WO2023143236A1

WO2023143236A1 - 2h-indazole-7-formamide compound, preparation method, pharmaceutical composition, and application

Info

Publication number: WO2023143236A1
Application number: PCT/CN2023/072562
Authority: WO
Inventors: 徐云根; 郝海平; 邹毅; 古宏峰; 许文博; 严文昕; 汪勇; 杨解平; 黄磊; 王洪; 苏宇佩; 朱启华
Original assignee: 中国药科大学
Priority date: 2022-01-26
Filing date: 2023-01-17
Publication date: 2023-08-03

Abstract

Disclosed are a 2H-indazole-7-formamide compound, a preparation method, a pharmaceutical composition, and an application. The structure of the compound is represented by formula (I), and comprises an isomer or pharmaceutically acceptable salt thereof or a mixture of said isomer and salt. The compound and a pharmaceutical composition thereof have excellent pharmacokinetic properties in vivo, and have remarkable advantages as a ready-made medicine. The present invention has a highly effective inhibitory effect on PARP7, PRAP1, and a variety of tumor cells, a prepared anti-tumor drug can achieve a good medicinal effect on the molecular level, the cell level, and the animal level, and in particular has excellent anti-tumor activity in vivo versus relatively malignant colon cancer, lung adenocarcinoma, and triple-negative breast cancer. Additionally, the preparation method for the compound is simple and easy to carry out.

Description

2H-indazole-7-carboxamide compounds, preparation method, pharmaceutical composition and application

technical field

The present invention relates to a class of 2H-indazole-7-carboxamide compounds, a preparation method, a pharmaceutical composition and applications, in particular to a class of 2H-indazole-7-carboxamides which are PARP7 inhibitors and have antitumor activity Compounds, preparation methods, pharmaceutical compositions and applications.

Background technique

Studies have shown that most of the PARP family members in the human body exhibit monoADP ribosyltransferase activity. The MonoPARP family of proteins has been implicated in the development of cancer, inflammation and neurodegenerative diseases. PARP7, a member of the monoPARP protein family, is a novel negative regulator of nucleic acid sensors in cells and is overexpressed in a variety of tumor cells. Because cancer cells can use PARP-7 to suppress interferon signaling, making it "hide" from the immune system, many cancer cells rely on PARP-7 for survival. The study found that inhibiting PARP7 can restore intracellular interferon signaling, restore the body's innate and adaptive immunity, and thereby inhibit the growth of cancer cells. In cancer models such as lung cancer and colorectal cancer, PARP7 inhibitors showed durable tumor growth inhibition.

At present, no PARP-7 inhibitor has been approved for marketing. RBN-2397 developed by Ribon is the first compound with strong inhibitory activity and selectivity for PARP-7, and it has entered clinical phase I research (NCT04053673). However, RBN-2397 has a high in vivo clearance rate, resulting in low in vivo exposure and oral bioavailability, and its drug efficacy in animals shows that it is difficult to achieve an anti-tumor effect with a single administration of RBN-2397, which must be combined with CYP450 inhibitors are used in combination to slow down their clearance to be effective.

Contents of the invention

Purpose of the invention: Aiming at the shortcomings of the existing compounds such as poor pharmacokinetic properties and difficulty in exerting single-drug effects, the present invention aims to provide a class of 2H-indazole-7- Formamide compound, preparation method, pharmaceutical composition and application.

Technical solution: As the first aspect involved in the present invention, the 2H-indazole-7-carboxamide compound of the present invention has the structure of formula (I), and the compound includes its isomers, pharmaceutically acceptable salts or Their mixture:

in:

n is selected from 0, 1, 2, 3 or 4;

m is selected from 0 or 1;

^R is selected from hydrogen or halogen;

R ² or R ³ are independently selected from hydrogen, C ₁ -C ₆ alkyl, substituted C ₃ -C ₆ cycloalkyl or heterocycloalkyl, cyano, halogen, difluoromethyl, trifluoromethyl , or R ² and R ³ form a C ₃ -C ₆ cycloalkyl group together with the connected carbon atoms; the substituents of the C ₃ -C ₆ cycloalkyl group are selected from hydrogen, methyl, trifluoromethyl, 2, 2-Difluoroethyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetamido, hydroxyl, acetoxy, carboxyl or methoxycarbonyl, the substituent is one or more;

