2h-indazole-7-carboxamides as parp7 inhibitors and uses

Abstract

The application discloses a 2H-indazole-7-formamide PARP7 inhibitor, a preparation method, a pharmaceutical composition and application. The compound structure is as shown in formula (I), and the compound comprises isomers, pharmaceutically acceptable salts or mixtures thereof. The compound structure is reasonable, can effectively target PARP7, and has an enzyme inhibition activity reaching a nanomolar concentration level, so that the prepared pharmaceutical composition can be used as an effective antitumor drug. In addition, the preparation method of the compound is simple and easy to operate.

Description

Technical Field

[0001] This invention relates to a 2H-indazole-7-carboxamide PARP7 inhibitor, its preparation method, pharmaceutical composition, and application, and particularly to a 2H-indazole-7-carboxamide PARP7 inhibitor with antitumor activity, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] PARP7, a member of the monoPARP protein family, is a novel negative regulator of nucleic acid sensors in cells and is overexpressed in various tumor cells. Because cancer cells can use PARP7 to suppress interferon signaling, allowing them to "hide" outside the immune system, many cancer cells depend on PARP7 for survival. Studies have found that inhibiting PARP7 can restore intracellular interferon signaling, restore the body's innate and adaptive immunity, and thus inhibit cancer cell growth. In cancer models such as lung cancer and colorectal cancer, PARP7 inhibitors have shown durable tumor growth inhibition.

[0003] Most currently marketed PARP inhibitors are PARP1 inhibitors, which have limited efficacy against immune evasion by tumor cells. Increasing the dosage and frequency of administration can also lead to drug resistance in tumor cells. Currently, only Ribon's small molecule PARP7 inhibitor RBN-2397 has entered clinical trials. However, its monotherapy is unlikely to exert anti-tumor activity. Therefore, effective PARP7 inhibitors have become a clinically urgent need. Summary of the Invention

[0004] Purpose of the invention: In view of the problems of limited structural types and limited activity of existing compounds, the present invention aims to provide a 2H-indazole-7-carboxamide PARP7 inhibitor with reasonable structural design and excellent enzyme inhibitory activity, its preparation method, pharmaceutical composition and its application.

[0005] Technical solution: As a first aspect of the present invention, the 2H-indazole-7-carboxamide PARP7 inhibitor of the present invention has the structure of formula (I), and further comprises its isomers, pharmaceutically acceptable salts, or mixtures thereof:

[0006]

[0007] in:

[0008] A 1 Selected from benzene rings or 6-7 membered nitrogen-containing aromatic heterocycles, wherein any position on the ring system is substituted by one or more of the following groups: hydrogen, halogen, methyl, trifluoromethyl, amino, or methoxy;

[0009] A 2 Selected from Among them, R 1 R 2 or R 3 Each group is independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxy, methoxy, amino, methylamino, dimethylamino, acetamino, carboxyl, or methoxycarbonyl.

[0010] R is selected from aryl, heteroaryl, or 1,3-benzodioxanepentyl groups substituted at any position with one or more of the following groups: hydrogen, halogen, cyano, trifluoromethyl, 2,2,-difluoroethyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, methoxy, amino, methylamino, dimethylamino, acetamino, carboxyl, methoxycarbonyl, or nitro.

[0011] Preferably, in the above PARP7 inhibitor structure:

[0012] A 1 Selected from Among them, X 1 X 2 or X 3 Each is independently selected from CH or N, R 4 It is selected from one or more hydrogen, halogen, methyl, trifluoromethyl, amino, or methoxy groups;

[0013] A 2 Selected from

[0014] R is selected from Among them, Y 1 Or Y 2 Each can independently represent CH or N, R 5 It is selected from one or more of hydrogen, trifluoromethyl, methyl, fluorine, chlorine, bromine, cyano, methoxy, methanesulfonyl, 2,2-difluoroethyl or 4-trifluoromethylphenyl.

[0015] Preferably, in the above PARP7 inhibitor structure:

[0016] A 1 Selected from

[0017] A 2 Selected from

[0018] Preferably, in the above PARP7 inhibitor structure:

[0019] R is selected from

[0020] More specifically, the aforementioned PARP7 inhibitors are selected from any of the following compounds:

[0021]

[0022]

[0023]

[0024] The pharmaceutically acceptable salt of the above-mentioned PARP7 inhibitor is a salt formed by the above-mentioned compound and an acid 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, or ferulic acid.

