Nitrogen-containing tricyclic derivative as PARG inhibitor

Abstract

The present application relates to a compound of formula I or a pharmaceutically acceptable salt, isomer or isotope derivative thereof, and the use thereof as a PARG inhibitor for the treatment of cancer, wherein each group is as defined herein.

Description

Nitrogen-containing tricyclic derivatives as PARG inhibitors Technical Field

[0001] The present invention relates to a poly (ADP-ribose) glycohydrolase (PARG) inhibitor and a preparation method thereof. Background Art

[0002] PARG is a cellular enzyme that hydrolyzes poly(ADP-ribose), primarily regulating the function of DNA repair proteins. As a supplement and alternative to poly(ADP-ribose) polymerase (PARP) inhibitors in clinical practice, the development of PARG inhibitors has been a key focus in cancer treatment research.

[0003] Single strand break (SB) is the most common type of DNA damage in cells. In the repair mechanism of this type of DNA damage, PARG, PARP and some other proteins are known to participate in DNA single strand break repair (SBR) and base excision repair (BER). During the single-strand DNA repair process, PARP first binds to the damaged break site of DNA and rapidly catalyzes its own synthesis of poly (ADP-ribose) (PAR). The molecular structure of PAR acts as a signal to recruit other DNA repair proteins to participate in the repair of DNA breaks. The signal for recruiting DNA repair proteins triggered by these PAR chains is short-lived because the PAR chains are quickly degraded by PARG. When the PARP protein binds to the PAR chain, its catalytic activity is significantly reduced, so the hydrolysis activity of PARG helps to restore PARP to a catalytically active state.

[0004] PARG's primary function is a direct role in DNA repair, but it also influences PAR signaling in splicing, transcription, and epigenetic pathways. Cancer cells may become heavily reliant on a specific DNA repair pathway when other DNA repair mechanisms are ineffective. Studies have shown that PARG knockout can inhibit SSBR and reduce the survival of BRCA2-deficient cells. Furthermore, mouse cells harboring nonsense mutations or PARG knockouts exhibit increased sensitivity to DNA-damaging agents.

[0005] PARG knockout sensitizes human lung, cervical, and pancreatic cancer cells to γ-irradiation or experimental DNA-damaging agents (e.g., hydrogen peroxide, methyl methanesulfonate). Furthermore, because PARG knockout reduces SSBR rates consistent with PARP1 knockout, and PARG acts through distinct mechanisms from PARP, PARG inhibitors may offer advantages in treating PARP inhibitor-resistant cells. Summary of the Invention

[0006] The purpose of this application is to provide a PARG selective inhibitor and a preparation method thereof.

[0007] In one aspect, the present application provides a compound of formula I, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof:

[0008] in:

[0009] R1 is H, cyano, formyl, -CONH2, -CH2OH, -CH2OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 alkyl halide;

[0010] R2 and R2' are each independently C 1-6 Alkyl; or

[0011] R2 and R2' together with the carbon atom to which they are attached constitute a C optionally substituted by halogen 3-6 a cycloalkyl group or a 3- to 8-membered heterocyclic group;

[0012] Y is NH or CH2;

[0013] X1 is N or CR5; R5 is H or halogen;

[0014] X2 is N or CR6; R6 is H or halogen;

[0015] X3 is N or CR7; R7 is H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0016] X4 is N or CR8; R8 is H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0017] R3 is H, halogen, cyano, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, ethynyl or -L2-(R3') n A group in which:

[0018] L2 is C 3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl;

[0019] n is 0, 1, 2 or 3, and n R3' are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, C 1-6 alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, NR 3a R 3b , OR 3a 、C(O)R 3a 、C(O)OR 3a 、OC(O)R 3a 、C(O)NR 3a R 3b NR 3a C(O)R 3b SR 3a 、SOR 3a 、SO2R 3a 、SO2NR 3a R 3b NR 3a SO2R 3b or (CH2) z NR 3a R 3b , where z is 1, 2, or 3, R 3a and R 3b Each is independently C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, or R 3a and R 3b together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl;

[0020] R4 is a group having the following structural formula:

[0021] -COR4' or

[0022] in:

[0023] R4' is C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0024] Ar is a 5-membered heteroaryl group;

[0025] R 4a It is C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, -C(O)H or cyano;

[0026] R 4b and R 4c Or each does not exist independently is C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl or C 1-6 Halogenated alkoxy.

[0027] On the other hand, the present application provides a pharmaceutical composition comprising a compound of the present application, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, and one or more pharmaceutically acceptable excipients.

[0028] On the other hand, the present application provides the use of the compound of the present application, or a pharmaceutically acceptable salt, isomer or isotope derivative thereof, in the preparation of a PARG inhibitor.

[0029] On the other hand, the present application provides use of the compound of the present application, or a pharmaceutically acceptable salt, isomer or isotope derivative thereof, in the preparation of a medicament for treating cancer.

[0030] In another aspect, the present application provides the compound of the present application, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, which is used as a PARG inhibitor.

[0031] In another aspect, the present application provides a compound of the present application, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, for use in treating cancer.

[0032] In another aspect, the present application provides a method for inhibiting PARG activity in a patient in need thereof, comprising administering to the patient an inhibitory effective amount of a compound of the present application, or a pharmaceutically acceptable salt, isomer, or isotopic derivative thereof.

[0033] In another aspect, the present application provides a method for treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present application, or a pharmaceutically acceptable salt, isomer, or isotopic derivative thereof. DETAILED DESCRIPTION

[0034] definition

[0035] Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms found in the specified chemical group. For example, C 1-6 Alkyl describes an alkyl group as defined below having a total of 1 to 6 carbon atoms, and C 3-6 Cycloalkyl describes a cycloalkyl group as defined below having a total of 3 to 6 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in substituents of the group being described.

[0036] In addition to the foregoing, when used in the specification and the appended claims, unless otherwise indicated, the following terms have the meanings indicated below:

[0037] "Amino" refers to a -NH2 group.

[0038] "Cyano" refers to a -CN group.

[0039] "Formyl" refers to a -C(O)H group.

[0040] "Hydroxy" refers to an -OH group.

[0041] "Carboxyl" refers to a -C(O)OH group.

[0042] "Halogen" means fluorine, chlorine, bromine or iodine, especially fluorine or chlorine, especially fluorine.

[0043] "Sulfonyl" refers to a -S(O)2R radical where R can be alkyl, cycloalkyl, aryl or heteroaryl as defined below.

[0044] "Alkyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 8 carbon atoms, e.g., 1 to 6, 1 to 4, 1 to 3, 1 to 2 carbon atoms, and attached to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, tert-butyl, and the like.

[0045] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens as defined above, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, and the like.

[0046] "Hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxy groups as defined above.

[0047] "Alkoxy" refers to a group of the formula -OR a Group, where R a is an alkyl group as defined above.

[0048] "Haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halogen groups as defined above.

[0049] "Alkynyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having 2 to 8 carbon atoms, e.g., 2 to 6, 2 to 4 carbon atoms, and connected to the rest of the molecule by a single bond, such as ethynyl, propynyl, etc.

[0050] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may comprise a fused ring system or a bridged or spirocyclic ring system, having from 3 to 15 carbon atoms, e.g., from 3 to 10, from 3 to 8, or from 3 to 6 carbon atoms, and which is saturated or unsaturated and is attached to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[1.1.1]pentane, adamantyl, norbornyl, decahydronaphthyl, and the like.

[0051] "Heterocyclyl" refers to a stable 3- to 12-membered (e.g., 3- to 10-membered, 3- to 8-membered, 4- to 10-membered, 4- to 9-membered, 4- to 8-membered, 5- to 10-membered, 5- to 9-membered) non-aromatic ring group consisting of 1 to 6 (e.g., 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1) heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system or a bridged or spirocyclic ring system; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl group may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl group may be partially or fully saturated. Examples of heterocyclic groups include, but are not limited to, piperazinyl, piperidinyl, tetrahydropiperidinyl, piperidonyl, morpholinyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 2,8-diazaspiro[4.5]decan-2-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, and 2,6-diazaspiro[3.4]octan-6-yl.

[0052] "Aryl" refers to a hydrocarbon ring system containing hydrogen, 6 to 18 (e.g., 6 to 10) carbon atoms and at least one aromatic ring. For the purposes of the present invention, aryl can be a monocyclic or bicyclic fused ring system, such as phenyl, naphthyl, etc.

[0053] "Heteroaryl" refers to a stable 5- to 14-membered (e.g., 5- to 10-membered, 5- to 9-membered) system radical containing 1 to 6 (e.g., 1 to 5, 1 to 4, 1 to 3, or 1 to 2) heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring. For the purposes of this invention, the aromatic ring of the heteroaryl group need not contain heteroatoms, as long as one ring of the heteroaryl group contains heteroatoms. For the purposes of this invention, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, indolyl, isoindolyl, benzoxazolyl, benzisoxazolyl, imidazopyridinyl, pyrazolopyridinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzimidazolidinidazolyl, benzopyrazolyl, triazolopyridinyl, quinolinyl, and isoquinolinyl.

[0054] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs as well as instances where it does not. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups. As used herein, when a group is described as "optionally substituted", it may or may not be substituted at appropriate positions with a group selected from alkyl, cyano, haloalkyl, hydroxyalkyl, halogen, hydroxy, amino, cycloalkyl, and heterocyclyl.

[0055] "Pharmaceutically acceptable salts" refers to salts formed with acids or bases that retain the biological effectiveness and properties of the free drug and which are not biologically or otherwise undesirable.

[0056] Certain compounds of Formula I have asymmetric carbon atoms (optical centers) or double bonds. Therefore, racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) of compounds of Formula I are intended to fall within the scope of the present invention. When stereochemical descriptions are made, it is meant that there is one isomer and a compound that is substantially free of another isomer. "Substantially free" of another isomer means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or higher. In some embodiments, one isomer will be present in an amount of at least 99%.

[0057] 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, radioactive isotopes, such as deuterium ( 2 H), tritium (3 H), iodine 125 ( 125 I) or carbon 14 ( 14 C) to label the compound. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. In some embodiments of the present invention, when H is mentioned, deuterium or tritium is included.