A ¹ is selected from -NH-, -O-, -CH ₂ -, C ₃ ~C ₆ cycloalkyl or heterocycloalkyl or 5-10 membered aromatic ring or heteroaryl ring; wherein, the C ₃ ~C Any position of _6- cycloalkyl or heterocycloalkyl or 5-10 membered aromatic ring or heteroaryl ring is replaced by one or more The following group substitutions: hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, difluoromethylsulfonyl, trifluoromethyl, trifluoromethylsulfonyl, methylsulfonyl, cyano, hydroxyl, Amino, methylamino, dimethylamino, diethylamino, acetamido, formamido, nitro, methoxy or ethoxy;

A ² from: A ² from Wherein, R ⁵ , R ⁶ or R ⁷ are independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, methylamino, dimethylamino, acetamido, carboxyl or methoxy carbonyl;

^R is selected from aryl, heteroaryl or 1,3-benzodioxanyl substituted at any position by one or more of the following groups: hydrogen, halogen, cyano, trifluoromethyl, 2,2, -Difluoroethyl, C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, aryl, C ₁ to C ₆ alkoxy, hydroxyl, methoxy, amino, methylamino, di Methylamino, acetylamino, carboxyl, methoxycarbonyl or nitro.

Preferably, in the above structure:

n is selected from 0, 1 or 2;

^R is selected from hydrogen or fluorine;

R ² or R ³ are independently selected from hydrogen, methyl, fluorine or ethyl; when R ² and R ³ are different, the carbon atom connected to R ² and R ³ is racemic configuration, R configuration or S structure;

A ¹ is selected from -NH-, -CH ₂ -, Wherein, X ¹ , X ² or X ³ are each independently selected from CH or N, and R ⁸ is selected from one or more of hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, difluoromethanesulfonate Acyl, trifluoromethyl, trifluoromethanesulfonyl, methanesulfonyl, cyano, hydroxyl, amino, methylamino, dimethylamino, diethylamino, acetamido, formamido, nitro, methoxy, or ethyl Oxygen;

A ² from

^R4 is selected from Wherein, ^Y1 and ^Y2 independently represent CH or N, and ^R9 is selected from one or more hydrogen, trifluoromethyl, _C3 - _C6 cycloalkyl, aryl, methyl, fluorine, chlorine, Bromo, cyano, methoxy, methanesulfonyl, 2,2-difluoroethyl or 4-trifluoromethylphenyl.

More preferably, in the above structure:

R ² or R ³ are independently selected from hydrogen or methyl, and when R ² and R ³ are different, the carbon atom connected to R ² and R ³ is in a racemic configuration;

A ¹ is selected from -CH ₂ -,

A ² from

More preferably, in the above structure:

^R4 is selected from

More specifically, the above-mentioned 2H-indazole-7-carboxamide compounds are selected from any of the following compounds:

The pharmaceutically acceptable salt of the above-mentioned 2H-indazole-7-carboxamide compound is a salt formed by the above-mentioned compound and an acid, and the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzene Sulfonic 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 arginine Wei acid.

As the second aspect involved in the present invention, the preparation method of the above-mentioned 2H-indazole-7-carboxamide compounds is as follows:

(1) When ^R is hydrogen, the preparation method of compound IA is as follows:

Specifically, compound IV is prepared from compound II by dissolving II and III in a solvent and adding an acid-binding agent for 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.

Compound V is prepared from compound IV by dissolving IV in a solvent and adding an aqueous alkali solution to carry out hydrolysis reaction. The reaction solvent is THF, methanol, ethanol, acetonitrile or a mixed solvent of any two, preferably a mixed solvent of THF and methanol; the base is sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide.