[0025] As a second aspect of the present invention, the method for preparing the above-mentioned PARP7 inhibitor is as follows:

[0026] Compound (II) and compound (III) were subjected to substitution, hydrolysis and acylation reactions to obtain compound (I);

[0027]

[0028] Among them, A 1 Y 1 Y 2 R 2 R 3 R 5 The definition is the same as before.

[0029] Specifically, compound IV is prepared from compound II by dissolving II and III in a solvent and adding an acid-binding agent to carry out a substitution reaction. The reaction solvent is N,N-dimethylformamide (DMF), N,N-dimethylacetamide, tetrahydrofuran (THF), 1,4-dioxane, ethylene glycol dimethyl ether, or acetonitrile, preferably DMF; the acid-binding agent is sodium carbonate, potassium carbonate, triethylamine, or N,N-diisopropylethylamine (DIPEA), preferably potassium carbonate.

[0030] Compound V is prepared from compound IV by dissolving IV in a solvent and then hydrolyzing it in an aqueous solution of an alkali. The reaction solvent is THF, methanol, acetonitrile, or a mixture of any two, preferably a mixture of THF and methanol; the alkali is sodium hydroxide, lithium hydroxide, or potassium hydroxide, preferably sodium hydroxide.

[0031] Compound I is prepared from compound V by dissolving V in a solvent, adding a condensing agent, and then adding a base and compound VI to carry out a condensation reaction. The solvent is dichloromethane, THF, DMF, 1,4-dioxane, ethylene glycol dimethyl ether, or acetonitrile, preferably DMF; the condensing agent is selected from N,N'-carbonyldiimidazolium (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), benzotriazole-1-yl-oxytripyrrolidine hexafluorophosphate (PyBop), preferably EDCI and HOBT; the base is triethylamine, sodium carbonate, potassium carbonate, or DIPEA, preferably DIPEA.

[0032] The corresponding acid is salted with the compound (I) prepared by the above method to obtain a pharmaceutically acceptable salt of the compound.

[0033] As a third aspect of the present invention, the above-mentioned PARP7 inhibitor and a pharmaceutically acceptable carrier constitute a pharmaceutical composition to be formulated into common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions or injections. The preparations may contain commonly used pharmaceutical excipients such as flavorings, sweeteners, liquid / solid fillers, and diluents.

[0034] As a fourth aspect of the present invention, the above-mentioned PARP7 inhibitor and its pharmaceutical composition can be prepared as an anti-tumor drug for the specific treatment of cancers such as pancreatic cancer, lung squamous cell carcinoma, colon cancer, and breast cancer.

[0035] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0036] (1) These compounds can effectively inhibit PARP7 enzyme activity and the proliferation of various tumor cells, with an inhibitory IC50 value for both enzyme and cell activity. 50 The values ​​all reached nanomolar concentration levels, with the enzyme inhibition IC50 value being [value missing]. 50 The optimal value is less than 50 nM, and the drug composition prepared from it can be used as an effective anti-tumor drug;

[0037] (2) The compound has a novel structure and is rationally designed to target PARP7, enabling it to exert therapeutic effects at both the molecular and cellular levels.

[0038] (3) The preparation method is simple and feasible. Detailed Implementation

[0039] The technical solution of the present invention will be further described below with reference to the embodiments.

[0040] Example 1: Synthesis of 2-(4-fluoro-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-1)

[0041] Synthesis of methyl 5-(7-carbamoyl-2H-indazol-2-yl)methyl)-2-fluorobenzoate (IV-1)

[0042] Compound 1H-indazole-7-carboxamide (II) (161.2 mg, 1.0 mmol) was dissolved in 3 mL of DMF, followed by the addition of methyl 5-(bromomethyl)-2-fluorobenzoate (III-1) (256.3 mg, 1.04 mmol) and potassium carbonate (414.6 mg, 3.0 mmol). The reaction was carried out at 80 °C for 2 hours. Thin-layer chromatography (V dichloromethane:V methanol = 15:1) was used to monitor the completion of the reaction. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 1:2) to give 267.1 mg of a yellowish-white solid (IV-1), with a yield of 81.7%. ESI-MS [M+H] + 328.1.

