Pyridazinone PARP inhibitors, their preparation, pharmaceutical compositions and uses

Abstract

The present invention discloses pyridazinone compounds represented by formula (I), as well as their preparation methods, pharmaceutical compositions, and uses. These compounds have potential advantages as PARP inhibitors in terms of blood-brain barrier permeability, and their inhibitory activity against PARP enzyme reaches nanomolar concentrations. They can be used to prepare drugs for preventing and / or treating stroke. In addition, the preparation method of such PARP inhibitors is simple and easy to operate. [C40] TIFF2026505719000064.tif26168

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical field, and particularly relates to pyridazinone compounds and their preparation methods, pharmaceutical compositions and uses. [Background technology]

[0002] Poly(ADP-ribose) polymerase-1 (PARP1) is a poly(ADP-ribosylation) catalyzing enzyme found in eukaryotic cells and includes many family members. PARP1 was the first nuclear enzyme to be discovered, and subsequent isoforms, including PARP2, PARP3, PARP4 (VPARP), PARP5a (tankyrase 1), PARP5b (tankyrase 2), PARP7 (TiPARP), and PARP1, were subsequently isolated.

[0003] PARP7 is a gene regulated by AHR and an important member of the PARP family. PARP7 can transfer only one mono-ADP-ribose (MAR) and belongs to the MonoPARP family. The PARP catalytic domain of PARP7 contains one zinc finger motif that can confer DNA binding and one WWE domain that can mediate protein interaction. The mono-ADP-ribosylation mediated by it is a reversible post-translational modification involved in several important biological processes, such as immune cell function, transcriptional regulation, protein expression, and DNA repair.

[0004] PARP7 is also part of a negative feedback loop that regulates AHR activity, which in turn regulates immune function, inflammation, and stem cell differentiation, and may function in cancer. PARP7 has been shown to be overactive in tumors and play an important role in cancer cell survival. More importantly, many cancer cells rely on PARP7 to achieve their inherent cell survival, and research has shown that PARP7 can enable cancer cells to "hide" from the immune system. Inhibiting PARP7 can effectively inhibit cancer cell growth, restore interferon signaling, and inhibit the "brakes" of innate and adaptive immune systems. In several cancer models, PARP7 inhibitors have demonstrated sustained tumor growth inhibition, effective antiproliferative activity, and restoration of interferon signaling.

[0005] Stroke is primarily divided into two types: hemorrhagic stroke and ischemic stroke. The former mainly includes cerebral hemorrhage and subarachnoid hemorrhage, while the latter mainly includes transient ischemic attack, cerebral thrombosis, and cerebral embolism. Studies have revealed that circular RNAs (circRNAs) are highly expressed in the central nervous system and are involved in regulating physiological and pathophysiological processes. Using circRNA microarrays, we found that the level of the circRNA Hect1 (circHect1) was significantly increased in ischemic brain tissue in a mouse model of stroke following transient middle cerebral artery occlusion (tMCAO). This finding was further verified in plasma samples from patients with acute ischemic stroke (AIS). Reduced circHect1 expression significantly reduced infarct size, alleviated neuronal loss, and improved astrocyte activation in tMCAO mice. Mechanistically, circHect1 functions as an endogenous MIR142 (microRNA 142) sponge and inhibits PARP7 expression by inhibiting MIR142 activity, which subsequently inhibits astrocyte activation through macroautophagy / autophagy. These results suggest that circHect1 and its coupling mechanism are involved in cerebral ischemia, and that inhibition of PARP7 expression could also be used to treat stroke.

[0006] Stroke is a common disease among middle-aged and elderly people, and survivors still suffer from varying degrees of disability, some even suffering from severe disability. Existing drug-based stroke treatments aim to block neuronal necrosis caused by ischemia, extend the ischemic tolerance time and treatment time frame, enhance neuronal viability, reverse ischemic penumbra, reduce infarct volume, and promote neuronal function recovery, but currently no drug has been widely recognized as having a definite therapeutic effect.

[0007] RBN-2397 is the first compound to have relatively strong inhibitory activity and selectivity against PARP7. However, this compound is only applicable to antitumor treatments, and its relatively large molecular weight makes it difficult to penetrate the blood-brain barrier, making it difficult to use in central nervous system diseases such as stroke. Summary of the Invention [Problem to be solved by the invention]

[0008] The first object of the present invention is to provide a pyridazinone compound having PARP inhibitory activity, the second object is to provide a method for producing the compound, the third object is to provide a pharmaceutical composition containing the compound, and the fourth object is to provide uses of the compound and the pharmaceutical composition. [Means for solving the problem]

[0009] In order to improve the technical problems existing in the prior art, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt thereof, [ka] Among them, n is selected from 0, 1, 2, 3 or 4; R 1 is hydrogen, deuterium, halogen, cyano group, nitro group, C1-C 12 Haloalkyl groups, C1-C 12 Alkyl groups, C1-C 12 Alkyloxy group, C1-C 12 Alkylthio groups, C1-C 12 Alkylsulfonyl group or -C(O)N(R 11 )(R 12 ) and R 11 or R 12 are identical or different and are independently selected from H, deuterium, and C1-C6 alkyl groups; A 1 -O-, -S-, [ka] or -N(R 3 )-, wherein x and y are each independently selected from 0, 1, or 2; R 3 H, deuterium, C1 to C 12Alkyl groups, C3-C 14 cycloalkyl groups, A 2 is absent or is a methylene group, a vinylidene group, an ethynylene group, [ka] , unsubstituted or optionally one, two or more (preferably one) R a2 replaced with [ka] , C6~C 14 aryl group or 5- to 14-membered heteroaryl group (preferably 5- to 14-membered heteroaryl group containing one nitrogen atom), wherein p and q are each independently selected from 0, 1, or 2; a2 are the same or different and independently represent hydrogen, deuterium, halogen, cyano group, hydroxy group, nitro group, C1 to C 12 Alkyl groups, C1-C 12 Alkyloxy group, C1-C 12 Haloalkyl groups, C1-C 12 Haloalkyloxy group, -C(O)OR a21 , -C(O)R a22 , -N(R a23 )(R a24 ), -S(O)R a25 , -S(O)R a26 Each R a21 , R a22 , R a23 , R a24 , R a25 , R a26 are the same or different and independently represent H, deuterium, C1 to C 12 Alkyl groups, C1-C 12 alkyl-C(O)-; R 2 is unsubstituted or optionally substituted with one, two or more (preferably one or two) R 21 C6~C substituted with 14an aryl group, a 5- to 14-membered heteroaryl group (preferably a 5- to 14-membered heteroaryl group containing one or two nitrogen or sulfur atoms), a 3- to 8-membered heterocyclyl group (preferably a 3- to 8-membered heterocyclyl group containing one nitrogen atom), a C1-C 12 alkyl-S(O)2-NH-, -C(O)NH2, NH2-S(O)2-NH-, each R 21 are the same or different and independently represent hydrogen, deuterium, halogen, cyano group, hydroxy group, nitro group, C1 to C 12 Alkyl groups, C1-C 12 Haloalkyl groups, C6-C 14 an aryl group, a 5- to 14-membered heteroaryl group (preferably a 5- to 14-membered heteroaryl group containing one or two nitrogen or sulfur atoms), a 3- to 8-membered heterocyclyl group (preferably a 3- to 8-membered heterocyclyl group containing one nitrogen atom), R 21 -O-, -C(O)OR 22 , -C(O)R 23 , -N(R 24 )(R 25 ), -S(O)R 26 , -S(O)R 27 Each R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 are the same or different and independently represent H, deuterium, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a 3- to 14-membered cycloalkyl group, a 3- to 14-membered cycloalkyl-C1-C6 alkyl group, a C6-C 14 It is selected from an aryl group, a 5- to 14-membered heteroaryl group, and a 3- to 8-membered heterocyclyl group.