Compound IA is prepared from compound V by dissolving V in a solvent, adding a condensing agent, adding a base and compound VI is obtained by 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'-carbonyldiimidazole (CDI), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), N,N'-dicyclohexylcarbodiimide (DCC) , N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBop), preferably EDCI and HOBT; the base is triethylamine, sodium carbonate, potassium carbonate or DIPEA, preferably DIPEA.

(2) When R is ^fluorine , the preparation method of compound IB is as follows:

Specifically, compound I-B is prepared from compound I-A by dissolving I-A in a solvent and adding a fluorinated reagent for reaction. The reaction solvent is acetic acid, acetonitrile, THF and a mixed solvent of acetonitrile and acetic acid, preferably a mixed solvent of acetic acid and acetonitrile, and the fluorinated reagent is 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2 ] Octane bis(tetrafluoroborate).

The definitions of m, n, A ¹ , Y ¹ , Y ² , R ² , R ³ , R ⁶ , R ⁷ , and R ⁹ in the synthetic route of the above preparation method are as described above; the corresponding acid and the compound prepared by the above method (1) forming a salt, namely obtaining a pharmaceutically acceptable salt of the compound.

As the third aspect of the present invention, the pharmaceutical composition comprises the above-mentioned 2H-indazole-7-carboxamide compound and a pharmaceutically acceptable carrier.

The above-mentioned 2H-indazole-7-carboxamide compounds can be added with pharmaceutically acceptable carriers to make common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions or injections, and the preparations can be added with spices, sweeteners, Common pharmaceutical excipients such as liquid/solid fillers and diluents.

As the third aspect involved in the present invention, the above-mentioned 2H-indazole-7-carboxamide compounds and their pharmaceutical compositions can be prepared as PARP7 inhibitor antitumor drugs; more specifically, they can be prepared for the treatment of lung squamous adenocarcinoma, Drugs for colon cancer, breast cancer and other cancers.

Beneficial effect: compared with the prior art, the present invention has the following significant advantages:

1. This type of compound has excellent in vivo pharmacokinetic properties, and its half-life, in vivo exposure and bioavailability have all been significantly improved, and it has significant advantages as a drug;

2. This type of compound has excellent in vivo pharmacodynamic properties, and a lower dose can achieve better tumor suppression activity, especially for colon cancer, lung adenocarcinoma, and triple-negative breast cancer with a high degree of malignancy. inhibitory effect;

3. This type of compound can effectively inhibit the enzyme activity of PARP7, with an optimal IC ₅₀ value of less than 50nM, reaching the nanomolar concentration level; it can also effectively inhibit the enzyme activity of PARP1, with an optimal inhibitory IC ₅₀ value of less than 0.5nM, reaching the picomolar concentration level ; And it has a significant inhibitory effect on the proliferation of various tumor cells, and the IC ₅₀ value for inhibiting the proliferation of tumor cells is optimally less than 0.1 μM, reaching the nanomolar concentration level;

4. This type of compound and its pharmaceutical composition are widely used and can be prepared as anti-tumor drugs; the drugs can exert drug effects at the molecular level, cellular level and animal level, especially have better pharmacokinetics in vivo pharmacological and pharmacodynamic properties;

5. The preparation method of the compound is simple and feasible.

Description of drawings

Fig. 1 is the anti-colon cancer result of compound I-A-20 of the present invention in mice for 14 days;

Fig. 2 is the anti-colon cancer result of compound I-A-25 of the present invention for 14 days in mice;

Fig. 3 is the anti-lung adenocarcinoma result of compound I-A-20 of the present invention for 21 days in mice;

Fig. 4 is the anti-triple-negative breast cancer result of compound I-B-1 of the present invention in mice for 27 days.

Detailed ways

The technical solutions of the present invention will be further described below in conjunction with the embodiments.

Example 1: 2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)-2H-indazole-7- Synthesis of formamide (I-A-1)

Synthesis of ethyl 3-(7-carbamoyl-2H-indazol-2-yl)propionate (IV-1)

Compound 1H-indazole-7-carboxamide (II) (161.2mg, 1.0mmol) was dissolved in DMF (3mL), and ethyl 3-bromopropionate (III-1) (199.1mg, 1.1mmol) was added React with potassium carbonate (414.0mg, 3.0mmol), react at 90°C for 2 hours, monitor the completion of the reaction by thin layer chromatography (V dichloromethane:V methanol = 15:1), add 10mL water, and extract with ethyl acetate (8mL×3) , the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (V petroleum ether: V ethyl acetate = 1:2) to obtain 251.1 mg of yellow oil (IV-1), with a yield of 96.1%. ESI-MS [M+H] ⁺ 262.1.

