PARG inhibitors, methods of making and uses thereof

Abstract

A PARG inhibitor and its preparation method and use, specifically, to a compound as shown in formula (1) and its preparation method, and a composition containing the compound as shown in formula (1) and / or its pharmaceutically acceptable salt, the preparation method and its use as a PARG inhibitor in the preparation of antitumor drugs.

Description

PARG inhibitors and their preparation methods and uses Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and more specifically, to a class of PARG inhibitors having a structure as shown in formula (1), a preparation method thereof, and the use of such compounds in preparing pharmaceutical compositions for treating, regulating and / or preventing diseases mediated by PARG. Background Art

[0002] Poly(ADP-ribosyl)ation (PAR) is a process in eukaryotic cells whereby poly(ADP-ribose) polymers are covalently linked to glutamate and aspartate residues of receptor proteins under the catalysis of poly(ADP-ribose) polymerase, thereby achieving post-translational modification of proteins. Two types of enzymes participate in this modification process: poly(ADP-ribose) polymerase (PARP), which is responsible for modification, and poly(ADP-ribose) glycohyfrolase (PARG), which is responsible for demodification.

[0003] DNA breaks activate PARP, which recognizes and binds to DNA strand breaks, activating it and catalyzing the synthesis of PAR, which causes itself and its associated nuclear protein to become PARylated. PARylated nuclear proteins transmit DNA break signals, activating the DNA repair system. Self-modified PARP loses its affinity for DNA and falls off the DNA, allowing DNA repair enzymes to access the damaged site, excise, and repair the DNA strand break. Finally, PARG degrades the PAR on the PARP nuclear protein, restoring it to its unmodified form, completing the repair process. PARG has numerous biological functions, including involvement in cell cycle regulation, spindle assembly during mitosis, development, differentiation, cell death, and DNA repair. Existing studies have linked PARG to clinical diseases such as cancer, inflammation, and autoimmune disorders.

[0004] PARG gene silencing can reduce cell proliferation and enhance cell sensitivity to chemotherapeutic drugs, leading to the development of PARG inhibitors for oncology. Studies have shown that ovarian cancer cell lines and in vitro models derived from patient tissue are sensitive to PARG inhibitors. This sensitivity is due to DNA replication vulnerabilities that lead to replication fork stalling and sustained replication stress. PARG inhibitors cause synthetic lethality by inhibiting DNA replication factors [Cancer Cell, 2019, 35:519-533]. Other studies have found that PARG can act as an oncogene in hepatocellular carcinoma (HCC) by regulating PARG / DDB1 / c-Myc signaling and can be used as a biomarker to identify HCC patients who may benefit from anti-PD-1 therapy. These results suggest that combined inhibition of PARG and PD-1 is an effective novel combination strategy for HCC patients [J. Hepatol, 2022, 77:140-151]. Further studies have shown that PARG is a potential target for the treatment of pancreatic ductal adenocarcinoma (PDAC). In PDAC cell lines and mouse models, knocking down PARG can significantly inhibit PDAC tumor growth. Compared with cells with normal homologous repair, cells with homologous repair defects are more sensitive to PARG inhibitors [Cancer Res., 2019, 79: 4491-4502].

[0005] The development of PARG inhibitors is a significant unmet clinical need, but previously reported PARG inhibitors are primarily compounds such as tannic acid and gallic tannic acid, which suffer from poor drugability, including poor specificity and low oral bioavailability. Patent WO2021055744 discloses the following class of novel PARG inhibitors, which effectively inhibit PARG enzymatic activity in vivo. Representative compounds include Ref-01 (Example 38 in the patent, used as a control compound below).

[0006] However, current PARG inhibitors still have disadvantages such as insufficient activity or poor oral absorption. Therefore, there is an urgent need in this field to develop new PARG inhibitors with high activity and excellent oral absorption.

[0007] Summary of the Invention

[0008] The purpose of the present invention is to provide a new PARG inhibitor with high activity and excellent oral absorption, as well as its preparation method and application.

[0009] In the first aspect of the present invention, there is provided a compound having a structure as shown in formula (1), or an isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate thereof:

[0010] In formula (1):

[0011] The dotted line represents a chemical bond or does not exist, and the same ring atom in ring B does not form two double bond structures at the same time. Ring A and ring B are both aromatic;

[0012] U and V are each independently N or C, and U and V are not N at the same time;

[0013] W and X are each independently N, NR 7 or CR 7 ;

[0014] n is 0, 1, 2, 3 or 4;

[0015] Ring Y is a 4-14 membered heterocycloalkyl group; wherein the heterocycloalkyl group is optionally substituted with an oxo group (=O);

[0016] L is selected from the group consisting of none, a chemical bond, or -C(O)-;

[0017] R 1 and R 2 Independent as C 1-3 Alkyl, or R 1 and R 2 The C atoms connected to them form a 3-6 membered cyclic structure, the cyclic structure optionally containing 0, 1 or 2 heteroatoms independently selected from N, O, and S; and the cyclic structure is a saturated ring;

[0018] R 3 H, CN, C 1-3 Alkyl or halogenated C 1-3 alkyl;

[0019] R 4 Independent as C 1-3 Alkyl, optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkoxy or C 3-6 Cycloalkyl, or two R on the same C atom 4 The C atom connected thereto forms a 3-6 membered spirocyclic structure, the spirocyclic structure optionally containing 0, 1 or 2 heteroatoms selected from N, O, and S; and the spirocyclic structure is a saturated ring;

[0020] R 5 Selected from the following group: H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, NR a R b or -C 1-3 Alkylene-NR aR b , wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of: -OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl;

[0021] R a and R b Independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, or R a and R b The alkyl, cycloalkyl or heterocycloalkyl group is optionally substituted by one or more groups selected from the group consisting of OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl;

[0022] R 6 Selected from the following group: H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl or C 2-4 alkenyl;

[0023] When R 7 When connected to a C atom, R 7 Selected from the group consisting of H, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl; or when R 7 When connected to a N atom, R 7 Selected from the following group: H, C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0024] In another preferred embodiment, the compound of formula (1) has the structure shown in (2-1), (2-2) or (2-3):

[0025] Wherein, the definition of each group is as described in the first aspect of the present invention.

[0026] In another preferred embodiment, wherein the compound of formula (1) Select from the following groups:

[0027] Wherein, the definition of each group is as described in the first aspect of the present invention.

[0028] In another preferred embodiment, wherein the compound of formula (1) Select from the following groups:

[0029] Among them, L and R 5 Definitions are as described in the first aspect of the present invention.

[0030] In another preferred embodiment, wherein the compound of formula (1) Select from the following groups:

[0031] Wherein, L is selected from the following group: none, chemical bond or -CO-; R 5 Select from the following groups:

[0032] H, Me, Et,

[0033] In another preferred embodiment, wherein the compound of formula (1) Select from the following groups:

[0034] Among them, R 3 Definitions are as described in the first aspect of the present invention.

[0035] In another preferred embodiment, wherein the compound of formula (1) Select from the following groups:

[0036] In another preferred embodiment, wherein R 6 Selected from the group consisting of H, Me, Et, CH2F, CHF2, CF3, cyclopropyl or vinyl.

[0037] In another preferred embodiment, wherein R 7 Selected from the group consisting of H, F, Cl, Me, Et, CH2F, CHF2, CF3, CH2CF3 or cyclopropyl.

[0038] In another preferred embodiment, it is characterized in that the compound has a structure selected from the following group:

[0039] In the second aspect of the present invention, a pharmaceutical composition for treating, regulating and / or preventing diseases mediated by PARG is provided, which comprises a pharmaceutically acceptable excipient or carrier, and a compound as described in the first aspect of the present invention, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate as an active ingredient.

[0040] In another preferred embodiment, the PARG-mediated related disease is cancer, and the cancer is selected from solid tumors or blood tumors.

[0041] In another preferred embodiment, the solid tumor is selected from the group consisting of breast cancer, liver cancer, pancreatic ductal adenocarcinoma, ovarian cancer, cervical cancer, endometrial cancer, colorectal cancer, gastric cancer, lung cancer, kidney cancer, or a combination thereof.

[0042] In another preferred embodiment, the blood tumor is selected from the group consisting of leukemia, lymphoma, or a combination thereof.

[0043] In the third aspect of the present invention, there is provided a use of the compound as described in the first aspect of the present invention, or its isomers, polymorphs, pharmaceutically acceptable salts, hydrates or solvates, for preparing drugs for treating, regulating and / or preventing related diseases mediated by PARG.

[0044] In the fourth aspect of the present invention, a method for treating, regulating and / or preventing diseases mediated by PARG is provided, comprising the steps of administering the compound described in the first aspect of the present invention, or its isomers, polymorphs, pharmaceutically acceptable salts, hydrates or solvates to an individual in need.