[0010] According to an embodiment of the present invention, n is selected from 0, 1 or 2.

[0011] According to an embodiment of the present invention, R 1 is selected from halogen, a cyano group, or a trifluoromethyl group; According to an embodiment of the present invention, R 1 is a trifluoromethyl group.

[0012] According to an embodiment of the present invention, A 1 teeth [ka] or -N(R 3 )-, wherein x and y are each independently selected from 0, 1, or 2; R 3 is selected from H and C1-C6 alkyl groups, According to an embodiment of the present invention, A 1 -NH-, -N(CH3)-, [ka] Selected from According to an embodiment of the present invention, A 1 is selected from -NH-.

[0013] According to an embodiment of the present invention, A 2 is absent or is a vinylidene group, an ethynylene group, [ka] , C6~C 10 selected from an arylene group or a 5- to 10-membered heteroarylene group (preferably a 5- to 10-membered heteroaryl group containing one nitrogen atom), wherein p and q are each independently selected from 0, 1, or 2; According to an embodiment of the present invention, A 2 is absent or is a vinylidene group, an ethynylene group, a phenylene group, [ka] Selected from According to an embodiment of the present invention, A 2 is an ethynylene group, [ka] Selected from.

[0014] According to an embodiment of the present invention, [ka] is unsubstituted or optionally substituted with one, two or more (preferably one) R a2 Each R is replaced by a2 are the same or different and are each independently selected from a C1 to C6 alkyl group, a C1 to C6 alkyloxy group, a trifluoromethyl group, a 2,2-difluoroethyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a carboxy group, a methoxycarbonyl group, a methylsulfonyl group, and a nitro group.

[0015] According to an embodiment of the present invention, R 2 is unsubstituted or optionally substituted with one, two or more (preferably one) R 21 C6~C substituted with 10 an aryl group, a 5- to 10-membered heteroaryl group (preferably a 5- to 10-membered heteroaryl group containing one or two nitrogen or sulfur atoms), or a 3- to 8-membered heterocyclyl group (preferably a 3- to 8-membered heterocyclyl group containing one nitrogen atom), and each R 21 are the same or different and independently represent hydrogen, halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkyloxy group, a C1-C6 haloalkyloxy group, a 3- to 8-membered cycloalkyloxy group, a 3- to 8-membered cycloalkyl-C1-C6 alkyloxy group, a C6-C 10 aryl-C(O)-;

[0016] According to an embodiment of the present invention, R 2 is the substituted C6~C 14 an aryl group or a substituted 5- to 14-membered heteroaryl group (preferably a 5- to 14-membered heteroaryl group containing one or two nitrogen or sulfur atoms), 14The aryl group or 5- to 14-membered heteroaryl group is a monocyclic or fused ring, and the substituent is selected from hydrogen, halogen, cyano group, trifluoromethyl group, 2,2-difluoroethyl group, C1 to C6 alkyl group, hydroxy group, C1 to C6 alkyloxy group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, C3 to C6 azacycloalkyl group (preferably a C3 to C6 azacycloalkyl group containing one nitrogen atom), formyl group, acetyl group, acetamido group, carbamoyl group, and sulfamoyl group, and the substituent is mono- or di-substituted.

[0017] According to an embodiment of the present invention, R 2 is the substituted C6~C 10 an aryl group or a substituted 5- to 10-membered heteroaryl group (preferably a 5- to 10-membered heteroaryl group containing one or two nitrogen or sulfur atoms), and 10 The aryl group is a phenyl group, a naphthyl group, an anthryl group, an indanyl group, an indenyl group, or a 1,2,3,4-tetrahydronaphthyl group, and the 5- to 10-membered heteroaryl group is selected from a pyridyl group, a thienyl group, a pyrrolyl group, a furanyl group, an imidazolyl group, a pyrazolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an indolyl group, an indolinyl group, a quinolyl group, an isoquinolyl group, a tetrahydroisoquinolyl group, an indazolyl group, a benzothienyl group, a benzofuranyl group, or a benzimidazolyl group. The substituents are selected from hydrogen, halogen, cyano, trifluoromethyl, 2,2-difluoroethyl, methyl, ethyl, hydroxy, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, azetidinyl, tetrahydropyrrol-1-yl, piperidin-1-yl, morpholinyl, piperazinyl, N-methylpiperazinyl, acetyl, acetamido, carbamoyl, and sulfamoyl, and the substituents are mono- or di-substituted.

[0018] According to an embodiment of the present invention, R 2 teeth, [ka] Selected from.

[0019] According to an embodiment of the present invention, the compound of formula (I) is the following compound: [ka] Selected from TIFF2026505719000014.tif220169TIFF2026505719000015.tif226169TIFF2026505719000016.tif104169.

[0020] According to an embodiment of the present invention, the pharmaceutically acceptable salt is a salt formed from the compound and an acid, and the acid is at least one selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and ferulic acid.

[0021] According to an embodiment of the present invention, the isotope label is deuterium (D or 2 H) with hydrogen ( 1 It is preferred to substitute H).

[0022] The present invention provides a method for producing the above-mentioned compound, its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, or pharmaceutically acceptable salt thereof, comprising the steps of: (1) reacting compound I-1 with compound I-2 to obtain compound I-3; (2) removing PG from compound I-3 to obtain a compound of formula (I); Including, [ka] wherein Y is selected from leaving groups, for example, halogens such as Cl and Br, and PG is selected from protecting groups, for example, (trimethylsilyl)ethoxymethyl (SEM) and p-methoxybenzyl (PMB); A method of manufacture is also provided.

[0023] According to an embodiment of the present invention, the above-mentioned manufacturing method further includes at least one of the following methods: Plan 1:R 1 is selected from a trifluoromethyl group, a cyano group, or a halogen atom; 1 represents -NH- or -N(CH3)-, A 2 When n is an ethynylene group, and n=1, the structure of the compound of formula (I) is represented by formula (IA), and the method for preparing it comprises the steps of: [ka] wherein each group has the definition described herein, X is Cl, Br, or I, and SEM is (trimethylsilyl)ethoxymethyl; (1-1) reacting compound II with compound III to obtain compound IV, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is ethanol, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, tetrahydrofuran (THF), 1,4-dioxane, ethylene glycol dimethyl ether, or acetonitrile, preferably 1,4-dioxane or ethanol; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid-binding agent, which is sodium carbonate, potassium carbonate, triethylamine or N,N-diisopropylethylamine (DIPEA), preferably DIPEA or triethylamine.

[0024] (1-2) reacting compound IV with compound V to obtain compound VI, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is DMF, N,N-dimethylacetamide, THF, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably THF; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid binding agent, wherein the acid binding agent is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably triethylamine; According to an embodiment of the present invention, the reaction may be carried out in the presence of a catalyst, and the catalyst may be selected from a copper catalyst or a palladium catalyst, wherein the copper catalyst is cuprous iodide or cuprous bromide, and preferably cuprous iodide, and the palladium catalyst is palladium acetate, bistriphenylphosphinepalladium dichloride, tetrakis(triphenylphosphine)palladium, or 1,1′-bisdiphenylphosphinoferrocenepalladium dichloride, and preferably bistriphenylphosphinepalladium dichloride.

[0025] (1-3) removing the protecting group SEM from compound VI and reacting to obtain compound IA, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is THF, acetonitrile or dichloromethane, preferably dichloromethane; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid, and the acid is hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.

