Heterocyclic structure compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a heterocyclic structure compound as shown in a formula I, and pharmaceutically acceptable salts, stereoisomers, tautomers or isotope compounds thereof. The structure of the heterocyclic structure compound shown in the formula I is shown in the formula I. The heterocyclic structure compound as shown in the formula I can block OGG1 enzyme activity, so that the heterocyclic structure compound is expected to be applied to treatment of OGG1 mediated diseases.

Description

Technical Field

[0001] This invention relates to a heterocyclic compound, its pharmaceutical composition, and its applications. Background Technology

[0002] In cells, reactive oxygen species (ROS) damage genomic DNA, particularly by oxidizing individual nucleotide bases. Guanylate bases are especially susceptible to oxidation, forming 8-oxo-guanine (8-oxo-G) or 2,6-diamino-4-hydroxy-5-carboxamide pyrimidine (FapyGua). Without repair, DNA polymerase misreads the 8-oxo-G base, and adenine replaces cytosine as the complementary base. Therefore, after DNA replication, 8-oxo-G lesions lead to G:C to T:A base transversions. Accumulated transversions cause replication stress, eventually triggering cell cycle arrest and, in extreme cases, cell death. To avoid the mutagenic effects of oxidized bases in DNA, cells have specialized enzymes that recognize and remove offending bases through the base excision repair (BER) pathway. 8-oxo-guanine glycosylase-1 (OGG1) is responsible for recognizing 8-oxo-G lesions in DNA and initiating the removal of 8-oxo-G by cleaving glycosidic bonds. Especially in cells with high levels of ROS, OGG1 is crucial for removing 8-oxo-G lesions to maintain the integrity of genomic DNA. In addition to its enzymatic role in BER, OGG1 also acts as a transcriptional activator of pro-inflammatory genes by binding to oxidative sites in DNA.

[0003] Cancer cells with high levels of ROS and / or defective mismatch repair mechanisms (MMR) are particularly reliant on proficient OGG1 to avoid the accumulation of 8-oxo-G lesions in cellular and mitochondrial DNA. Inhibition of OGG1 enzymatic activity in these cells leads to replication stress, cell cycle arrest, and apoptosis. Small molecule OGG1 inhibitors hold promise for directly killing cancer cells with high ROS and MMR deficiencies and sensitizing them to chemotherapeutic drugs that increase ROS or otherwise increase 8-oxo-G lesion levels in genomic DNA. Therefore, OGG1 inhibitor compounds can be used as monotherapy for OGG1-dependent cancers and as combination therapy for OGG1-sensitive cancers. Simultaneously, blocking OGG1 enzymatic activity can prevent the transcriptional activation of pro-inflammatory genes. Therefore, OGG1 inhibitor compounds can be used as therapeutic agents for inflammatory and autoimmune diseases.

[0004] Currently, there is a need to find compounds and therapeutics that can block the activity of the OGG1 enzyme in order to treat OGG1-mediated diseases, including cancer, inflammation, and autoimmune diseases. Summary of the Invention

[0005] The technical problem this invention aims to solve is the lack of effective OGG1 inhibitors in the prior art, by providing a heterocyclic compound, its pharmaceutical composition, and its applications. The heterocyclic compound of this invention offers possibilities for meeting various clinical needs.

[0006] This invention provides a heterocyclic compound as shown in Formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its isotopic compound:

[0007]

[0008] in, Represents a single bond or a double bond;

[0009] Ring A is aromatic;

[0010] A1, A4, and A5 are independently N or C;

[0011] A2 and A3 are independently N, S, O, NR. 2 or CR 3 ;

[0012] R 1 Halogen, C 1-6 Alkyl, with one or more R 1-1 Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, hydroxyl, cyano, -OC 1-6 Alkyl, -C(=O)R 1a -NR 1b1 R 1b2 -C(=O)OR 1c -C(=O)NR 1d1 R 1d2 C 3-10 Cycloalkyl, or, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from 4 to 12-membered heterocycloalkyl groups of O, S and N";

[0013] R 1-1 For deuterium, halogens, C 2-6 alkenyl, C 2-6 Alkyne, hydroxyl, cyano, -OC 1-6 Alkyl, -C(=O)R 11a -NR 11b1 R 11b2 -C(=O)OR 11c -C(=O)NR 11d1 R 11d2 C 3-10 Cycloalkyl, or, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from 4 to 12-membered heterocycloalkyl groups of O, S and N";

[0014] R 1a R 1b1 R 1b2 R 1c R 1d1 R 1d2 R 11a R 11b1 R 11b2 R 11c R 11d1 and R 11d2 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms. 1-6 alkyl;

[0015] R 2 For hydrogen, C 1-6 Alkyl, -C(=O)OR 2’ C substituted by one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms. 1-6 Alkyl; R 2’ C 1-6 alkyl;

[0016] R 3 For hydrogen, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms. 1-6 alkyl;

[0017] B 1 For CHR 21 CD2 or CDR 21 ;

[0018] B 2 For O, S, CD2, CHR 22 or NR 23 ;

[0019] R 21 R 22 and R 23 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms. 1-6 alkyl;

[0020] G is either O or S;