[0043] Synthesis of 5-((7-carbamoyl-2H-indazol-2-yl)methyl)-2-fluorobenzoic acid (V-1)

[0044] Compound IV-1 (261.8 mg, 0.8 mmol) was dissolved in 3 mL of methanol, and 2 mL of 5 mol / L sodium hydroxide aqueous solution was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. Thin-layer chromatography (V petroleum ether:V ethyl acetate = 1:1) confirmed the reaction was complete. 5 mL of water was added, and the mixture was extracted with ethyl acetate (6 mL × 2). The pH of the aqueous layer was adjusted to 4 with dilute hydrochloric acid, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was washed with 5 mL of water. The filter cake was collected and dried under vacuum to give 210.1 mg of a white solid (V-1), with a yield of 83.8%. ESI-MS [M+H] + 314.1.

[0045] Synthesis of tert-butyl 4-(5-iodopyrimidin-2-yl)piperazine-1-carboxylate (VI-1-1)

[0046] 2-Chloro-5-iodopyrimidine (7.2 g, 0.03 mol) was dissolved in 25 mL of N-methylpyrrolidone (NMP), followed by the addition of piperazine-1-carboxylic acid tert-butyl ester (5.6 g, 0.03 mol) and potassium carbonate (8.3 g, 0.06 mol). The mixture was heated to 80 °C and reacted for 5 hours. Thin-layer chromatography (V petroleum ether:V ethyl acetate = 8:1) was used to monitor the reaction until complete. 100 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 4). The organic phases were combined and washed successively with saturated saline solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 15:1) to give 11.7 g of a yellow solid (VI-1-1), in 100% yield. ESI-MS [M+H] + 391.0.

[0047] Synthesis of 4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (VI-1-2)

[0048] VI-1-1 (11.7 g, 0.03 mol) was dissolved in 25 mL of NMP, and cuprous iodide (1.2 g, 0.06 mol) was added. Under nitrogen protection, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (11.6 g, 0.06 mol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was heated to 100 °C and reacted for 8 hours. The reaction was monitored for completeness by thin-layer chromatography (V petroleum ether:V dichloromethane:V methanol = 15:10:2). 100 mL of water was added, and the mixture was extracted with ethyl acetate (40 mL × 4). The organic phases were combined, washed with saturated saline solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (V dichloromethane:V methanol = 30:1) to give 8.2 g of a pale yellow solid (VI-1-2), with a yield of 81.0%. ESI-MS [M+H] + 333.2; 1 H NMR (300MHz, DMSO-d6) δ8.72(s,2H),3.87-3.77(m,4H),3.47-3.37(m,4H),1.47(s,9H).

[0049] Synthesis of 2-(piperazin-1-yl)-5-trifluoromethylpyrimidine (VI-1)

[0050] 3.3 g (10.0 mmol) of 4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in 15 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. After stirring at room temperature for 0.5 hours, the reaction was monitored for completion by thin-layer chromatography (Vdichloromethane:Vmethanol = 15:1). The solution was concentrated, and the pH was adjusted to 7–8 using saturated sodium bicarbonate aqueous solution. Extraction was performed with dichloromethane (15 mL × 5). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 2.1 g of a white solid (VI-1), with a yield of 91.0%. ESI-MS [M+H] + 233.1; 1 H NMR (300MHz, DMSO-d6) δ8.52(s,2H),3.87-3.77(m,4H),3.47-3.37(m,4H),1.75(s,1H).

[0051] Synthesis of 2-(4-fluoro-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-1)

[0052] Compound V-1 (219.3 mg, 0.7 mmol) was dissolved in 4 mL of DMF, followed by the addition of HOBT (135.1 mg, 1.0 mmol) and EDCI (165.1 mg, 1.0 mmol). The reaction was allowed to proceed at room temperature for 0.5 h, then VI-1 (186.4 mg, 0.8 mmol) and DIPEA (387.1 mg, 3.0 mmol) were added, and the reaction was allowed to proceed at room temperature for 3 h. Thin-layer chromatography (V petroleum ether:V ethyl acetate = 1:1) confirmed the reaction was complete. The mixture was extracted with 10 mL of water and ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (V petroleum ether:V ethyl acetate = 1:2) to give 262.9 mg of a white solid (I-1), with a yield of 71.2%. ESI-MS [M+H] + 528.2; 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.74(s,2H),8.53(s,1H),8.00-7.96(m,2H),7.83(s,1H),7.58-7.51(m,2H),7.35(t,J=9. 2Hz,1H),7.21(dd,J=8.3,7.0Hz,1H),5.77(s,2H),3.97-3.90(m,2H),3.84-3.78(m,2H),3.77-3.71(m,2H),3.35-3.31(m,2H).