[0045] In another preferred embodiment, the individual includes humans and non-human mammals.

[0046] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0047] After extensive and intensive research, including extensive screening and testing, the present inventors have discovered for the first time a class of compounds represented by formula (1) that exhibit significant therapeutic effects against diseases mediated by PARG. The compounds of the present invention exhibit excellent inhibitory activity against the PARG enzyme and also exhibit excellent cell proliferation inhibition activity against the ZR-75-1 cell line. Furthermore, the compounds exhibit favorable pharmacokinetic properties and are expected to exhibit significant tumor suppression and drugability. This is the basis for the completion of the present invention.

[0048] Compounds of the present invention and their synthesis

[0049] The present invention provides an inhibitor targeting PARG, namely a compound of formula (1), or its isomers, polymorphs, pharmaceutically acceptable salts (inorganic or organic salts), hydrates or solvates. Preferably, the compound of the present invention is as described in the first aspect.

[0050] The present invention also provides a method for preparing the compound of formula (1). The following specifically describes the method for preparing the compound of general formula (1), but these specific methods do not constitute any limitation to the present invention.

[0051] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, the amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art. On the one hand, the present invention also provides a method for preparing the compound represented by the general formula (1), which is prepared using the following general reaction scheme 1, reaction scheme 2 or reaction scheme 3:

[0052] General reaction scheme 1:

[0053] The embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein Y 1 、Y 2 、Y 3 Halogen alone, R 1 、R 2 、R 3 、R 4 、R 5 、R 6, U, W, X, A, B, Y, L and n are as defined above.

[0054] General reaction scheme 2:

[0055] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 2, wherein Y 1 、Y 2 、Y 3 Halogen alone, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , Y, L and n are as defined above.

[0056] General reaction scheme 3:

[0057] Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 3, wherein Y 1 、Y 2 、Y 3 , halogen alone, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , Y, L and n are as defined above.

[0058] Related definitions

[0059] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0060] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0061] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0062] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0063] In another preferred embodiment, the isomer is selected from the group consisting of enantiomers, cis-trans isomers, diastereomers, stereoisomers, or a combination thereof.

[0064] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically enriched diastereomerically enriched mixtures, are contemplated by the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are contemplated by the present invention.

[0065] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0066] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0067] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0068] Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

[0069] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0070] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0071] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, separation of enantiomers and diastereomers is typically accomplished by using chromatography, which utilizes a chiral stationary phase and is optionally combined with chemical derivatization (e.g., carbamate formation from an amine).

[0072] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14( 14 C). For example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0073] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0074] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0075] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0076] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0077] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0078] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring and a 6-10-membered ring, etc.

[0079] Unless otherwise specified, “C 1-6 "Alkyl" is used to represent a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 2-4 、C 2-6 、C 3-5 , C5 and C6 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and various branched chain isomers thereof, and the like.

[0080] Unless otherwise specified, “C 1-3 "Alkyl" is used to represent a straight or branched saturated aliphatic hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Non-limiting examples of alkyl groups include methyl, ethyl, propyl, n-propyl, isopropyl, and the like.

[0081] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic aliphatic hydrocarbon group consisting of 3 to 6 carbon atoms, including monocyclic and bicyclic ring systems. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0082] Unless otherwise specified, “C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. 1-3 Alkoxy groups include C 1-2 , C2 and C3 alkoxy, etc.; C 1-3 Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, and the like.

[0083] Unless otherwise specified, “C 2-6 "Alkenyl" is used to represent a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-3 、C 2-4 、C 2-6 、C 3-5 、C 4-6 , C5 and C6 alkenyl, etc.; the C 2-6 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-6 Non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, 2-methylpropenyl, 2-methylbutenyl, and the like.

[0084] Unless otherwise specified, “C 2-6 "Alkynyl" is used to represent a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-6 Alkynyl groups include C 2-3 、C 2-4 、C 2-6 、C 3-5 、C 4-6, C5 and C6 alkynyl, etc.; the C 2-6 Alkynyl groups can be monovalent, divalent, or polyvalent. 2-6 Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, 1-hexynyl, 2-methylpropynyl, 2-methylbutynyl, and the like.

[0085] Unless otherwise specified, "4-14 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4-14 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur atoms are optionally oxidized (i.e., C(=O), NO, SO and SO2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein the bicyclic and tricyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "4-14 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 4-14 membered heterocycloalkyl includes 5-7 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Non-limiting examples of 4-14 membered heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.

[0086] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0087] "Hydroxyl" refers to -OH.

[0088] "Cyano" refers to -CN.

[0089] Specific pharmaceutical and medical terms

[0090] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0091] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0092] "Active ingredient" refers to the compound shown in the general formula (1), as well as the pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0093] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0094] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0095] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0096] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0097] Route of administration

[0098] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0099] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0100] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0101] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0102] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0103] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0104] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0105] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0106] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0107] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0108] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0109] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0110] Compared with the prior art, the main advantages of the present invention include:

[0111] (a) Unexpectedly, compared with the control compound Ref-01, the compound of formula (1) of the present invention showed good in vitro PARG enzyme inhibitory activity.

[0112] (b) The compound of the present invention exhibits strong anti-proliferative activity against ZR-75-1 cells and HCC1806 XRCC1 KO cells and is more suitable for drug development.

[0113] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features.

[0114] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various modifications or alterations to the present invention, and such equivalents are also within the scope of the present invention.

[0115] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is performed by collecting diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer with CuKα phase irradiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0116] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were all by volume.

[0117] The present invention uses the following abbreviations: ACN represents acetonitrile; AcOH represents acetic acid; DIBAL-H represents diisobutylaluminum hydride; °C represents degrees Celsius; CuBr2 represents copper bromide; Cs2CO3 represents cesium carbonate; DCM represents dichloromethane; DIEA (DIPEA) represents diisopropylethylamine; NMM represents N-methylmorpholine; Dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA (EtOAc) represents ethyl acetate; EtOH represents ethanol; h represents hour; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; KOAc represents potassium acetate; K3PO4 represents potassium phosphate; LC-MS represents liquid chromatography-mass spectrometry; LiOH represents lithium hydroxide; MeI represents iodomethane; Me OH represents methanol; MS represents mass spectrometry; MTBE represents methyl tert-butyl ether; NaBH4 represents sodium borohydride; NaHCO3 represents sodium bicarbonate; NCS represents N-chlorosuccinimide; NBS represents N-bromosuccinimide; NIS represents N-iodosuccinimide; NMR represents nuclear magnetic resonance; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; Pd(OAc)2 represents palladium acetate; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; [Ir(OMe)(1,5-cod)]2 represents methoxy(cyclooctadiene)iridium dimer; PE represents petroleum ether; P2O5 represents phosphorus pentoxide; POCl3 represents phosphorus oxychloride; pre-HPLC represents preparative liquid chromatography; Se represents selenium; t- BuONO represents tert-butyl nitrite; TEA(Et3N) represents triethylamine; TFA represents trifluoroacetic acid; TLC represents thin layer chromatography; TsOH represents p-toluenesulfonic acid; Ruphos-Pd-G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); Ruphos represents 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; and Xantphos represents 4,5-bis(diphenylphosphino-9,9-dimethylxanthene).

[0118] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0119] Preparation Example 1: Synthesis of 2-bromo-5-(difluoromethyl)-1,3,4-selenadiazole (Intermediate 1)

[0120] Step 1: Synthesis of intermediate 1-1

[0121] Thiosemicarbazide (5 g, 54.9 mmol) was dissolved in EtOH (30 mL), and MeI (7.79 g, 54.9 mmol) was added. The reaction was heated to 80°C. TLC and LC-MS monitoring indicated that the reaction was complete. The reaction was cooled to 0°C to precipitate a white solid, which was filtered to obtain the intermediate 1-1 (10.1 g, yield exceeding 100%). ESI-MS m / z: 106.0 [M+H] + .

[0122] Step 2: Synthesis of Intermediate 1-2

[0123] Selenium powder (4.33 g, 54.9 mmol) was dissolved in EtOH (40 mL). NaBH4 (4.15 g, 109.8 mmol) was added portionwise under ice-cooling. A suspension of Intermediate 1-1 (10.1 g, 54.9 mmol) in EtOH (100 mL) was then added and the mixture was slowly warmed to room temperature. LC-MS monitoring indicated that the reaction was complete, with a large amount of solid precipitated. Intermediate 1-2 (4.9 g, 64% yield) was obtained by direct filtration as an off-white solid. ESI-MS m / z: 139.9 [M+H] + .