[0026] Plan 2:R 1 is selected from a trifluoromethyl group, a cyano group, or a halogen atom; 1 -NH-, [ka] or -N(CH3)-, where n=1 or 0, and A 2 is -NH- or [ka] wherein p and q are each independently selected from 0, 1, or 2, the structure of the compound of formula (I) is represented by formula (IB), and the method for preparing the compound includes the following steps: [ka] wherein each group has the definition described herein, and SEM is a (trimethylsilyl)ethoxymethyl group; (2-1) A step of reacting compound VII with compound VIII to obtain compound IX, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is dichloromethane, toluene, DMF, N,N-dimethylacetamide, THF, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably dichloromethane; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid binding agent, wherein the acid binding agent is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably triethylamine; According to an embodiment of the present invention, the reaction may be carried out in the presence of a catalyst, which may be selected from copper catalysts, for example, copper acetate.

[0027] (2-2) A step of removing the tert-butoxycarbonyl group from compound IX and reacting to obtain compound X, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is THF, acetonitrile or dichloromethane, preferably dichloromethane; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid, which is hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably trifluoroacetic acid.

[0028] (2-3) reacting compound X with compound II to obtain compound XI, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is ethanol, DMF, N,N-dimethylacetamide, THF, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-dioxane or ethanol; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid binding agent, and the acid binding agent is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA or triethylamine.

[0029] (2-4) A step of removing the protecting group SEM from compound XI and reacting to obtain compound IB, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is THF, acetonitrile or dichloromethane, preferably dichloromethane; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid, which is hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably trifluoroacetic acid.

[0030] Plan 3:R 1 is selected from a trifluoromethyl group, a cyano group, or a halogen atom; 1 -NH-, -N(CH3)-, [ka] represents A 2 -CH=CH-, benzene ring, -CH2-, [ka] and n is 0, 1 or 2, the structure of the compound of formula (I) is represented by formula (IC), and the method for preparing it comprises the steps of: [ka] wherein each group has the definition described herein, and SEM is a (trimethylsilyl)ethoxymethyl group; (3-1) A step of reacting compound II with compound XII to obtain compound XIII, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is ethanol, DMF, N,N-dimethylacetamide, THF, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-dioxane or ethanol; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid binding agent, and the acid binding agent is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA or triethylamine.

[0031] (3-2) A step of removing the protecting group SEM from compound XIII and reacting to obtain compound IC, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is THF, acetonitrile or dichloromethane, preferably dichloromethane; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid, which is hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably trifluoroacetic acid.

[0032] Plan 4:R 1 is selected from a trifluoromethyl group, a cyano group, or a halogen atom; 1 represents -NH- or -N(CH3)-, A 2 but [ka] and n is 1 or 2, the structure of the compound of formula (I) is represented by formula (ID), and the method for preparing it comprises the steps of: [ka] wherein each group has the definition described herein, and SEM is a (trimethylsilyl)ethoxymethyl group; (4-1) A step of reducing compound XIV under a hydrogen gas atmosphere to obtain compound XV, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, the solvent being THF, ethanol or methanol, preferably methanol; According to an embodiment of the present invention, the reaction may be carried out in the presence of a catalyst, and the catalyst is palladium on carbon or palladium hydroxide, preferably palladium on carbon.

[0033] (4-2) A step of reacting compound XV with compound II to obtain compound XVI, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is ethanol, DMF, N,N-dimethylacetamide, THF, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-dioxane or ethanol; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid binding agent, and the acid binding agent is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA or triethylamine.

[0034] (4-3) A step of oxidizing compound XVI to obtain compound XVII, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is THF or dichloromethane, preferably dichloromethane; According to an embodiment of the present invention, the reaction may be carried out in the presence of an oxidizing agent, which may be a Dess-Martin reagent, hydrogen peroxide, or pyridinium chlorochromate (PCC), preferably PCC.

[0035] (4-4) A step of removing the protecting group SEM from compound XVII and reacting to obtain compound ID, According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent, and the solvent is THF, acetonitrile or dichloromethane, preferably dichloromethane; According to an embodiment of the present invention, the reaction may be carried out in the presence of an acid, and the acid is hydrochloric acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.

[0036] According to an embodiment of the present invention, a pharmaceutically acceptable salt of a compound of formula (I) is obtained by salt formation with a corresponding acid.

[0037] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of a compound of formula (I), its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable auxiliary materials.

[0038] According to an embodiment of the present invention, the above pharmaceutical composition can be prepared into a common pharmaceutical preparation, such as a tablet, capsule, syrup, suspension, or injection, by adding a pharmaceutically acceptable carrier, and the preparation can contain common pharmaceutical auxiliary materials such as flavorings, sweeteners, liquid / solid fillers, diluents, etc.

[0039] The present invention further provides use of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt thereof, or the pharmaceutical composition, in the manufacture of a drug for preventing and / or treating a PARP-mediated disease, for example, a PARP inhibitor drug.

[0040] According to an embodiment of the present invention, the PARP isoform may be selected from PARP2, PARP3, PARP4 (VPARP), PARP5a (tankyrase 1), PARP5b (tankyrase 2), PARP7 (TiPARP) and / or sPARP1, preferably PARP7.

[0041] According to an embodiment of the present invention, the PARP-mediated disease may be a central nervous system disease, cancer, infection, immune disease, cardiovascular disease or metabolic disease, wherein the central nervous system disease is, for example, stroke such as ischemic stroke, and the cancer is selected from lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, renal cancer, melanoma, ovarian cancer, brain glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer.

[0042] The present invention further provides use of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the manufacture of a medicament for preventing and / or treating a central nervous system disease, a cerebral ischemia-related disease, a cancer, an infection, an immune disease, a cardiovascular disease or a metabolic disease, According to an embodiment of the present invention, the central nervous system disease may be, for example, a stroke such as an ischemic stroke, and the cerebral ischemia-related disease may be a transient ischemic attack, cerebral thrombosis, or cerebral embolism, and the cancer may be selected from lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, renal cancer, melanoma, ovarian cancer, cerebral glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer.

[0043] The present invention further provides a method for preventing and / or treating a PARP-mediated disease, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of the compounds represented by formula (I), its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, or pharmaceutically acceptable salt thereof, or administering to a patient a prophylactically or therapeutically effective amount of the pharmaceutical composition.

[0044] The present invention further provides at least one of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing and / or treating a PARP-mediated disease.

[0045] According to an embodiment of the present invention, the disease may be a central nervous system disease, cancer, infection, immune disease, cardiovascular disease or metabolic disease, and the central nervous system disease is, for example, stroke such as ischemic stroke, and the cancer is selected from lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, brain glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer.

[0046] The present invention further provides a method for preventing and / or treating a cerebral ischemia-related disease, which comprises administering to a patient a prophylactically or therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, or pharmaceutically acceptable salt thereof, or administering to a patient a prophylactically or therapeutically effective amount of the pharmaceutical composition.

[0047] The present invention further provides at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing and / or treating a cerebral ischemia-related disease.

[0048] According to an embodiment of the present invention, the cerebral ischemia-related disease may be transient ischemic attack, cerebral thrombosis, or cerebral embolism. [Effects of the Invention]

[0049] Compared with the prior art, the present invention has the following significant advantages: (1) The compound described in the present invention has good membrane permeability, and the calculated physicochemical parameters comply with the Clark and Lobell rules (the physicochemical property rules for blood-brain barrier permeable drugs: the total number of nitrogen atoms and oxygen atoms (N+O) is less than 6, the polar surface area (PSA) is less than 60-70, and the molecular weight is less than 450). (2) The compound and pharmaceutical composition according to the present invention further have antitumor activity, exhibit good efficacy at the molecular level, and inhibit PARP7 enzyme at nanomolar concentration levels; (3) The method for preparing the compound is simple and easy to operate.