[0058] Embodiments of the present invention

[0059] One embodiment of the present invention is a compound of formula I described in the Summary of the Invention, or a pharmaceutically acceptable salt, isomer, and isotopic derivative thereof:

[0060] in:

[0061] R1 is H, cyano, formyl, -CONH2, -CH2OH, -CH2OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 alkyl halide;

[0062] R2 and R2' are each independently C 1-6 Alkyl; or

[0063] R2 and R2' together with the carbon atom to which they are attached constitute a C optionally substituted by halogen 3-6 a cycloalkyl group or a 3- to 8-membered heterocyclic group;

[0064] Y is NH or CH2;

[0065] X1 is N or CR5; R5 is H or halogen, the halogen is preferably fluorine;

[0066] X2 is N or CR6; R6 is H or halogen, the halogen is preferably fluorine;

[0067] X3 is N or CR7; R7 is H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0068] X4 is N or CR8; R8 is H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0069] R3 is H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, ethynyl or -L2-(R3') n A group in which:

[0070] L2 is C 3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl;

[0071] n is 0, 1, 2 or 3, and n R3' are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, amino, cyano, hydroxy, carboxyl, carbamoyl, aminosulfonyl, C 1-6 alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, NR 3a R 3b , OR 3a 、C(O)R 3a 、C(O)OR 3a 、OC(O)R 3a 、C(O)NR 3a R 3b NR 3a C(O)R 3b SR 3a 、SOR 3a 、SO2R 3a 、SO2NR 3a R 3b NR 3a SO2R 3b or (CH2) z NR 3a R 3b , where z is 1, 2, or 3, R 3a and R 3b Each is independently C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, or R 3a and R 3b together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl;

[0072] R4 is a group having the following structural formula:

[0073] -COR4' or

[0074] in:

[0075] R4' is C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0076] Ar is a 5-membered heteroaryl group;

[0077] R 4a It is C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, -C(O)H or cyano;

[0078] R 4b and R 4c Does not exist or is independently C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl or C 1-6 Halogenated alkoxy.

[0079] In one embodiment of the present invention, R1 is cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0080] In one embodiment of the present invention, R1 is cyano, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0081] In one embodiment of the present invention, R1 is C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0082] In one embodiment of the present invention, R1 is methyl or fluoromethyl.

[0083] In one embodiment of the present invention, R2 and R2' together with the carbon atom to which they are attached form cyclopropyl or oxetan-3-yl.

[0084] In one embodiment of the invention, Y is NH.

[0085] In one embodiment of the present invention, X1 and X2 are both CH.

[0086] In one embodiment of the present invention, X3 and X4 are each independently N or CH.

[0087] In one embodiment of the present invention, X3 is CH and X4 is N or CH.

[0088] In one embodiment of the present invention, X3 and X4 are both CH.

[0089] In one embodiment of the present invention, R3 is of the formula -L2-(R3') nwherein L2 is a 5- to 10-membered heterocyclic group.

[0090] In one embodiment of the present invention, R3 is of the formula -L2-(R3') n wherein L2 is selected from piperazinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, morpholinyl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,8-diazaspiro[4.5]decane-2-yl and 2-oxa-7-azaspiro[3.5]nonane-7-yl.

[0091] In one embodiment of the present invention, R3 is of the formula -L2-(R3') n wherein L2 is selected from piperazinyl, piperidinyl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,8-diazaspiro[4.5]decane-2-yl and 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0092] In one embodiment of the present invention, R3 is of the formula -L2-(R3') n wherein L2 is selected from piperazinyl, piperidinyl, 2,6-diazaspiro[3.4]octan-6-yl, 2,8-diazaspiro[4.5]decan-2-yl and 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0093] In one embodiment of the present invention, R3 is of the formula -L2-(R3') n wherein L2 is selected from piperazinyl, piperidinyl and 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0094] In one embodiment of the present invention, R3 is of the formula -L2-(R3') n A group wherein L2 is selected from piperazinyl and 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0095] In one embodiment of the present invention, R3 is of the formula -L2-(R3') n wherein n is 0, 1, 2 or 3.

[0096] In one embodiment of the present invention, R3 is of the formula -L2-(R3') n wherein n is 0, 1 or 2.

[0097] In one embodiment of the present invention, R3 is of the formula -L2-(R3') n wherein n is 0 or 1.

[0098] In one embodiment of the present invention, n R3' are each independently selected from halogen, C 1-6 Alkyl, amino, hydroxy, C(O)R 3a 、C(O)NR 3a R 3b , where R 3a and R 3b Each is independently C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 haloalkyl, optionally substituted C 3-8 cycloalkyl or an optionally substituted 4- to 8-membered heterocyclyl.

[0099] In one embodiment of the present invention, n R3' are each independently selected from halogen, C 1-6 Alkyl, amino, hydroxy, C(O)R 3a 、C(O)NR 3a R 3b , where R 3a and R 3b Each is independently C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl or an optionally substituted 4- to 8-membered heterocyclyl.

[0100] In one embodiment of the present invention, n R3' are each independently selected from halogen, C 1-6 Alkyl, amino, C(O)R 3a 、C(O)NR 3a R 3b , where R 3a and R 3b Each is independently C 1-6 Alkyl, C 1-6 haloalkyl, optionally substituted C 3-8 cycloalkyl or an optionally substituted 4- to 8-membered heterocyclyl.

[0101] In one embodiment of the present invention, n R3' are each independently C(O)R 3a , where R 3a For optionally C 1-3 Alkyl substituted C 3-8 Cycloalkyl.

[0102] In one embodiment of the present invention, R4 is a group having the following structural formula:

[0103] in:

[0104] Ar is thiadiazolyl, especially 1,3,4-thiadiazol-2-yl;

[0105] R4a It is C 1-6 Halogenated alkyl, preferably C 1-3 haloalkyl, especially difluoromethyl; and

[0106] R 4b and R 4c Does not exist.

[0107] In one embodiment of the invention, the compound of the invention is selected from:

[0108] Preparation of the compounds of the present application

[0109] In the preparation examples below, the abbreviations used represent the following meanings: Boc: tert-butyloxycarbonyl DIPEA: N,N-diisopropylethylamine HATU: 1-(bis(dimethylamino)methylene-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphate HPLC: high performance liquid chromatography m-CPBA: m-chloroperbenzoic acid MeI: iodomethane NCS: N-chlorosuccinimide Oxone: potassium monopersulfate Pd2(dba)3: tris(dibenzylideneacetone)dipalladium SFC: supercritical fluid chromatography TEA: triethylamine TFA: trifluoroacetic acid XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0110] Example B-1

[0111] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(4-(1-methylcyclopropylcarbonyl)piperazin-1-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0112] 5-Bromo-1,3-difluoro-2-nitrobenzene (7.50 g, 31.51 mmol) and cesium carbonate (15.4 g, 47.27 mmol) were dissolved in N,N-dimethylformamide (15.0 mL). 5-Difluoromethyl-1,3,4-thiadiazol-2-amine (4.76 g, 31.51 mmol) was added at 20°C. The reaction mixture was stirred at 60°C for 2 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 80 / 20) to obtain the target product B-1a (5.00 g, purity 93.6%, yield 40.2%). LCMS (ESI+): m / z = 368.9 [M+H] + .

[0113] Compound B-1a (11.00 g, 29.80 mmol) and DIPEA (15.6 mL, 89.41 mmol) were dissolved in N-methyl-2-pyrrolidone (100 mL), and anhydrous piperazine (2.82 g, 32.78 mmol) was added. The reaction mixture was stirred at 90°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (80 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, dichloromethane / methanol = 100 / 0 to 90 / 10) to obtain the target product B-1b (4.20 g, purity 88.4%, yield 28.6%). LCMS (ESI+): m / z = 434.9 [M+H] + .

[0114] 1-Methylcyclopropyl-1-carboxylic acid (1.06 g, 10.62 mmol), HATU (4.40 g, 11.58 mmol), and triethylamine (4.0 mL, 28.95 mmol) were dissolved in N,N-dimethylformamide (10.0 mL). B-1b (4.20 g, 9.65 mmol) was added at 30°C. The reaction mixture was stirred at 40°C for 2 hours. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (40 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 60 / 40) to obtain the target product B-1c (3.90 g, purity 62.47%, yield 48.8%). LCMS (ESI+): m / z = 517.2 [M+H] + .

[0115] Compound B-1c (3.90 g, 7.54 mmol) and ammonium chloride (1.21 g, 22.62 mmol) were dissolved in a mixed solvent of ethanol (32.0 mL) and water (8.0 mL), and iron powder (1.68 g, 30.08 mmol) was added. The reaction solution was stirred at 80°C for 1 hour. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 30 / 70) to obtain the target product B-1d (2.60 g, purity 78.06%, yield 55.2%). LCMS (ESI+): m / z = 487.0 [M+H] + .

[0116] Compound B-1d (2.60 g, 5.33 mmol) and triethylamine (1.48 mL, 10.67 mmol) were dissolved in N,N-dimethylformamide (20.0 mL), and 1,1-diethoxy-2-isothiocyanatoethane (1.12 g, 6.40 mmol) was added. The reaction solution was microwaved at 100°C for 1 hour. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 60 / 40) to obtain the target product B-1e (750.0 mg, purity 94.3%, yield 21.1%). LCMS (ESI+): m / z = 628.0 [M+H] + .

[0117] Trifluoroacetic acid (6.0 mL) was added to compound B-1e (750.0 mg, 1.19 mmol). The reaction solution was stirred at 85 ° C for 8 hours. The reaction solution was cooled to room temperature, sodium hydroxide aqueous solution was added to adjust the pH to 8, and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, dichloromethane / tetrahydrofuran = 100 / 0 to 95 / 5) to obtain the target product B-1f (210.0 mg, purity 99.77%, yield 32.7%). LCMS (ESI+): m / z = 536.1 [M+H] + .

[0118] B-1f (110.0 mg, 0.21 mmol), methyl 3-mercaptopropionate (73.9 mg, 0.62 mmol), Xantphos (11.9 mg, 0.021 mmol), and DIPEA (67.9 μL, 0.41 mmol) were dissolved in toluene (4.0 mL), and Pd2(dba)3 (18.8 mg, 0.021 mmol) was added at 30°C. The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 50 / 50) to obtain the target product B-1g (100.0 mg, yield 82.7%). LCMS (ESI+): m / z = 576.1 [M+H] + .

[0119] B-1g (100.0 mg, 0.17 mmol) was dissolved in dioxane (2.0 mL), and a 50% aqueous solution of Oxone (320.3 mg, 0.52 mmol) (1.0 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 0 / 100) to obtain the target product B-1h (60.0 mg, purity 97.73%, yield 56.8%). LCMS (ESI+): m / z = 608.1 [M+H] + .

[0120] B-1h (60.0 mg, 0.099 mmol) was dissolved in MeOH (2.0 mL) and 60% NaH (7.9 mg, 0.20 mmol) was added at 0°C. The reaction mixture was stirred at 30°C for 30 minutes. The pH of the reaction mixture was adjusted to 5 with acetic acid and then concentrated under reduced pressure to obtain the target product B-1i (60.0 mg, crude product). LCMS (ESI+): m / z = 522.1 [M+H] + .

[0121] B-1i (60.0 mg, crude) was dissolved in AcOH (2.0 mL) and H2O (0.8 mL), and NCS (14.7 mg, 0.11 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product B-1j (60.0 mg, crude). LCMS (ESI+): m / z = 556.0 [M+H] + .

[0122] 1-Methylcyclopropylamine hydrochloride (34.8 mg, 0.32 mmol) and triethylamine (74.8 μL, 0.54 mmol) were dissolved in dichloromethane (1.0 mL), and a solution of compound B-1j (60.0 mg, crude product) in dichloromethane (1.0 mL) was added at 0°C. The reaction solution was stirred at 25°C for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the target product B-1. LCMS (ESI+): m / z = 591.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.82-8.78 (m, 1H), 8.27 (s, 1H), 7.81-7.52 (m, 3H), 7.42-7.36 (m, 1H), 4.03-3.76 (m, 4H), 3.1 6-3.02(m,4H),1.30(s,3H),1.07(s,3H),0.89-0.85(m,2H),0.67-0.62(m,2H),0.61-0.56(m,2H),0.42-0.37(m,2H).