[0021] Ring Y is C 3-10 cycloalkyl, with one or more R 2-1 Replacement C 3-10Cycloalkyl, "a 4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S, and N", and surrounded by one or more R 2-2 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4- to 12-membered heterocyclic alkyl groups", C 6-20 aryl, with one or more R 2-3 Replacement C 6-20 Aryl, "a 5-12 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from O, S, and N", and bonded by one or more R 2-4 Substituted "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N 5-12 membered heteroaryl groups", C 5-7 Cycloalkenyl, with one or more R 2-5 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 2-6 The substituents are “5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N”; when there are multiple substituents, they may be the same or different;

[0022] R 2-1 R 2-2 R 2-3 R 2-4 R 2-5 and R 2-6 Independently halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -C(=O)R 2a -NR 2b1 R 2b2 -C(=O)OR 2c or -C(=O)NR 2d1 R 2d2 ;

[0023] R 2a R 2b1 R 2b2 R 2c R 2d1 and R 2d2 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms. 1-6 alkyl;

[0024] X is a single bond, CH2, NH, O, or S;

[0025] R 4 C6-20 aryl, with one or more R 4-1 Replacement C 6-20 aryl, "a 5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 4-2 Substitutions are defined as "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from 5 to 12-membered heteroaryl groups of O, S, and N"; when there are multiple substituents, they may be the same or different;

[0026] R 4-1 and R 4-2 Independently halogen, hydroxyl, cyano, C 1-6 Alkyl, one or more deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -C(=O)R 4a -NR 4b1 R 4b2 -C(=O)OR 4c or -C(=O)NR 4d1 R 4d2 ;

[0027] R 4a R 4b1 R 4b2 R 4c R 4d1 and R 4d2 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms. 1-6 alkyl.

[0028] In one scheme, in the heterocyclic compound represented by Formula I,

[0029] Represents a single bond or a double bond;

[0030] Ring A is aromatic;

[0031] A1, A4, and A5 are independently N or C;

[0032] A2 and A3 are independently N, S, O, NR2, or CR 3 ;

[0033] R 1 C 1-6 alkyl;

[0034] R 2 For hydrogen, C 1-6 Alkyl or -C(=O)OR 2’;R 2’ C 1-6 alkyl;

[0035] R 3 It is hydrogen;

[0036] B 1 For CHR 21 Or CD2;

[0037] B 2 For CHR 22 or NR 23 ;

[0038] R 21 R 22 and R 23 Independently hydrogen;

[0039] G is O;

[0040] Ring Y is C 3-10 Cycloalkyl, "a 4- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from O, S, and N", and surrounded by one or more R 2-2 The substituted "contains 1 to 3 heteroatoms, the heteroatoms being independently selected from 4 to 12-membered heterocyclic alkyl groups of O, S and N";

[0041] R 2-2 Independently for C 1-6 alkyl;

[0042] X is a single bond;

[0043] R 4 For one or more R 4-1 Replacement C 6-20 Aryl group; when there are multiple substituents, they may be the same or different;

[0044] R 4-1 Independently halogen, cyano, C 1-6 Alkyl or -OC 1-6 alkyl.

[0045] In one embodiment, the heterocyclic compound shown in Formula I can also have the structure shown in Formula II:

[0046]

[0047] The definitions of each group are as described above.

[0048] In one of the solutions, for

[0049] In one possible solution, ring Y is...

[0050] In a certain scheme, when ring Y is C 3-10 When cycloalkyl, the ring Y is C 4-6 Cycloalkyl, for example, cyclobutyl, cyclopentyl or cyclohexyl.

[0051] In one particular scheme, the structure of the heterocyclic compound of formula I is shown below:

[0052]

[0053]

[0054] The present invention also provides a pharmaceutical composition comprising substance A and a pharmaceutical excipient; wherein substance A is a therapeutically effective amount of the above-described heterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

[0055] The present invention also provides the use of substance A in the preparation of a drug for treating or preventing OGG1-mediated diseases; wherein substance A is a heterocyclic compound of the above-described formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

[0056] In one scenario, the OGG1-mediated diseases are cancer, inflammation, and autoimmune diseases.

[0057] The present invention also provides a method for using substance A to inhibit OGG1, comprising administering an effective amount of substance A to a subject. The substance A is a heterocyclic compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

[0058] The present invention also provides a method for treating or preventing OGG1-mediated diseases using substance A, comprising administering an effective amount of substance A to a subject. The substance A is a heterocyclic compound of Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

[0059] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. The term "a plurality of" refers to 2, 3, 4, or 5.

[0060] The term "stereoisomer" refers to isomers of molecules that have the same order of interconnection of atoms or groups of atoms but different spatial arrangements, such as cis-trans isomers, optical isomers, or trans-blocked isomers. These stereoisomers can be separated, purified, and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin-layer chromatography, rotational chromatography, column chromatography, gas chromatography, high-performance liquid chromatography, etc.). They can also be obtained through chiral resolution by bonding (chemical bonding, etc.) or salt formation (physical bonding, etc.) with other chiral compounds.

[0061] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of a single atom between two positions in a molecule. For example, acetone and 1-propen-2-ol can interconvert through the rapid movement of hydrogen atoms to the oxygen and α-carbon.