[0124] Step 3: Synthesis of Intermediates 1-3

[0125] Intermediate 1-2 (4.8 g, 34.8 mmol) was dissolved in POCl3 (20 mL), and difluoroacetic acid (3.3 g, 34.8 mmol) was added. The reaction was heated to 75°C and monitored by LC-MS. The reaction mixture was slowly poured into ice water, and the pH was adjusted to approximately 8 with saturated NaHCO3. The mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford Intermediate 1-3 (2.9 g, 42% yield) as a yellow solid. ESI-MS m / z: 199.9 [M+H] + .

[0126] Step 4: Synthesis of Intermediate 1

[0127] Intermediate 1-3 (2.8 g, 14.1 mmol) was dissolved in ACN (80 mL), and CuBr2 (3.8 g, 17.0 mmol) and tert-butyl nitrite (2.2 g, 21.2 mmol) were added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. Water was added, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford Intermediate 1 (2.4 g, 65% yield) as a yellow solid. ESI-MS m / z: 262.8 [M+H] + .

[0128] Intermediates 2 to 5 can be synthesized by a method similar to that of Intermediate 1.

[0129] Preparation Example 2: Synthesis of [(2R,5S)-5-methyl-1,4-oxazepine-2-yl]methanol (Intermediate 6)

[0130] Step 1: Synthesis of Intermediate 6-1

[0131] (S)-2-(Benzylamino)propan-1-ol (5 g, 30.26 mmol) and S-epichlorohydrin (4.20 g, 45.39 mmol) were dissolved in toluene (50 mL). Lithium perchlorate (4.83 g, 45.39 mmol) was added at room temperature and allowed to react for 24 hours. A solution of NaOH (2.42 g, 60.52 mmol) in MeOH (50 mL) was then slowly added under an ice bath and allowed to react for 3 days. The mixture was quenched with water and extracted with EA (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by reverse phase column chromatography to obtain intermediate 6-1 (1.3 g, 19%) as a colorless oil. ESI-MS m / z: 222.1 [M+H] + .

[0132] Step 2: Synthesis of Intermediate 6

[0133] Intermediate 6-1 (300 mg, 1.36 mmol) was dissolved in MeOH (20 mL), and Pd / C (30 mg, 10%) was added. The mixture was replaced with a hydrogen balloon and allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. Intermediate 6 (210 mg, yield exceeding 100%) was obtained by direct filtration as a grayish-colorless oil. ESI-MS m / z: 132.1 [M+H] + .

[0134] Preparation Example 3: Synthesis of (2R,5S)-2-(methoxymethyl)-5-methyl-1,4-oxazacyclohexane (Intermediate 7)

[0135] Step 1: Synthesis of Intermediate 7-1

[0136] Intermediate 6-1 (300 mg, 1.36 mmol) was dissolved in THF (20 mL). NaH (82 mg, 2.04 mmol) was added under ice-cooling and stirred for 30 minutes. MeI (290 mg, 2.04 mmol) was then added and the reaction mixture was slowly warmed to room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was quenched with water and extracted with EA (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 7-1 (240 mg, 75%) as a yellow oil. ESI-MS m / z: 236.2 [M+H] + .

[0137] Step 2: Synthesis of Intermediate 7

[0138] Intermediate 7-1 (240 mg, 1.02 mmol) was dissolved in MeOH (15 mL), and Pd / C (24 mg, 10%) was added. The mixture was replaced with a hydrogen balloon and allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. Intermediate 7 (190 mg, yield exceeding 100%) was obtained by direct filtration as a grayish-colorless oil. ESI-MS m / z: 146.1 [M+H] + .

[0139] Preparation Example 4: Synthesis of (2R,6S)-2-(methoxymethyl)-6-methyl-1,4-oxazacyclohexane (Intermediate 8)

[0140] Step 1: Synthesis of Intermediate 8-1

[0141] (S)-1-(Benzylamino)-2-propanol (1.4 g, 8.47 mmol) was dissolved in isopropanol (7 mL) and water (7 mL). S-epichlorohydrin (627 mg, 6.78 mmol) was added and allowed to react at room temperature for 5 h. NaOH (678 mg, 16.95 mmol) was then slowly added and allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was quenched with water and extracted with EA (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 8-1 (780 mg, 42%) as a colorless oil. ESI-MS m / z: 222.1 [M+H] + .

[0142] Step 2: Synthesis of Intermediate 8-2

[0143] Intermediate 8-1 (300 mg, 1.36 mmol) was dissolved in THF (20 mL). NaH (82 mg, 2.04 mmol) was added under ice-cooling and stirred for 30 minutes. MeI (290 mg, 2.04 mmol) was then added and the reaction mixture was slowly warmed to room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was quenched with water and extracted with EA (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford Intermediate 8-2 (250 mg, 78%) as a yellow oil. ESI-MS m / z: 236.2 [M+H] + .

[0144] Step 3: Synthesis of Intermediate 8

[0145] Intermediate 8-2 (250 mg, 1.06 mmol) was dissolved in MeOH (15 mL), and Pd / C (25 mg, 10%) was added. The mixture was replaced with a hydrogen balloon and allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. Intermediate 8 (196 mg, yield exceeding 100%) was obtained by direct filtration as a grayish-colorless oil. ESI-MS m / z: 146.1 [M+H] + .

[0146] Preparation Example 5: Synthesis of (6S,9aR)-6-methyl-1,3,4,6,7,8,9,9a-octahydro[1,4]oxazino[4,3-a]pyrazine (Intermediate 9)

[0147] Step 1: Synthesis of Intermediate 9-1

[0148] (S)-(-)-Diaminopropane dihydrochloride (10 g, 68 mmol) was dissolved in MeOH (100 mL). DIEA (14.03 g, 108.81 mmol) and benzaldehyde (14.43 g, 136 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. NaBH4 (7.79 g, 54.9 mmol) was then added and the reaction was continued at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 30 / 1 to 10 / 1) to afford Intermediate 9-1 (10.3 g, 60%) as a colorless oil. ESI-MS m / z: 255.2 [M+H] + .

[0149] Step 2: Synthesis of Intermediate 9-2

[0150] Intermediate 9-1 (10.3 g, 40.55 mmol) was dissolved in toluene (50 mL), and TEA (12.29 g, 121.65 mmol) was added. The temperature was raised to 40°C, and a solution of ethyl 2,3-dibromopropionate (11.60 g, 44.61 mmol) in toluene (50 mL) was slowly added dropwise. The temperature was raised to 80°C for reaction. LC-MS monitoring confirmed the complete reaction of the starting material. Extraction was performed with EA (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 30 / 1 to 10 / 1) to afford Intermediate 9-2 (7.1 g, 50%) as a colorless oil. ESI-MS m / z: 353.2 [M+H] + .

[0151] Step 3: Synthesis of Intermediate 9-3

[0152] Intermediate 9-2 (7.1 g, 20.17 mmol) was dissolved in THF (50 mL) and LiAlH4 (1 M, 24.20 mmol) was added under ice-cooling. The reaction was continued under ice-cooling. LC-MS monitoring indicated that the reaction of the starting material was complete. Water and 15% aqueous sodium hydroxide solution were added to quench the reaction. The mixture was filtered and concentrated to obtain Intermediate 9-3 (6.1 g, 98%) as a colorless oil. ESI-MS m / z: 311.2 [M+H] + .

[0153] Step 4: Synthesis of Intermediate 9-4

[0154] Intermediate 9-3 (6.1 g, 19.68 mmol) was dissolved in MeOH (50 mL) and Pd / C (610 mg, 10%) was added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was filtered, concentrated, and purified by column chromatography (DCM / MeOH = 20 / 1 to 5 / 1) to afford Intermediate 9-4 (2.8 g, yield exceeding 100%) as a colorless oil. ESI-MS m / z: 131.1 [M+H] + .

[0155] Step 5: Synthesis of Intermediate 9-5

[0156] Intermediate 9-4 (2.8 g, 21.54 mmol) was dissolved in methanol (50 mL). TEA (6.53 g, 64.62 mmol) and (Boc)2O (9.40 g, 43.08 mmol) were added under ice-cooling. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The reaction was then concentrated, and EtOH (50 mL) and water (50 mL) were added, followed by NaOH (2.58 g, 64.62 mmol). The reaction was heated to 80°C, and LC-MS monitoring indicated that the reaction was complete. The reaction was concentrated to remove most of the ethanol, and the pH was adjusted to approximately 10 with 1N hydrochloric acid. The product was extracted with DCM (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 30 / 1 to 20 / 1) to afford Intermediate 9-5 (3.8 g, 77%) as a colorless oil. ESI-MS m / z: 231.2 [M+H] + .