[0123] Example B-2

[0124] N-(1-Cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(4-(1-methylcyclopropylcarbonyl)piperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0125] Compound B-2 was synthesized using a method similar to that of compound B-1, in which 1-methylcyclopropylamine hydrochloride was replaced with 1-aminocyclopropylnitrile hydrochloride. In the final step, 10 equivalents of pyridine were used as a base. After the reaction was completed, the reaction solution was concentrated under reduced pressure and dried, and saturated sodium bicarbonate solution (10 mL) and ethyl acetate (10 mL) were added and stirred for 5 minutes. After filtration, the filter cake was washed with water (10 mL) and ethyl acetate (10 mL) in sequence. The filter cake was lyophilized to obtain B-2. LCMS (ESI+): m / z=602.1[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 8.64 (s, 1H), 7.77 (s, 1H), 7.67 (t, J = 53.6Hz, 1H), 7.51 (s, 1H), 7.35-7.32 (m, 1H), 3.94-3.80(m,4H),3.09-3.02(m,4H),1.29(s,3H),0.89-0.83(m,4H),0.80-0.74(m,2H),0.62-0.54(m,2H).

[0126] Example B-3

[0127] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-5-(4-(1-methylcyclopropylcarbonyl)piperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0128] Compound B-3 was synthesized using a method similar to that used for compound B-1, except that 1-methylcyclopropylamine hydrochloride was replaced with 1-(fluoromethyl)cyclopropylamine hydrochloride. The crude product was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 44%-74%, 7 minutes) to yield compound B-3. LCMS (ESI+): m / z = 609.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=8.80-8.75(m,1H),8.67(s,1H),7.83-7.35(m,4H),4.12(d,J=48.8Hz,2H),4.0 2-3.75(m,4H),3.16-3.01(m,4H),1.30(s,3H),0.90-0.84(m,2H),0.77-0.67(m,4H),0.62-0.55(m,2H).

[0129] Example B-4

[0130] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-5-(4-(1-methylcyclopropylcarbonyl)piperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0131] Compound B-4 was synthesized using a method similar to that used for compound B-1, except that 1-methylcyclopropylamine hydrochloride was replaced with 3-(fluoromethyl)oxetan-3-amine hydrochloride. The crude product was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 43%-73%, 7 minutes) to yield compound B-4. LCMS (ESI+): m / z = 625.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=8.84-8.80(m,1H),7.84-7.38(m,4H),4.57(d,J=46.8Hz,1H),4.56-4.52(m,2H),4 .36-4.30(m,2H),4.00-3.81(m,4H),3.15-3.04(m,4H),1.30(s,3H),0.90-0.84(m,2H),0.62-0.57(m,2H).

[0132] Intermediate B-5e

[0133] Compound B-1a (7.10 g, 19.24 mmol) and ammonium chloride (3.09 g, 57.8 mmol) were dissolved in a mixed solvent of ethanol (56.0 mL) and water (14.0 mL). Iron powder (4.30 g, 76.8 mmol) was added, and the reaction solution was heated to 80°C and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 70 / 30) to obtain the target product B-5a (4.80 g, purity 89.17%, yield 65.6%). LCMS (ESI+): m / z = 339.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.08-9.75 (br.s., 1H), 7.74-7.68 (m, 1H), 7.37 (t, J = 53.2Hz, 1H), 7.23-7.15 (m, 1H), 5.24 (br.s., 2H).

[0134] Compound B-5a (4.80 g, 14.15 mmol) was dissolved in isopropanol (40.0 mL), and 1,1-diethoxy-2-isothiocyanatoethane (3.72 g, 21.23 mmol) was added. The reaction solution was heated to 90°C and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 85 / 15) to obtain the target product B-5b (3.60 g, purity 92.14%, yield 48.8%). LCMS (ESI+): m / z = 480.0 [M+H] + .

[0135] Compound B-5b (3.60 g, 7.50 mmol) was dissolved in trifluoroacetic acid (40.0 ml), the reaction solution was heated to 85 ° C and stirred for 5 hours. The reaction solution was cooled to room temperature and the pH was adjusted to 8 with aqueous sodium hydroxide solution. It was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The reaction solution was purified by silica gel column chromatography (silica, dichloromethane / tetrahydrofuran = 100 / 0 to 99.5 / 0.5) to obtain the target product B-5c (1.78 g, purity 82.02%, yield 50.1%). LCMS (ESI+): m / z = 387.9 [M+H] + .

[0136] Compound B-5c (300.0 mg, 0.77 mmol) and piperazine (666.0 mg, 7.73 mmol) were dissolved in 1-methyl-2-pyrrolidone (1.0 mL), and the reaction mixture was stirred at 130°C for 2 hours. The reaction mixture was cooled to room temperature, added with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, dichloromethane / methanol = 100 / 0 to 94 / 6) to obtain the target product B-5d (240.0 mg, purity 83.8%, yield 57.1%). LCMS (ESI+): m / z = 454.0 [M+H] + .

[0137] Compound B-5d (190.0 mg, 0.42 mmol), isobutyric acid (44.2 mg, 0.50 mmol), and TEA (0.18 ml, 1.26 mmol) were dissolved in N,N-dimethylformamide (3.0 ml). HATU (239.0 mg, 0.63 mmol) was added, and the reaction mixture was stirred at 25°C for 1 hour. Ice water (20 mL) was added, and the mixture was filtered. The filter cake was washed with petroleum ether (20 mL) and dried under reduced pressure to obtain the desired product B-5e (158.3 mg, purity 98.12%, yield 70.5%). LCMS (ESI+): m / z = 524.0 [M+H] + .

[0138] Example B-5

[0139] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-5-(4-isobutyrylpiperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0140] Compound B-5 was synthesized using a method similar to that of compound B-1, wherein (4-(7-bromo-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-benzo[d]imidazo[1,2-a]imidazol-5-yl)piperazin-1-yl)(1-methylcyclopropyl)methanone (B-1f) was replaced by 1-(4-(7-bromo-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-benzo[d]imidazo[1,2-a]imidazol-5-yl)piperazin-1-yl)-2-methylpropan-1-one (B-5e), and 1-methylcyclopropylamine hydrochloride was replaced by 3-(fluoromethyl)oxetan-3-amine hydrochloride. The crude product was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 33%-63%) to give B-5. LCMS (ESI+): m / z = 613.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.84-8.80 (m, 1H), 7.82 (s, 1H), 7.80-7.52 (m, 2H), 7.40 (s, 1H), 4.64 (d, J = 46.8Hz, 2H), 4. 56-4.52(m,2H),4.37-4.31(m,2H),3.93-3.75(m,4H),3.16-3.02(m,4H),3.01-2.93(m,1H),1.06(d,J=6.8Hz,6H).

[0141] Example B-6

[0142] 9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-cyanocyclopropyl)-5-(4-isobutyrylpiperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0143] Compound B-6 was synthesized using a method similar to that used for compound B-5, except that piperazine, Oxone, NaH, and 3-(fluoromethyl)oxetan-3-amine hydrochloride were replaced with N,N-dimethylpiperazine-1-carboxamide, m-chloroperbenzoic acid, potassium tert-butoxide in tetrahydrofuran, and 1-aminocyclopropylcarbonitrile hydrochloride, respectively. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 43%-73%, 7 minutes) to yield B-6. LCMS (ESI+): m / z = 591.2 [M+H] + ; 1 H NMR(400MHz,CHLOROFORM-d)δ9.08-8.96(m,1H),7.78-7.69(m,1H),7.61-7.57(m,1H),7.39-7.34(m,1H),6.99(t,J=53 .2Hz,1H),6.64(s,1H),3.58-3.52(m,4H),3.25-3.19(m,4H),2.95-2.91(m,6H),1.67-1.63(m,2H),1.47-1.41(m,2H).

[0144] Example B-7

[0145] N-(1-Cyanocyclopropyl)-5-(4-(cyclopentylcarbonyl)piperazin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0146] Compound B-7 was synthesized using a method similar to that used for compound B-5, except that isobutyric acid was replaced with cyclopentanecarboxylic acid, and 3-(fluoromethyl)oxetan-3-amine hydrochloride was replaced with 1-aminocyclopropylcarbonitrile hydrochloride (the base was replaced with pyridine and the solvent with acetonitrile in the final step). The crude product was purified by preparative HPLC (column: Xtimate C18 150*40mm*10μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 50%-80%) to yield B-7. LCMS (ESI+): m / z = 616.2 [M+H]+ ; 1 H NMR(400MHz,CHLOROFORM-d)δ9.01(s,1H),7.75(s,1H),7.61-7.54(m,1H),7.40-7.34(m,1H),6.99(t,J=53.6Hz,1H),6.45(s,1H),4 .06-3.75(m,4H),3.25-3.14(m,4H),3.03-2.93(m,1H),1.93-1.85(m,4H),1.82-1.75(m,2H),1.70-1.64(m,4H),1.47-1.43(m,2H).

[0147] Example B-8

[0148] N-(1-Cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(4-isobutyrylpiperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0149] Compound B-8 was synthesized using a method similar to that used for compound B-5, except that 3-(fluoromethyl)oxetan-3-amine hydrochloride was replaced with 1-aminocyclopropylcarbonitrile hydrochloride (the base was replaced with 10 equivalents of pyridine in the final step). The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30 mm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 38%-68%) to afford B-8. LCMS (ESI+): m / z = 590.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.84 (s, 1H), 7.83 (s, 1H), 7.82-7.43 (m, 2H), 7.41 (s, 1H), 3.93-3.76 (m, 4H) ),3.17-3.05(m,4H),3.01-2.93(m,1H),1.47-1.38(m,2H),1.33-1.26(m,2H),1.07(d,J=6.8Hz,6H).

[0150] Example B-9

[0151] N-(1-Cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0152] Compound B-9 was synthesized using a method similar to that used for compound B-5, except that piperazine was replaced with 2-oxa-7-azaspiro[3.5]nonane, and 3-(fluoromethyl)oxetan-3-amine hydrochloride was replaced with 1-aminocyclopropylcarbonitrile hydrochloride (the base was replaced with 15 equivalents of pyridine in the final step). The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]: B%: 40%-70%) to afford B-9. LCMS (ESI+): m / z = 561.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 9.37-9.09 (m, 1H), 8.80 (s, 1H), 7.73-7.50 (m, 3H),, 7.40 (s, 1H), 4. 45-4.41(m,4H),3.08-2.94(m,4H),2.16-2.10(m,4H),1.46-1.39(m,2H),1.31-1.27(m,2H).

[0153] Intermediate B-10a

[0154] Compound B-5d (170.0 mg, 0.37 mmol), 4-dimethylaminopyridine (4.57 mg, 0.037 mmol), and triethylamine (189.0 mg, 1.87 mmol) were dissolved in dichloromethane (0.5 mL). 1-Pyrrolidinecarbonyl chloride (100.0 mg, 0.75 mmol) was added, and the reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 30 / 70) to obtain the target product B-10a (170.0 mg, purity 94.11%, yield 78.4%). LCMS (ESI+): m / z = 551.1 [M+H] + .