[0062] The term "isotopic compound" refers to a compound in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 17O, 18F, 35S, and 36Cl). The isotopic compounds of the present invention can generally be prepared according to the methods described herein by replacing non-isotopic labeled reagents with isotopically labeled reagents.

[0063] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0064] The term "alkyl" refers to a straight-chain or branched alkyl group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and similar alkyl groups.

[0065] The term "cycloalkyl" refers to a saturated cyclic group consisting only of carbon atoms, having a specified number of carbon atoms (e.g., C3 to C6), and can be monocyclic, bridged, or spirocyclic. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0066] The term "aryl" refers to an aromatic group consisting of carbon atoms, with each ring possessing aromaticity. Examples include phenyl or naphthyl.

[0067] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5 to 12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, and at least one ring is aromatic (conforming to Hückel's rule). Heteroaryl groups are linked to other segments of a molecule through either an aromatic or non-aromatic ring. Heteroaryl groups include, but are not limited to, furanyl, pyrroleyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and indoleyl.

[0068] The term "heterocyclic" or "heterocyclic alkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 8), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which can be monocyclic, bridged, or spirocyclic, and each ring is saturated. Heterocyclic alkyl groups include, but are not limited to, nitrogen-containing heterocyclic butyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, etc.

[0069] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0070] The reagents and raw materials used in this invention are all commercially available.

[0071] The positive and progressive effects of this invention are as follows: This invention provides a heterocyclic compound, its pharmaceutical composition, and its application. The heterocyclic compound can block OGG1 enzyme activity, and thus is expected to be used to treat OGG1-mediated diseases. Detailed Implementation

[0072] The present invention is further illustrated below by way of examples, but these examples do not limit the invention to the scope of the embodiments described. Experimental methods in the following examples, unless otherwise specified, were performed according to conventional methods and conditions, or as selected in the product instructions. All solvents used in the following examples are of analytical grade or chromatographic grade. When the solvents used in the following examples are mixed solvents, unless otherwise stated, all ratios are by volume.

[0073] In this invention, room temperature refers to ambient temperature, which is 10℃-35℃. Overnight refers to 8-15 hours. Reflux refers to the solvent reflux temperature under normal pressure.

[0074] The following is a list of abbreviations used in the examples:

[0075] DMF N,N-dimethylformamide

[0076] CDI carbonyl diimidazole

[0077] DIPEA (Diisopropylethylamine)

[0078] HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0079] DCM dichloromethane

[0080] TFA (trifluoroacetic acid)

[0081] Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene

[0082] Synthetic route of compound 1

[0083]

[0084] Synthesis of compound 1-d

[0085] (1S,4S)-4-tert-butoxycarbonylaminocyclohexanecarboxylic acid (6000 mg, 24.66 mmol), 3-methoxy-4-methylaniline (4398 mg, 32.06 mmol), DMF (30 mL), HATU (12190 mg, 32.06 mmol), and DIPEA (9562 mg, 73.98 mmol) were added sequentially to a reaction flask at room temperature. The mixture was protected with N2 displacement and reacted overnight at room temperature. 100 mL of water was added to the reaction mixture, and the solution was extracted with 200 mL of ethyl acetate. The organic phase was washed three times with water, washed with brine, dried over anhydrous sodium sulfate, concentrated, stirred into silica gel, and purified by column chromatography (mobile phase: PE / EA 10 / 0 to 1 / 1) to give compound 1-d (8000 mg, 89%). LC-MS (ESI): m / z 363.3 (M+H) + .

[0086] Synthesis of compound 1-c

[0087] At room temperature, 1-d (8000 mg, 22.07 mmol), DCM (60 mL), and trifluoroacetic acid (20 mL) were added sequentially to the reaction flask. The mixture was protected with N2 displacement and reacted overnight at room temperature. The reaction solution was concentrated at room temperature, adjusted to alkalinity with saturated sodium bicarbonate aqueous solution, and extracted with 200 mL of ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give compound 1-c (3000 mg, 52%). LC-MS (ESI): m / z 263.7 (M+H) + .

[0088] Synthesis of compound 1-b

[0089] 5-Amino-1,3-dimethylpyrazole (5 g, 44.98 mmol) and DMF (14.48 mL, 179.94 mmol) were added to the reaction flask, and phosphorus oxychloride (17.61 mL, 188.93 mmol) was added dropwise with stirring at room temperature. After the addition was complete, the reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, and crushed ice was slowly poured in. The pH was adjusted to 7 with 40% NaOH solution (exothermic reaction), and the mixture was extracted five times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0–100%) to give 5.7 g of intermediate. The intermediate was dissolved in ethanol (40 mL), and 20% NaOH (60 mL, 9.00 mmol) was added. The mixture was refluxed at 100 °C for 2 hours. The reaction mixture was heated to separate into two layers. The ethanol layer was evaporated to dryness and purified by column chromatography (mobile phase: methanol: dichloromethane = 0–2%) to give compound 1-b (3.2 g, 51%). LC-MS (ESI): m / z 140.4 (M+H) + .