[0157] Step 6: Synthesis of Intermediate 9-6

[0158] Intermediate 9-5 (2 g, 8.70 mmol) was dissolved in DCM (30 mL). TEA (2.63 g, 26.09 mmol) and chloroacetyl chloride (983 mg, 8.70 mmol) were added under ice-cooling. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 1 / 1) to afford Intermediate 9-6 (1.5 g, 56%) as a colorless oil. ESI-MS m / z: 307.1 [M+H] + .

[0159] Step 7: Synthesis of Intermediate 9-7

[0160] Intermediate 9-6 (1.5 g, 4.90 mmol) was dissolved in THF (30 mL) and potassium tert-butoxide (660 mg, 5.88 mmol) was added under ice-cooling. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (30 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 1 / 1) to afford Intermediate 9-7 (940 mg, 71%) as a colorless oil. ESI-MS m / z: 271.2 [M+H] + .

[0161] Step 8: Synthesis of Intermediate 9-8

[0162] Intermediate 9-7 (940 mg, 3.48 mmol) was dissolved in DCM (20 mL) and HCl / Dioxane (4 M, 2 mL) was added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was concentrated to afford intermediate 9-8 as a pale yellow solid (880 mg, yield exceeding 100%). ESI-MS m / z: 171.1 [M+H] + .

[0163] Step 9: Synthesis of Intermediates 9-9 and 9

[0164] Intermediate 9-8 (880 mg, 5.18 mmol) was dissolved in THF (20 mL) and LiAlH4 (688 mg, 18.12 mmol) was added under ice-cooling. The temperature was raised to 80°C for reaction. LC-MS monitoring indicated that the reaction was complete. Isopropanol was added under ice-cooling for quenching. The mixture was filtered and concentrated to obtain Intermediate 9-9 (520 mg, 64%) as a colorless oil. ESI-MS m / z: 157.1 [M+H] + Intermediate 9-9 was further resolved by SFC to obtain intermediate 9, ESI-MS m / z: 157.1 [M+H] + .

[0165] Example 1: Synthesis of 1-(5-(difluoromethyl)-1,3,4-selenadiazole-2-yl)-N-(1-methylcyclopropyl)-4-(piperazin-1-yl)-1H-indazole-6-sulfonamide (Compound 1)

[0166] Step 1: Synthesis of 1-1

[0167] 6-Bromo-4-fluoro-1H-indazole (5 g, 23.26 mmol) and benzyl mercaptan (2.89 g, 23.26 mmol) were dissolved in dioxane (50 mL). Pd2(dba)3 (2.10 g, 2.33 mmol), Xantphos (2.70 g, 4.65 mmol), and DIEA (6 g, 46.52 mmol) were then added. The mixture was reacted at 100°C under nitrogen atmosphere. LC-MS monitoring indicated that the reaction was complete. The filtrate was filtered, diluted with water, and extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford compound 1-1 (4.80 g, 80% yield) as a yellow solid. ESI-MS m / z: 259.0 [M+H] + .

[0168] Step 2: Synthesis of 1-2

[0169] 1-1 (4.80 g, 18.53 mmol) and intermediate 1 (4.86 g, 18.53 mmol) were dissolved in DMF (50 mL), and Cs2CO3 (12.08 g, 37.06 mmol) was added. The reaction temperature was raised to 60°C. LC-MS monitoring indicated that the reaction was complete. The reaction solution was slowly poured into water and extracted with EA (50 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford compound 1-2 (7.20 g, 88% yield) as a yellow solid. ESI-MS m / z: 440.9 [M+H] + .

[0170] Step 3: Synthesis of 1-3

[0171] 1-2 (7.20 g, 16.36 mmol) was dissolved in ACN (60 mL), and acetic acid (6 mL) and water (6 mL) were added. 1,3-dichloro-5,5-dimethylhydantoin (8.06 g, 40.90 mmol) was added under ice-cooling. The reaction was maintained at 0°C, and solids gradually precipitated. LC-MS monitoring indicated that the reaction of the raw material was complete. The mixture was directly filtered and rinsed with a small amount of ACN to obtain compound 1-3 (5.10 g, 88% yield) as a white solid. ESI-MS m / z: 416.8 [M+H] + .

[0172] Step 4: Synthesis of 1-4

[0173] 1-3 (200 mg, 0.48 mmol) was dissolved in DCM (10 mL). 1-Methylcyclopropylamine hydrochloride (62 mg, 0.58 mmol) and TEA (145 mg, 1.44 mmol) were added under ice-cooling. The reaction temperature was gradually raised to room temperature. LC-MS monitoring confirmed the complete reaction of the starting material. Extraction was performed with DCM (20 mL x 3). The organic phases were combined, dried, and concentrated to afford compound 1-4 as a light yellow solid (180 mg, 83% yield). ESI-MS m / z: 451.9 [M+H] + .

[0174] Step 5: Synthesis of 1-5

[0175] 1-4 (180 mg, 0.40 mmol) was dissolved in DMSO (10 mL), and N-Boc-piperazine (75 mg, 0.40 mmol) and DIEA (206 mg, 1.60 mmol) were added. The reaction temperature was raised to 130°C. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to obtain compound 1-5 (160 mg, 65% yield) as a pale yellow solid. ESI-MS m / z: 618.1 [M+H] + .

[0176] Step 5: Synthesis of compound 1

[0177] 1-5 (160 mg, 0.26 mmol) was dissolved in DCM (10 mL) and TFA (2 mL) was added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The product was then spin-dried and neutralized with saturated NaHCO₃. The product was extracted with EA (20 mL x 3). The organic phases were combined, dried, and concentrated. Pre-HPLC analysis yielded compound 1 (80 mg, 60% yield) as a pale yellow solid.

[0178] 1 H NMR (400MHz, DMSO-d6): δ9.49(s,1H),8.55(s,1H),8.38(s,1H),7.46(t,J=54.6Hz,1H),7.22(s, 1H),3.83(m,2H),3.67-3.60(m,2H),3.39(m,4H),1.07(s,3H),0.66(m,2H),0.41(m,2H); ESI-MS m / z:518.0[M+H] + .

[0179] Example 2-60: Synthesis of Compounds 2-36, B1-B8, B13-B20, B25-B32

[0180] Intermediates 1-5 were reacted with nitrogen atoms of differently substituted indazoles for substitution reaction, corresponding amines were used as raw materials for substitution reaction with sulfonyl chloride, intermediates 6-9 and other corresponding amines were used as raw materials for substitution or coupling reaction with the parent core skeleton, and target compounds 2-36, B1-B8, B13-B20, and B25-B32 were obtained according to a similar synthesis method in Example 1.

[0181] Example 61: Synthesis of 1-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-N-(1-methylcyclopropyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-6-sulfonamide (Compound 37)

[0182] Step 1: Synthesis of 37-1

[0183] 6-Bromo-4-chloro-1H-indazole (2 g, 8.64 mmol) and benzyl mercaptan (1.07 g, 8.64 mmol) were dissolved in dioxane (50 mL). Pd2(dba)3 (791 mg, 0.86 mmol), Xantphos (1.00 g, 1.73 mmol), and DIEA (2.23 g, 17.28 mmol) were added. The mixture was reacted at 100°C under nitrogen atmosphere. LC-MS monitoring indicated that the reaction was complete. The filtrate was filtered, diluted with water, and extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford compound 37-1 (2.10 g, 88% yield) as a yellow solid. ESI-MS m / z: 275.0 [M+H] + .

[0184] Step 2: Synthesis of 37-2

[0185] 37-1 (2.10 g, 7.66 mmol) and intermediate 1 (2.00 g, 7.66 mmol) were dissolved in DMF (30 mL), and Cs2CO3 (4.99 g, 15.32 mmol) was added. The reaction temperature was raised to 60°C. LC-MS monitoring indicated that the reaction was complete. The reaction solution was slowly poured into water and extracted with EA (50 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 20 / 1 to 10 / 1) to afford compound 37-2 (2.90 g, 83% yield) as a yellow solid. ESI-MS m / z: 456.9 [M+H] + .

[0186] Step 3: Synthesis of 37-3

[0187] 37-2 (2.90 g, 6.36 mmol) was dissolved in ACN (30 mL), and acetic acid (3 mL) and water (3 mL) were added. 1,3-Dichloro-5,5-dimethylhydantoin (3.13 g, 15.90 mmol) was then added under ice-cooling. The reaction was maintained at 0°C, and solids gradually precipitated. LC-MS monitoring indicated that the reaction was complete. The mixture was directly filtered and rinsed with a small amount of ACN to obtain compound 37-3 (2.62 g, 95% yield) as a white solid. ESI-MS m / z: 432.8 [M+H]+ .

