absent expression of the BRCA2 gene, absence or mutation of the BRCA2 gene, or reduced function of the BRCA2 protein.

[0248] Implementation 71. In implementation 71, the use according to any one of implementations 58 to 70 is provided, wherein the cancer is ER positive.

[0249] Implementation 72. In implementation 72, the use according to any one of implementations 58 to 71 is provided, wherein the cancer is PR positive.

[0250] Implementation 73. In implementation 73, the use according to any one of implementations 58 to 72 is provided, wherein the cancer is HER2 negative.

[0251] Implementation 74. In implementation 74, the use according to any one of implementations 58 to 73 is provided, wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, pancreatic cancer, colorectal cancer, non-small cell lung cancer (NSCLC), and prostate cancer.

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

[0253] Implementation 75. In implementation 75, an application according to any one of implementations 58 to 74 is provided, wherein the cancer is breast cancer or ovarian cancer.

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

[0255] Implementation 77. In implementation 77, the PARG inhibitor according to implementation 76 is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0256] Implementation 78. In implementation 78, the PARG inhibitor according to implementation 77 is a compound of formula (I) as defined in any one of implementations 4-22 or a pharmaceutically acceptable salt thereof.

[0257] Implementation Method 79. In Implementation Method 79, the PARG inhibitor according to Implementation Method 76 or 77 is compound A1 or a pharmaceutically acceptable salt thereof.

[0258] Implementation Method 80. In Implementation Method 80, the PARG inhibitor according to Implementation Method 76 or 77 is compound A or a pharmaceutically acceptable salt thereof.

[0259] Implementation Method 81. In Implementation Method 81, the topoisomerase inhibitor according to any one of Implementation Methods 76 to 80 is a type I topoisomerase inhibitor.

[0260] Implementation Method 81A. In Implementation Method 81A, the topoisomerase inhibitor according to Implementation Method 81 is compound H or its pharmaceutically acceptable salt or hydrate.

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

[0262] Implementation Method 83. In Implementation Method 83, the topoisomerase inhibitor according to Implementation Method 82 is compound B, compound C, compound D, compound E, compound F or compound G or a pharmaceutically acceptable salt thereof.

[0263] Implementation Method 84. In Implementation Method 84, the topoisomerase inhibitor according to Implementation Method 83 is compound B or a pharmaceutically acceptable salt thereof.

[0264] Embodiment 85. In Embodiment 85, the use of a PARG inhibitor in the preparation of a medicament for treating cancer is provided, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor; wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof; and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0265] Embodiment 85A. In Embodiment 85A, the use of a PARG inhibitor in the preparation of a medicament for treating cancer is provided, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor; wherein the PARG inhibitor is compound A or a pharmaceutically acceptable salt thereof; and the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0266] Embodiment 86 In Embodiment 86, an application according to any one of Embodiments 76 to 85A is provided, wherein the cancer is homologous recombination defective (HRD) cancer.

[0267] Embodiment 87. In Embodiment 87, an application according to any one of Embodiments 76 to 86 is provided, wherein the cancer is characterized by a reduction or absence of BRCA1 gene expression, a deletion or mutation of the BRCA1 gene, or a reduction in the function of the BRCA1 protein.

[0268] Implementation 88. In implementation 88, the use according to any one of implementations 76 to 87 is provided, wherein the cancer is characterized by a reduction or absence of BRCA2 gene expression, a deletion or mutation of the BRCA2 gene, or a reduction in the function of the BRCA2 protein.

[0269] Implementation 89. In implementation 89, the use according to any one of implementations 76 to 88 is provided, wherein the cancer is ER positive.

[0270] Implementation 90. In implementation 90, the use according to any one of implementations 76 to 89 is provided, wherein the cancer is PR positive.

[0271] Implementation 91. In implementation 91, the use according to any one of implementations 76 to 90 is provided, wherein the cancer is HER2 negative.

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

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

[0274] Implementation 93. In implementation 93, an application according to any one of implementations 76 to 92 is provided, wherein the cancer is breast cancer or ovarian cancer.

[0275] When referring to the above embodiments, reference will include those embodiments having letter symbols or combinations thereof. For example, reference to embodiments 1-3 will include embodiments 1, 1A, 1A1, 1A2, 1A3, 1A4, 2, 2A, 2A1, 2A2, 2A3, 2A4, 3, 3A, 3A1, 3A2, 3A3, and 3A4.

[0276] Other non-limiting exemplary implementations: Implementation Method 1. In Implementation Method 1, a method for treating cancer in a subject with this need is provided, the method comprising administering to the subject a therapeutically effective amount of a PAGR inhibitor and administering to the subject a therapeutically effective amount of a topoisomerase inhibitor, wherein the PAGR inhibitor is a compound of Formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazole-yl; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0277] Implementation Method 2. In Implementation Method 2, a method according to Implementation Method 1 is provided, wherein X 2 It is CH.

[0278] Implementation Method 3. In Implementation Method 3, a method according to Implementation Method 1 or 2 is provided, wherein R 1 It is a methyl group.

[0279] Implementation Method 4. In Implementation Method 4, a method according to Implementation Method 1 or 2 is provided, wherein R 1 It is a cyano group.

[0280] Implementation 5. In implementation 5, a method according to any one of implementations 1 to 4 is provided, wherein Ar is 1,3,4-thiadiazole-2-yl.