[0090] Synthesis of compound 1-a

[0091] Add 1-b (100 mg, 0.72 mmol), 1-c (226 mg, 0.86 mmol), dichloromethane (20 mL), and tetraethyl titanate (0.75 mL, 3.59 mmol) to the reaction flask. Stir the mixture overnight at room temperature under nitrogen. Add sodium borohydride (54 mg, 1.44 mmol) and 1 mL of methanol to the reaction mixture, continue stirring for 30 minutes, add silica gel, evaporate to dryness, and purify by column chromatography (mobile phase: methanol: dichloromethane = 0–10%) to give compound 1-a (230 mg, 83%). LC-MS (ESI): m / z 386.4 (M+H) + .

[0092] Synthesis of Compound 1

[0093] CDI (290 mg, 1.79 mmol) was added to a 15 mL solution of acetonitrile (230 mg, 0.60 mmol) of 1-a at room temperature, and the mixture was stirred at room temperature under nitrogen for 3 hours. The solution was evaporated to dryness, purified by HPLC (ammonium bicarbonate), and lyophilized to give compound 1 (17 mg, 7%). LC-MS (ESI): m / z 412.2 (M+H) + . 1H NMR (400M, CDCl3): δ9.68(1H,s),9.64(1H,s),7.28(1H,d,J=1.6Hz),7.11(1H,dd,J=1.6Hz,J=8.0Hz),7.01(1H,d,J=8.4Hz),4.29-4.18(1H ,m),4.16(2H,s),3.75(3H,s),3.50(3H,s),2.70-2.61(1H,m),2.17- 2.05(5H,m),2.03-1.88(5H,m),1.72-1.57(2H,m),1.50-1.37(2H,m).

[0094] Synthetic routes of compounds 2 and 3

[0095]

[0096] Synthesis of compound 2-b

[0097] 3-Amino-5-methylpyrazole (1 g, 10.30 mmol) and DMF (10 mL) were added to a reaction flask, and phosphorus oxychloride (4.03 mL, 43.25 mmol) was added dropwise with stirring at room temperature. After the addition was complete, the reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, and crushed ice was slowly poured in. The pH was adjusted to 7 with 40% NaOH solution (exothermic reaction), and the mixture was extracted five times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: methanol: dichloromethane = 0–10%) to give 193 mg of intermediate. This intermediate was dissolved in ethanol (10 mL), and 20% NaOH (15 mL) aqueous solution was added. The mixture was refluxed at 100 °C for 2 hours. The reaction mixture was separated into two layers while hot. The ethanol layer was evaporated to dryness and purified by column chromatography (mobile phase: methanol: dichloromethane = 0–5%) to give compound 2-b (90 mg, 7%). LC-MS(ESI): m / z 126.3(M+H) + .

[0098] Synthesis of compound 2-a

[0099] 2-b (90 mg, 0.72 mmol), 1-c (226 mg, 0.86 mmol), dichloromethane (20 mL), and tetraethyl titanate (0.75 mL, 3.60 mmol) were added to a reaction flask, and the mixture was stirred overnight at room temperature under nitrogen. The next day, sodium borohydride (54 mg, 1.44 mmol) and 1 mL of methanol were added to the reaction mixture, and stirring was continued for 30 minutes. Silica gel was added, the mixture was evaporated to dryness, and purified by column chromatography (mobile phase: methanol: dichloromethane = 0–20%) to give compound 2-a (126 mg, 47%). LC-MS (ESI): m / z 372.2 (M+H) + .

[0100] Synthesis of compounds 2 and 3

[0101] CDI (440 mg, 2.71 mmol) and tetrahydrofuran (6 mL) were added to a 20 mL acetonitrile solution of compound 2-a (126 mg, 0.34 mmol) at room temperature. The mixture was stirred overnight at room temperature under nitrogen. The next day, the reaction solution was evaporated to dryness, methanol was added, and the mixture was heated to 50 °C and stirred until dissolved. The solution was then evaporated to dryness, purified by preparative HPLC (ammonium bicarbonate), and lyophilized to give compound 2 (15 mg, 11%) and compound 3 (45 mg, 29%).

[0102] Compound 2: LC-MS (ESI): m / z 398.2 (M+H) + ;1H NMR (400M, DMSO-d6): δ11.61(1H,s),9.68(1H,s),9.11(1H,s),7.29(1H,d,J=1.6Hz),7.12(1H,dd,J=1.6Hz,J=8.0Hz),7.01(1H,d,J=8.4Hz) ,4.31-4.18(1H,m),4.14(2H,s),3.75(3H,s),2.70-2.60(1H,m),2.18 -2.04(8H,m),2.03-1.88(2H,m),1.73-1.57(2H,m),1.49-1.36(2H,m).

[0103] Compound 3: LC-MS (ESI): m / z 456.2 (M+H) + ; 1 H NMR (400M, DMSO-d6): δ9.78(1H,s),9.68(1H,s),9.30(1H,d,J=1.2Hz),7.11(1H,dd,J=1.6Hz,J=8.0Hz),7.02(1H,d,J=8.4Hz),4.30-4.15(3 H,m),3.86(3H,s),3.75(3H,s),2.70-2.60(1H,m),2.37(3H,s),2.19- 2.04(5H,m),2.03-1.89(2H,m),1.74-1.58(2H,m),1.51-1.39(2H,m).