Synthesis of 3-(7-carbamoyl-2H-indazol-2-yl)propionic acid (V-1)

Dissolve compound IV-1 (234.9 mg, 0.9 mmol) in 3 mL of tetrahydrofuran, add 3 mL of methanol, and then add 2 mL of 5 mol/L sodium hydroxide aqueous solution, after the addition is complete, react at room temperature for 1 hour, and monitor by thin-layer chromatography (V petroleum ether: V ethyl acetate=1:1) The reaction is complete. Add 5 mL of water, extract with ethyl acetate (6 mL×2), adjust the pH of the aqueous layer to 4 with dilute hydrochloric acid, and precipitate a white solid, filter with suction, wash the filter cake with 5 mL of water, collect the filter cake, and dry in vacuo to obtain a white solid (V-1 ) 200.5mg, yield 95.5%. ESI-MS[M+H] ⁺ 234.1

Synthesis of 4-tert-butyl-1-(5-iodopyrimidin-2-yl)piperazinecarboxylate (VI-1-1)

Dissolve 2-chloro-5-iodopyrimidine (7.2g, 0.03mol) in 25mL of N-methylpyrrolidone (NMP), add piperazine-1-carboxylic acid tert-butyl ester (5.6g, 0.03mol) and potassium carbonate in sequence (8.3g, 0.06mol), heated to 80°C for 5 hours. Thin-layer chromatography (V petroleum ether: V ethyl acetate = 8:1) monitored the completion of the reaction, added 100mL of water, extracted with ethyl acetate (30mL×4), combined the organic phases, and successively washed them with saturated sodium chloride solution (40mL×4). 3) Wash, dry over anhydrous sodium sulfate, filter with suction, concentrate the filtrate, and purify the crude product by silica gel column chromatography (V petroleum ether: V ethyl acetate = 15:1) to obtain 10.6 g of yellow solid (VI-1-1), Yield 90.6%. ESI-MS[M+H] ⁺ 391.0

Synthesis of tert-butyl 4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carboxylate (VI-1-2)

Dissolve 4-tert-butyl-1-(5-iodopyrimidin-2-yl)piperazinecarboxylate (11.7g, 0.03mol) in 25mL NMP, add cuprous iodide (1.2g, 0.06mol), nitrogen For protection, slowly add 2,2-difluoro-2-(fluorosulfonyl)methyl acetate (11.6g, 0.06mol) dropwise at room temperature, after the addition is complete, heat up to 100°C, react for 8 hours, thin-layer chromatography (V Petroleum ether: V dichloromethane: V methanol = 15:10:2) to monitor the complete reaction, add 100mL water, extract with ethyl acetate (40mL×4), combine the organic phases, and wash with saturated sodium chloride solution (40mL×3 ), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (V dichloromethane: V methanol = 30:1) to obtain 8.2 g light yellow solid (VI-1-2). rate of 81%. ESI-MS [M+H] ⁺ 333.2; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.72 (s, 2H), 3.87–3.77 (m, 4H), 3.47–3.37 (m, 4H), 1.47 (s,9H).

2-(Piperazin-1-yl)-5-trifluoromethylpyrimidine (VI-1)

Dissolve tert-butyl 4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carboxylate (3.3g, 10.0mmol) in 15mL of dichloromethane, add 10mL of trifluoroacetic acid, and stir at room temperature After 0.5 hours, the reaction was complete as monitored by thin layer chromatography (V dichloromethane: V methanol = 15:1). Concentrate, use saturated aqueous sodium bicarbonate solution to adjust the pH to 7-8, add dichloromethane 15mL×5 for extraction, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and concentrate to obtain a white solid ( VI-1) 2.1 g, yield 90.1%. ESI-MS [M+H] ⁺ 233.1; ¹ H NMR (300MHz, DMSO-d ₆ )δ8.52(s,2H),3.87–3.77(m,4H),3.47–3.37(m,4H),1.75(s,1H).