[0155] Example B-10

[0156] N-(1-Cyanocyclopropyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0157] Compound B-10 was synthesized using a method similar to that used for compound B-5, except that B-5e was replaced with B-10a, and 3-(fluoromethyl)oxetan-3-amine hydrochloride was replaced with 1-aminocyclopropylcarbonitrile hydrochloride (in the final step, the base was replaced with 10 equivalents of pyridine, and the solvent was replaced with anhydrous dichloromethane). The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 47%-77%) to afford B-10. LCMS (ESI+): m / z = 617.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6)δ=9.42-9.18(m,1H),8.84(s,1H),7.80(s,1H),7.79-7.50(m,2H),7.40(s,1H),3.56- 3.49(m,4H),3.37-3.34(m,4H),3.15-3.09(m,4H),1.80-1.76(m,4H),1.46-1.41(m,2H),1.33-1.27(m,2H).

[0158] Example B-11

[0159] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(4-(1-methylcyclopropylcarbonyl)piperazin-1-yl)-N-(3-methyloxetan-3-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0160] Compound B-11 was synthesized using a method similar to that used for compound B-1, except that 1-methylcyclopropylamine hydrochloride was replaced with 3-methyloxetan-3-amine hydrochloride (the reaction solvent was changed to N,N-dimethylformamide). The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30mm, 3μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 41%-71%, 7 minutes) to obtain B-11. LCMS (ESI+): m / z = 607.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 8.81 (s, 1H), 8.66-8.46 (m, 1H), 7.81 (s, 1H), 7.78-7.50 (m, 2H), 7.40 (s, 1H), 4.60-4.52 (m, 2H), 4.15-4.08(m,2H),3.96-3.84(m,4H),3.13-3.08(m,4H),1.45(s,3H),1.30(s,3H),0.89-0.84(m,2H),0.61-0.56(m,2H).

[0161] Example B-12

[0162] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-(fluoromethyl)cyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0163] Compound B-12 was synthesized using a method similar to that used for compound B-9, except that 1-aminocyclopropylnitrile hydrochloride was replaced with 1-(fluoromethyl)cyclopropyl-1-amine hydrochloride (the base was replaced with 10 equivalents of triethylamine). The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 45%-75%) to yield B-12. LCMS (ESI+): m / z = 568.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.74 (s, 1H), 8.64 (s, 1H), 7.80-7.51 (m, 3H), 7.38 (s, 1H), 4.48-4. 40(m,4H),4.18(d,J=48.8Hz,2H),3.13-2.90(m,4H),2.21-2.03(m,4H),0.76-0.67(m,4H).

[0164] Example B-13

[0165] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0166] Compound B-13 was synthesized using a method similar to that used for compound B-9, except that 1-aminocyclopropylcarbonitrile hydrochloride was replaced with 3-(fluoromethyl)oxetan-3-amine hydrochloride (the base was replaced with 10 equivalents of triethylamine). The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 45%-75%) to yield B-13. LCMS (ESI+): m / z = 584.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=8.97-8.83(m,1H),8.78(s,1H),7.85-7.48(m,3H),7.38(s,1H),4.63(d,J=4 6.8Hz,2H),4.56-4.51(m,2H),4.43(s,4H),4.38-4.28(m,2H),3.08-2.94(m,4H),2.16-2.08(m,4H).

[0167] Example B-14

[0168] 4-(7-(N-(1-cyanocyclopropyl)sulfamoyl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-benzo[d]imidazo[1,2-a]imidazol-5-yl)-N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide

[0169] Compound B-14 was synthesized using a method similar to that used for compound B-6, except that N,N-dimethylpiperazine-1-carboxamide was replaced with N-(2,2-difluoroethyl)-N-methylpiperazine-1-carboxamide. The crude product was purified by preparative HPLC (column: C18 150*30mm; mobile phase: [water (formic acid)-acetonitrile]; B%: 50%-90%) to yield B-14. LCMS (ESI+): m / z = 641.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.84 (s, 1H), 7.91-7.49 (m, 3H), 7.41 (s, 1H), 6.19 (t, J = 55.6Hz, 1H), 3.68-3 .59(m,2H),3.54-3.47(m,4H),3.18-3.10(m,4H),3.01(s,3H),1.46-1.40(m,2H),1.32-1.27(m,2H).

[0170] Example B-15

[0171] 9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0172] Compound B-15 was synthesized using a method similar to that used for compound B-9, except that 1-aminocyclopropylnitrile hydrochloride was replaced with 1-methylcyclopropylamine hydrochloride. The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 40%-70%) to yield B-15. LCMS (ESI+): m / z = 550.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.76 (s, 1H), 8.25 (s, 1H), 7.70–7.55 (m, 3H), 7.38 (d, J = 1.6Hz, 1H), 4.46-4 .41(m,4H),3.05-2.93(m,4H),2.15-2.07(m,4H),1.07(s,3H),0.66-0.61(m,2H),0.42-0.36(m,2H).

[0173] Example B-16

[0174] N-(2,2-difluoroethyl)-4-(9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(N-(3-(fluoromethyl)oxetan-3-yl)sulfamoyl)-9H-benzo[d]imidazo[1,2-a]imidazol-5-yl)-N-methylpiperazine-1-carboxamide

[0175] Compound B-16 was synthesized using a method similar to that used for compound B-14, except that 1-aminocyclopropylnitrile hydrochloride was replaced with 3-(fluoromethyl)oxetan-3-amine hydrochloride (triethylamine was used as the base and N,N-dimethylformamide was used as the solvent in this step). The crude product was first purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (formic acid)-acetonitrile]; B%: 55%-85%) and then by preparative HPLC (column: Welch Xtimate C18 150*30 mm*5 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 47%-77%) to yield compound B-16. LCMS (ESI+): m / z = 664.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6)δ=9.01-8.90(m,1H),8.84-8.78(m,1H),7.81-7.51(m,3H),7.38(s,1H),6.37-6.04(m,1H),4.63(d, J=47.2Hz,2H),4.56-4.52(m,2H),4.37-4.28(m,2H),3.65-3.59(m,2H),3.52-3.49(m,4H),3.14-3.09(m,4H),3.00(s,3H).

[0176] Example B-17

[0177] 5-(4-(Cyclopentanecarbonyl)piperazin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(3-(fluoromethyl)oxetan-3-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0178] Compound B-17a was synthesized using a method similar to that used for compound B-7, except that 1-aminocyclopropylnitrile hydrochloride was replaced with 2,3,4,5,6-pentafluorophenol (triethylamine was used as the base and dichloromethane was used as the solvent in this step). The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 50 / 50) to obtain B-17a. LCMS (ESI+): m / z = 718.0 [M+H] + .

[0179] B-17a (57.0 mg, 0.079 mmol) and pyridine (64.0 μL, 0.79 mmol) were dissolved in 1-methyl-2-pyrrolidone (0.8 mL). 3-(Fluoromethyl)oxetan-3-amine hydrochloride (56.2 mg, 0.40 mmol) was added at 25°C, and the reaction solution was stirred in a microwave at 80°C for 1 hour. Diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 52%-82%) to obtain B-17. LCMS (ESI+): m / z = 639.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 9.00-8.86 (m, 1H), 8.83 (s, 1H), 7.83-7.50 (m, 3H), 7.41 (s, 1H), 4.64 (d, J = 46.8Hz, 2H), 4.56-4.52(m,2H),4.37-4.32(m,2H),3.91-3.79(m,4H),3.13-3.03(m,5H),1.88-1.72(m,4H),1.66-1.52(m,4H).

[0180] Example B-18

[0181] 4-(9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(N-(3-(fluoromethyl)oxetan-3-yl)sulfamoyl)-9H-benzo[d]imidazo[1,2-a]imidazol-5-yl)-N,N-dimethylpiperazine-1-carboxamide

[0182] Compound B-18a was synthesized using a method similar to that used for compound B-6, except that 1-aminocyclopropylnitrile hydrochloride was replaced with 2,3,4,5,6-pentafluorophenol. Compound B-18 was synthesized using a method similar to that used for compound B-17. The crude product was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 35%-65%) to yield B-18. LCMS (ESI+): m / z = 550.1 [M+H] + ; 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.07 (d, J = 1.6Hz, 1H), 7.68 (d, J = 1.2Hz, 1H), 7.59 (d, J = 1.2Hz, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.05 (t, J = 53.6Hz, 1H), 4.85-4.68 (m, 4H), 4.48-4.45 (m, 2H), 3.58-3.50 (m, 4H), 3.22-3.17 (m, 4H), 2.94 (s, 6H).

[0183] Example B-19

[0184] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-5-(piperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0185] Compound B-19a was synthesized using a method similar to that used for compound B-1, except that B-1f, Oxone, and NaH were replaced with B-5c, m-chloroperbenzoic acid, and potassium tert-butoxide in tetrahydrofuran, respectively. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 60 / 40) to yield the desired product, B-19a. LCMS (ESI+): m / z = 443.0 [M+H] + .

[0186] Compound B-19a (15.0 mg, 0.034 mmol) and piperazine (14.6 mg, 0.17 mmol) were dissolved in 1-methyl-2-pyrrolidone (1.0 mL). Triethylamine (47.0 μL, 0.34 mmol) was added, and the reaction mixture was stirred at 140°C for 12 hours. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 50%-80%) to obtain B-19. LCMS (ESI+): m / z = 509.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=8.77(d,J=1.6Hz,1H),8.28-8.22(m,1H),7.75–7.48(m,3H),7.65(t,J=53.2 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 3.04-2.99 (m, 8H), 1.09 (s, 3H), 0.67-0.63 (m, 2H), 0.42-0.37 (m, 2H).

[0187] Example B-20

[0188] 9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-5-(2,6-diazaspiro[3.4]octan-6-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0189] Compound B-20a was synthesized using a method similar to that used for compound B-19, except that piperazine was replaced with tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (diisopropylethylamine was used as the base in this step, and the reaction was carried out at 130°C for 2 hours). The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 50 / 50) to obtain the desired product B-20a. LCMS (ESI+): m / z = 635.2 [M+H] + .

[0190] B-20a (30.0 mg, 0.047 mmol) was dissolved in dichloromethane (1.6 mL). Trifluoroacetic acid (0.60 mL) was added at 0°C, and the reaction mixture was stirred at 0°C for half an hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: 44-Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 56%-86%) to obtain B-20. LCMS (ESI+): m / z = 535.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.68 (s, 1H), 8.34-8.16 (m, 1H), 7.87 (s, 1H), 7.66 (t, J = 52.8Hz, 1H), 7.45 (s, 1H), 7.37 (s, 1H), 3.78-3.68(m,4H),3.57(s,2H),3.23-3.17(m,2H),2.35-2.26(m,2H),1.08(s,3H),0.68-0.62(m,2H),0.42-0.36(m,2H).