[0104] Synthetic route of compound 4

[0105]

[0106] Synthesis of compound 4-c

[0107] (1S,4S)-4-tert-butoxycarbonylaminocyclohexanecarboxylic acid (4.93 g, 20.25 mmol), 5-amino-2-methoxybenzonitrile (3 g, 20.25 mmol), N,N-dimethylformamide (50 mL), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (11.55 g, 30.37 mmol), and N,N-diisopropylethylamine (10.04 mL, 60.74 mmol) were added to the reaction flask. The mixture was stirred overnight at room temperature under nitrogen. The next day, the reaction solution was quenched with water and extracted three times with ethyl acetate. The organic phase was washed three times with saturated brine, evaporated to dryness, and purified by column chromatography (mobile phase: ethyl acetate: petroleum ether = 0–100%) to give compound 4-c (7.5 g, 99%). LC-MS (ESI): m / z 374.3 (M+H) + .

[0108] Synthesis of compound 4-b

[0109] Compound 4-c (7.5 g, 20.08 mmol), dichloromethane (50 mL), and trifluoroacetic acid (10 mL, 130.59 mmol) were added to a reaction flask. The mixture was stirred at room temperature under nitrogen for 2 hours. The reaction solution was evaporated to dryness, ethyl acetate was added, and the solution was neutralized to pH 7–8 with saturated sodium bicarbonate solution. Anhydrous sodium sulfate was added, and the mixture was extracted five times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and slurried with 30 mL of ethyl acetate to give compound 4-b (5.5 g). LC-MS (ESI): m / z 274.4 (M+H) + .

[0110] Synthesis of compound 4-a

[0111] Compound 2-b (75 mg, 0.60 mmol), compound 4-b (197 mg, 0.72 mmol), dichloromethane (20 mL), and tetraethyl titanate (0.63 mL, 3.00 mmol) were added to a reaction flask and stirred overnight at room temperature under nitrogen. The next day, sodium borohydride (45 mg, 1.20 mmol) was added, followed by 1 mL of methanol. The mixture was stirred for another 30 minutes, then silica gel was added, the mixture was evaporated to dryness, and purified by column chromatography (mobile phase: methanol: dichloromethane = 0–100%) to give compound 4-a (190 mg, 83%). LC-MS (ESI): m / z 383.2 (M+H) + .

[0112] Synthesis of Compound 4

[0113] CDI (106 mg, 0.65 mmol) was added to a 15 mL solution of 4-a (50 mg, 0.13 mmol) in acetonitrile at room temperature. The mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was quenched with methanol, evaporated to dryness, purified by preparative HPLC (ammonium bicarbonate), and lyophilized to give compound 4 (10 mg, 19%). LC-MS (ESI): m / z 409.2 (M+H) + ; 1 H NMR (400M, DMSO-d6): δ

[0114] 11.61(1H,s),9.92(1H,s),9.10(1H,s),8.01(1H,d,J=2.8Hz),7.76(1H,dd,J=2.4Hz,J=8.8Hz),7.22(1H,d,J=9.2Hz),4.33-4.19 (1H,m),4.14(2H,s),3.88(3H,s),2.71-2.60(1H,m),2.18-2.04(5H,m),2.02-1.86(2H,m),1.73-1.58(2H,m),1.48-1.35(2H,m).

[0115] Synthetic route of compound 5

[0116]

[0117] Synthesis of compound 5-c

[0118] 4-Bromo-1-methylpyrazole-5-carboxaldehyde (500 mg, 2.65 mmol), tert-butyl carbamate (680 mg, 5.81 mmol), palladium acetate (31 mg, 0.14 mmol), Xantphos (152 mg, 0.26 mmol), cesium carbonate (2.75 g, 8.44 mmol), and anhydrous 1,4-dioxane (10 mL) were added to a reaction flask. After purging with nitrogen three times, the reaction mixture was heated to 95 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate, 100 / 0 to 80 / 20) to give compound 5-c (450 mg, 76% yield). LC-MS (ESI): m / z 226.2 (M+H) + .

[0119] Synthesis of compound 5-b

[0120] Add 5-c (180 mg, 0.80 mmol), 1-c (230 mg, 0.88 mmol), DCM (15 mL), and tetraethyl titanate (0.75 mL, 3.58 mmol) to a reaction flask and stir overnight at room temperature under nitrogen. Add sodium cyanoborohydride (240 mg, 3.82 mmol) and acetic acid (0.029 mL, 0.50 mmol) to an ice bath, and stir the reaction mixture in an ice bath for 15 minutes, then at room temperature for 2 hours. Add a cold aqueous solution of potassium sodium tartrate (3.0 g), ethyl acetate, and a small amount of methyl tert-butyl ether to the reaction mixture. Separate the solutions, and extract the turbid aqueous phase twice with ethyl acetate. Combine the organic phases, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and purify by column chromatography (mobile phase: dichloromethane / methanol, 100 / 0 to 95 / 5) to give compound 5-b (350 mg, 93% yield) as a light brown viscous solid. LC-MS(ESI): m / z 472.7(M+H) + .