[0281] Implementation Method 6. In Implementation Method 6, a method according to any one of Implementation Methods 1 to 5 is provided, wherein R 2 A carbon atom attached to Ar is located at a metaposition with the nitrogen atom of the rest of the molecule.

[0282] Implementation 7. In implementation 7, a method according to any one of implementations 1 to 6 is provided, wherein R 2 It is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano.

[0283] Implementation Method 8. In Implementation Method 8, a method according to any one of Implementation Methods 1 to 7 is provided, wherein R 2 It is difluoromethyl.

[0284] Embodiment 9. In Embodiment 9, a method according to any one of Embodiments 1 to 8 is provided, wherein ring B is morpholino, 1,1-dioxothiomorpholino, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazine.

[0285] Embodiment 10. In Embodiment 10, a method according to any one of Embodiments 1 to 9 is provided, wherein ring B is piperazine group.

[0286] Implementation 11. In implementation 11, a method according to any one of implementations 1 to 10 is provided, wherein R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0287] Implementation 12. In implementation 12, a method according to any one of implementations 1 to 11 is provided, wherein Ra It is hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; and R b and R c Selected independently from C 1-6 Alkyl groups and hydrogen.

[0288] Implementation Method 13. In Implementation Method 13, a method according to any one of Implementation Methods 1 to 12 is provided, wherein R a It is hydrogen; R b and R c Each is C independently 1-6 Alkyl or hydrogen.

[0289] Embodiment 14. In Embodiment 14, a method according to any one of Embodiments 1 to 13 is provided, wherein the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0290] Embodiment 15. In Embodiment 15, a method according to any one of Embodiments 1 to 14 is provided, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

[0291] Embodiment 16. In Embodiment 16, a method according to any one of Embodiments 1 to 15 is provided, wherein the topoisomerase inhibitor is selected from: compound B, compound C, compound D, compound E, compound F and compound G or their pharmaceutically acceptable salts or hydrates.

[0292] Embodiment 17. In Embodiment 17, a method according to any one of Embodiments 1 to 16 is provided, wherein the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0293] Embodiment 18. In Embodiment 18, a method according to any one of Embodiments 1 to 14 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0294] Embodiment 19. In Embodiment 19, a method according to any one of Embodiments 1 to 14 is provided, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0295] Implementation 20. In implementation 20, a method according to any one of implementations 1 to 19 is provided, wherein the cancer is homologous recombination defective (HRD) cancer.

[0296] Implementation 21. In implementation 21, a method according to any one of implementations 1 to 20 is provided, 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.

[0297] Implementation 22. In implementation 22, a method according to any one of implementations 1 to 21 is provided, wherein the cancer is breast cancer, lung cancer, or ovarian cancer.

[0298] Embodiment 23. In Embodiment 23, a method according to any one of Embodiments 1 to 22 is provided, wherein the PARG inhibitor and the topoisomerase inhibitor are in separate formulations.

[0299] Embodiment 24. In Embodiment 24, a method according to any one of Embodiments 1 to 22 is provided, wherein the PARG inhibitor and the topoisomerase inhibitor are in the same formulation.

[0300] Implementation 25. In implementation 25, a combination is provided comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0301] Implementation Method 26. In Implementation Method 26, a combination according to Implementation Method 25 is provided, wherein the PAGR inhibitor is a compound of Formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazole-yl; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0302] Implementation 27. In implementation 27, a combination according to implementation 25 or 26 is provided, wherein the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0303] Embodiment 28. In Embodiment 28, a combination according to any one of Embodiments 25 to 27 is provided, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[0304] Implementation 29. In implementation 29, a combination according to any one of implementations 25 to 28 is provided, wherein the topoisomerase inhibitor is selected from: compound B, compound C, compound D, compound E, compound F and compound G or pharmaceutically acceptable salts thereof.

[0305] Embodiment 30. In Embodiment 30, a combination according to any one of Embodiments 25 to 29 is provided, wherein the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0306] Implementation 31. In implementation 31, a combination according to any one of implementations 25 to 27 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0307] Implementation 32. In implementation 32, a combination according to any one of implementations 25 to 27 is provided, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0308] Embodiment 33. In Embodiment 33, a PARG inhibitor for treating cancer is provided, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor.

[0309] Embodiment 34. In Embodiment 34, the use according to Embodiment 33 is provided, wherein the PAGR inhibitor is a compound of Formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazole-yl; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0310] Embodiment 35. In Embodiment 35, the use according to Embodiment 33 or 34 is provided, wherein the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0311] Embodiment 36. In Embodiment 36, the use according to any one of Embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[0312] Embodiment 37. In Embodiment 37, use according to any one of Embodiments 33 to 36 is provided, wherein the topoisomerase inhibitor is selected from: compound B, compound C, compound D, compound E, compound F and compound G or pharmaceutically acceptable salts thereof.

[0313] Embodiment 38. In Embodiment 38, use according to any one of Embodiments 33 to 37 is provided, wherein the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0314] Embodiment 39. In Embodiment 39, the use according to any one of Embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0315] Embodiment 40. In Embodiment 40, use according to any one of Embodiments 33 to 35 is provided, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0316] Embodiment 41. In Embodiment 41, the use of a PARG inhibitor in the preparation of a medicament for treating cancer is provided, wherein the PARG inhibitor is administered simultaneously or sequentially with a topoisomerase inhibitor.