[0191] Example B-21

[0192] 9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-5-(2,8-diazaspiro[4.5]decan-2-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0193] Compound B-21 was synthesized using a similar method to compound B-20, except that tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate was replaced with tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate. The crude product from the final step was purified by preparative HPLC (column: 44-Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 77%-100%) to yield B-21. LCMS (ESI+): m / z = 563.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 8.67 (s, 1H), 8.33-8.21 (m, 1H), 7.82 (d, J = 1.2Hz, 1H), 7.66 (t, J = 52.8Hz, 1H), 7.48 (s, 1H), 7.36 (d, J = 1.2Hz, 1H), 3.43-3.41(m,2H),3.21(s,2H),2.83-2.72(m,4H),1.96-1.90(m,2H), 1.66-1.58(m,4H),1.08(s,3H),0.68-0.62(m,2H),0.42-0.37(m,2H).

[0194] Example B-22

[0195] (3S,5S)-9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0196] Compound B-22 was synthesized using a method similar to that used for compound B-19, except that piperazine was replaced with (2S,6S)-2,6-dimethylpiperazine (heating and stirring at 160°C for 12 hours in the final step). The crude product from the final step was purified by preparative HPLC (column: Welch Xtimate C18 150×30mm, 5μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 20%-50%) to yield B-22. LCMS (ESI+): m / z = 537.2 [M+H] + ; 1 H NMR(400MHz, DMSO-d6)δ=8.78(s,1H),8.29(s,1H),7.81–7.47(m,3H),7.40(s,1H),3.49-3.46(m,2H),3.20 -3.17(m,2H),2.67-2.60(m,2H),1.18(d,J=6.4Hz,6H),1.09(s,3H),0.68-0.59(m,2H),0.44-0.36(m,2H).

[0197] Example B-23

[0198] 5-(3-aminopiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0199] Compound B-23a was synthesized using a method similar to that used for compound B-15, except that 2-oxa-7-azaspiro[3.5]nonane was replaced with tert-butylpiperidin-3-ylcarboxylate. The crude product was purified by silica gel column chromatography (silica, dichloromethane / methanol = 100 / 0 to 60 / 40) to yield the desired product, B-23a. LCMS (ESI+): m / z = 623.2 [M+H] + .

[0200] B-23a (40.0 mg, 0.064 mmol) was dissolved in dichloromethane (2.0 mL). Trifluoroacetic acid (0.5 mL) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 50%-80%) to obtain B-23. LCMS (ESI+): m / z = 523.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.77 (s, 1H), 8.45-8.09 (m, 1H), 7.86-7.48 (m, 3H), 7.39 (s, 1H), 3.22-3.10 (m, 3H), 2.83-2.7 3(m,1H),2.70-2.65(m,1H),2.02-1.79(m,3H),1.41-1.28(m,1H),1.08(s,3H),0.69-0.58(m,2H),0.46-0.35(m,2H).

[0201] Example B-24

[0202] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(3-hydroxypiperidin-1-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0203] Compound B-24 was synthesized using a method similar to that used for compound B-19, except that piperazine was replaced with piperidin-3-ol (stirring was performed at 135°C for 12 hours). The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 54%-84%) and lyophilized to yield B-24. LCMS (ESI+): m / z = 524.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 8.76 (s, 1H), 8.32-8.23 (m, 1H), 7.98-7.91 (m, 1H), 7.8 7-7.49(m,2H),7.37(s,1H),7.37(d,J=1.6Hz,1H),5.09(d,J=4.4Hz,1H),3.97- 3.83(m,1H),3.23-3.13(m,2H),2.93-2.78(m,2H),2.00-1.88(m,2H),1.85-1.7 3(m,1H),1.54-1.42(m,1H),1.07(s,3H),0.69-0.58(m,2H),0.42-0.35(m,2H).

[0204] Example B-25

[0205] (R)-5-(3-aminopiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0206] Compound B-25 was synthesized using a method similar to that used for compound B-23, except that tert-butylpiperidin-3-ylcarboxylate was replaced with (R)-tert-butylpiperidin-3-ylcarboxylate. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 47%-77%) and lyophilized to yield B-25. LCMS (ESI+): m / z = 523.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.77 (d, J = 1.6Hz, 1H), 8.48-8.15 (m, 1H), 7.82-7.51 (m, 3H), 7.39 (d, J = 1.2Hz, 1H), 3.22-3.11 (m, 3H), 2.82-2.74(m,1H),2.71-2.64(m,1H),2.02-1.85(m,3H),1.37-1.29(m,1H),1.08(s,3H),0.66-0.62(m,2H),0.44-0.36(m,2H).

[0207] Example B-26

[0208] (S)-5-(3-aminopiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0209] Compound B-26 was synthesized using a method similar to that used for compound B-23, except that tert-butylpiperidin-3-ylcarboxylate was replaced with (S)-tert-butylpiperidin-3-ylcarboxylate. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 44%-74%) and lyophilized to yield B-26. LCMS (ESI+): m / z = 523.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (d, J = 1.2Hz, 1H), 8.48-8.15 (m, 1H), 7.82-7.51 (m, 3H), 7.39 (d, J = 1.2Hz, 1H), 3.24-3.11 (m, 3H), 2.86-2.71(m,2H),2.04-1.94(m,2H),1.90-1.79(m,1H),1.45-1.36(m,1H),1.08(s,3H),0.68-0.61(m,2H),0.43-0.37(m,2H).

[0210] Intermediate B-27a

[0211] Compound B-27a was synthesized using a method similar to that used for compound B-5c, except that 5-bromo-1,3-difluoro-2-nitrobenzene was replaced with 5-bromo-1-chloro-3-fluoro-2-nitrobenzene. The crude product was purified by silica gel column chromatography (silica, petroleum ether / dichloromethane = 100 / 0 to 50 / 50) to yield the desired product, B-27a. LCMS (ESI+): m / z = 403.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.62 (d, J = 1.2Hz, 1H), 8.00 (d, J = 1.2Hz, 1H), 7.89 (s, 1H), 7.65 (t, J = 53.2Hz, 1H), 7.35 (d, J = 1.2Hz, 1H).

[0212] Example B-27

[0213] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-5-(piperidin-3-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0214] Compound B-27b was synthesized using a method similar to compound B-1h, where B-1f was substituted for B-27a.

[0215] B-27b (700.0 mg, 1.47 mmol) was dissolved in tetrahydrofuran (8.0 mL). A 2M solution of sodium tert-butoxide (1.47 mL, 2.94 mmol) in tetrahydrofuran was added at 0°C, and the reaction mixture was stirred at 0°C for 10 minutes. Dichloromethane (8.0 mL) and 1-methylcyclopropylamine hydrochloride (475.0 mg, 4.41 mmol) were added at 0°C, and the reaction mixture was stirred until the solid dissolved. The reaction mixture was concentrated under reduced pressure and dried by spin drying. The crude product was dissolved in N,N-dimethylformamide (8.0 mL), and triethylamine (0.62 mL, 4.41 mmol) and NCS (589.0 mg, 4.41 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Water (40 mL) and sodium bicarbonate solution (40 mL) were added, and the mixture was extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, dichloromethane / ethyl acetate = 100 / 0 to 95 / 5) to afford the desired product B-27c (240.0 mg, purity 93.88%, yield 33.4%). LCMS (ESI+): m / z = 450.9 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.97 (d, J = 1.2Hz, 1H), 8.47 (s, 1H), 8.11 (d, J = 1.6Hz, 1H), 7.94 (s, 1H),7.67(t,J=53.2Hz,1H),7.42(s,1H),1.12(s,3H),0.68-0.62(m,2H),0.46-0.40(m,2H).

[0216] Compound B-27c (60.0 mg, 0.13 mmol), compound B-27d (121.0 mg, 0.39 mmol) and potassium carbonate (9.04 mg, 0.065 mmol) were dissolved in tert-butanol (3.0 mL) and water (0.6 mL). CataCXium A Pd G3 (9.5 mg, 0.013 mmol) was added at 20°C, and the reaction solution was microwaved at 100°C under nitrogen protection for 1 hour. After cooling to room temperature, the reaction solution was concentrated and dried. The crude product was first purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 0 / 100) and then purified by thin layer chromatography (petroleum ether / ethyl acetate = 3:1) to obtain the target product B-27e (17.0 mg, purity 94.77%, yield 20.3%). LCMS (ESI+): m / z = 606.1 [M+H] + .

[0217] Compound B-27e (5.0 mg, 8.26 μmol) and triethylsilane (9.6 mg, 0.083 mmol) were dissolved in dichloromethane (0.3 mL). Trifluoroacetic acid (0.3 mL) was slowly added dropwise at 0°C, and the reaction mixture was stirred at 0°C for 40 minutes. The reaction mixture was concentrated and dried. The crude product was purified by preparative HPLC (column: 52-Welch Xtimate C18 150×30 mm, 5 μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; B%: 20%-50%) and lyophilized to obtain B-27. LCMS (ESI+): m / z = 508.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.94 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.66 (t, J = 53.2Hz, 1H), 7.43 (s, 1H), 3.19-3.16 (m, 1H), 3.10- 3.06(m,1H),2.69-2.64(m,2H),2.10-1.96(m,2H),1.91-1.84(m,1H), 1.82-1.73(m,2H),1.07(s,3H),0.66-0.61(m,2H),0.41-0.37(m,2H).

[0218] Example B-28

[0219] (R)-9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(3-hydroxypiperidin-1-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0220] Compound B-28 was synthesized using a method similar to that used for compound B-24, except that piperidin-3-ol was replaced with (R)-piperidin-3-ol. The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 50%-80%) and lyophilized to yield B-28. LCMS (ESI+): m / z = 524.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.75 (s, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.90-7.48 (m, 2H), 7.37 (s, 1H), 5.09 (d, J = 4.8Hz, 1H), 3.96-3.81 (m, 1H), 3.2 1-3.14(m,2H),2.90-2.78(m,2H),2.01-1.89(m,2H),1.86-1.72(m,1H) ,1.55-1.39(m,1H),1.07(s,3H),0.69-0.57(m,2H),0.46-0.35(m,2H).

[0221] Example B-29

[0222] (S)-9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(3-hydroxypiperidin-1-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0223] Compound B-29 was synthesized using a method similar to that used for compound B-24, except that piperidin-3-ol was replaced with (S)-piperidin-3-ol. The crude product was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 54%-84%) and lyophilized to yield B-29. LCMS (ESI+): m / z = 524.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 8.75 (s, 1H), 8.56-8.05 (m, 1H), 7.98-7.91 (m, 1 H),7.90-7.48(m,2H),7.37(s,1H),5.20-4.95(m,1H),3.95-3.84(m,1H), 3.20-3.13(m,2H),2.90-2.77(m,2H),2.01-1.89(m,2H),1.84-1.73(m,1 H),1.54-1.40(m,1H),1.07(s,3H),0.67-0.61(m,2H),0.42-0.37(m,2H).