[0188] Step 4: Synthesis of 37-4

[0189] 37-3 (200 mg, 0.46 mmol) was dissolved in DCM (10 mL). 1-Methylcyclopropylamine hydrochloride (58 mg, 0.55 mmol) and TEA (139 mg, 1.38 mmol) were added under ice-cooling. The reaction was gradually warmed to room temperature. LC-MS monitoring confirmed the complete reaction of the starting material. Extraction was performed with DCM (20 mL*3). The organic phases were combined, dried, and concentrated to afford compound 37-4 as a light yellow solid (130 mg, yield 61%). ESI-MS m / z: 467.9 [M+H] + .

[0190] Step 5: Synthesis of 37-5

[0191] 37-4 (130 mg, 0.28 mmol) and tert-butyl 3,6-dihydro-4-[[(trifluoromethyl)sulfonyl]oxy]-1(2H)-picolinate (139 mg, 0.42 mmol) were dissolved in Dioxane / H2O (10 mL / 1 mL). Pd(dppf)Cl2 (20 mg, 0.03 mmol) and K3PO4 (119 mg, 0.56 mmol) were added. The reaction temperature was raised to 100°C. LC-MS monitoring indicated that the reaction was complete. Extraction with EA (20 mL*3) was performed, and the organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to obtain compound 37-5 (60 mg, 35% yield) as a pale yellow solid. ESI-MS m / z: 615.1 [M+H] + .

[0192] Step 5: Synthesis of compound 37

[0193] 37-5 (60 mg, 0.10 mmol) was dissolved in DCM (5 mL) and TFA (1 mL) was added. The reaction was allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was then spin-dried and neutralized with saturated NaHCO₃. The mixture was extracted with EA (20 mL x 3). The organic phases were combined, dried, and concentrated. Pre-HPLC analysis yielded compound 37 (30 mg, 59% yield) as a pale yellow solid.

[0194] 1H NMR (400MHz, DMSO-d6): δ9.41(s,1H),8.52(s,1H),8.35(s,1H),7.56(t,J=52.6Hz,1H),7.32(s,1H) ,5.52(s,1H),3.69(m,2H),3.49(m,2H),2.23(m,2H),1.09(s,3H),0.65(m,2H),0.43(m,2H); ESI-MS m / z:515.0[M+H] + .

[0195] Example 62: Synthesis of Compound 38

[0196] Using 1-cyanocyclopropylamine hydrochloride as raw material, the target compound 38 was obtained according to a similar synthesis method in Example 61.

[0197] Example 63: Synthesis of 1-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-N-(1-methylcyclopropyl)-4-(piperidin-4-yl)-1H-indazole-6-sulfonamide (Compound 39)

[0198] 37 (20 mg, 0.04 mmol) was dissolved in MeOH (5 mL), and Pd / C (5 mg, 10%) was added. The atmosphere was replaced with hydrogen and the reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The product was filtered, concentrated, and pre-HPLC analysis was performed to obtain compound 39 (15 mg, 75% yield) as a pale yellow solid.

[0199] 1 H NMR (400MHz, DMSO-d6): δ9.42(s,1H),8.50(s,1H),8.36(s,1H),7.53(t,J=53.6Hz,1H),7.31 (s,1H),3.49(m,4H),2.09(m,1H),1.69(m,4H),1.07(s,3H),0.67(m,2H),0.44(m,2H); ESI-MS m / z:517.0[M+H] + .

[0200] Example 64: Synthesis of Compound 40

[0201] Using 38 as starting material, the target compound 40 was obtained according to a similar synthetic method in Example 63.

[0202] Example 65: Synthesis of 1-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-4-(4-isobutyrylpiperazin-1-yl)-N-(1-methylcyclopropyl)-1H-indazole-6-sulfonamide (Compound 41)

[0203] 1 (30 mg, 0.06 mmol) and isobutyric acid (6 mg, 0.06 mmol) were dissolved in DMF (2 mL), followed by the addition of DIEA (15 mg, 0.12 mmol) and HATU (27 mg, 0.07 mmol). The reaction was allowed to react at room temperature. LC-MS monitoring indicated the reaction was complete. The product was poured into water (20 mL) and extracted with EA (10 mL x 3). The combined organic phases were dried, concentrated, and purified by column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to afford Compound 41 (25 mg, 74% yield) as a yellow solid.

[0204] 1 H NMR (400MHz, DMSO-d6): δ9.29(s,1H),8.65(s,1H),8.33(s,1H),7.45(t,J=54.4Hz,1H),7.23(s,1H),3.81(m,2 H),3.65(m,2H),3.49(m,4H),2.29(m,1H),1.46(d,J=6.6Hz,6H),1.09(s,3H),0.67(m,2H),0.43(m,2H); ESI-MS m / z:588.1[M+H] + .

[0205] Examples 66-82: Synthesis of Compounds 42-50, B9-B12, B21-B24

[0206] Using 1, 18 and the corresponding carboxylic acids as raw materials, the target compounds 42-50, B9-B12, B21-B24 were obtained according to a similar synthetic method in Example 65.

[0207] Examples 83-88: Synthesis of Compounds B33-B34, B36-B39

[0208] Using 1-(fluoromethyl)cyclopropylamine hydrochloride as a starting material, compound B33-3 was obtained according to a similar synthesis method in Example 1. Subsequently, using B33-3 and the corresponding carboxylic acid as starting materials, target compounds B33-B34 and B36-B39 were obtained according to a similar synthesis method in Example 65.

[0209] Example 89: Synthesis of 4-(1-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-6-(N-(1-methylcyclopropyl)sulfamoyl)-1H-indazol-4-yl)-N,N-dimethylpiperazine-1-carboxamide (Compound 51)

[0210] 1 (50 mg, 0.10 mmol) was dissolved in DCM (5 mL), followed by the addition of DIEA (62 mg, 0.48 mmol) and triphosgene (12 mg, 0.04 mmol). The mixture was allowed to react at room temperature for 1 h, followed by the addition of dimethylamine hydrochloride (10 mg, 0.12 mmol). LC-MS monitoring indicated the reaction was complete. The mixture was poured into water (20 mL) and extracted with DCM (10 mL x 3). The organic phases were combined, dried, and concentrated. Pre-HPLC analysis yielded Compound 51 (13 mg, 23% yield) as a yellow solid.

[0211] 1 H NMR (400MHz, DMSO-d6): δ8.91(s,1H),8.49(s,1H),8.29(s,1H),7.45(t,J=53.6Hz,1H),7.17(s,1H ),3.46–3.36(m,8H),2.81(s,6H),1.08(s,3H),0.66(t,J=5.5Hz,2H),0.40(q,J=4.8Hz,2H); ESI-MS m / z:589.1[M+H] + .

[0212] Examples 90-95: Synthesis of Compounds 52-56 and B35

[0213] Using 1, 18, B33-3 and the corresponding amine as raw materials, the target compounds 52-56 and B35 were obtained according to a similar synthetic method in Example 89.

[0214] Example 96: Synthesis of 3-(5-(difluoromethyl)-1,3,4-selenadiazol-2-yl)-7-((3S,5S)-3,5-dimethylpiperazin-1-yl)-1-methyl-N-(1-methylcyclopropyl)-1H-indazole-5-sulfonamide (Compound 57)

[0215] Step 1: Synthesis of 57-1

[0216] 5-Bromo-7-chloroindazole (10 g, 43.20 mmol) and benzyl mercaptan (16.10 g, 129.60 mmol) were dissolved in dioxane (200 mL). Pd2(dba)3 (1.98 g, 2.16 mmol), Xantphos (2.50 g, 4.32 mmol), and DIEA (16.72 g, 129.60 mmol) were then added. The mixture was reacted at 100°C under nitrogen atmosphere. LC-MS monitoring indicated that the reaction was complete. The filtrate was filtered, diluted with water, and extracted with EA (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford compound 57-1 (11.20 g, 95% yield) as a pale yellow solid. ESI-MS m / z: 275.0 [M+H] + .

[0217] Step 2: Synthesis of 57-2

[0218] 57-1 (11.20 g, 40.88 mmol) was dissolved in DCM (100 mL), followed by the addition of 3,4-dihydro-2H-pyran (10.32 g, 122.64 mmol) and p-toluenesulfonic acid monohydrate (1.56 g, 8.18 mmol). The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was diluted with water and extracted with DCM (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to afford compound 57-2 (8.78 g, 60% yield) as a yellow solid. ESI-MS m / z: 359.1 [M+H] + .