[0050] Definitions and explanations of terms Unless specified to the contrary, terms used in the specification and claims have the following meanings.

[0051] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 (Alkyl groups). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted.

[0052] The term "alkyloxy group" refers to an -O-(alkyl group), wherein the definition of alkyl is as described herein. Preferably, alkyloxy groups (C) contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. 1-12 alkyloxy group), more preferably an alkyloxy group containing 1 to 6 carbon atoms (C 1-6 Alkyloxy groups are substituted or unsubstituted. Non-limiting examples of alkyloxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkyloxy groups can be substituted or unsubstituted.

[0053] The term "alkylene group" refers to a saturated divalent hydrocarbon group obtained after removing two H from a saturated straight- or branched-chain hydrocarbon group, which may contain 1 to 12 carbon atoms. Non-limiting examples include methylene (-CH-), ethylene (-CHCH-), etc. The alkylene group may be substituted or unsubstituted.

[0054] The term "alkenyl group" should be understood to denote a straight or branched chain hydrocarbon group, preferably containing one or more double bonds and having 2 to 12 carbon atoms, and "C 2-10 "Alkenyl group" is preferred. 2-10 An "alkenyl group" preferably contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 alkenyl groups), having 2 or 3 carbon atoms (i.e., C 2-3Alkenyl group) should be understood to represent a linear or branched monovalent hydrocarbon group. When the alkenyl group contains more than one double bond, it should be understood that the double bonds may be separated or conjugated with each other. The alkenyl group can be, for example, a vinyl group, an allyl group, an (E)-2-methylvinyl group, a (Z)-2-methylvinyl group, an (E)-but-2-enyl group, a (Z)-but-2-enyl group, an (E)-but-1-enyl group, a (Z)-but-1-enyl group, a pent-4-enyl group, an (E)-pent-3-enyl group, a (Z)-pent-3-enyl group, an (E)-pent-2-enyl group, a (Z)-pent-2-enyl group, an (E)-pent- 1-enyl group, (Z)-pent-1-enyl group, hex-5-enyl group, (E)-hex-4-enyl group, (Z)-hex-4-enyl group, (E)-hex-3-enyl group, (Z)-hex-3-enyl group, (E)-hex-2-enyl group, (Z)-hex-2-enyl group, (E)-hex-1-enyl group, (Z)-hex-1-enyl group, isopropenyl group, 2-methylprop-2-enyl group, 1-methylprop- 2-enyl group, 2-methylprop-1-enyl group, (E)-1-methylprop-1-enyl group, (Z)-1-methylprop-1-enyl group, 3-methylbut-3-enyl group, 2-methylbut-3-enyl group, 1-methylbut-3-enyl group, 3-methylbut-2-enyl group, (E)-2-methylbut-2-enyl group, (Z)-2-methylbut-2-enyl group, (E)-1-methylbut-2-enyl group, (Z)-1-methylbut-2-enyl group Examples of alkenyl groups include (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, and 1-isopropylvinyl. The alkenyl groups may be substituted or unsubstituted.

[0055] The term "alkynyl group" should be understood to denote a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 12 carbon atoms, and "C 2-10"Alkynyl group" is preferred. 2-10 The term "alkynyl group" preferably includes one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, 2, 3, 4, 5, or 6 carbon atoms (i.e., C 2-6 alkynyl groups), having 2 or 3 carbon atoms (i.e., C 2-3 Alkynyl groups are understood to denote straight-chain or branched monovalent hydrocarbon groups. The alkynyl groups include, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-5-ynyl, 2-methylpent-6-ynyl, 2-methylpent-7-ynyl, 2-methylpent-8-ynyl, 2-methylpent-9-ynyl, 2-methylpent-10-ynyl, 2-methylpent-11-ynyl, 2-methylpent-12-ynyl, 2-methylpent-13-ynyl, 2-methylpent-14-ynyl, 2-methylpent-15-ynyl, 2-methylpent-16-ynyl, 2-methylpent-17-ynyl, 2-methylpent-18-ynyl, 2-methylpent-19 ... alkynyl groups include ethylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, and 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl. The alkynyl group may be substituted or unsubstituted.

[0056] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 14 carbon atoms, preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms, and the ring atoms may optionally be substituted with oxo groups, where the oxo group (=O) on the ring is part of the ring. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., and polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0057] The term "heterocyclyl group" refers to a saturated or unsaturated non-aromatic ring or ring system having 3 to 14 members, for example, a 3-, 4-, 5-, 6-, or 7-membered monocyclic, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic (e.g., fused, bridged, spiro) ring, or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and containing at least one heteroatom selected from O, S, and N, e.g., 1, 2, 3, 4, 5, or more, of which N and S can be optionally oxidized to various oxidation states to form nitrogen oxides, -S(O)-, or -S(O)-. Unless otherwise specified, a heterocyclyl group can be a carbon or nitrogen group, and -CH- groups can be optionally replaced with -C(=O)-. Sulfur atoms in the ring may be optionally oxidized to S-oxides. Nitrogen atoms in the ring may be optionally oxidized to N-acid compounds. In some embodiments, the heterocyclyl group is a heterocyclyl group of 5 to 12 atoms; in other embodiments, the heterocyclyl group is a heterocyclyl group of 5 to 8 atoms; in further embodiments, the heterocyclyl group is a heterocyclyl group of 5 to 7 atoms; and in still further embodiments, the heterocyclyl group is a heterocyclyl group of 5 to 6 atoms. The heterocyclyl group may be a bicyclic heterocyclyl group; in some embodiments, the heterocyclyl group is a bicyclic heterocyclyl group of 7 to 12 atoms; in other embodiments, the heterocyclyl group is a bicyclic heterocyclyl group of 7 to 10 atoms; and in still further embodiments, the heterocyclyl group is a bicyclic heterocyclyl group of 8 to 10 atoms.

[0058] The term "aryl group" refers to a monovalent aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring, preferably having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms ("C 6-14aryl groups), in particular rings having 6 carbon atoms ("C aryl groups"), such as phenyl or biphenyl groups, or rings having 9 carbon atoms ("C aryl groups"), such as indanyl or indenyl groups, or rings having 10 carbon atoms ("C 10 aryl group), such as a tetrahydronaphthyl group, a dihydronaphthyl group, or a naphthyl group, or a ring having 13 carbon atoms ("C 13 aryl group), such as a fluorenyl group, or a ring having 14 carbon atoms ("C 14 It should be understood that the above C refers to an aryl group, such as an anthryl group. 6-20 When an aryl group is substituted, it may be mono-substituted or poly-substituted. The substitution position is not limited, and it may be substituted, for example, at the ortho-, para-, or meta-position. The aryl group includes a ring system formed by condensing an aromatic ring with an aromatic ring, or an aromatic ring with a non-aromatic carbocyclic ring. Examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, a 1,2,3,4-tetrahydronaphthyl group, a 2,3-dihydro-1H-indenyl group, and a bicyclo[4,2,0]octa-1(6),2,4-trienyl group. The aryl group may be substituted or unsubstituted, and the substituents include, but are not limited to, fluorine, chlorine, bromine, oxo (=O), cyano, nitro, carboxy, hydroxy, amino, aminomethyl, aminoacyl, methylamino, phenylamino, hydroxymethyl, methylsulfonyl, aminosulfonyl, acetyl, methoxy, phenoxy, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, imidazolyl, imidazolinyl, piperidinyl, piperazinyl, morpholinyl, thienyl, thiazolyl, furanyl, pyrrolyl, phenyl, pyridyl, pyrimidinyl, -C(=NH)NH, or trifluoromethyl.