[0224] Example B-30

[0225] (cis)-5-(3-amino-4-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0226] Compound B-30 was synthesized using a method similar to that used for compound B-20, except that tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate was replaced with (cis)-tert-butyl(4-fluoropiperidin-3-yl)carbamate (10 equivalents of amine and 15 equivalents of triethylamine were added as bases in this step, and the reaction was carried out at 160°C for 8 hours). The crude product was first purified by preparative HPLC (column: Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 46%-76%), then further purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 42%-72%), and lyophilized to obtain B-30. LCMS (ESI+): m / z = 541.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (s, 1H), 8.35-8.21 (m, 1H), 7.98-7.88 (m, 1H), 7.82-7.48 (m, 2H), 7.38 (s, 1H), 4.97-4.76 (m, 1H), 3.27-3.22(m,1H),3.14-3.07(m,2H),3.03-2.90(m,2H),2.30-1.48(m,4H),1.07(s,3H),0.69-0.60(m,2H),0.44-0.34(m,2H).

[0227] Example B-31

[0228] 5-(3-amino-3-methylpiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0229] Compound B-31 was synthesized using a method similar to that used for compound B-20, except that tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate was replaced with tert-butyl (3-methylpiperidin-3-yl)carbamate (10 equivalents of amine were added in this step, with diisopropylethylamine as the base, and the reaction was carried out at 160°C for 5 hours). The crude product was purified by preparative HPLC (column: Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 50%-80%) and lyophilized to yield B-31. LCMS (ESI+): m / z = 537.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (s, 1H), 8.34-8.24 (m, 1H), 7.83-7.48 (m, 2H), 7.40-7.36 (m, 1H), 3.04-2.98 (m, 2H), 2.81-2.75 (m ,2H),2.13-1.98(m,2H),1.85-1.79(m,1H),1.62-1.49(m,1H),1.17(s,3H),1.09(s,3H),0.70-0.62(m,2H),0.44-0.37(m,2H).

[0230] Example B-32

[0231] 9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-5-(3-methylpiperazin-1-yl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0232] Compound B-32 was synthesized using a method similar to that used for compound B-20, except that tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate was replaced with tert-butyl 2-methylpiperazine-1-carboxylate. The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 43%-73%) and lyophilized to yield B-32. LCMS (ESI+): m / z = 523.2 [M+H]+ ; 1 H NMR (400MHz, DMSO-d6) δ=8.77(d,J=1.6Hz,1H),8.30(s,1H),7.90-7.43(m,3H),7.39(d,J=1.6Hz,1H),3.25-3.20(m,2H),3.17 -3.12(m,2H),2.87-2.78(m,1H),2.59-2.53(m,2H),1.11(d,J=6.4Hz,3H),1.07(s,3H),0.69-0.61(m,2H),0.44-0.37(m,2H).

[0233] Example B-33

[0234] (3R,4R)-5-(3-amino-4-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0235] Compound B-33 was synthesized using a method similar to that used for compound B-20, except that tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate was replaced with tert-butyl ((3R,4R)-4-fluoropiperidin-3-yl)carbamate. The crude product was purified by preparative HPLC (column: Phenomenex Gemini NX C18 150×30 mm, 3 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 41%-71%) and lyophilized to yield B-33. LCMS (ESI+): m / z = 541.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6)δ=8.79(s,1H),8.32(s,1H),8.00-7.90(m,1H),7.87- 7.49(m,2H),7.39(s,1H),4.66-4.48(m,1H),3.56-3.45(m,1H),3.21-3.14( m,1H),3.08-3.02(m,1H),3.02-2.94(m,1H),2.91-2.84(m,1H),2.35-2.31( m,1H),2.13-2.04(m,1H),1.07(s,3H),0.70-0.59(m,2H),0.45-0.35(m,2H).

[0236] Example B-34

[0237] (3R,5R)-5-(3-amino-5-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0238] Compound B-27c (200.0 mg, 0.44 mmol), potassium iodide (72.4 mg, 0.44 mmol) and cesium carbonate (284.0 mg, 0.87 mmol) were dissolved in acetonitrile (4.0 mL) and 1-(chloromethyl)-4-methoxybenzene (137.0 mg, 0.87 mmol) was added at 20°C. The reaction solution was stirred at 60°C for 3 hours. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 60 / 40) to obtain the target product B-34a (130.0 mg, purity 66.0%, yield 34.0%). LCMS (ESI+): m / z = 579.1 [M+H] + .

[0239] Compounds B-34a (60.0 mg, 0.10 mmol), B-34b (45.2 mg, 0.21 mmol), and cesium carbonate (101.0 mg, 0.31 mmol) were dissolved in 1,4-dioxane (3.0 mL). RuPhos (9.7 mg, 0.021 mmol) and RuPhos-Pd-G3 (17.4 mg, 0.021 mmol) were added at 20°C. The reaction mixture was stirred at 100°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 70 / 30) to obtain the target product B-34c (60.0 mg, purity 54.9%, yield 43.3%). LCMS (ESI+): m / z = 761.1 [M+H] + .

[0240] Compound B-34c (50.0 mg, 0.066 mmol) was dissolved in trifluoroacetic acid (4.0 mL). The reaction mixture was stirred at 20°C for 2 hours and at 50°C for 2 hours. The reaction mixture was concentrated and dried. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 21%-51%) and lyophilized to obtain B-34 (TFA salt). LCMS (ESI+): m / z = 541.1 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ = 8.81 (d, J = 1.6Hz, 1H), 8.35 (s, 1H), 8.17 (s, 0.6H) ,7.94-7.87(m,1H),7.82-7.51(m,2H),7.39(d,J=1.6Hz,1H),5.27-5.11(m, 1H),3.58-3.53(m,2H),3.04-2.98(m,1H),2.95-2.81(m,2H),2.36-2.29(m ,1H),1.75-1.57(m,1H),1.09(s,3H),0.67-0.61(m,2H),0.43-0.37(m,2H).

[0241] Example B-35

[0242] (3S,4S)-5-(3-amino-4-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0243] Compound B-35 was synthesized using a method similar to that used for compound B-20, except that tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate was replaced with tert-butyl ((3S,4S)-4-fluoropiperidin-3-yl)carbamate. The crude product was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; B%: 40%-70%) and lyophilized to yield B-35 (TFA salt). LCMS (ESI+): m / z = 541.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (d, J = 1.2Hz, 1H), 8.40-8.33 (m, 2H), 7.98-7.92 (m, 1 H),7.85-7.51(m,2H),7.38(d,J=1.6Hz,1H),4.63-4.33(m,1H),3.28-3.27(m,1H), 3.20-3.12(m,2H),3.01-2.93(m,1H),2.86-2.77(m,1H),2.56-2.53(m,2H),2.32- 2.24(m,1H),2.09-1.98(m,1H),1.06(s,3H),0.67-0.62(m,2H),0.44-0.36(m,2H).

[0244] Example B-36

[0245] (3S,5S)-5-(3-amino-5-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0246] Compound B-36 was synthesized using a similar method to compound B-34, except that B-34b was replaced with tert-butyl ((3S,5S)-5-fluoropiperidin-3-yl)carbamate. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 21%-51%) and lyophilized to yield B-36 (TFA salt). LCMS: MS m / z (ESI) [M+H] + =541.0; 1 H NMR (400MHz, DMSO-d6) δ = 8.80 (d, J = 1.2Hz, 1H), 8.40-8.30 (m, 1H), 8.21 (s, 0 .5H),7.94-7.88(m,1H),7.80-7.50(m,2H),7.41-7.37(m,1H),5.27-5.09(m ,1H),3.58-3.54(m,2H),3.04-2.97(m,1H),2.94-2.80(m,2H),2.38-2.27(m ,1H),1.77-1.55(m,1H),1.08(s,3H),0.68-0.61(m,2H),0.43-0.36(m,2H).

[0247] Example B-37

[0248] (3S,5R)-5-(3-amino-5-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0249] Compound B-37 was synthesized using a similar method to compound B-34, except that B-34b was replaced with tert-butyl ((3S,5R)-5-fluoropiperidin-3-yl)carbamate. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 20%-50%) and lyophilized to yield B-37. LCMS: MS m / z (ESI) [M+H] +=541.1; 1 H NMR (400MHz, DMSO-d6) δ = 8.81 (d, J = 1.2Hz, 1H), 8.50-8.17 (m, 1H), 7.92 (s, 1H), 7.81-7.52 (m, 2H), 7.39 (s, 1H), 5.24-4.98 (m, 1H), 3.44-3 .29(m,3H),3.16-3.02(m,1H),2.93-2.81(m,1H),2.43-2.29(m,1H), 1.84-1.67(m,1H),1.08(s,3H),0.71-0.58(m,2H),0.47-0.35(m,2H).

[0250] Example B-38

[0251] 5-(5-amino-3,3-difluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0252] Compound B-38 was synthesized using a similar method to compound B-34, except that B-34b was replaced with tert-butyl (5,5-difluoropiperidin-3-yl)carbamate. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 22%-52%) and lyophilized to yield B-38. LCMS: MS m / z (ESI) [M+H] + =559.0; 1 H NMR (400MHz, DMSO-d6) δ = 8.82 (d, J = 1.2Hz, 1H), 8.39-8.28 (m, 1H), 7.86-7.80 (m, 1H), 7.78-7.50 (m, 2H), 7.40 (d, J = 1.2Hz, 1H), 3.58-3.4 5(m,2H),3.27-3.21(m,2H),2.89-2.78(m,1H),2.46-2.40(m,1H),2.01-1.81(m,1H),1.08(s,3H),0.67-0.62(m,2H),0.43-0.36(m,2H).

[0253] Example B-39

[0254] 5-(3-amino-4,4-difluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0255] Compound B-39 was synthesized using a similar method to compound B-34, except that B-34b was replaced with tert-butyl (4,4-difluoropiperidin-3-yl)carbamate. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 21%-51%) and lyophilized to yield B-39. LCMS: MS m / z (ESI) [M+H] + =559.2; 1 H NMR (400MHz, DMSO-d6) δ = 8.82 (d, J = 1.2Hz, 1H), 8.30 (s, 1H), 8.09-8.03 (m, 1H), 7.81-7.50 (m, 2H), 7.40 (d, J = 1.6Hz, 1H), 3.77-3.60 ( m,1H),3.43-3.38(m,1H),3.28-3.22(m,2H),3.16-3.01(m,2H),2.47-2.36(m,1H),1.08(s,3H),0.69-0.62(m,2H),0.44-0.38(m,2H).

[0256] Example B-40

[0257] 5-(3,8-diazabicyclo[3.2.1]octan-3-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0258] Compound B-40 was synthesized using a similar method to compound B-34, except that B-34b was replaced with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. The crude product was purified by preparative HPLC (column: Xtimate C18 150*40mm*10μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; B%: 24%-54%) and lyophilized to yield B-40. LCMS: MS m / z (ESI) [M+H] + =535.1; 1H NMR (400MHz, DMSO-d6) δ = 8.85 (d, J = 1.2Hz, 1H), 8.37-8.32 (m, 1H), 8.16 (s, 0.4H), 7.85-7.51 (m, 3H), 7.42 (d, J = 1.6Hz, 1H), 3 .96-3.86(m,2H),3.20-3.15(m,4H),2.21-2.13(m,2H),2.02-1.93(m,2H),1.09(s,3H),0.69-0.60(m,2H),0.45-0.35(m,2H).