[0317] Embodiment 42. In Embodiment 42, the use according to Embodiment 41 is provided, wherein the PAGR inhibitor is a compound of Formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazole-yl; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d (where R) d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R band R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0318] Embodiment 43. In Embodiment 43, the use according to Embodiment 41 or 42 is provided, wherein the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0319] Embodiment 44. In Embodiment 44, the use according to any one of Embodiments 41 to 43 is provided, wherein the topoisomerase inhibitor is a type II topoisomerase inhibitor.

[0320] Embodiment 45. In Embodiment 45, use according to any one of Embodiments 41 to 44 is provided, wherein the topoisomerase inhibitor is selected from: compound B, compound C, compound D, compound E, compound F and compound G or pharmaceutically acceptable salts thereof.

[0321] Embodiment 46. In Embodiment 46, use according to any one of Embodiments 41 to 45 is provided, wherein the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof and the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 47. In Embodiment 47, the use according to any one of Embodiments 41 to 43 is provided, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0323] Embodiment 48. In Embodiment 48, use according to any one of Embodiments 41 to 43 is provided, wherein the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0324] Implementation 49. In implementation 49, the use according to any one of implementations 33 to 48 is provided, wherein the cancer is homologous recombination defective (HRD) cancer.

[0325] Embodiment 50. In Embodiment 50, the use according to any one of Embodiments 33 to 49 is provided, 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.

[0326] Implementation 51. In implementation 51, an application according to any one of implementations 33 to 50 is provided, wherein the cancer is breast cancer, lung cancer, or ovarian cancer.

[0327] Pharmaceutical Composition In one aspect, this article provides a pharmaceutical composition comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof, a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0328] In one embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a PARG inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of a topoisomerase inhibitor are provided.

[0329] In another aspect, this article provides a combination product comprising a first pharmaceutical composition containing a therapeutically effective amount of a PARG inhibitor and a second pharmaceutical composition containing a therapeutically effective amount of a topoisomerase inhibitor.

[0330] In one implementation, the PARG inhibitor is a compound of formula (I): (Formula I) Or its pharmaceutically acceptable salt; where the variables are as defined above.

[0331] In another embodiment, the topoisomerase inhibitor is a type II topoisomerase inhibitor or a pharmaceutically acceptable salt thereof. In yet another embodiment, the topoisomerase inhibitor is a type I topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

[0332] In another embodiment, the topoisomerase inhibitor is selected from the compounds in Table 1 or their pharmaceutically acceptable salts or hydrates.

[0333] In another embodiment, the topoisomerase inhibitor is topotecan (compound H) or its pharmaceutically acceptable salt or hydrate.

[0334] In another embodiment, the PAGR inhibitor is compound A or a pharmaceutically acceptable salt thereof.

[0335] In another embodiment, the topoisomerase inhibitor is compound B or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound C or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound D or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound E or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound F or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound G or a pharmaceutically acceptable salt thereof. In another embodiment, the topoisomerase inhibitor is compound H or a pharmaceutically acceptable salt thereof.

[0336] In yet another aspect, this article provides a combination product comprising a first pharmaceutical composition containing a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition containing a therapeutically effective amount of compound B or a pharmaceutically acceptable salt thereof.

[0337] In yet another aspect, this document provides a combination product comprising a first pharmaceutical composition containing a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition containing a therapeutically effective amount of compound H or a pharmaceutically acceptable salt thereof.

[0338] In yet another aspect, this document provides a combination product comprising a first pharmaceutical composition containing a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition containing a therapeutically effective amount of compound C, compound D, compound E, compound F or compound G or a pharmaceutically acceptable salt thereof.

[0339] In another aspect, this article provides a pharmaceutical composition comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; compound B or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0340] In another aspect, this article provides a pharmaceutical composition comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; compound H or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0341] In yet another aspect, a pharmaceutical composition is provided comprising a therapeutically effective amount of compound A or a pharmaceutically acceptable salt thereof; compound C, compound D, compound E, compound F or compound G or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0342] Application / Dosage / Formulation In another aspect, this document provides a pharmaceutical composition or combination of pharmaceuticals comprising the compounds disclosed herein and a pharmaceutically acceptable carrier.

[0343] In one embodiment of the combination product, the PARG inhibitor, or a pharmaceutically acceptable salt thereof, and the topoisomerase inhibitor, or a pharmaceutically acceptable salt thereof, are in the same formulation. In another embodiment of the combination product, the PARG inhibitor and the topoisomerase inhibitor are in separate dosage forms. In yet another embodiment of this product, the formulation is intended for simultaneous or sequential administration.

[0344] Combination administration includes administering a combination of single-drug formulations or unit dosage forms via any suitable route, administering individual agents of the combination simultaneously but separately, or administering individual agents of the combination sequentially. The dosage of individual agents in a combination may require one agent to be administered more frequently compared to the others in the combination. Therefore, to allow for appropriate dosing, packaged pharmaceutical products may contain one or more dosage forms of a combination of drugs, and one or more dosage forms of other agents in the combination but not the combination itself.

[0345] The actual dose level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of active ingredient that effectively achieves the therapeutic response required for a particular patient, composition, and administration method without causing toxicity to the patient.

[0346] In particular, the selected dosage will depend on a variety of factors, including the activity of the specific compound used, the time of administration, the rate of compound excretion, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health status and medical history of the patient being treated, and similar factors well known in the medical field.