2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)-2H-indazole-7-carboxamide (I-A -1) Synthesis

Dissolve compound V-1 (186.6mg, 0.8mmol) in 4mL DMF, add HOBT (135.1mg, 1.0mmol) and EDCI (165.1mg, 1.0mmol) successively, react at room temperature for 0.5 hours, then add VI-1 (186.4 mg, 0.8 mmol) and DIPEA (387.1 mg, 3.0 mmol) were reacted at room temperature for 3 hours, and the reaction was complete as monitored by thin-layer chromatography (V petroleum ether: V ethyl acetate = 1:1). Add 10 mL of water, extract with ethyl acetate (8 mL×3), combine the organic phases, wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate. The crude product was purified by silica gel column chromatography (V petroleum ether: V ethyl acetate = 1:2) to obtain 264.1 mg of white solid (IA-1), with a yield of 73.4%. ESI-MS [M+H] ⁺ 448.2; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.72(s, 2H), 8.63(s, 1H), 8.55(s, 1H), 8.01–7.92(m ,2H),7.82(s,1H),7.21-7.14(m,1H),4.76(t,J=6.7Hz,2H),3.86-3.73(m,4H),3.60-3.50(m,4H), 3.17(t,J=6.7Hz,2H).

With reference to the preparation method of compound IA-1, the following compounds were prepared:

Example 2: 3-fluoro-2-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pentyl)-2H-ind Synthesis of azole-7-carboxamide (I-B-1)

Compound IA-20 (475.0 mg, 1.0 mmol) was dissolved in acetic acid (2 mL) and acetonitrile (2 mL), and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane was added Alkane di(tetrafluoroborate) (531.4mg, 1.5mmol), react at 90°C for 1 hour, TLC (V dichloromethane: V methanol = 15:1) monitors the completion of the reaction, add 10mL of water, ethyl acetate (10mL×3) extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (V petroleum ether: V ethyl acetate = 1:2) to obtain 354.0 mg of white solid (IB-1), with a yield of 71.7%. ESI-MS [M+H] ⁺ 494.2.

¹ H NMR (300MHz,DMSO-d ₆ )δ(ppm):8.72(s,2H),8.34(s,1H),8.01-7.97(m,1H),7.92(s,1H),7.89-7.85( m,1H),7.23-7.16(m,1H),4.45(t,J＝7.2Hz,2H),3.84–3.76(m,4H),3.56-3.48(m,4H),2.42(t,J＝ 7.4Hz, 2H), 2.00-1.90(m, 2H), 1.60-1.48(m, 2H).

Example 3: 2-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pentyl)-2H-indazole-7- Synthesis of Formamide (I-A-20)

Synthesis of ethyl 3-(7-carbamoyl-2H-indazol-2-yl)butanoate (IV-3)

Compound 1H-indazole-7-carboxamide (II) (161.2g, 1.0mol) was dissolved in DMF (1.0L), and then ethyl 3-bromobutyrate (III-3) (230.0g, 1.1mol) was added ), potassium carbonate (414.0g, 3.0mol), reacted at 90°C for about 2 hours, after the completion of the reaction as monitored by thin-layer chromatography (V dichloromethane: V methanol = 15:1), slightly cooled, suction filtered, and the filter cake Wash with 300 mL of ethyl acetate, collect the filtrate, distill off most of the solvent under reduced pressure, add 1.0 L of water to the residue, extract with ethyl acetate (1 L×3), combine the organic phases, wash with saturated sodium chloride solution, Dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to obtain 261.5 g of yellow oil (IV-3), with a yield of 90.5%.