[0121] Synthesis of compound 5-a

[0122] 5-b (350 mg, 0.74 mmol) and dichloromethane (5 mL) were added to a reaction flask. Trifluoroacetic acid (2.5 mL) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The organic solvent was removed by evaporation, and methyl tert-butyl ether and a small amount of petroleum ether were added to the residue. A precipitate formed, and the supernatant was discarded. The precipitate was washed once with a mixture of methyl tert-butyl ether and a small amount of petroleum ether, and then evaporated to dryness to give compound 5-a (400 mg). LC-MS (ESI): m / z 372.7 (M+H) + .

[0123] Synthesis of Compound 5

[0124] 5-a (400 mg, 0.67 mmol) was added to a reaction flask. Anhydrous acetonitrile (10 mL), DIPEA (259 mg, 2.00 mmol), and CDI (433 mg, 2.67 mmol) were added under ice bath conditions, and the reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated, ethyl acetate was added, and the mixture was washed once with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by HPLC (ammonium bicarbonate) to give compound 5 (59 mg, 20% yield in two steps). LC-MS (ESI): m / z 398.7 (M+H) + ; 1H NMR(DMSO-d6,400MHz): δ9.68(1H,s),8.61(1H,s),7.30(1H,d,J=1.6Hz),7 .13(1H,dd,J=8.0,1.6Hz),7.05–6.98(1H,m),6.82(1H,s),4.45(2H,s),4. 30–4.20(1H,m),3.75(3H,s),3.67(3H,s),2.69–2.61(1H,m),2.19–2.10(2 H,m),2.08(3H,s),2.05–1.90(2H,m),1.71–1.59(2H,m),1.48–1.39(2H,m).

[0125] Synthetic route of compound 6

[0126]

[0127] Synthesis of compound 6-a

[0128] 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazolium (100 mg, 0.45 mmol), 1-c (179 mg, 0.68 mmol), acetonitrile (10 mL), and triethylamine (0.316 mL, 2.27 mmol) were added to a reaction flask, and the mixture was stirred at room temperature under nitrogen for 2 hours. The reaction solution was directly purified by column chromatography (mobile phase: methanol: dichloromethane = 0–5%) to give compound 6-a (182 mg, 100%). LC-MS (ESI): m / z 402.7 (M+H) + .

[0129] Synthesis of Compound 6

[0130] Stannous chloride (756 mg, 3.99 mmol) was added to a 20 mL solution of compound 6-a (80 mg, 0.20 mmol) in acetonitrile at room temperature, and the mixture was stirred under nitrogen at room temperature for 3 hours. The reaction solution was filtered, and CDI (323 mg, 1.99 mmol) was added to the filtrate. The mixture was stirred under nitrogen at room temperature overnight. The reaction solution was quenched with methanol, evaporated to dryness, purified by HPLC (ammonium bicarbonate), and lyophilized to give compound 6 (10 mg, 13%). LC-MS (ESI): m / z 398.3 (M+H) + ; 1H NMR (400M, DMSO-d6): δ9.68(1H,s),8.85(1H,s),7.29(1H,d,J=1.2Hz),7.24(1H,s),7.12(1H,dd,J=1.6Hz,J=8.0Hz),7.02(1H,d,J=8.4Hz),4.39( 2H,s),4.34-4.22(1H,m),3.75(3H,s),3.53(3H,s),2.69-2.62(1H,m),2. 19-2.05(5H,m),2.04-1.90(2H,m),1.73-1.58(2H,m),1.49-1.38(2H,m).

[0131] Synthetic route of compound 7

[0132]

[0133] Synthesis of compound 7-d

[0134] At room temperature, 1.0 g (7.24 mmol) of 2-amino-4-methylthiophene-3-carboxynitrile was dissolved in 20 mL of 1,4-dioxane. Di-tert-butyl dicarbonate (1.90 g, 8.68 mmol) and DMAP (88 mg, 0.72 mmol) were added, and the mixture was stirred overnight at 60 °C under nitrogen. Di-tert-butyl dicarbonate (1.90 g, 8.68 mmol) and DMAP (88 mg, 0.72 mmol) were then added, and the mixture was stirred for another 5 hours at 60 °C under nitrogen. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid separation column chromatography (petroleum ether / ethyl acetate).

[0135] =2:1), to obtain mixture 7-d (1.47g). 1 H NMR(DMSO_d6,400MHz,2BOC): δ1.42(18H,s),2.27(3H,s),7.40(1H,s). 1 H NMR(DMSO_d6,400MHz,1BOC): δ1.48(9H,s),2.17(3H,s),6.77(1H,s),11.01(1H,s).

[0136] Synthesis of compound 7-c

[0137] Compound 7-d (200 mg, 0.59 mmol, calculated as containing two Bocs) was dissolved in 10 mL of anhydrous nitrogen at room temperature.

[0138] In DCM, DIBAL-H (1.77 mL, 1.77 mmol, 1 M) was added dropwise under an ice-water bath. The mixture was then heated to room temperature and stirred for 3 hours. Potassium sodium tartrate (667 mg, 2.36 mmol) was then dissolved in 5 mL of water and cooled under an ice-water bath. The above reaction mixture was added dropwise to the potassium sodium tartrate solution, heated to room temperature, and stirred for 30 minutes. The mixture was diluted with water (50 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude mixture 7-c (143 mg). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z = 242.1 [M-Boc+H] + .