[0259] Example B-41

[0260] (3R,5S)-5-(3-amino-5-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0261] Compound B-41 was synthesized using a similar method to compound B-34, except that B-34b was replaced with tert-butyl ((3R,5S)-5-fluoropiperidin-3-yl)carbamate. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 20%-50%) and lyophilized to yield B-41. LCMS: MS m / z (ESI) [M+H] + =541.1; 1 H NMR (400MHz, DMSO-d6)δ=8.82(s,1H),8.41-8.24(m,1H),8.20(s,0.3H),8.00-7.88(m,1H),7.69-7.48(m,2H),7.40(s,1H),5.28-4.98(m,1H),3 .36-3.35(m,3H),3.17-3.13(m,1H),2.94-2.86(m,1H),2.39-2.31(m,1H ),1.87-1.74(m,1H),1.08(s,3H),0.72-0.59(m,2H),0.49-0.36(m,2H).

[0262] Intermediates B-42b and B-43a

[0263] Compound B-42a was synthesized using a method similar to that used for compound B-34c, except that tert-butyl ((3R,5R)-5-fluoropiperidin-3-yl)carbamate was replaced with tert-butyl 2-methylpiperazine-1-carboxylate. Compound B-42a (60.0 mg, 0.081 mmol) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm), mobile phase: carbon dioxide-ethanol (0.1% ammonia water), flow rate: 80 mL / min, B%: 60%) and lyophilized to afford B-42b (retention time: 1.74 min, 30.0 mg, purity 91.66%, yield 45.8%) and B-43a (retention time: 2.39 min, 25.0 mg, purity 90.80%, yield 37.8%).

[0264] Example B-42

[0265] Compound B-42b (30.0 mg, 0.040 mmol) was dissolved in trifluoroacetic acid (1.0 mL, 12.98 mmol). The reaction solution was stirred at 50°C for 2 hours. The reaction solution was directly concentrated to dryness, adjusted to pH 8 with triethylamine, and purified by preparative HPLC (column: Phenomenex Gemini NX C18 150*30 mm*10 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 43%-73%) and lyophilized to obtain B-42. LCMS: MS m / z (ESI) [M+H] + =523.1; 1 H NMR (400MHz, DMSO-d6) δ=8.77(d,J=1.2Hz,1H),8.35-8.22(m,1H),7.85–7.51(m,3H),7.39(d,J=1.2Hz,1H),3.22-3.16(m,2H),3 .12-3.00(m,3H),2.82-2.71(m,1H),2.50-2.40(m,2H),1.09(s,3H),1.06(d,J=6.4Hz,3H),0.68-0.62(m,2H),0.42-0.37(m,2H).

[0266] Example B-43

[0267] Compound B-43a (25.0 mg, 0.034 mmol) was dissolved in trifluoroacetic acid (1.0 mL, 12.98 mmol). The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was directly concentrated to dryness, adjusted to pH 8 with triethylamine, and purified by preparative HPLC (column: Phenomenex Gemini NX C18 150*30 mm*10 μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 43%-73%) and lyophilized to obtain B-43. LCMS: MS m / z (ESI) [M+H] + =523.2; 1 H NMR (400MHz, DMSO-d6)δ=8.78-8.74(m,1H),8.34-8.23(m,1H),7.81-7.51(m,3H),7.42-7.35(m,1H),3.22-3.16(m,2 H),3.11-3.04(m,3H),2.79-2.74(m,1H),2.56-2.53(m,2H),1.11-0.98(m,6H),0.70-0.58(m,2H),0.45-0.36(m,2H).

[0268] Examples B-44 and B-45

[0269] (3*S,4*R)-5-(3-amino-4-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0270] (3*R,4*S)-5-(3-amino-4-fluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0271] Compounds B-44 and B-45 were synthesized using a method similar to that of compounds B-42 and B-43, wherein tert-butyl 2-methylpiperazine-1-carboxylate was replaced with tert-butyl cis-(4-fluoropiperidin-3-yl)carbamate. The resulting intermediates were separated by SFC (column: (S,S) Whelk-01 (100 mm*4.6 mm, 5 μm), mobile phase: carbon dioxide-methanol (0.1% diethylamine), flow rate: 2.5 mL / min, B%: 60%) to give intermediates B-44a (retention time: 5.19 minutes) and B-45a (retention time: 4.21 minutes).

[0272] The crude B-44 product was purified by preparative HPLC (column: Boston Prime C18 150*30mm*10μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 46%-76%) and lyophilized to obtain B-44. LCMS: MS m / z (ESI) [M+H] + =541.1; 1 H NMR (400MHz, DMSO-d6) δ = 8.77 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.01-7.87 (m, 1H), 7.81-7.51 (m, 2H), 7.38 (d, J = 1.6Hz, 1H), 4.97-4.76 (m, 1H), 3. 27-3.18(m,1H),3.17-3.06(m,2H),3.04-2.89(m,2H),2.33-2.10(m,2H ),1.99-1.65(m,2H),1.07(s,3H),0.74-0.56(m,2H),0.48-0.29(m,2H).

[0273] The crude B-45 product was first purified by preparative HPLC (column: Boston Prime C18 150*30mm*10μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; B%: 46%-76%), then purified by preparative HPLC (column: Boston Prime C18 150*30mm*10μm; mobile phase: [water (0.2% formic acid)-acetonitrile]; B%: 15%-45%) and lyophilized to obtain B-45. LCMS: MS m / z (ESI) [M+H] + =541.1; 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (d, J = 1.6Hz, 1H), 8.31-8.26 (m, 1H), 8.22 (s, 0.7H), 7.97-7.88 (m, 1H), 7.81-7.51 (m, 2H), 7.39 (d, J = 1.2Hz, 1H), 5 .01-4.77(m,1H),3.24-3.18(m,1H),3.15-3.07(m,2H),3.02-2.91(m,2H ),2.26-2.12(m,2H),1.07(s,3H),0.69-0.60(m,2H),0.44-0.36(m,2H).

[0274] Intermediate B-46i

[0275] Compound B-46a was synthesized using a method similar to compound B-1a, wherein 5-bromo-1,3-difluoro-2-nitrobenzene was replaced with 5-bromo-1-chloro-3-fluoro-2-nitrobenzene.

[0276] Compound B-46a (2.8 g, 7.87 mmol) was dissolved in N,N-dimethylformamide (20.0 mL), and N,N'-thiocarbonyldiimidazole (1.54 g, 8.66 mmol) was added at 20°C. The reaction mixture was stirred at 80°C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 50 / 50) to obtain the target product B-46b (2.9 g, purity 95.2%, yield 88%). LCMS:MS m / z (ESI) [M+H] + =396.9.

[0277] Compound B-46b (2.9 g, 7.29 mmol) and cesium carbonate (3.56 g, 10.94 mmol) were dissolved in N,N-dimethylformamide (25.0 mL), and iodomethane (0.50 mL, 8.02 mmol) was added at 20°C. The reaction solution was stirred at 20°C under nitrogen for 30 minutes. Water (100 mL) was added and extracted with ethyl acetate (80 mL x 4). The organic phases were combined, washed with saturated brine (50 mL x 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / dichloromethane = 100 / 0 to 70 / 30) to obtain the target product B-46c (2.7 g, purity 95.2%, yield 86%). LCMS:MS m / z (ESI) [M+H] + =410.9.

[0278] Compound B-46c (2.60 g, 6.32 mmol) was dissolved in anhydrous dichloromethane (80.0 mL). Meta-chloroperbenzoic acid (3.85 g, 18.95 mmol, 85% purity) was added at 0°C. The reaction solution was stirred at 25°C for 8 hours. The reaction solution was diluted with dichloromethane (120 mL) and washed with 10% aqueous sodium bisulfite solution (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL), respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the target product B-46d (3.0 g, purity 69.8%, yield 74.8%). LCMS:MS m / z(ESI)[M+H] + =442.8.

[0279] Compound B-46d (3.0 g, 6.76 mmol) was dissolved in anhydrous 1,4-dioxane (30.0 mL). A solution of hydrazine hydrate (2.71 g, 54.1 mmol) in 1,4-dioxane (30.0 mL) was added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (30 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the target product B-46e (2.7 g, purity 61.3%, yield 61.8%). LCMS:MS m / z (ESI) [M+H] + =394.9.

[0280] Compound B-46e (2.65 g, 6.70 mmol) was dissolved in anhydrous 1,4-dioxane (100.0 mL), and triethyl orthoformate (9.93 g, 67.0 mmol) and formic acid (0.93 g, 20.1 mmol) were added at 25°C. The reaction solution was heated to 110°C and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and dried. The crude product was slurried (petroleum ether / ethyl acetate = 8 / 1, 50 mL), filtered, and the filter cake was collected and dried under reduced pressure to obtain the target product B-46f (2.0 g, purity 93.2%, yield 68.6%). LCMS:MS m / z (ESI) [M+H] + =404.9; 1 H NMR (400MHz, DMSO-d6) δ = 9.44 (s, 1H), 8.58 (d, J = 1.2Hz, 1H), 7.97 (d, J = 1.6Hz, 1H), 7.66 (t, J = 52.8Hz, 1H).

[0281] Compound B-46f (650.0 mg, 1.60 mmol), methyl 3-mercaptopropionate (193.0 mg, 1.60 mmol), Xantphos (5.65 mg, 9.77 μmol) and diisopropylethylamine (93.0 mg, 0.72 mmol) were dissolved in toluene (18.0 mL) and Pd2(dba)3 (147.0 mg, 0.16 mmol) was added at 30°C. The reaction solution was stirred at 100°C under nitrogen for 2 hours. The reaction solution was cooled to room temperature and directly concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 60 / 40) to obtain the target product B-46g (600.0 mg, purity 75%, yield 63.1%). LCMS:MS m / z (ESI) [M+H] + =444.9.

[0282] Compound B-46g (200.0 mg, 0.45 mmol), tert-butyl piperazine-1-carboxylate (167.0 mg, 0.90 mmol) and cesium carbonate (439.0 mg, 1.35 mmol) were dissolved in 1,4-dioxane (10.0 mL), and RuPhos-Pd-G3 (75.0 mg, 0.090 mmol) and RuPhos (42.0 mg, 0.090 mmol) were added at 20 ° C. The reaction solution was stirred at 100 ° C under nitrogen protection for 12 hours. The reaction solution was cooled to room temperature, water (2 mL) was added thereto, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, petroleum ether / ethyl acetate = 100 / 0 to 50 / 50) to give the target product B-46h (150.0 mg, purity 83%, yield 46.6%). LCMS: MS m / z (ESI) [M+H] + =595.0.

[0283] Compound B-46h (150.0 mg, 0.25 mmol) was dissolved in dichloroethane (12.0 mL) and m-chloroperbenzoic acid (159.0 mg, 0.92 mmol) was added at 0°C. The reaction solution was stirred at 25°C for 1 hour. Water (10 mL) was added, the pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica, dichloromethane / ethyl acetate = 100 / 0 to 50 / 50) to obtain the target product B-46i (60.0 mg, purity 82%, yield 31.4%). LCMS:MS m / z (ESI) [M+H] + =627.1.