[0059] The term "heteroaryl group" is understood to mean a monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic ring system containing 5 to 14 ring atoms and 1 to 5 heteroatoms independently selected from N, O, and S, wherein at least one ring (or the ring as a whole) is aromatic. The heteroaryl group has one or more points of attachment to the remainder of the molecule. The term "heteroaryl group" may be used interchangeably with the terms "heteroaryl ring" or "heteroaromatic compound." Heteroaryl groups include ring systems formed by fused heteroaryl rings with aromatic rings, heteroaryl rings with heteroaryl rings, or heteroaryl rings with non-aromatic carbocyclic or heterocyclic rings. In some embodiments, heteroaryl groups of 5 to 10 atoms contain 1, 2, 3, or 4 heteroatoms independently selected from oxygen, sulfur, and nitrogen. In some embodiments, the heteroaryl group is a 7-12 atom heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, and the 7-12 atom heteroaryl group may be a monocyclic ring or a bicyclic ring. In other embodiments, the heteroaryl group is a 7-10 atom heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and the 7-10 atom heteroaryl group may be a monocyclic ring or a bicyclic ring.

[0060] The term "halogen" refers to F, Cl, Br or I.

[0061] The term "hydroxy group" refers to -OH.

[0062] The term "amino group" refers to -NH2.

[0063] The term "cyano" refers to -CN.

[0064] The term "nitro group" refers to -NO2.

[0065] The term "oxo group" or "oxo" refers to "=O".

[0066] The term "carbonyl group" refers to C=O.

[0067] The term "carboxy" refers to -C(O)OH.

[0068] The term "patient" refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse or primate, and most preferably a human.

[0069] The term "therapeutically effective amount" refers to an amount of an active compound or drug that elicits the biological or medical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human, including one or more of the following: (1) disease prevention: e.g., preventing a disease, disorder, or condition in an individual susceptible to the disease, disorder, or condition but not experiencing or developing the pathology or symptoms of the disease; (2) disease inhibition: e.g., inhibiting a disease, disorder, or condition (i.e., preventing further progression of the pathology and / or symptoms) in an individual experiencing or developing the pathology or symptoms of the disease, disorder, or condition; or (3) disease amelioration: e.g., ameliorating a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual experiencing or developing the pathology or symptoms of the disease, disorder, or condition. DETAILED DESCRIPTION OF THE INVENTION

[0070] The technical solutions of the present disclosure will be described in more detail below in conjunction with specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present disclosure. Any technology realized based on the above content of the present disclosure is included within the scope of the claims of the present disclosure.

[0071] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or may be prepared by known methods.

[0072] Example 1: Synthesis of 4-trifluoromethyl-5-((3-(2-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyridazin-3(2H)-one (IA-1) [ka] Synthesis of 5-(prop-2-yn-1-ylamino)-4-trifluoromethyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (IV-1) Compound 5-chloro-4-trifluoromethyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (II-1) (7.0 g, 22.0 mmol) was dissolved in 20 mL of 1,4-dioxane, and propargylamine (III-1) (1.3 g, 24.2 mmol) and DIPEA (8.5 g, 66.0 mmol) were added. The mixture was heated to 70 °C and reacted for 0.5 h. The reaction was monitored for completeness by thin-layer chromatography (V petroleum ether:V ethyl acetate = 4:1). 15 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 8:1) to give 4.1 g of brown oil (IV-1) in a 53.7% yield. ESI-MS [M+H] + 348.1.

[0073] Synthesis of 4-trifluoromethyl-5-((3-(2-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (VI-1) Compound IV-1 (365.4 mg, 1.0 mmol) was dissolved in 3 mL of anhydrous tetrahydrofuran, and o-iodobenzotrifluoride (V-1) (299.2 mg, 1.1 mmol) was added. Cuprous iodide (38.1 mg, 0.2 mmol), bistriphenylphosphinepalladium dichloride (70.2 mg, 0.1 mmol), and triethylamine (303.0 mg, 3.0 mmol) were then added. The mixture was purged with nitrogen gas, heated to 70 °C, and reacted for 0.5 h. Complete reaction was monitored by thin-layer chromatography (V petroleum ether:V ethyl acetate = 2:1). 10 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 8:1) to give 0.4 g of a yellow solid (VI-1), with a yield of 81.5%. ESI-MS [M+H] + 492.1.

[0074] Synthesis of 4-trifluoromethyl-5-((3-(2-(trifluoromethyl)phenyl)prop-2-yn-1-yl)amino)pyridazin-3(2H)-one (IA-1) Compound VI-1 (245.5 mg, 0.5 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the mixture was allowed to react at room temperature for 3 h. The reaction was monitored for completeness by thin-layer chromatography (V dichloromethane:V methanol = 15:1). The solvent was removed under reduced pressure, the pH was adjusted to 8 by adding saturated aqueous sodium bicarbonate, 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (V dichloromethane:V methanol = 50:1) to give 124.0 mg of a white solid (IA-1), a 68.9% yield. ESI-MS [M+H] + 362.1; 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 7.94 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.63-7.56 (m, 1H), 7.56-7.52 (m, 1H), 4.50 (d, J = 5.9 Hz, 2H).

[0075] The following compounds were prepared with reference to the preparation method of compound IA-1: [Table A-1] [Table A-2] [Table A-3]

[0076] Example 21: Synthesis of 5-(((1-phenylpiperidin-4-yl)methyl)amino)-4-trifluoromethylpyridazin-3(2H)-one (IB-1) [ka] Synthesis of tert-butyl ((1-phenylpiperidin-4-yl)methyl)carbamate (IX-1) 4-tert-Butoxycarbonylaminomethylpiperidine (VII-1) (500.0 mg, 2.5 mmol) was added to a 25 mL eggplant-shaped flask and dissolved in 10 mL of dichloromethane. Phenylboronic acid (VIII-1) (1.5 g, 12.2 mmol) was added, followed by Cu(AcO) (978.0 mg, 4.9 mmol) and EtN (2.5 g, 24.5 mmol). The mixture was allowed to react at room temperature for 48 h. 10 mL of water was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed three times with saturated brine solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 8:1) to give 638 mg of yellow oil (IX-1) in 90% yield. ESI-MS: [M+H] + 291.2. Synthesis of (1-phenylpiperidin-4-yl)methanamine (X-1) Compound IX-1 (520.0 mg, 1.8 mmol) was placed in a 50 mL eggplant-shaped flask, dissolved in 5 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added. The mixture was incubated at room temperature for 10 min. Complete reaction was monitored by thin-layer chromatography (Petroleum ether:Ethyl acetate = 4:1). The solvent and remaining trifluoroacetic acid were removed by vacuum distillation. 10 mL of water was added, and the mixture was back-extracted with DCM (5 mL x 3). The aqueous layer was adjusted to pH 9-10 with NaOH solution, extracted with dichloromethane (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, affording 265 mg of a yellow oil (X-1) in a 78% yield. ESI-MS: [M+H] + 191.2. Synthesis of 5-(((1-phenylpiperidin-4-yl)methyl)amino)-4-trifluoromethyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (XI-1) Compound X-1 (234.0 mg, 1.23 mmol) was added to a 25 mL eggplant-shaped flask and dissolved in 6 mL of 1,4-dioxane. DIPEA (477.0 mg, 3.7 mmol) and compound II-1 (470.0 mg, 1.5 mmol) were added, followed by the reaction at room temperature for 40 min. The reaction was monitored for completeness by thin-layer chromatography (petroleum ether:ethyl acetate = 2:1). 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give 230 mg of a yellow solid (XI-1) in 40% yield. ESI-MS: [M+H] + 483.2. Synthesis of 5-(((1-phenylpiperidin-4-yl)methyl)amino)-4-trifluoromethylpyridazin-3(2H)-one (IB-1) Compound XI-1 (110.0 mg, 0.23 mmol) was added to a 25 mL eggplant-shaped flask, dissolved in 4 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. After the addition was complete, the mixture was allowed to react at room temperature for 15 min. The reaction was monitored for completeness by thin-layer chromatography (V petroleum ether:V ethyl acetate = 1:1). The solvent and remaining trifluoroacetic acid were removed by distillation under reduced pressure, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 1.5:1) to give 40 mg of a yellow solid (IB-1) in 57% yield. ESI-MS [M+H] + :353.2; 1H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H), 7.96 (s, 1H), 7.05 (t, J = 7.7 Hz, 2H), 6.56 (d, J = 7.9 Hz, 2H), 6.49 (t, J = 7.2 Hz, 1H), 5.66 (s, 1H), 3.70-3.61 (m, 2H), 3.20-3.10 (m, 2H), 2.94-2.89 (m, 2H), 2.78 (s, 1H), 1.85-1.79 (m, 2H), 1.27-1.22 (m, 2H).