[0139] Synthesis of compound 7-b

[0140] Compound 7-c (143 mg, 0.42 mmol, calculated as containing two Bocs) was dissolved in 10 mL of DCM at room temperature. Compound 1-c (110 mg, 0.42 mmol) and tetraethyl titanate (442 μL, 2.09 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (20 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was dissolved in 10 mL of dichloromethane. Methanol (1 mL), sodium cyanoborohydride (66 mg, 1.05 mmol), and acetic acid (24 μL, 0.42 mmol) were added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was quenched with saturated sodium bicarbonate (50 mL), extracted with dichloromethane (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid separation column chromatography (DCM / MeOH = 10:1) to give compound 7-b (93 mg, 38%). LC-MS (ESI): m / z = 488.5 [M-Boc+H] + .

[0141] Synthesis of compound 7-a

[0142] Compound 7-b (80 mg, 0.14 mmol, calculated as containing two Bocs) was dissolved in 6 mL of DCM at room temperature, and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred under nitrogen at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and dried under nitrogen to give crude compound 7-a (68 mg). The crude product was used directly in the next reaction without purification. LC-MS (ESI): m / z = 388.3 [M+H] + .

[0143] Synthesis of Compound 7

[0144] At room temperature, compound 7-a (68 mg, 0.14 mmol) was dissolved in 10 mL of acetonitrile, and compound CDI (220 mg,

[0145] 1.36 mmol), the reaction mixture was stirred at room temperature under nitrogen for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (alkaline method, ammonium bicarbonate) to give compound 7 (15 mg, 26%). LC-MS (ESI): m / z = 414.2 [M+H] + ; 1 HNMR(DMSO_d6,400MHz): δ9.68(1H,s),9.37(1H,s),7.28(1H,d,J=2.0Hz),7.11 (1H,dd,J1=8.0Hz,J2=2.0Hz),7.01(1H,d,J=8.0Hz),6.37(1H,d,J=1.2Hz),4.28 -4.14(1H,m),4.20(2H,s),3.75(3H,s),2.68-2.61(1H,m),2.17-2.05(2H,m),2. 07(3H,s),2.01(3H,s),2.03-1.91(2H,m),1.72-1.57(2H,m),1.49-1.39(2H,m).

[0146] Bioactivity test

[0147] Biological Example 1: Biochemical Assay Method for Testing hOGG1 Enzyme Activity

[0148] The experimental method was modified based on the reported fluorescence-based detection method (Donley et al ACS ChemBiol 2015; 10(10), 2334-2343). In the experiment, the following oligonucleotide was used as the substrate, with 8-oxo-guanine at X.

[0149]

[0150] The experimental buffer consisted of 20 mM Tris pH 7.5, 100 mM KCl, 0.01% BSA, and 0.01% Tween. 200 nmL of DMSO or DMSO solutions of different concentrations of the compound were added to each well of a 384-well plate. 10 μL of hOGG1 buffer solution was added (for wells without enzyme, the buffer solution was used instead), and the plate was incubated at room temperature for 15 minutes. Then, 10 μL of substrate buffer solution was added, and the plate was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 40 minutes. The final concentrations of hOGG1 and substrate were 25 nM and 100 nM, respectively. Ex530 / Em585 fluorescence signals were read, and the inhibition rate / compound concentration was calculated (Inhibition (%) = (Max mean – value) / (Max mean – Min mean) × 100%). A dose-response curve was fitted, and the IC50 was calculated. 50 Values. The activity results of representative compounds of this invention are shown in the table below.

[0151]

[0152] Example IC 50 (nM) 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 +++

[0153] It should be understood that the embodiments and implementations described in this invention are for illustrative purposes only, and various modifications or variations therein will be suggested to those skilled in the art, and these are included within the spirit and scope of this application and the appended claims. All publications, patents and patent applications referenced in this invention are incorporated herein by reference and used for all purposes.