[0284] Example B-46

[0285] 9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-5-(piperazin-1-yl)-9H-benzo[4,5]imidazo[2,1-c][1,2,4]triazole-7-sulfonamide

[0286] Compound B-46 was synthesized using a method similar to that used for compound B-23, except that methyl 3-((5-(3-((tert-butyloxycarbonyl)amino)piperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-9H-benzo[d]imidazo[1,2-a]imidazol-7-yl)sulfonyl)propanoate was replaced with B-46i. The crude product was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water(formic acid)-acetonitrile]; B%: 20%-50%) and lyophilized to yield B-46. LCMS: MS m / z (ESI) [M+H] + =510.1; 1 H NMR (400MHz, DMSO-d6) δ = 9.02 (s, 1H), 8.71 (s, 1H), 8.43-8.34 (m, 1H), 8.26-8.18 (m, 1H), 7.81-7.50(m,2H),3.12-3.04(m,8H),1.09(s,3H),0.70-0.61(m,2H),0.45-0.37(m,2H).

[0287] Examples B-47 and B-48

[0288] (*R)-5-(3-amino-4,4-difluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0289] (*S)-5-(3-amino-4,4-difluoropiperidin-1-yl)-9-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-N-(1-methylcyclopropyl)-9H-benzo[d]imidazo[1,2-a]imidazole-7-sulfonamide

[0290] B-39 was separated by SFC (column: CO2-EtOH (0.1% NH3H2O), mobile phase B: carbon dioxide-ethanol (0.1% ammonia water), flow rate: 150 mL / min, B%: 50%) to obtain the target products B-47 (retention time: 2.26 minutes) and B-48 (retention time: 3.34 minutes).

[0291] B-47: LCMS:MS m / z (ESI) [M+H] + =559.1; 1H NMR (400MHz, DMSO-d6) δ = 8.81 (d, J = 1.2Hz, 1H), 8.31 (s, 1H), 8.16-8.01 (m, 1H), 7.85-7.50 (m, 2H), 7.39 (d, J = 1.2Hz, 1H), 3.33-3.18 ( m,4H),3.16-3.04(m,1H),3.03-2.92(m,1H),2.44-2.35(m,1H),2.04-1.96(m,2H),1.07(s,3H),0.67-0.63(m,2H),0.42-0.38(m,2H).

[0292] B-48: LCMS:MS m / z (ESI) [M+H] + =559.1; 1 H NMR (400MHz, DMSO-d6) δ = 8.80 (d, J = 1.2Hz, 1H), 8.32-8.25 (m, 1H), 8.13-8.02 (m, 1H), 7.85-7.50 (m, 2H), 7.40-7.35 (m, 1H), 3.33-3.18 (m,4H),3.14-3.06(m,1H),3.01-2.91(m,1H),2.46-2.38(m,1H),2.08-1.94(m,2H),1.06(s,3H),0.66-0.62(m,2H),0.42-0.38(m,2H).

[0293] Example B-49

[0294] (3S,5S)-9-(5-(Difluoromethyl)-1,3,4-thiadiazol-2-yl)-5-(3,5-dimethylpiperazin-1-yl)-N-(1-methylcyclopropyl)-9H-benzo[4,5]imidazo[2,1-c][1,2,4]triazole-7-sulfonamide

[0295] Compound B-49 was synthesized using a method similar to that used for compound B-46, except that tert-butyl piperazine-1-carboxylate was replaced with (2S,6S)-2,6-dimethylpiperazine. The crude product was purified by preparative HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 20%-50%) and lyophilized to yield B-49. LCMS: MS m / z (ESI) [M+H] + =538.1; 1H NMR (400MHz, DMSO-d6)δ=9.06-9.03(m,1H),8.74-8.71(m,1H),8.43-8.37(m,1H),8.20(s,0.8H),7.85-7.51(m,2H),3.64-3 .55(m,2H),3.28-3.21(m,2H),2.74-2.64(m,2H),1.21(d,J=6.8Hz,6H),1.10(s,3H),0.68-0.59(m,2H),0.45-0.38(m,2H).

[0296] The following compounds were also prepared using a similar method to the above compounds and different starting compounds:

[0297] Test Example 1: Inhibitory effect of the compound of the present invention on PARG enzyme activity

[0298] The enzymatic detection experimental method is as follows:

[0299] 1) Incubate DMSO or a compound serially diluted with DMSO (maximum concentration 100 μM, 3-fold dilutions for 10 concentrations) with 5 μL of PARG enzyme in a 384-well microplate at room temperature for 60 minutes;

[0300] 2) Add 5 μL of biotinylated-PARylated PARP1 substrate to start the reaction and incubate at room temperature for 10 minutes;

[0301] 3) Add 5 μL of detection reagent streptavidin-EU and 2.5 μL of detection antibody (anti-6HIS-XL665) to the microplate and incubate at room temperature for 60 minutes;

[0302] 4) The fluorescence value was then read using the Envision multi-label detector in TRF mode: using 337 nm excitation light and reading emission light at 620 nm and 665 nm.

[0303] Data analysis: The enzyme activity inhibition IC of the compound was obtained by computer fitting. 50 value.

[0304] Test results: IC of the compounds of the present invention for inhibition of PARG enzyme activity 50 The values ​​are shown in Table 1 below. 50 The range of values ​​is defined as follows: A: ≤1 nM; 5 nM ≥ B >1 nM; C: >5 nM.

[0305] Test Example 2: Inhibitory effect of the compound of the present invention on HCC1806XRCC1-KO cell activity

[0306] The experimental method for detecting the inhibitory effect of HCC1806 XRCC1-KO cell activity is as follows:

[0307] 1) Cultivation and passaging of HCC1806 XRCC1-KO cells: Culture medium: RPMI1640 medium supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin in a 37°C incubator (5% CO2). Cells were passaged every 3-4 days.

[0308] 2) Cell plating: Add 40 μL / well of cell suspension (approximately 250 cells) to a 384-well plate and culture overnight in a 37°C incubator with 5% CO2.

[0309] 3) Add 120 nL of serially diluted compound or DMSO control solution to the microplate and incubate in a 37°C incubator containing 5% CO2 for 7 days;

[0310] 4) Add 20 μL of CTG reagent (Vazyme, DD1101-03) to each well and incubate at room temperature in the dark for 30 minutes;

[0311] 5) Read the plate on a microplate reader (BMG, PHERAstar FSX).

[0312] Data analysis: The Y-axis is the inhibition rate, the X-axis is the compound concentration, and the inhibition rate curve is fitted using XLFit to obtain the IC value of the compound's inhibition on cell activity. 50 The inhibition rate was calculated as follows: Inhibition% = (Ave_H - Sample) / (Ave_H - Ave_L); Ave_H = the average fluorescence signal value of the DMSO-treated group, Sample = the fluorescence signal value of the compound-treated group, and Ave_L = the average fluorescence signal value of the blank culture medium.

[0313] Test results: IC of the compounds of the present invention against HCC1806XRCC1-KO cell activity inhibition 50 The values ​​are shown in Table 1 below. 50 The range of values ​​is defined as follows: A: ≤10 nM; 50 nM ≥ B>10 nM; C:>50 nM. Table 1: IC values ​​of the compounds of the present invention for inhibition of PARG enzyme activity and HCC1806XRCC1-KO cell activity 50 Value (expressed in nM)

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof: in: R1 is H, cyano, formyl, -CONH2, -CH2OH, -CH2OC 1-6 Alkyl, C 1-6 Alkyl or C 1-6 Haloalkyl; R2 and R2' are each independently C 1-6 Alkyl; or R2 and R2' together with the carbon atom to which they are attached constitute a C optionally substituted by halogen. 3-6 Cycloalkyl or 3 to 8 membered heterocyclic group; Y is NH or CH2; X1 is N or CR5; R5 is H or halogen, the halogen is preferably fluorine; X2 is N or CR6; R6 is H or halogen, the halogen is preferably fluorine; X3 is N or CR7; R7 is H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; X4 is N or CR8; R8 is H, halogen, cyano, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; R3 is H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, ethynyl or -L2-(R3') n A group in which: L2 is C 3-6 cycloalkyl, aryl, heterocyclyl or heteroaryl; n is 0, 1, 2 or 3, and n R3's are each independently selected from halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, amino, cyano, hydroxyl, carboxyl, carbamoyl, aminosulfonyl, C 1-6 alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, NR 3a R 3b , OR 3a 、C(O)R 3a 、C(O)OR 3a 、OC(O)R 3a 、C(O)NR 3a R 3b NR 3a C(O)R 3b , SR 3a , SOR 3a 、SO2R 3a 、SO2NR 3a R 3b NR 3a S02R 3b or (CH2) z NR 3a R 3b , where z is 1, 2 or 3, R 3a and R 3b Each independently is C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 haloalkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, or R 3a and R 3b together with the N atom to which they are attached form an optionally substituted heterocyclyl; R4 is a group having the following structural formula: -COR4' or in: R4' is C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl; Ar is a 5-membered heteroaryl group; R 4a It is C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkyl, -C(O)H or cyano; R 4b and R 4c Does not exist or is independently C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogen, C 1-6 Haloalkyl or C 1-6 Halogenated alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, isomer or isotope derivative thereof, wherein R1 is cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, wherein R2 and R2' together with the carbon atom to which they are attached constitute a cyclopropyl group or an oxetan-3-yl group.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, wherein Y is NH.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, wherein X1 and X2 are both CH.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, wherein X3 and X4 are each independently N or CH.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, wherein R3 is of the formula -L2-(R3') n A group wherein L2 is a 5- to 10-membered heterocyclic group; or, L2 is selected from piperazinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, morpholinyl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 2,6-diazaspiro[3.4]octan-6-yl, 2,8-diazaspiro[4.5]decane-2-yl and 2-oxa-7-azaspiro[3.5]nonane-7-yl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, wherein R3 is of the formula -L2-(R3') n wherein n is 0, 1, 2 or 3.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, wherein R3 is of the formula -L2-(R3') n wherein n R3' are independently selected from halogen, C 1-6 Alkyl, amino, hydroxyl, C(O)R 3a 、C(O)NR 3a R 3b , where R 3a and R 3b Each independently is C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 haloalkyl, optionally substituted C 3-8 Cycloalkyl or an optionally substituted 4- to 8-membered heterocyclyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isomer and isotopic derivative thereof, wherein R4 is a group having the following structural formula: in: Ar is thiadiazolyl, especially 1,3,4-thiadiazol-2-yl; R 4a It is C 1-6 haloalkyl; and R 4b and R 4c Does not exist.

11. The compound of claim 1, or a pharmaceutically acceptable salt, isomer, and isotopic derivative thereof, wherein the compound is selected from:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isomer or isotopic derivative thereof, and one or more pharmaceutically acceptable excipients.

13. Use of the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isomer or isotope derivative thereof, in the preparation of a PARG inhibitor.

14. Use of the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isomer or isotope derivative thereof, in the preparation of a medicament for treating cancer.

Images