[0053] Following the preparation method of Example 1, the following compounds were prepared:

[0054]

[0055]

[0056]

[0057] Example 2: Inhibitory activity of the compound against PARP7

[0058] Experimental materials: PARP7 Chemiluminescent Assay Kit, BPS Bioscience; DMSO, Sinopharm, Nivo, PerkinElmer.

[0059] Experimental methods:

[0060] (1) Preparation of solutions and buffer solutions:

[0061] Preparation of 10X PBS: Weigh 720 mg KH2PO4, 45 g NaCl and 5.311 g Na2HPO4·12H2O and dissolve them in 500 mL of deionized water. Adjust the pH of the system to 7.4, sterilize at 121 °C for 30 minutes, cool and store at 4 °C for later use.

[0062] Preparation of 1X PBS: Dilute 10X PBS with deionized water 10 times, that is, add 1 part of 10X PBS to 9 parts of deionized water for dilution.

[0063] Wash buffer preparation: 1X PBS contains 0.05% Tween-20.

[0064] Preparation of 1X PARP buffer: (Prepare fresh for immediate use) Dilute 10X PARP buffer 10 times with deionized water and place on ice for later use.

[0065] (2) Preparation of the working solution concentration of the compound:

[0066] According to the testing requirements, the compound to be tested is diluted with 100% DMSO to the required concentration, and then diluted 10 times with 1X PARP buffer to prepare a 10X compound working solution.

[0067] (3) Experimental steps:

[0068] a. Thaw the 5X histone mixture on ice the day before the experiment;

[0069] b. Preparation of 1X histone mixture: Prepare 1X histone mixture by mixing 5X histone mixture with 1X PBS; add 25 μL of 1X histone mixture to each well of the test plate and incubate overnight at 4°C.

[0070] c. Add 100 μL of Blocking buffer to each well into the test plate and incubate at 25°C for 90 minutes;

[0071] d. After incubation, shake off the liquid in the test plate and wash the plate three times.

[0072] e. Take 2.5 μL of the compound working solution for 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 well, and add the corresponding volume of 1X PARP buffer to the blank control well.

[0073] f. After the enzyme is completely dissolved, dilute the enzyme stock solution to 6 ng / μL with 1X PARP buffer;

[0074] g. Add 10 μL of enzyme solution per well to the test plate, and add the corresponding volume of 1X PARP buffer to the blank control wells. The enzyme amount is now 60 ng per well. Note: This step must be performed on ice.

[0075] h. Add 12.5 μL of master mixture (12.5 μL master mixture includes 1.25 μL of 10X PARP buffer, 1.25 μL of Opti-PARP 10X Assay mixture and 10 μL of water) to each well of the test plate; seal the test plate and incubate at 25°C for 60 minutes.

[0076] i. After incubation, shake off the liquid in the test plate and wash the plate three times.

[0077] j. Dilute the Streptavidin-HRP in the kit 50 times with Blocking buffer solution, add 25 μL to each well of the test plate, and incubate at 25°C for 30 minutes;

[0078] k. After incubation, shake off the liquid in the test plate and wash the plate three times.

[0079] 1. Mix ELISA ECL Substrate A and ELISA ECL Substrate B in the 1:1 kit, add 50 μL of the mixture to each well of the test plate, and immediately perform Luminescence detection using Nivo to read the luminescence value (RLU).

[0080] m. Enzyme activity calculation: %Enzyme Activity = ((RLU(Sample) - RLU(Blank)) / (RLU(Pos.Ctrl) - RLU(Blank)) × 100%; Enzyme inhibition rate = 1 - %Enzyme Activity, IC50 analysis was performed using PrismGraphPad software. 50 The fitting results are shown in Table 1 below.

[0081] Table 1. Inhibitory activity (IC50) of the test compounds against PARP7 50

[0082]

[0083] Note: "++" indicates IC. 50 <0.05μM; "++" indicates IC 50 ≥0.05μM and <0.5μM.