[0347] A physician or veterinarian with ordinary skills in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may begin administration of the disclosed compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0348] In certain embodiments, it is particularly advantageous to formulate the compound in dose-unit form for ease of administration and dosage uniformity. As used herein, dose-unit form refers to a physically discrete unit suitable as a unit dose to a patient to be treated; each unit contains a predetermined amount of the disclosed compound, which, in combination with a desired drug carrier, is calculated to produce the desired therapeutic effect. The dose-unit form is determined by and directly depends on: (a) the unique characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations of techniques for mixing / formulating such disclosed compounds for treating pain, depression, or addiction in patients.

[0349] In one embodiment, the compound provided herein is formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition provided herein comprises a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier.

[0350] The optimal ratio, individual and combined doses, and concentrations of drug compounds that produce non-toxic therapeutic effects are based on the availability kinetics of the active ingredient to the target site.

[0351] Routes of administration for any of the compositions discussed herein include oral, intranasal, rectal, intravaginal, parenteral, oral, sublingual, or topical. The compounds can be formulated for administration via any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, translingual, buccal, transurethral, ​​transvaginal (e.g., vaginal or perivallary), intranasal, and transrectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, oral administration is preferred.

[0352] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gels, lozenges, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, granules, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or nebulized formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that formulations and compositions are not limited to the specific formulations and compositions described herein.

[0353] For oral applications, tablets, dragees, liquids, drops, suppositories or capsules, caplets, and gel tablets are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more agents selected from inert, non-toxic pharmaceutical excipients suitable for the preparation of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated, or may be coated by known techniques for aesthetic purposes, or to delay the release of the active ingredient. Oral formulations may also be presented in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert diluent.

[0354] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, such as intravenous, intramuscular, or subcutaneous injection or infusion, or for single-bolus dose or continuous infusion administration. Suspensions, solutions, or emulsions in oil or aqueous carriers can be used, optionally containing other formulation agents such as suspending agents, stabilizers, or dispersants.

[0355] In one embodiment, particularly when the topoisomerase inhibitor is doxorubicin, it can be administered by injection in some embodiments. In one embodiment, doxorubicin is administered via capsule. In another embodiment, doxorubicin is administered intravenously.

[0356] Reagent test kit In one aspect, this disclosure provides a kit for treating cancer, comprising a PARG inhibitor or a pharmaceutically acceptable salt thereof and a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.

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

[0358] In some embodiments, the kit comprises a pharmaceutical composition containing a PARG inhibitor or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

[0359] In other embodiments, a pharmaceutical kit is provided. The kit comprises a sealed container approved for storing a pharmaceutical composition containing one of the pharmaceutical compositions described above. In some embodiments, the sealed container minimizes contact between air and the ingredients, for example, an airless bottle. In other embodiments, the sealed container is a sealed tube. The kit should include instructions for use of the composition and information about the composition.

[0360] In one particular embodiment, the combined compounds can be administered on the same schedule, either by administering a single formulation or unit containing all the compounds in the combination, or by administering a single formulation or unit containing one of the combined compounds. However, some compounds used in the composition may be administered more frequently than once daily, or at a different frequency than the other compounds in the combination. Therefore, in one embodiment, the kit contains in a container a formulation or unit containing all the compounds in the combination, and another formulation or unit containing one of the compounds in the combination but no other active compounds, along with instructions for administering the formulation on a fixed schedule.

[0361] The kits described herein include, for example, prescription information for patients or healthcare providers, or as a label on a packaged pharmaceutical preparation. Prescription information may include, for example, information about the effectiveness, dosage and administration, contraindications, and adverse reactions of the pharmaceutical preparation.

[0362] In all of the above cases, the combination of compounds of this disclosure may be applied alone, as a mixture, or together with other active agents.

[0363] This document provides kits that can be designed to maintain the conditions (e.g., refrigeration or freezing) required to properly preserve the components contained therein. Kits may include labels or packaging inserts containing identification information for the components and instructions for use (e.g., dosing parameters, clinical pharmacology of the active ingredient, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse reactions, contraindications, etc.).

[0364] Each component of the kit can be contained in a separate container, and all the different containers can be packaged separately. Labels or inserts may include manufacturer information such as batch number and expiration date. Labels or packaging inserts may be integrated into the physical structure containing the components, contained separately within the physical structure, or affixed to components of the kit (e.g., ampoules, syringes, or vials).

[0365] Those skilled in the art will recognize or be able to determine numerous equivalents to the particular procedures, implementations, claims, and examples described herein using no more than conventional experimentation. Such equivalents are considered to be within the scope of this disclosure and are covered by the appended claims.

[0366] It should be understood that whatever values ​​and ranges are provided herein, all values ​​and ranges included herein are intended to be included within the scope of this disclosure. Furthermore, this application also considers all values ​​falling within these ranges, as well as the upper or lower limits of the ranges of values.

[0367] The following examples further illustrate aspects of this disclosure. However, they are by no means intended to limit the teachings of this disclosure.

[0368] Example The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limitations. Unless otherwise stated, practice of this disclosure will be undertaken using conventional techniques within the scope of the art, including organic synthesis, cell biology, cell culture, and molecular biology.