[0077] The following compounds were prepared with reference to the preparation method of compound IB-1: [Table B]

[0078] Example 23: Synthesis of 5-(((1,1'-biphenyl-4-yl)methyl)amino)-4-trifluoromethylpyridazin-3(2H)-one (IC-1) [ka] Synthesis of 5-(((1,1'-biphenyl-4-yl)methyl)amino)-4-trifluoromethyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (XIII-1) Compound (1,1'-biphenyl-4-yl)methanamine (XII-1) (155.0 mg, 0.85 mmol) was added to a 25 mL eggplant-shaped flask and dissolved in 10 mL of 1,4-dioxane. DIPEA (219.0 mg, 1.7 mmol) was added and stirred at room temperature for 15 min. Compound II-1 (404.0 mg, 1.3 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction was monitored for completeness by thin-layer chromatography (V petroleum ether:V ethyl acetate = 4:1). 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 4). The combined organic phases were washed three times with saturated brine solution (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by column chromatography (V petroleum ether:V ethyl acetate = 10:1) to give 165 mg of a pale yellow solid (XIII-1) in 41% yield. ESI-MS: [M+H] + 184.3.

[0079] Synthesis of 5-(((1,1'-biphenyl-4-yl)methyl)amino)-4-trifluoromethylpyridazin-3(2H)-one (IC-1) Compound XIII-1 (150.0 mg, 0.3 mmol) was placed in a 25 mL eggplant-shaped flask, dissolved in 4 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was incubated at room temperature for 15 min. Complete reaction was monitored by thin-layer chromatography (V petroleum ether:V ethyl acetate = 2:1). The solvent and remaining trifluoroacetic acid were removed by distillation under reduced pressure. The pH was adjusted to 8 with saturated sodium bicarbonate solution, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 2:1) to give 110 mg of a yellow solid (IC-1) in 99% yield. ESI-MS: [M+H] + 346.1; 1H NMR (300 MHz, DMSO-d6) δ 12.52 (s, 1H), 7.86-7.78 (m, 1H), 7.73 (s, 1H), 7.70-7.61 (m, 4H), 7.50-7.29 (m, 5H), 4.66 (d, J = 6.3 Hz, 2H).

[0080] The following compounds were prepared by referring to the preparation method of compound IC-1: [Table C-1] [Table C-2] [Table C-3] [Table C-4]

[0081] Example 42: Synthesis of 5-((3-oxo-3-phenylpropyl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (ID-1) [ka] Synthesis of 3-amino-1-phenylpropan-1-ol (XV-1) 3-Oxo-3-phenylpropanenitrile (XIV-1) (1.0 g, 6.89 mmol) was placed in a 100 mL three-neck flask and dissolved in 12 mL of methanol. 100 mg of 10% palladium on carbon was added, and the reaction mixture was purged with hydrogen gas three times. The hydrogenation reaction was carried out for 8 h. The reaction was monitored for completeness by TLC (V dichloromethane:V methanol = 10:1). The mixture was then suction filtered, and the filter cake was washed four times with methanol. The solvent was removed by vacuum distillation to give 0.9 g of a yellow oil (XV-1), which was used directly in the next step without further purification.

[0082] Synthesis of 5-((3-hydroxy-3-phenylpropyl)amino)-4-trifluoromethyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (XVI-1) XV-1 (0.9 g, 5.96 mmol) was added to a 100 mL eggplant-shaped flask and dissolved in 16 mL of ethanol. EtN (1.8 g, 18.00 mmol) and II-1 (2.0 g, 6.55 mmol) were added and reacted at room temperature for 1 h. Complete reaction was monitored by TLC (V dichloromethane:V methanol = 10:1). The solvent was removed by evaporation under reduced pressure, 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 100:1) to give 900 mg of a pale yellow solid (XVI-1) in 78% yield. ESI-MS: [M+H] + 434.2.

[0083] Synthesis of 5-((3-oxo-3-phenylpropyl)amino)-4-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (XVII-1) XVI-1 (0.9 g, 2.08 mmol) was added to a 100 mL eggplant-shaped flask and dissolved in 10 mL of DCM. PCC (1.3 g, 6.23 mmol) was added and the mixture was allowed to react at room temperature for 1 h. The reaction was monitored for completeness by thin-layer chromatography (V dichloromethane:V methanol = 10:1). 20 mL of water was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 5:1) to give 643 mg of a yellow oil (XVII-1) in 72% yield. ESI-MS: [M+H] + 432.2.

[0084] Synthesis of 5-(3-oxo-3-phenylpropylamino)-4-trifluoromethylpyridazin-3(2H)-one (ID-1) XVII-1 (0.6 g, 1.49 mmol) was added to a 50 mL eggplant-shaped flask, and dichloromethane (5 mL) and trifluoroacetic acid (5 mL) were added. The mixture was incubated at room temperature for 30 min. Complete reaction was monitored by thin-layer chromatography (V dichloromethane:V methanol = 1:1). The solvent and excess trifluoroacetic acid were removed by evaporation under reduced pressure. The pH was adjusted to 8 with saturated sodium bicarbonate solution. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 2:1) to give 343 mg of a yellow solid (ID-1) in 74% yield. ESI-MS: [M+H] + 312.1; 1 H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 7.99 (s, 1H), 7.98-7.96 (m, 2H), 7.67-7.62 (m, 1H), 7.55-7.49 (m, 2H), 7.04-6.97 (m, 1H), 3.74 (q, J = 6.6 Hz, 2H), 3.39 (t, J = 6.8 Hz, 2H).

[0085] The following compounds were prepared by referring to the preparation method of compound ID-1: [Table D-1] [Table D-2] [Table D-3] [Table D-4]

[0086] Example 60: Enzyme inhibitory activity of compounds against PARP7 Experimental materials: PARP7 Chemiluminescent Assay Kit, BPS Bioscience, DMSO, National Pharmaceutical, Nivo, PerkinElmer.

[0087] Experimental Method: (1) Preparation of solutions and buffer solutions To prepare 10X PBS, weigh 720 mg of KH2PO4, 45 g of NaCl, and 5.311 g of Na2HPO4·12H2O and dissolve them in 500 mL of deionized water. The pH of the solution was adjusted to 7.4, sterilized at 121°C for 30 minutes, and then cooled to 4°C for use.

[0088] Preparation of 1X PBS: 10X PBS was diluted 10 times with deionized water, i.e., 1 part 10X PBS was diluted with 9 parts deionized water.

[0089] Wash buffer preparation: 1X PBS containing 0.05% Tween-20.

[0090] Preparation of 1X PARP buffer: (Prepared at the time of use) Dilute 10X PARP buffer 10 times with deionized water and place on ice for use.