Synthesis of 3-(7-carbamoyl-2H-indazol-2-yl)butanoic acid (V-3)

Put compound IV-3 (260.4g, 0.9mol) in a 3L three-necked flask, add tetrahydrofuran (800mL) and methanol (800mL), stir to dissolve, then add 5mol/L sodium hydroxide aqueous solution (300mL), the addition is complete, React at room temperature for 1 hour, monitor by thin-layer chromatography (V petroleum ether: V ethyl acetate = 1:1) After the reaction is complete, concentrate under reduced pressure, add 1 L of water to the residue, extract with ethyl acetate (600mL×2), and the aqueous layer The pH was adjusted to 4 with dilute hydrochloric acid, and a white solid was precipitated. The filter cake was washed with water (800 mL×2), collected, and vacuum-dried to obtain 214.2 g of a white solid (V-3), with a yield of 91.1%.

2-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pentyl)-2H-indazole-7-carboxamide (I-A -20) synthesis

Dissolve compound V-3 (209.0g, 0.8mol) in 900mL DMF, add HATU (380.2g, 1.0mol), stir at room temperature for 0.5 hours, then add VI-1 (186.4g, 0.8mol) and DIPEA (387.1g , 3.0mol), reacted at room temperature for 3 hours, after TLC monitoring (V petroleum ether: V ethyl acetate = 1:1) the reaction was complete, added 1.8L of water, stirred at room temperature for 0.5 hours, a white solid precipitated, suction filtered, and the filter cake Wash with water (500mL×2), collect the filter cake, and dry in vacuo to obtain the crude product of I-A-20. Add 600 mL of methyl tert-butyl ether to the crude product, stir at room temperature for 30 minutes, filter with suction, and wash the filter cake with 200 mL of methyl tert-butyl ether. , collected the filter cake, and vacuum-dried to obtain 320.1 g of white solid (I-A-20), with a yield of 84.2%.

Example 4: 2-(1-oxo-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yl)-2H-indazole -Synthesis of 7-formamide (I-A-25)

Synthesis of ethyl 2-(7-carbamoyl-2H-indazol-2-yl)propionate (IV-4)

Compound 1H-indazole-7-carboxamide (II) (161.2g, 1.0mol) was dissolved in DMF (1.0L), and ethyl 2-bromopropionate (III-4) (199.1g, 1.1mol) was added ), potassium carbonate (414.0g, 3.0mol), reacted at 90°C for about 2 hours, after the completion of the reaction as monitored by thin-layer chromatography (V dichloromethane: V methanol = 15:1), slightly cooled, suction filtered, and the filter cake Wash with ethyl acetate (300mL×2), combine the filtrates, evaporate most of the solvent under reduced pressure, add 1.0L water to the residue, extract with ethyl acetate (800mL×3), combine the organic phases, and Wash with sodium solution, dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain 234.4 g of yellow oil (IV-4), with a yield of 89.7%.

Synthesis of 2-(7-carbamoyl-2H-indazol-2-yl)propionic acid (V-4)

Compound IV-4 (230.0 g, 0.88 mol) was dissolved in 800 mL of tetrahydrofuran, 800 mL of methanol was added, and 300 mL of 5 mol/L sodium hydroxide aqueous solution was added. After the addition was complete, the reaction was carried out at room temperature for 1 hour, and monitored by thin-layer chromatography (V petroleum ether: V ethyl acetate=1:1) The reaction is complete. Add 1.5L of water, extract with ethyl acetate (600mL×2), adjust the pH of the aqueous layer to 4 with dilute hydrochloric acid, precipitate a white solid, filter with suction, wash the filter cake with 1.5L of water, collect the filter cake, and dry it in vacuo to obtain a white solid (V -4) 196.6g, yield 95.7%.

2-(1-Oxo-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yl)-2H-indazole-7-metha Synthesis of Amide (I-A-25)

Compound V-4 (186.6g, 0.8mol) was dissolved in 900mL DMF, HATU (380.2g, 1.0mol) was added, stirred and reacted at room temperature for 0.5 hour, then VI-1 (186.4g, 0.8mol) and DIPEA ( 387.1g, 3.0mol), stirred at room temperature for about 3 hours, after the reaction was completed by TLC monitoring (V petroleum ether: V ethyl acetate = 1:1), added 1.8L of water, stirred at room temperature for 0.5 hours, and a white solid was precipitated. Suction filtration, the filter cake was washed with water (500mL×2), the filter cake was collected, and vacuum-dried to obtain the crude product of I-A-25. Add 600 mL of methyl tert-butyl ether to the crude product, stir at room temperature for 1 hour, filter with suction, wash the filter cake with methyl tert-butyl ether (150 mL×2), collect the filter cake, and dry in vacuo to obtain a white solid (I-A-25) 300.2g, yield 83.8%.