[0369] Example 1 Preparation of compound A (Compound A) Step 1: Preparation of 2,6-difluoro-4-iodobenzaldehyde LDA (80 mL, 625.0 mmol) and DMF (48.3 mL, 625 mmol) were added to a stirred solution of 1,3-difluoro-5-iodobenzene (compound 1) (50 g, 208.3 mmol, Oakwood Chemical, CAS 2265-91-0, catalog number #024566) in THF (500 mL) at -78 °C, and the mixture was stirred at 78 °C for 2 h. After the starting material was completely consumed, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 x 300 mL). The combined organic phases were washed with a saline 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) with a gradient elution of 20% EtOAc / hexane. The product was then eluted with a gradient of 30% EtOAc / hexane. The purified fraction was concentrated under reduced pressure to give 2,6-difluoro-4-iodobenzaldehyde (compound 2) (23 g) in solid form. 1 H NMR (500MHz, CHLOROFORM-d) δ: 10.29 (s, 1H), 7.37-7.46 (m, 2H).

[0370] Step 2: Preparation of 4-fluoro-6-iodo-1H-indazole Hydrazine hydrate (18.6 mL, 373.1 mmol) was added to a stirred solution of 2,6-difluoro-4-iodobenzaldehyde (compound 2) (5 g, 18.6 mmol) in 1,4-dioxane (110 mL) at room temperature, and 100 o The mixture was stirred at C for 24 h. The reaction mixture was concentrated under reduced pressure, and ice-cold water (100 mL) was added. The mixture was stirred for 30 min, during which time a solid precipitated. The mixture was filtered. The solid was washed with water (100 mL) and n-pentane (50 mL) and dried under vacuum to give the product 4-fluoro-6-iodo-1H-indazole (compound 3) (2.3 g) as a solid. MS ESI C7H4FIN2[M+H] + The calculated value is 262.94, and the experimental value is 262.99. 1 H NMR (CDCl3, 400 MHz): 10.12 (s, 1 H), 8.10 (s, 1H), 7.70 (s, 1H), 7.15 (dd, J = 9 Hz, 1H).

[0371] Step 3: Preparation of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4-thiadiazole Add 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, CAS 1340313-49-6, catalog number #EN300-108825) to a stirred solution of 4-fluoro-6-iodo-1H-indazole (compound 3) (5 g, 19.0 mmol) in DMF (50 mL) to a stirred solution. Heat the resulting mixture at 60 °C. o The mixture was stirred at C for 2 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with ice-cold water (50 mL) and stirred for 30 min, during which time a solid precipitated. The mixture was filtered. The collected solid was washed with water (100 mL), followed by washing with n-pentane (100 mL), and dried under vacuum to give 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4-thiadiazole (compound 5) (4.2 g) as a solid. MS ESI C 10 H4F3IN4S [M+H] +The calculated value is 396.92, and the experimental value is 396.91. 1 H NMR (CDCl3, 500 MHz): 8.87 (s, 1 H), 8.29 (s, 1H), 7.40 (dd, J = 17 Hz, 1H), 7.0 (t, J = 53.5 Hz, 1H).

[0372] Step 4: Preparation of S-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazol-6-yl)thiobenzoate At room temperature, CuI (5 mg, 0.025 mmol), 1,10-phenanthroline (phen) (11 mg, 0.05 mmol), and potassium thiobenzoate (67 mg, 0.378 mmol) were added to a stirred solution of 2-(difluoromethyl)-5-(4-fluoro-6-iodo-1H-indazol-1-yl)-1,3,4-thiadiazole (compound 5) (100 mg, 0.25 mmol) degassed in toluene (1 mL) for 5 min. The resulting mixture was then heated in 100 mL of water. o The mixture was stirred at C for 16 h. The reaction progress was monitored by LCMS. The crude mixture was purified by column chromatography using silica gel (100-200) with a gradient elution of 10% EtOAc / hexane. The purified fraction was 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) in solid form. MS ESI C 17 H9F3N4OS2[M+H] + The calculated value is 407.02, and the experimental value is 407.01. 1 HNMR (CDCl3, 400 MHz): 8.68 (s, 1 H), 8.39 (s, 1H), 8.03 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.27 (s, 1H), 6.99 (t, J = 53.2Hz, 1H).

[0373] Step 5: Preparation of N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-1H-indazole-6-sulfonamide In 0 o At C, a solution of BnMe3NCl (682 mg, 3.69 mmol) and TCCA (trichloroisocyanuric acid) (370 mg, 1.59 mmol) in acetonitrile (40 mL) was added 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). The reaction mixture was stirred for 20 min. Then at 0 o A solution of 1-methylcyclopropane-1-amine (1.71 g, 7.38 mmol, Combi-Blocks, CAS 22936-83-0, catalog number #QH-3639) in pyridine (2.5 mL) and cesium carbonate (198 mg, 0.61 mmol) was added to the reaction mixture at C, and the mixture was 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 x 30 mL). The combined organic layers were washed with aqueous brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography using silica gel (100-200) with a gradient elution of 5 to 50% EtOAc / hexane. The product was eluted with 20% EtOAc / hexane. The purified fraction was collected and concentrated under reduced pressure to give 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (compound 7) (90 mg) as a solid. MS ESI C 14 H9F3N6O2S2[M+H] + The calculated value is 404.04, and the experimental value is 404.18. 1 HNMR (CDCl3, 400 MHz): 9.00 (s, 1 H), 8.80 (s, 1H), 8.54 (s, 1H), 7.63 (t, J=48.8 Hz, 2H), 1.10 (s, 3H), 0.65 (s, 2H), 0.44 (s, 2H).