[0084] As shown in Table 1, all the compounds tested in this invention exhibited good inhibitory activity against PARP7 enzyme, IC50. 50 All values ​​reached nanomolar concentration levels. Among them, compounds I-1, I-3–I-4, I-6, I-8–I-10, and I-12–I-13 inhibited PARP7 enzyme activity at IC50 levels. 50 The values ​​are all less than 0.05 μM.

[0085] Example 3: Antiproliferative activity of the compound against tumor cells

[0086] Experimental procedure:

[0087] a. A group of cancer cell lines cultured to the logarithmic growth phase were plated into 96-well plates at a pre-specified density in a medium containing fetal bovine serum;

[0088] b. Cells were treated with a compound or medium (DMSO) 24 hours later, and day 0 plates were collected for analysis;

[0089] c. After application, the 96-well plate was placed in a 37°C, 4.5% CO2 incubator and cultured for 6 days. 20 μL of 1.0% MTT thiazolyl blue solution was added to each well.

[0090] d. Continue to place in a constant temperature incubator. After 4 hours, use aspirate to remove the supernatant culture medium, add 150 μL of DMSO to each well, and mix on a decolorizing shaker until the crystals dissolve.

[0091] e. Measure the absorbance at 570 nm using a multi-functional microplate reader, and calculate the IC50 using the modified Kohl's method. 50 Value: lg IC 50 =Xm-I[P-(3-Pm-Pn) / 4], and the specific results are shown in Table 2 below.

[0092] Table 2. Data on the antiproliferative activity of the tested compounds against tumor cells.

[0093] cell lines <![CDATA[Example 1 (IC 50 : μM)]]> <![CDATA[RBN-2397(IC 50 :μM)]]> CT26 0.54±0.071 5.295±0.380 SW1990 0.47±0.07 ＞20

[0094] The above data show that Example 1 (compound I-1) of the present invention has a good inhibitory effect on the proliferation of various tumor cells, and its anti-proliferative effect is better than that of the positive control compound RBN-2397.

Claims

1. A 2H-indazole-7-carboxamide PARP7 inhibitor, characterized in that, Having the structure of formula (I), the compound comprises a pharmaceutically acceptable salt: in: A 1 Selected from A 2 Selected from R is selected from 2. A PARP7 inhibitor, characterized in that, Selected from any of the following compounds: 2-(4-fluoro-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-1), 2-(2-fluoro-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-2), 2-(6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-carbonyl)pyridin-2-yl)methyl)-2H-indazole-7-carboxamide (I-3), 2-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-4), 2-(4-fluoro-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-5), 2-(2-fluoro-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-6), 2-(3-(4-(2,2-difluorobenzo[d][1,3]dioxanepent-5-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-7), 2-(3-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-8), 2-(3-(4-(5-bromopyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-9), 2-(3-(4-(5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-10), 2-(3-(4-(2,2-difluorobenzo[d][1,3]dioxanepent-5-yl)piperazine-1-carbonyl)-4-fluorobenzyl)-2H-indazole-7-carboxamide (I-11), 2-(4-fluoro-3-(4-(5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-12), 2-(4-fluoro-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-13), 2-(5-(4-(2,2-difluorobenzo[d][1,3]dioxanepent-5-yl)piperazine-1-carbonyl)-2-fluorobenzyl)-2H-indazole-7-carboxamide (I-14), 2-(6-(4-(2,2-difluorobenzo[d][1,3]dioxanepent-5-yl)piperazin-1-carbonyl)pyridin-2-yl)methyl)-2H-indazole-7-carboxamide (I-15), 2-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-16), 2-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-17).

3. The PARP7 inhibitor according to claim 1, characterized in that, The pharmaceutically acceptable salt is a salt formed by the compound and an acid 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, or ferulic acid.

4. A method for preparing the PARP7 inhibitor according to any one of claims 1 to 3, characterized in that, The preparation method is as follows: Compound (II) and compound (III) were subjected to substitution, hydrolysis and acylation reactions to give compound I; Among them, A 1 The definition is as described in claim 1. The definition of A as in claim 1 2 The above, The definition is as described in claim 1, R; The corresponding acid is salted with the compound (I) prepared by the above method to obtain a pharmaceutically acceptable salt of the compound.

5. A pharmaceutical composition, characterized in that, It comprises the PARP7 inhibitor as described in any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

6. The use of a PARP7 inhibitor according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 5 in the preparation of an anti-pancreatic cancer or colon cancer drug.

Images