[0219] Step 3: Synthesis of 57-3

[0220] Methoxy(cyclooctadiene)iridium dimer (2.44 g, 3.68 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.98 g, 7.36 mmol), and pinacol diboron (18.68 g, 73.59 mmol) were added to MTBE (100 mL), replaced with argon, and stirred at room temperature for 10 minutes. A solution of 57-2 (8.78 g, 24.53 mmol) in MTBE (50 mL) was then added, replaced with argon, and reacted at 80°C. LC-MS monitoring indicated that the reaction of the raw materials was complete. The mixture was diluted with water and extracted with EA (100 mL*3). The organic phases were combined, dried, and concentrated to give compound 57-3 (11.72 g, 99% yield) as a brown viscous substance. ESI-MS m / z: 485.2 [M+H] + .

[0221] Step 4: Synthesis of 57-4

[0222] 57-3 (11.72 g, 24.20 mmol) and intermediate 1 (6.34 g, 24.20 mmol) were dissolved in toluene / water (100 mL / 50 mL). Pd(OAc)2 (4.99 g, 15.32 mmol), Xantphos (4.99 g, 15.32 mmol), and N-methylmorpholine (4.99 g, 15.32 mmol) were added and reacted at room temperature. LC-MS monitoring indicated that the reaction of the starting materials was complete. The mixture was diluted with water and extracted with EA (100 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to give compound 57-4 (3.27 g, 25% yield) as a brown solid. ESI-MS m / z: 541.0 [M+H] + .

[0223] Step 5: Synthesis of 57-5

[0224] 57-4 (3.27 g, 6.06 mmol) was dissolved in DCM (50 mL) and TFA (5 mL) was added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. Saturated NaHCO₃ was added for neutralization and the mixture was extracted with EA (50 mL*3). The organic phases were combined, dried, and concentrated to afford compound 57-5 (2.70 g, yield 99%) as a white solid. ESI-MS m / z: 456.9 [M+H] + .

[0225] Step 6: Synthesis of 57-6

[0226] 57-5 (2.70 g, 5.92 mmol) was dissolved in DMF (30 mL), and Cs2CO3 (3.86 g, 11.84 mmol) and MeI (1.68 g, 11.84 mmol) were added and reacted at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was diluted with water and extracted with EA (50 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford compound 57-6 (1.95 g, 70% yield) as a brown solid. ESI-MS m / z: 471.0 [M+H] + .

[0227] Step 7: Synthesis of 57-7

[0228] 57-6 (1.95 g, 4.15 mmol) was dissolved in ACN (20 mL), and acetic acid (2 mL) and water (2 mL) were added. 1,3-Dichloro-5,5-dimethylhydantoin (2.04 g, 10.38 mmol) was then added under ice-cooling. The reaction was maintained at 0°C, and solids gradually precipitated. LC-MS monitoring indicated that the reaction was complete. The mixture was directly filtered and rinsed with a small amount of ACN to obtain compound 57-7 (1.57 g, 85% yield) as a white solid. ESI-MS m / z: 446.9 [M+H] + .

[0229] Step 8: Synthesis of 57-8

[0230] Compound 57-7 (300 mg, 0.67 mmol) was dissolved in DCM (10 mL). 1-Methylcyclopropylamine hydrochloride (72 mg, 0.67 mmol) and TEA (204 mg, 2.02 mmol) were added under ice-cooling. The reaction mixture was gradually warmed to room temperature. LC-MS monitoring confirmed the complete reaction. Extraction was performed with DCM (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford compound 57-8 (246 mg, 76% yield) as a pale yellow solid. ESI-MS m / z: 482.0 [M+H] + .

[0231] Step 9: Synthesis of 57-9

[0232] 57-8 (246 mg, 0.51 mmol) and tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (110 mg, 0.51 mmol) were dissolved in dioxane (10 mL). Ruphos-Pd-G3 (42 mg, 0.05 mmol), Ruphos (47 mg, 0.10 mmol), and Cs2CO3 (332 mg, 1.02 mmol) were added. The reaction temperature was raised to 100°C. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (20 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain compound 57-9 (30 mg, 9% yield) as a pale yellow solid. ESI-MS m / z: 660.1 [M+H] + .

[0233] Step 10: Synthesis of compound 57

[0234] 57-9 (30 mg, 0.05 mmol) was dissolved in DCM (5 mL) and TFA (1 mL) was added. The reaction was allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. The product was then spin-dried and neutralized with saturated NaHCO₃. The product was extracted with EA (20 mL x 3). The organic phases were combined, dried, and concentrated. Pre-HPLC analysis yielded compound 57 (15 mg, 59% yield) as a pale yellow solid.

[0235] 1 H NMR (400MHz, DMSO-d6): δ8.56(s,1H),8.17(s,1H),7.70-7.38(m,2H),4.49(s,3H), 3.23-2.93(m,6H),1.15-1.08(m,3H),1.03(s,3H),0.98-0.93(m,3H),0.62(t,J=5.0Hz,2H),0.38(q,J=4.7Hz,2H); ESI-MS m / z:560.1[M+H] + .

[0236] Examples 97-115: Synthesis of Compounds 58-76

[0237] Using the corresponding amine and the corresponding halogenated hydrocarbon as raw materials, the target compound 58-76 was obtained according to a similar synthesis method in Example 96.

[0238] Example 116: Synthesis of 3-(5-(difluoromethyl)-1,3,4-selenadiazole-2-yl)-8-((3S,5S)-3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (Compound 77)

[0239] Step 1: Synthesis of 77-1

[0240] 5-Bromo-3-chloropyridine-2-carbonitrile (10 g, 45.99 mmol) was dissolved in DCM (150 mL). DIBAL-H (1.5 M, 137.96 mmol) was added at -78°C. The mixture was allowed to react for 2 h at -78°C, then slowly warmed to room temperature. LC-MS monitoring confirmed the complete reaction. The mixture was quenched by the slow addition of MeOH under ice-cooling, filtered, and concentrated to afford Compound 77-1 (9.10 g, 90% yield) as a yellow solid. ESI-MS m / z: 220.9 [M+H]+.

[0241] Step 2: Synthesis of 77-2

[0242] 77-1 (6.10 g, 27.73 mmol) was dissolved in DCM (100 mL), and TEA (5.6 g, 55.45 mmol) and ethyl oxalyl chloride (4.54 g, 33.28 mmol) were added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was diluted with water and extracted with DCM (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to afford compound 77-2 (6.40 g, 72% yield) as a white solid. ESI-MS m / z: 321.0 [M+H] + .

[0243] Step 3: Synthesis of 77-3

[0244] 77-2 (6.40 g, 20 mmol) was dissolved in POCl3 (60 mL), and P2O5 (14.20 g, 100 mmol) was added. The reaction was carried out at 110°C. LC-MS monitoring indicated that the reaction was complete. The mixture was concentrated, diluted with water, neutralized with NaHCO3, and extracted with EA (100 mL*3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to give compound 77-3 (4.70 g, yield 78%) as a yellow solid. ESI-MS m / z: 302.9 [M+H] + .

[0245] Step 4: Synthesis of 77-4

[0246] 77-3 (4.70 g, 15.56 mmol) and benzyl mercaptan (1.93 g, 15.56 mmol) were dissolved in dioxane (50 mL), followed by the addition of Pd2(dba)3 (1.43 g, 1.56 mmol), Xantphos (1.80 g, 3.11 mmol), and DIEA (4.01 g, 31.12 mmol). The reaction was carried out under nitrogen at 100°C. LC-MS monitoring indicated that the reaction was complete. The filtrate was filtered, diluted with water, and extracted with EA (100 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 3 / 1) to afford compound 77-4 (4.74 g, 88% yield) as a yellow solid. ESI-MS m / z: 347.0 [M+H] + .

[0247] Step 5: Synthesis of 77-5

[0248] 77-4 (4.74 g, 13.70 mmol) was dissolved in EtOH (80 mL), and hydrazine hydrate (8.06 g, 137.0 mmol) was added. The reaction was carried out at 80°C. LC-MS monitoring showed that the reaction of the raw material was complete. The reaction was cooled to 0°C, and a large amount of solid precipitated. The yellow solid compound 77-5 (4.02 g, yield 88%) was obtained by filtration. ESI-MS m / z: 333.0 [M+H] + .

[0249] Step 6: Synthesis of 77-6

[0250] 77-5 (4.02 g, 12.11 mmol) was dissolved in DCM (50 mL), and TEA (3.67 g, 36.33 mmol) and difluoroacetic anhydride (3.81 g, 18.17 mmol) were added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was extracted with DCM (50 mL*3), and the organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 10 / 1) to afford compound 77-6 (4.22 g, 85% yield) as a yellow solid. ESI-MS m / z: 411.0 [M+H] + .