[0374] Step 6: Preparation of (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminesulfonyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester Add (2S,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (85 mg, 0.39 mmol, BLD Pharmatech, CAS 574007-66-2, catalog number #BD233798) and DIPEA (N,N-diisopropylethylamine) (0.1 mL, 0.59 mmol) to a stirred solution of 1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-4-fluoro-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonyl (compound 7) (80 mg, 0.19 mmol) in DMSO (dimethyl sulfoxide) (2 mL) and stir. o The reaction mixture was stirred at C for 2 h. The reaction mixture was quenched with ice-cold water (20 mL) and stirred for 30 min. The resulting solid was filtered, washed with water (10 mL), dried under vacuum, and purified by silica gel column chromatography (100-200). The purified fraction was concentrated under reduced pressure using a gradient elution with 50% EtOAc / hexane to give (2S,6S)-4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminesulfonyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (compound 8) (110 mg, yield: 92%). MS ESI C 25 H 33 F2N7O4S2[M+H] + The calculated value is 598.20, and the experimental value is 598.26.

[0375] 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 (compound A) In 0 o C down, towards ( 2S, 6S4-(1-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-6-(N-(1-methylcyclopropyl)aminesulfonyl)-1H-indazol-4-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (compound 8) (100 mg, 0.16 mmol) was added to a stirred solution in DCM (3 mL) with trifluoroacetic acid (0.07 mL, 0.98 mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (preparative HPLC conditions: mobile phase - 10 mM ammonium bicarbonate aqueous solution: MeCN, column - Inertsil ODS (20 x 250) 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: acceptable, 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 (Compound A) (18 mg, yield: 21%). MS ESI C 20 H 25 F2N7O2S2[M+H] + The calculated value is 498.15, and the experimental value is 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 = 52.8 Hz, 1H), 7.10 (d, J = 1.0 Hz, 1H), 3.37 (br dd, J = 11.5, 2.9 Hz, 2H), 3.22-3.30 (m,2H), 3.08 (br dd, J = 11.7, 6.1 Hz, 2H), 1.17 (d, J = 6.4 Hz, 6H), 1.08 (s, 3H), 0.58-0.76 (m, 2H), 0.29-0.49 (m, 2H).

[0376] Example 2 An evaluation of the efficacy of the combination of compound A and doxorubicin (compound B) in HCC1428, a xenograft model derived from the HR-deficient breast cancer cell line. The combination effect of compound A and doxorubicin was evaluated using a cell line-derived xenograft (CDX) model of the BRCA2-mutated breast cancer cell line HCC1428. For this study, cells were expanded in RPMI containing 10% fetal bovine serum and implanted into BALB / c nude mice. Once they reached approximately 180 mm... 3 Animals were randomly assigned to the treatment arm as described in Table 2 based on the average tumor volume, and the treatment lasted for 35 days. For this xenograft, treatment began one week before cell implantation and continued until the end of treatment, with subcutaneous administration of estradiol benzoate injection (40 µg / 20 µl / mouse) twice a week.

[0377] Compound A, administered once daily (QD) at doses of 30 mg / kg and 100 mg / kg, resulted in tumor growth inhibition (TGI) of 63.2% and 102.5%, respectively, while doxorubicin, administered intravenously at 5 mg / kg once weekly for 5 weeks, produced a TGI of 57%. Combination administration led to a more potent and sustained response, with TGIs of 85% and 110% in the 30 mg / kg and 100 mg / kg groups, respectively, and complete regression achieved in 50% of the animals in the 100 mg / kg compound A combination group. Statistically significant differences in TGI were observed between the single-agent and combination groups at both 30 mg / kg and 100 mg / kg doses of compound A, highlighting the enhanced antitumor effect of the combination (Table 3 and...). Figure 1 (FIG. 1)). Although no deaths were observed in this study, weight loss of >10% was observed in the high-dose combination group.

[0378] Table 2: CDX HCC1428 study group treated with compound A and / or doxorubicin

[0379] Table 3: CDX HCC1428 treated with compound A and / or doxorubicin

[0380] Example 3 A study evaluating the efficacy of the combination of compound A and topotecan (compound H) in the small cell lung cancer cell line NCI-H69. The combination effect of compound A and topotecan was evaluated using a cell line-derived xenograft (CDX) model of the small cell lung cancer cell line NCI-H69 carrying an ATM variant of unknown significance. For this study, NCI-H69 cells were expanded in RPMI containing 10% fetal bovine serum and implanted into NOD SCID mice. Once they reached approximately 100–150 mm... 3 The average tumor volume was used to randomly assign animals to different treatment arms. The study consisted of six treatment arms, each containing ten mice, with treatment lasting 42 days. TGI was calculated on day 21 when the load cell group was terminated, at which point the maximum permissible tumor burden was reached.

[0381] Administration of compound A at 100 mg / kg resulted in a 53% TGI, while administration of topotecan at 0.25 mg / kg and 1 mg / kg produced TGI values ​​of 79% and 80%, respectively (dosing schedule shown in Table 4). The two doses of topotecan demonstrated a combination effect, with the 0.25 mg / kg dose having a 79% TGI and the 1 mg / kg dose having a 105% TGI, with complete regression observed in 7 out of 10 animals by day 42. These results highlight the potent anticancer efficacy of compound A in combination with the topoisomerase I inhibitor topotecan (see Table 4). Figure 2 (FIG. 2)).