[0091] (2) Preparation of compound working solution concentration Depending on the detection requirements, compounds to be measured were diluted to the desired concentration with 100% DMSO, and then diluted 10-fold with 1X PARP buffer to prepare a 10X compound working solution.

[0092] (3) Experimental Procedure a. Thaw the 5X histone mixture on ice the day before the experiment. b. Prepare a 1X histone mixture, and then adjust the 5X histone mixture to 1X histone mixture with 1X PBS. Take 25 μL of the 1X histone mixture from each well and add it to the test plate. Incubate at 4°C overnight. c. 100 μL of blocking buffer was taken from each well and added to the test plate, and the plate was incubated at 25°C for 90 minutes. d. After incubation, the liquid in the test plate is spun dry and the plate is washed three times. e. Take 2.5 μL of compound working solution from each well and add it to the test plate according to the experimental layout diagram. Add the corresponding volume of 1X PARP buffer containing 10% DMSO to the positive control wells, and add the corresponding volume of 1X PARP buffer to the blank control wells. f. After the enzyme is completely dissolved, dilute the enzyme stock solution to 6ng / μL with 1X PARP buffer. g. Add 10 μL / well of the enzyme solution to the test well plate, and add the corresponding volume of 1X PARP buffer to the blank control wells, resulting in an enzyme amount of 60 ng / well. Note: This step must be performed on ice. h. Add 12.5 μL of master mixture to each well of the test plate (12.5 μL of master mixture contains 1.25 μL of 10X PARP buffer, 1.25 μL of Opti-PARP 10X Assay mixture, and 10 μL of water), seal the test plate with film, place it at 25°C, and incubate for 60 minutes. i. After incubation, the liquid in the test plate is spun dry and the plate is washed three times. j. Dilute the Streptavidin-HRP in the reagent kit 50-fold with the blocking buffer solution, add 25 μL / well to the test plate, and incubate at 25°C for 30 minutes. k. After incubation, spin-dry the liquid in the test plate and wash the plate three times. l. Mix ELISA ECL Substrate A and ELISA ECL Substrate B in the reagent kit in a 1:1 ratio, add 50 μL / well of the mixture to the test plate, and immediately perform luminescence detection using Nivo to read the luminescence value (RLU); m. Calculation of enzyme inhibition rate: %Enzyme Activity=(RLU(Sample)-RLU(Blank)) / (RLU(Pos.Ctrl)-RLU(Blank))×100%, Enzyme inhibition rate = 1-% enzyme activity, IC calculated by GraphPad Prism 8 50 was calculated.

[0093] The specific results are shown in Tables 1 and 2 below.

[0094] [Table 1]

[0095] NOTE: "+++" indicates that the inhibition rate at 100 nM is ≥ 50%, and "++" indicates that the inhibition rate at 100 nM is ≥ 50% > inhibition rate ≥ 25%.

[0096] [Table 2]

[0097] Note: "+++" is IC 50 <0.1 μM, and "++" indicates 0.1 μM ≤ IC 50 <0.5 μM.

[0098] As shown in Tables 1 and 2, all of the test compounds of the present invention have good enzyme inhibitory activity against PARP7, and several compounds have IC 50 The value is less than 100 nM.

[0099] Example 61: Physicochemical properties of compounds (Table 3, among which tPSA was calculated by software ChemDraw Professional 17).

[0100] Experimental materials: Test compounds IA-1, IA-2, RBN-2397.

[0101] Experimental Method: (1) Seeding Caco-2 cells onto plates 1. Add 600 μL and 100 μL of cell culture medium to each well of the Transwell insert and reservoir, respectively. 2. Before inoculating the cells, place the Transwell horizontally at 37℃, 5% CO2, and pre-incubate for 1 hour. 3. 100 μL of cell suspension (4 × 10 5 The cells were inoculated into the medium at 1000 x 1000 cells / mL and cultured at 37°C, 5% CO2, and 95% relative humidity for 14 to 21 days. 4. Change the cell culture medium once every other day within 7 days, and once a day after 7 days. 5. The transepithelial electrical resistance (TEER) of the monolayer membrane was measured using EVOM3.

[0102] (2) ABBA process 1. The transwell plate was washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4) and then incubated at 37°C for 30 minutes.

[0103] Test compounds were prepared in 2.1 mM DMSO and diluted 200-fold to 5 μM in HBSS (10 mM HEPES, pH 7.4) and HBSS (100 μM Lucifer Yellow, 10 mM HEPES, pH 7.4).

[0104] 3. Apical to basolateral direction: 200 μL of working solution (100 μM Lucifer Yellow) at a concentration of 5 μM was added to the apical chamber, and 600 μL of HBSS (10 mM HEPES, pH 7.4) was added to the basolateral chamber.

[0105] 4. Basolateral to apical direction: 600 μL of working solution at a concentration of 5 μM was added to the basolateral chamber, and 200 μL of HBSS (100 μM Lucifer Yellow, 10 mM HEPES, pH 7.4) was added to the apical chamber.

[0106] 5. 100 μL of the working solution with a concentration of 5 μM was transferred to a sample plate containing 400 μL of cold methanol, where IS* was C0.

[0107] 6. The cell plates were incubated at 37°C, 5% CO2, and 95% relative humidity for 2 hours.

[0108] 7. 5 μL of working solution from the apical and basolateral chambers was transferred to the plate and incubated for 0.5 h before reading the Lucifer Yellow leak detector at excitation of 427 nM and emission of 536 nM.

[0109] After 8.2 h of incubation, 100 μL was transferred from the apical and basolateral chambers to a sample plate containing 400 μL of cold methanol using IS*.

[0110] 9. The sample plate was centrifuged at 3220 g for 40 minutes.

[0111] 10. For LC-MS / MS analysis, 100 μL of the supernatant was transferred to an analytical plate containing an appropriate volume of water.

[0112] (3) Calculation The apparent permeability coefficient (P app , cm / s) and Efflux Ratio were calculated.

[0113]

number

number

[0114] Note: tPSA is a predictive value.

[0115] As shown in Table 3, the compounds IA-1 and IA-2 of the present invention have better membrane permeability and a relatively low excretion rate, and are in line with the Clark and Lobell rules. In theory, they can penetrate the blood-brain barrier very well and can further treat stroke. However, the conventional compound RBN-2397 has poorer membrane permeability and does not comply with the Clark and Lobell rules, making it difficult to penetrate the blood-brain barrier.

[0116] The above is an illustrative description of the embodiments of the technical solution of the present disclosure. It should be understood that the scope of the claims of the present disclosure is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art without departing from the spirit and principle of the present disclosure should be included within the scope of the claims of the present application.