[0251] Step 7: Synthesis of 77-7

[0252] 77-6 (3.0 g, 7.32 mmol) was dissolved in toluene (50 mL), and 2,4-diphenyl-1,3,2,4-diselenadiphosphinane-2,4-diselenide (4.67 g, 8.78 mmol) was added. The reaction was carried out at 110°C. LC-MS monitoring indicated that the reaction was complete. The mixture was directly dried and DCM (50 mL) was added. The insoluble matter was filtered off, and the mother liquor was concentrated and purified by column chromatography (DCM / MeOH = 10 / 1) to give a light yellow solid compound 77-7 (1.74 g, yield 52%). ESI-MS m / z: 456.9 [M+H] + .

[0253] Step 8: Synthesis of 77-8

[0254] 77-7 (1.36 g, 2.98 mmol) was dissolved in ACN (20 mL), and NBS (796 mg, 4.47 mmol) was added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. The mixture was extracted with EA (30 mL*3), and the organic phases were combined, dried, concentrated, and purified by column chromatography (DCM / MeOH = 20 / 1) to afford compound 77-8 (1.21 g, 76% yield) as a yellow solid. ESI-MS m / z: 534.9 [M+H] + .

[0255] Step 9: Synthesis of 77-9

[0256] 77-8 (500 mg, 0.94 mmol) was dissolved in acetic acid (6 mL) and water (1 mL). NCS (500 mg, 3.74 mmol) was added under ice-cooling and the reaction was maintained at 0°C. Solids gradually precipitated. LC-MS monitoring indicated complete reaction. The mixture was filtered and rinsed with a small amount of water to obtain compound 77-9 (600 mg, yield exceeding 100%) as a yellow solid. ESI-MS m / z: 510.8 [M+H] + .

[0257] Step 10: Synthesis of 77-10

[0258] 77-9 (600 mg, 1.18 mmol) was dissolved in THF (30 mL) and water (3 mL). 1-Methylcyclopropylamine hydrochloride (254 mg, 2.36 mmol) and NaHCO₃ (694 mg, 8.26 mmol) were added under ice-cooling. The reaction was maintained at 0°C and monitored by LC-MS. The reaction was complete. Extraction was performed with EA (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 1 / 1) to afford compound 77-10 (320 mg, 50% yield) as a pale yellow solid. ESI-MS m / z: 545.9 [M+H] + .

[0259] Step 11: Synthesis of 77-11

[0260] 77-10 (320 mg, 0.59 mmol) was dissolved in MeOH (10 mL), and DIEA (76 mg, 0.59 mmol) and Pd / C (32 mg, 10%) were added. The mixture was replaced with hydrogen and reacted at 50°C. LC-MS monitoring indicated that the reaction was complete. The mixture was filtered, concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 1 / 1) to afford compound 77-11 (255 mg, 93% yield) as a yellow solid. ESI-MS m / z: 467.9 [M+H] + .

[0261] Step 12: Synthesis of 77-12

[0262] 77-11 (255 mg, 0.55 mmol) was dissolved in DMF (10 mL), and DIEA (355 mg, 2.75 mmol) and SEMCl (278 mg, 1.65 mmol) were added. The reaction was allowed to proceed at room temperature. LC-MS monitoring indicated that the reaction was complete. Extraction was performed with EA (20 mL x 3). The organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 2 / 1) to obtain compound 77-12 (270 mg, 82% yield) as a pale yellow solid. ESI-MS m / z: 598.0 [M+H] + .

[0263] Step 13: Synthesis of 77-13

[0264] 77-12 (100 mg, 0.17 mmol) and tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (31 mg, 0.17 mmol) were dissolved in dioxane (10 mL). Ruphos-Pd-G3 (17 mg, 0.02 mmol), Ruphos (19 mg, 0.04 mmol), and Cs2CO3 (111 mg, 0.34 mmol) were added. The reaction temperature was raised to 100°C. LC-MS monitoring indicated that the reaction was complete. EA extraction (20 mL*3) was performed, and the organic phases were combined, dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1 to 1 / 1) to obtain compound 77-13 (80 mg, yield 61%) as a light yellow solid. ESI-MS m / z: 776.2 [M+H] + .

[0265] Step 14: Synthesis of Compound 77

[0266] 77-13 (80 mg, 0.10 mmol) was dissolved in DCM (5 mL) and TFA (2 mL) was added. The reaction was allowed to react at room temperature. LC-MS monitoring indicated that the reaction was complete. The product was then spin-dried and neutralized with saturated NaHCO₃. The product was extracted with EA (20 mL x 3). The organic phases were combined, dried, and concentrated. Pre-HPLC analysis yielded compound 77 (33 mg, 59% yield) as a pale yellow solid.

[0267] 1 H NMR (400MHz, DMSO-d6): δ9.63(s,1H),8.45(s,1H),7.94(s,1H),7.55(t,J=53.6Hz,1H),6.73(s,1H),3.58-3. 50(m,4H),3.15-3.09(m,2H),1.30(d,J=6.2Hz,6H),1.18(s,3H),0.80-0.69(m,2H),0.52-0.43(m,2H); ESI-MS m / z:546.1[M+H] + .

[0268] Examples 117-169: Synthesis of Compounds 78-84, B40-B48, B57-B66, B75-B83, B92-B100, and B109-B117

[0269] The corresponding amines were used as raw materials for substitution with sulfonyl chloride, and intermediates 6-intermediate 9 and other corresponding amines were used as raw materials for coupling with the parent core skeleton. The target compounds 78-84, B40-B48, B57-B66, B75-B83, B92-B100 and B109-B117 were obtained according to a similar synthesis method in Example 116.

[0270] Examples 170-204: Synthesis of Compounds B49-B50, B52-B56, B67-68, B70-B74, B84-B85, B87-B91, B101-B102, B104-B108, B118-B119, and B121-B125

[0271] Using N-BOC-piperazine instead of (2S,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester, compound B49-2 was obtained according to a similar synthesis method in Example 116.

[0272] Compound B67-9 can be obtained by using trifluoroacetic anhydride instead of difluoroacetic anhydride in the synthetic route of compound B49-2.

[0273] Compound B84-5 can be obtained by using 1-amino-1-cyclopropylcyanide hydrochloride instead of 1-methylcyclopropylamine hydrochloride in the synthetic route of compound B49-2.

[0274] Compound B101-5 can be obtained by using 1-(fluoromethyl)cyclopropylamine hydrochloride instead of 1-methylcyclopropylamine hydrochloride in the synthetic route of compound B49-2.

[0275] By using 3-methyl 3-aminooxetane instead of 1-methylcyclopropylamine hydrochloride in the synthetic route of compound B49-2, compound B118-5 can be obtained.

[0276] Subsequently, B49-2, B67-9, B84-5, B101-5, B118-5 and the corresponding carboxylic acids were used as raw materials, and the target compounds B49-B50, B52-B56, B67-68, B70-B74, B84-B85, B87-B91, B101-B102, B104-B108, B118-B119 and B121-B125 were obtained according to a similar synthesis method in Example 65.

[0277] Examples 205-209: Synthesis of Compounds B51, B69, B86, B103, and B120

[0278] Using B49-2, B67-9, B84-5, B101-5, and B118-5 as raw materials, the target compounds B51, B69, B86, B103, and B120 were obtained according to a similar synthesis method in Example 89.

[0279] Example 210: PARG enzyme activity screening

[0280] This study evaluated the ability of compounds of the invention to inhibit PARG protease activity in vitro. This experiment used the HTRF assay to characterize PARG inhibitors at 80 nM PARylation (Ice-Biosci). In this experiment, the final concentration of the enzyme was 150 pM and the final concentration of the substrate was 80 nM.

[0281] Compounds were dissolved in DMSO to obtain a 10 mM stock solution. Dose gradient reactions were prepared with an initial compound concentration of 10 μM and then four-fold dilutions were performed in DMSO (control compounds were three-fold diluted) for a total of ten data points. Using an ECHO acoustic pipetting device (LABCYTE), 0.1 μL of the diluted compound solution was transferred to a 384-well assay plate (Cornning). 2.5 μL of PARylation working solution was added to the 384-well assay plate, centrifuged at 1000 rpm for 1 minute, and incubated at 25°C for 60 minutes. Then, 5 μL of a mixture of His-Tb (Cisbio) and SA-XL665 (Cisbio) was added to the reaction and incubated at 25°C for 50 minutes. Detection was then performed using an HTS high-throughput drug screening multi-function microplate reader (BMG), and HTRF signals were read.

[0282] The inhibition rate of the compound on PARG protein activity was calculated using the following formula: Inhibition percentage (%) = 100*(average value of the negative control group - average value of the compound) / (average value of the negative control group - average value of the positive control group). The IC value of the compound was fitted according to the nonlinear regression equation using Graphpad 8.0 software. 50 Table 1 provides the inhibitory activity of the compounds of the present invention on PARG protein.