Claims

1. A heterocyclic compound of Formula I, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, or an isotopic compound thereof: in, Represents a single bond or a double bond; Ring A is aromatic; A1, A4, and A5 are independently N or C; A2 and A3 are independently N, S, O, NR. 2 or CR 3 ; R 1 Halogen, C 1-6 Alkyl, with one or more R 1-1 Replacement C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, hydroxyl, cyano, -OC 1-6 Alkyl, -C(=O)R 1a -NR 1b1 R 1b2 -C(=O)OR 1c -C(=O)NR 1d1 R 1d2 C 3-10 Cycloalkyl, or, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from 4 to 12-membered heterocycloalkyl groups of O, S and N"; R 1-1 For deuterium, halogens, C 2-6 alkenyl, C 2-6 Alkyne, hydroxyl, cyano, -OC 1-6 Alkyl, -C(=O)R 11a -NR 11b1 R 11b2 -C(=O)OR 11c -C(=O)NR 11d1 R 11d2 C 3-10 Cycloalkyl, or, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from 4 to 12-membered heterocycloalkyl groups of O, S and N"; R 1a R 1b1 R 1b2 R 1c R 1d1 R 1d2 R 11a R 11b1 R 11b2 R 11c R 11d1 and R 11d2 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms 1-6 alkyl; R 2 For hydrogen, C 1-6 Alkyl, -C(=O)OR 2’ C substituted by one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms 1-6 Alkyl; R 2’ C 1-6 alkyl; R 3 For hydrogen, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms 1-6 alkyl; B 1 For CHR 21 CD2 or CDR 21 ; B 2 For O, S, CD2, CHR 22 or NR 23 ; R 21 R 22 and R 23 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms 1-6 alkyl; G is either O or S; Ring Y is C 3-10 cycloalkyl, with one or more R 2-1 Replacement C 3-10 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, of a 4 to 12-membered heterocycloalkyl group", and being bound by one or more R 2-2 Substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N in 4- to 12-membered heterocyclic alkyl groups", C 6-20 aryl, with one or more R 2-3 Replacement C 6-20 Aryl, "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N, a 5 to 12-membered heteroaryl", and bonded by one or more R 2-4 Substituted "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from O, S, and N 5-12 membered heteroaryl groups", C 5-7 Cycloalkenyl, with one or more R 2-5 Replacement C 5-7 Cycloalkenyl, "a 5-7 membered heterocyclic alkenyl group containing 1-3 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 2-6 The substituents are "5-7 membered heterocyclic alkenyl groups containing 1-3 heteroatoms, which are independently selected from O, S, and N"; when there are multiple substituents, they may be the same or different; R 2-1 R 2-2 R 2-3 R 2-4 R 2-5 and R 2-6 Independently halogen, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -C(=O)R 2a -NR 2b1 R 2b2 -C(=O)OR 2c or -C(=O)NR 2d1 R 2d2 ; R 2a R 2b1 R 2b2 R 2c R 2d1 and R 2d2 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms 1-6 alkyl; X is a single bond, CH2, NH, O, or S; R 4 C 6-20 aryl, with one or more R 4-1 Replacement C 6-20 aryl, "a 5-12 membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S, and N", or, surrounded by one or more R 4-2 The substituents are "containing 1 to 4 heteroatoms, the heteroatoms being independently selected from 5 to 12-membered heteroaryl groups of O, S, and N"; when there are multiple substituents, they may be the same or different; R 4-1 and R 4-2 Independently halogen, hydroxyl, cyano, C 1-6 Alkyl, one or more deuterated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OC 1-6 Alkyl, -C(=O)R 4a -NR 4b1 R 4b2 -C(=O)OR 4c or -C(=O)NR 4d1 R 4d2 ; R 4a R 4b1 R 4b2 R 4c R 4d1 and R 4d2 Independently hydrogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium atoms 1-6 alkyl.

2. The heterocyclic compound, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its isotopic compound as claimed in claim 1, characterized in that, In heterocyclic compounds as shown in Formula I Represents a single bond or a double bond; Ring A is aromatic; A1, A4, and A5 are independently N or C; A2 and A3 are independently N, S, O, NR2, or CR 3 ; R 1 C 1-6 alkyl; R 2 For hydrogen, C 1-6 Alkyl or -C(=O)OR 2’ ;R 2’ C 1-6 alkyl; R 3 It is hydrogen; B 1 For CHR 21 Or CD2; B 2 For CHR 22 or NR 23 ; R 21 R 22 and R 23 Independently hydrogen; G is O; Ring Y is C 3-10 Cycloalkyl, "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from O, S, and N, of a 4 to 12-membered heterocycloalkyl group", and being bound by one or more R 2-2 The substituted "containing 1 to 3 heteroatoms, the heteroatoms being independently selected from 4 to 12-membered heterocyclic alkyl groups of O, S and N"; R 2-2 Independently for C 1-6 alkyl; X is a single bond; R 4 For one or more R 4-1 Replacement C 6-20 Aryl group; when there are multiple substituents, they may be the same or different; R 4-1 Independently halogen, cyano, C 1-6 Alkyl or -OC 1-6 alkyl.

3. The heterocyclic compound, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its isotopic compound as described in claim 1 or 2, characterized in that, The heterocyclic compound shown in Formula I can also have the structure shown in Formula II: The definition of the group is as described in claim 1 or 2.

4. The heterocyclic compound, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its isotopic compound as described in claim 1 or 2, characterized in that, for And / or, ring Y is 5. The heterocyclic compound, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, or its isotopic compound as described in claim 1 or 2, characterized in that, The structures of heterocyclic compounds of Formula I are shown below: 。 6. A pharmaceutical composition comprising substance A and a pharmaceutical excipient; wherein substance A is a therapeutically effective amount of a heterocyclic compound of formula I as described in any one of claims 1-5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

7. The use of a substance A in the preparation of a medicament for the treatment or prevention of OGG1-mediated diseases; wherein the substance A is a heterocyclic compound of formula I as described in any one of claims 1-5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

8. The application as described in claim 7, characterized in that, The diseases mediated by OGG1 include cancer, inflammation, and autoimmune diseases.

9. A method for using substance A to inhibit OGG1, comprising administering an effective amount of substance A to a subject. The substance A is a heterocyclic compound of formula I as described in any one of claims 1-5, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic compound thereof.

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