Claims

1. A compound represented by formula (I), a racemate, a stereoisomer, a tautomer, an isotopically labeled compound, a solvate, or a pharmaceutically acceptable salt thereof, 【Chemistry 27】 Among them, n is selected from 0, 1, 2, 3 or 4; R １ is hydrogen, halogen, cyano group, nitro group, C １ ~C １２ Haloalkyl group, C １ ~C １２ Alkyl group, C １ ~C １２ Alkyloxy group, C １ ~C １２ Alkylthio group, C １ ~C １２ Alkylsulfonyl group or —C(O)N(R １１ ) (R １２ ) and R １１ or R １２ are homologous or different, and independently represent H, C １ ~C ６ selected from alkyl groups, A １ is -O-, -S-, 【Chemistry 28】 or -N(R ３ )-, wherein x and y are each independently selected from 0, 1, or 2; R ３ is H, C １ ~C １２ Alkyl group, C ３ ~C １４ cycloalkyl groups, A ２ is absent or is a methylene group, a vinylidene group, an ethynylene group, 【Chemistry 29】 , unsubstituted or optionally one, two or more R ａ２ replaced with 【Transformation 30】 , C ６ ~C １４ aryl group or 5- to 14-membered heteroaryl group, wherein p and q are each independently selected from 0, 1, or 2; ａ２ are the same or different and independently represent hydrogen, halogen, cyano group, hydroxy group, nitro group, C １ ~C １２ Alkyl group, C １ ~C １２ Alkyloxy group, C １ ~C １２ Haloalkyl group, C １ ~C １２ Haloalkyloxy group, —C(O)OR ａ２１ , -C(O)R ａ２２ , -N(R ａ２３ ) (R ａ２４ ), -S(O) ２ R ａ２５ , -S(O)R ａ２６ Each R ａ２１ , R ａ２２ , R ａ２３ , R ａ２４ , R ａ２５ , R ａ２６ are homologous or different, and independently represent H, C １ ~C １２ Alkyl group, C １ ~C １２ alkyl-C(O)—; R ２ is unsubstituted or optionally substituted with one, two or more R ２１ C substituted with ６ ~C １４ an aryl group, a 5- to 14-membered heteroaryl group, a 3- to 8-membered heterocyclyl group, C １ ~C １２ Alkyl group, —S(O) ２ -NH-, -C(O)NH ２ , N.H. ２ -S(O) ２ —NH—, and each R ２１ are the same or different and independently represent hydrogen, halogen, cyano group, hydroxy group, nitro group, C １ ~C １２ Alkyl group, C １ ~C １２ Haloalkyl group, C ６ ~C １４ aryl group, 5- to 14-membered heteroaryl group, 3- to 8-membered heterocyclyl group, R ２１ -O-, -C(O)OR ２２ , -C(O)R ２３ , -N(R ２４ ) (R ２５ ), -S(O) ２ R ２６ , -S(O)R ２７ Each R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ , R ２７ are homologous or different, and independently represent H, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, 3- to 14-membered cycloalkyl group, 3- to 14-membered cycloalkyl-C １ ~C ６ Alkyl group, C ６ ~C １４ selected from an aryl group, a 5- to 14-membered heteroaryl group, and a 3- to 8-membered heterocyclyl group; A compound, its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, or pharmaceutically acceptable salt thereof.

2. n is selected from 0, 1 or 2; R １ is selected from halogen, cyano, or trifluoromethyl; 2. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof.

3. A １ teeth 【Chemistry 31】 or -N(R ３ )-, wherein x and y are each independently selected from 0, 1, or 2; R ３ is H, C １ ~C ６ selected from alkyl groups, A １ is -NH-, -N(CH ３ ) -, 【Chemistry 32】 Selected from Preferably, A １ is selected from -NH-, A ２ is absent or is a vinylidene group, an ethynylene group, 【Transformation 33】 , C ６ ~C １０ an arylene group or a 5- to 10-membered heteroarylene group, wherein p and q are each independently selected from 0, 1, or 2; Preferably, A ２ is absent or is a vinylidene group, an ethynylene group, a phenylene group, 【Transformation 34】 Selected from More preferably, A ２ is an ethynylene group, 【Chemistry 35】 Selected from 【Transformation 36】 is unsubstituted or optionally substituted with one, two or more R ａ２ and each R ａ２ are homologous or different, and independently of each other, C １ ~C ６ Alkyl group, C １ ~C ６ selected from an alkyloxy group, a trifluoromethyl group, a 2,2-difluoroethyl group, a methoxy group, a hydroxy group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a carboxy group, a methoxycarbonyl group, a methylsulfonyl group, and a nitro group; 2. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof.

4. R ２ is unsubstituted or optionally substituted with one, two or more R ２１ C substituted with ６ ~C １０ an aryl group, a 5- to 10-membered heteroaryl group, and a 3- to 8-membered heterocyclyl group; ２１ are the same or different and independently represent hydrogen, halogen, C １ ~C ６ Alkyl group, C １ ~C ６ Haloalkyl group, C １ ~C ６ Alkyloxy group, C １ ~C ６ Haloalkyloxy group, 3- to 8-membered cycloalkyloxy group, 3- to 8-membered cycloalkyl-C １ ~C ６ Alkyloxy group, C ６ ~C １０ aryl-C(O)—; More preferably, R ２ is the substituted C ６ ~C １４ an aryl group or a substituted 5- to 14-membered heteroaryl group, the substituents being selected from hydrogen, halogen, cyano, trifluoromethyl, 2,2-difluoroethyl, C １ ~C ６ Alkyl group, hydroxy group, C １ ~C ６ Alkyloxy group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, C ３ ~C ６ azacycloalkyl group, formyl group, acetyl group, acetamido group, carbamoyl group, or sulfamoyl group, and the substituents are mono- or di-substituted; Even more preferably, R ２ is the substituted C ６ ~C １０ an aryl group or a substituted 5- to 10-membered heteroaryl group, ６ ~C １０ The aryl group is a phenyl group or a naphthyl group, the 5- to 10-membered heteroaryl group is selected from a pyridyl group, a thienyl group, a pyrrolyl group, a furanyl group, an imidazolyl group, a pyrazolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an indolyl group, a quinolyl group, an isoquinolyl group, an indazolyl group, a benzothienyl group, a benzofuranyl group, or a benzimidazolyl group, and the substituent is hydrogen, a halogen, a cyano group, a trifluoromethyl group, selected from a 2,2-difluoroethyl group, a methyl group, an ethyl group, a hydroxy group, a methoxy group, an ethoxy group, a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, an azetidinyl group, a tetrahydropyrrol-1-yl group, a piperidin-1-yl group, a morpholinyl group, a piperazinyl group, an N-methylpiperazinyl group, an acetyl group, an acetamido group, a carbamoyl group, and a sulfamoyl group, and the substituents are mono- or di-substituted; Most preferably, R ２ teeth, 【Chemistry 37】 Selected from 2. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof.

5. The compound of formula (I) is the following compound, namely: 【Transformation 38】 【change】 【change】 【change】 Selected from The compound according to any one of claims 1 to 4, its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, or pharmaceutically acceptable salt thereof, characterized in that:

6. The pharmaceutically acceptable salt is a salt formed from the compound and an acid, and the acid is at least one selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, and ferulic acid.

2. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof.

7. A method for producing the compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotope-labeled compound, solvate, or pharmaceutically acceptable salt thereof, comprising: (1) reacting compound I-1 with compound I-2 to obtain compound I-3; (2) removing PG from compound I-3 to obtain a compound of formula (I); Including, 【Chemistry 39】 wherein Y is selected from leaving groups, preferably halogen, more preferably Cl and Br; PG is selected from protecting groups, preferably (trimethylsilyl)ethoxymethyl (SEM) and p-methoxybenzyl (PMB); Manufacturing method.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable auxiliary materials.

9. Use of the compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotopically labeled compound, solvate or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the manufacture of a drug for preventing and / or treating a PARP-mediated disease, preferably a PARP inhibitor drug, More preferably, the PARP isoform is selected from PARP2, PARP3, PARP4, PARP5a, PARP5b, PARP7 and / or PARP1. use.

10. Use of the compound according to any one of claims 1 to 6, or a racemate, stereoisomer, tautomer, isotope-labeled compound, solvate or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the manufacture of a drug for preventing and / or treating a central nervous system disease, a cerebral ischemia-related disease, cancer, an infection, an immune disease, a cardiovascular disease or a metabolic disease, wherein the central nervous system disease is selected from stroke, preferably ischemic stroke, and the preceding The cerebral ischemia-related disease is selected from transient ischemic attack, cerebral thrombosis, and cerebral embolism, and the cancer is selected from lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, cerebral glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, and bladder cancer.

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