[0382] Table 4: CDX NCI-H69 study groups treated with compound A and / or topotecan

[0383] Example 4 A study evaluating the efficacy of the combination of compound A and topotecan (compound H) in the high-grade serous ovarian cancer cell line Kuramochi. The combination effect of compound A and topotecan (compound H) was evaluated using a cell line-derived xenograft (CDX) model of Kuramochchi, a high-grade serous ovarian cancer cell line carrying a BRCA2 mutation (significant). For this study, Kuramochchi cells were expanded in RPMI containing 10% fetal bovine serum and implanted into NOD SCID mice. Once they reached approximately 100–150 mm... 3 The average tumor volume was used to randomly assign animals to different treatment arms. The study consisted of four treatment arms, each containing six to eight mice, with treatment lasting 63 days. TGI was calculated on day 41 when the load cell group was terminated, at which point the maximum permissible tumor burden was reached.

[0384] Administration of compound A at 100 mg / kg resulted in a TGI of 103%, while administration of topotecan at 1 mg / kg produced a TGI of 77% (dosing schedule shown in Table 5). The TGI in the combination arm was 106%, with 6 out of 6 animals showing complete regression by day 52. ​​These results highlight the potent anticancer efficacy of compound A in combination with the topoisomerase I inhibitor topotecan (see Table 5). Figure 3 (FIG. 3)).

[0385] Table 5: CDX Kuramochi research group treated with compound A and / or topotecan

[0386] Example 5 PARG-inhibited enzyme assay (TR-FRET) Enzyme EC 50 Measurement In a microtiter plate, the PARG enzyme is incubated with a compound or carrier (DMSO) and a biotinylated PARP-1 substrate. After adding the detection antibody and streptavidin-europene, and then incubating again, the fluorescence intensity of the plate is read. A low fluorescence intensity (DMSO) indicates no inhibition of enzyme activity, while a high fluorescence intensity (no enzyme) indicates complete inhibition of enzyme activity.

[0387] Material: Enzyme: PARG o hPARG: 250 pM, 1-976, His-labeled, Proteos, 2.0 mg / mL (17.9 µM) Substrate: 30 nM o Pre-incubation time for test compounds / enzymes: 1 hour o Enzyme / substrate reaction time: 10 minutes Substrate: hPARP1, His6-TEV labeled, 1.2 mg / mL (10.3 µM) Antibody detection: Anti-His monoclonal antibody - ULight, Perkin Elmer catalog number TRF0134-M Streptomycin-Europium: Perkin Elmer catalog number AD0062 Assay buffer: 50 mM Tris-HCl pH 7.4, 50 mM KCl, 3 mM EDTA, 0.4 mM EGTA, 1 mM DTT, 0.01% Tween 20, 0.01% BSA Temperature: 23℃ Total reaction volume: 20 µL Comparison: 0% Inhibition: DMSO 100% inhibition: No enzyme Enzyme reaction and detection: 1. Transfer 200 nL of 100x compound or DMSO into the appropriate well of a 384-well white polystyrene microtiter plate (Corning catalog number 3574).

[0388] 2. Transfer 10 μL of the enzyme at 2x final concentration in assay buffer or assay buffer alone to the appropriate well.

[0389] 3. Centrifuge the plate at 1000 rpm for 30 seconds.

[0390] 4. Incubate the plate at room temperature for 1 hour.

[0391] 5. Transfer 10 μL of 2x substrate in assay buffer to all test wells.

[0392] 6. Incubate the plate at room temperature for 10 minutes.

[0393] 7. Transfer 10 μL of a 3x mixture of 42 nM detection antibody and 2.25 nM streptavidin-europium in 50 mM Tris-HCl pH 7.4 to all test wells.

[0394] 8. Incubate the plate at room temperature for 1 hour.

[0395] 9. Read the plate using an Envision microplate reader.

[0396] Excitation: 317 nM Launch: 620nm Launch: 665nm Data Analysis: Calculate EC in the Collaborative Drug Discovery (CDD) library 50 Values. Using the 4-parameter inhibition model of Equation 1, the CDD was used as the curve fitted to the reaction (%) versus compound concentration (μM).

[0397] Formula 1: A. Fitting = (A+((BA) / (1+((C / x)^D)))) B. Reaction = (y - Fitting) The TR-FRET EC values ​​for compound A are provided in Table 6 below. 50 value.

[0398] TR-FRET: <= 0.1 µM Table 6: TR-FRET determination results of compounds of formula (I)

[0399] Example 6 A study evaluating the efficacy of the combination of compound A and topotecan (compound H) in the breast cancer model HCC1395. The combination effect of compound A with topotecan was evaluated using a cell line-derived xenograft (CDX) model of HCC1395, a tumor-transmitted breast cancer (TMBC) cell line with BRCA1 and BRCA2 mutations. For this study, HCC1395 cells were expanded in RPMI containing 10% fetal bovine serum and implanted into NOD mice. Once they reached approximately 100–150 mm... 3 The average tumor volume was used to randomly assign animals to different treatment arms. The study consisted of four treatment arms, with eight mice in each group, and the treatment lasted for 35 days. TGI was calculated on day 35.

[0400] Administration of compound A at 100 mg / kg resulted in a TGI of 56%, and administration of topotecan at 1 mg / kg produced a TGI of 98% (dosing schedule shown in Table 7). The TGI for the combination arm was 102%. These results highlight the potent anticancer efficacy of the combination of compound A and the topoisomerase I inhibitor topotecan (see Table 7). Figure 4 (FIG. 4)).