[0283] Table 1: Inhibitory activity of compounds on PARG enzyme (IC 50 ) A stands for:IC 50 <50nM; B means: 50nM≤IC 50 <500nM; C represents IC 50 ≥500nM

[0284] From the data in the table above, it can be seen that the compounds of the present invention have a strong ability to inhibit PARG enzyme activity. The inhibitory activity IC of most compounds on PARG is 50 The value was less than 50 nM.

[0285] Example 211: Screening of antiproliferative activity of compounds against ZR-75-1 cells

[0286] This study used a cell proliferation assay to analyze the cytotoxicity of ZR-75-1 breast cancer cells after four days of treatment with a PARG inhibitor. The ZR-75-1 cell line was purchased from Wuhan Pronocell Life Science Co., Ltd. and cultured in a cell culture incubator (Thermo) at 37 degrees Celsius and 5% carbon dioxide using 1640 medium. In this experiment, the PARG inhibitor was dissolved in DMSO to an initial concentration of 30 μM and diluted threefold in DMSO for a total of eight data points. The final concentration of DMSO was 0.5%.

[0287] ZR-75-1 cells were seeded in a white 96-well plate, with 80 μL of cell suspension per well, containing 5,000 ZR-75-1 cells. The plate was incubated overnight in a CO2 incubator. Then, 20 μL of PARG inhibitor solution at varying concentrations was added to the plate, and the 96-well plate was incubated for four days. A separate plate was prepared, and the signal value was read on the day of drug addition, which was used as the maximum value (Max value in the equation below) for data analysis. 25 μL of cell viability chemiluminescent detection reagent was added to each well of this plate, and the plate was incubated at room temperature for 10 minutes to allow the luminescent signal to stabilize. The readings were performed using a multi-label analyzer.

[0288] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (derived using the "log (inhibitor) vs. response -- Variable slope" mode in GraphPad Prism). Min: 0.5% DMSO-treated cell wells; Max: Day 0 wells. Table 2 provides the inhibitory activity of the compounds of the present invention on ZR-75-1 cell proliferation.

[0289] Example 212: Screening of antiproliferative activity of compounds against HCC1806 (XRCC1 KO) cells

[0290] This study used a cell proliferation assay to analyze the cytotoxicity of HCC1806 XRCC1 KO breast cancer cells after seven days of treatment with a PARG inhibitor. HCC1806 XRCC1 KO breast cancer cells were constructed at Beijing Aisiyipu Biotechnology Co., Ltd., with the parent cell line HCC1806 purchased from ATCC (American type culture collection). HCC1806 XRCC1 KO cells were cultured in RPMI medium (30-2001, ATCC) at 37°C in a cell culture incubator (CLM-240B-8-TC, ESCO) with 5% carbon dioxide. For this experiment, PARG inhibitors were dissolved in DMSO to a starting concentration of 3 μM and diluted threefold in DMSO for a total of ten data points. The final DMSO concentration was 0.3%.

[0291] HCC1806 XRCC1 KO cells were seeded in black 384-well plates (3764, Corning) with 40 μL of cell suspension per well, containing 250 HCC1806 XRCC1 KO cells. The plates were incubated overnight in a CO2 incubator. Then, 120 nL of PARG inhibitor solution at varying concentrations was added to the plates, and the 384-well plates were incubated for seven days. A separate plate was prepared, and the signal value was read on the day of drug addition, which was used as the maximum value (Max value in the equation below) for data analysis. 20 μL of cell viability chemiluminescent detection reagent was added to each well of this plate, and the cells were incubated at room temperature for 10 minutes to allow the luminescent signal to stabilize. The signals were read using a multilabel analyzer.

[0292] Raw data were converted to inhibition using the equation (Sample-Min) / (Max-Min)*100%. IC50 values ​​were then calculated using a four-parameter curve fit (using the "log (inhibitor) vs. response" - Variable slope mode in GraphPad Prism). Min: 0.5% DMSO-treated wells; Max: Day 0 wells. Table 2 provides the inhibitory activity of the compounds of the present invention against HCC1806 XRCC1 KO cell proliferation.

[0293] Table 2: Antiproliferative activity of compounds against ZR-75-1 cells and HCC1806 (CRCC1-KO) cells (IC 50 ) Note: “*” indicates the experimental results of two independent tests

[0294] The data in the table above demonstrate that the compounds of the present invention exhibit potent antiproliferative activity against both ZR-75-1 and HCC1806 XRCC1 KO cells. Compared to the control drug Ref-01, the vast majority of the compounds of the present invention exhibited stronger antiproliferative activity against both ZR-75-1 and HCC1806 XRCC1 KO cells.

[0295] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having a structure as shown in formula (1), or an isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate thereof: In formula (1): The dotted line is a chemical bond or does not exist, and the same ring atom in ring B does not form two double bond structures at the same time, and both ring A and ring B are aromatic; U and V are each independently N or C, and U and V are not N at the same time; W and X are independently N, NR 7 or CR 7 ; n is 0, 1, 2, 3 or 4; Ring Y is a 4-14 membered heterocycloalkyl group; wherein, The heterocycloalkyl group is optionally substituted with an oxo group (=O); L is selected from the group consisting of none, a chemical bond, or -C(O)-; R 1 and R 2 Independent as C 1-3 Alkyl, or R 1 and R 2 The C atoms connected to them form a 3-6 membered cyclic structure, the cyclic structure optionally contains 0, 1 or 2 heteroatoms independently selected from N, O and S; and the cyclic structure is a saturated ring; R 3 H, CN, C 1-3 Alkyl or halogenated C 1-3 alkyl; R 4 Independent as C 1-3 Alkyl, the alkyl being optionally substituted by one or more groups selected from the group consisting of: -OH, halogen, CN, C 1-3 Alkoxy or C 3-6 Cycloalkyl, or two R on the same C atom 4 The C atom connected thereto forms a 3-6 membered spirocyclic structure, the spirocyclic structure optionally containing 0, 1 or 2 heteroatoms selected from N, O and S; and the spirocyclic structure is a saturated ring; R 5 Selected from the following group: H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4-7 membered heterocycloalkyl, NR a R b or -C 1-3 Alkylene-NR a R b The alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted by one or more groups selected from the group consisting of -OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; R a and R b Independently selected from the following group: H, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, or R a and R b With The alkyl, cycloalkyl, heterocyclic or heterocycloalkyl group is optionally substituted by one or more groups selected from the group consisting of: -OH, halogen, CN, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, hydroxy substituted C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkoxy substituted C 1-3 Alkyl, C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl; R 6 Selected from the following group: H, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 3-6 Cycloalkyl or C 2-4 alkenyl; When R 7 When connected to a C atom, R 7 Selected from the group consisting of H, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl; or when R 7 When connected to a N atom, R 7 Selected from the following group: H, C 1-3 Alkyl, halogenated C 1-3 Alkyl or C 3-6 Cycloalkyl.

2. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound of formula (1) has the structure shown in (2-1), (2-2) or (2-3): Wherein, the definitions of each group are as described in claim 1.

3. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound of formula (1) Select from the following group: Among them, n, L, R 4 and R 5 Definitions as set forth in claim 1.

4. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound of formula (1) Select from the following group: Among them, L and R 5 Definitions as set forth in claim 1.

5. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound of formula (1) Select from the following group: Wherein, L is selected from the group consisting of: none, a chemical bond or -CO-; R 5 Selected from the group consisting of H, Me, Et, 6. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound of formula (1) Select from the following group: Among them, R 3 Definitions as set forth in claim 1.

7. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound of formula (1) Select from the following group:

8. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: In the compound of formula (1), R 6 Selected from the group consisting of H, Me, Et, CH2F, CHF2, CF3, cyclopropyl or vinyl.

9. The compound according to claim 1, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: In the compound of formula (1), R 7 Selected from the group consisting of H, F, Cl, Me, Et, CH2F, CHF2, CF3, CH2CF3 or cyclopropyl.

10. The compound according to claim 1-9, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate, characterized in that: The compound has a structure selected from the group consisting of:

11. A pharmaceutical composition for treating, regulating and / or preventing diseases mediated by PARG, characterized in that: The pharmaceutical composition comprises a pharmaceutically acceptable excipient or carrier and, as an active ingredient, the compound according to any one of claims 1 to 10, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate.

12. Use of a compound according to any one of claims 1 to 10, or an isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate thereof, characterized in that: Used for preparing drugs for treating, regulating and / or preventing diseases mediated by PARG.

13. A method for treating, regulating and / or preventing diseases mediated by PARG, characterized in that: The method comprises the step of administering the compound according to any one of claims 1 to 10, or its isomer, polymorph, pharmaceutically acceptable salt, hydrate or solvate to an individual in need thereof.

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