[0401] Table 7: CDX HCC1395 study group treated with compound A and / or topotecan

[0402] Example 7 A study evaluating the efficacy of the combination of compound A and compound J (fam-trastuzumab-drutecan-nxki) in the human lung cancer cell line NCI-H650. The combination effect of compound A and compound J (fam-trastuzumab-drutecan-nxki) was evaluated using a cell line-derived xenograft (CDX) model of the non-small cell lung cancer cell line NCI-H650. For this study, NCI-H650 cells were expanded in RPMI containing 10% fetal bovine serum and implanted into BALB / c nude mice. Once they reached approximately 100-150 mm... 3 The average tumor volume was used to randomly assign animals to different treatment arms. The study consisted of four treatment arms, with eight mice in each group, and the treatment lasted for 26 days.

[0403] Administration of compound A at 100 mg / kg resulted in a 5% TGI, while a single dose of compound J at 10 mg / kg produced a 100% TGI, with complete regression achieved in 3 out of 8 animals (dosing schedule shown in Table 8). The combination arm had a 106% TGI, with complete regression observed in 6 out of 8 animals on day 26. These results highlight the potent anticancer efficacy of the combination of compound A and compound J (see Table 8). Figure 5 (FIG. 5)).

[0404] Table 8: CDX NCI-H650 study groups treated with compound A and / or compound J

[0405] The specific embodiments of this disclosure described herein include the best mode known to the inventors for carrying out this disclosure. Variations of the disclosed embodiments will become apparent to those skilled in the art upon reading the foregoing description, and it is anticipated that those skilled in the art will employ such variations as appropriate. Therefore, the invention is intended to be practiced in ways other than those specifically described herein, and this disclosure includes all modifications and equivalents of the subject matter recited in the appended claims as permitted by applicable law. Furthermore, unless otherwise stated herein or where the context clearly contradicts it, the invention covers any combination of the foregoing elements in all possible variations.

[0406] All patent applications, patents, and print publications cited herein are incorporated herein in their entirety, except for any definitions, subject matter disclaimers, or denials, and unless the incorporated material is inconsistent with the express disclosure herein, in which case the content herein shall prevail.

[0407] Other embodiments are within the scope of the following claims.

Claims

1. A method of treating cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of a PARG inhibitor and administering to the subject a therapeutically effective amount of a topoisomerase inhibitor, wherein the PARG inhibitor is a compound of formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazole-yl; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d , where R d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

2. The method according to claim 1, wherein X 2 It is CH.

3. The method according to claim 1 or 2, wherein R 1 It is a methyl group.

4. The method according to claim 1 or 2, wherein R 1 It is a cyano group.

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

6. The method according to any one of claims 1 to 5, wherein R 2 A carbon atom attached to Ar, the carbon atom being located at a metaposition with an Ar atom attached to a nitrogen atom in the rest of the molecule.

7. The method according to any one of claims 1 to 6, wherein R 2 It is methyl, ethyl, difluoromethyl, trifluoromethyl, or cyano.

8. The method according to any one of claims 1 to 7, wherein R 2 It is difluoromethyl.

9. The method according to any one of claims 1 to 8, wherein ring B is morpholino, 1,1-dioxothiomorpholino, pyrrolidinyl, piperidinyl, 6-oxo-1,6-dihydropyridinyl, or piperazine.

10. The method according to any one of claims 1 to 9, wherein ring B is piperazine-based.

11. The method according to any one of claims 1 to 10, wherein R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d , where R d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

12. The method according to any one of claims 1 to 11, wherein R a It is hydrogen, C 1-4 Alkyl or C 1-4 Haloalkyl; and R b and R c Selected independently from C 1-6 Alkyl groups and hydrogen.

13. The method according to any one of claims 1 to 12, wherein R a It is hydrogen; R b and R c Each is C independently 1-6 Alkyl or hydroxyl.

14. The method according to any one of claims 1 to 13, wherein the PARG inhibitor is compound A: Compound A Or its pharmaceutically acceptable salt.

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

16. The method according to any one of claims 1 to 15, wherein the topoisomerase inhibitor is selected from: compound B, compound C, compound D, compound E, compound F and compound G or their pharmaceutically acceptable salts or hydrates.

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

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

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

20. The method according to any one of claims 1 to 14, wherein the topoisomerase inhibitor is 10-hydroxycamptothecin and topotecan, hexylresorcinol, eczetidine, delutec, or belotecidine.

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

22. The method according to any one of claims 1 to 20, 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.

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

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

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

26. The method according to any one of claims 1 to 24, wherein the PARG inhibitor and the topoisomerase inhibitor are in the same dosage form.

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

28. Use of PARG inhibitors in the preparation of medicaments for the treatment of cancer, wherein the PARG inhibitors are administered simultaneously or sequentially with topoisomerase inhibitors.

29. The use according to claim 27 or 28, wherein the PAGR inhibitor is a compound of formula I: (Formula I) Or its pharmaceutically acceptable salt, wherein: R 1 Selected from: cyano, C 1-2 Alkyl and C 1-2 Halogenated alkyl groups; Ar is 1,3,4-thiadiazole-2-yl or 1,2,4-thiadiazole-yl; X 2 Is it CH or CF? R 2 Selected from: C 1-3 Haloalkyl, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl and cyano groups; Ring B is R a R b and R c Substituted 5- or 6-membered heterocyclic alkyl groups; R a It is hydrogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, halogen, hydroxyl or -C(O)R d , where R d It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups); and R b and R c Selected independently from C 1-6 Alkyl, hydrogen, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

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

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

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

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

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

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

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

37. The use according to any one of claims 27 to 36, 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.

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

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

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