Example 5: Inhibitory Activity of Compounds on PARP7 Enzyme

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

1. Experimental method

(1) Configuration of solution and buffer

10X PBS preparation: Weigh 720mg KH ₂ PO ₄ , 45g NaCl and 5.311g Na ₂ HPO ₄ 12H ₂ O and dissolve them in 500mL deionized water, adjust the pH of the system to 7.4, and sterilize at 121°C for 30 minutes. After cooling, place it at 4°C for later use.

1X PBS preparation: Dilute 10X PBS 10 times with deionized water, that is, add 1 part of 10X PBS to 9 parts of deionized water to dilute.

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

1X PARP buffer preparation: (Prepare now) Use deionized water to dilute 10X PARP buffer 10 times, and place it on ice for later use.

(2) Preparation of compound working solution concentration

According to the detection requirements, the compound to be tested was diluted to the desired concentration with 100% DMSO, and then diluted 10 times with 1X PARP buffer to prepare a 10X compound working solution.

(3) Experimental steps

a. The day before the experiment, thaw 5X histone mixture on ice;

b. Prepare 1X histone mixture, use 1X PBS to make 5X histone mixture into 1X histone mixture; take 25 μL of 1X histone mixture from each well into the test plate, and incubate overnight at 4°C;

c. Take 100μL Blocking buffer from each well and add it to the test plate, incubate at 25°C for 90 minutes;

d. After the incubation, dry the liquid in the test plate, and repeat the plate washing 3 times;

e. Take 2.5 μL compound working solution from each well, and add it to the test plate according to the experimental layout; add the corresponding volume of 1X PARP buffer containing 10% DMSO to the positive control well (Positive control), add to the blank control (Blank) 1X PARP buffer of corresponding volume;

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

g. Take 10 μL of enzyme solution per well and add it to the test well plate, and add the corresponding volume of 1X PARP buffer to the blank control well. At this time, the enzyme amount is 60 ng per well. Note: This step needs to be performed on ice;

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

i. After the incubation, dry the liquid in the test plate, and repeat the plate washing 3 times;

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

k. After the incubation, dry the liquid in the test plate, and repeat the plate washing 3 times;

l. According to the ELISA ECL Substrate A and ELISA ECL Substrate B in the 1:1 mixing kit, add 50 μL of the mixture to each well of the test plate, and immediately use Nivo for Luminescence detection, and read the luminescence value (RLU);

m. Enzyme rate calculation:

% Enzyme Activity = (RLU(Sample)-RLU(Blank))/(RLU(Pos.Ctrl)-RLU(Blank))×100%;

Enzyme inhibition rate = 1-% Enzyme Activity;

_IC50 fittings were performed using Prism GraphPad software.

2. Experimental results

The specific results are shown in Table 1.

Table 1. Enzyme inhibitory activity data of test compounds on PARP7

Note: "+++" means IC ₅₀ <0.05 μM; "++" means IC ₅₀ ≥0.05 μM and <0.5 μM.

As shown in Table 1, all test compounds of the present invention exhibited good inhibitory activity on PARP7 enzyme, and the IC ₅₀ values all reached the nanomolar concentration level. Among them, compounds IA-3, IA-8~IA-9, IA-11~IA-17, IA-19~IA-25, IA-28~IA-29, IA-31~IA-39, IA-41 The IC ₅₀ values of ~IA-42, IA-44, IA-46~IA-48, IA-50~IA-51 and IB-1 for inhibiting PARP7 enzyme activity were all less than 0.05 μM.

Example 6: Enzyme inhibitory activity of compounds against PARP1

1. Experimental reagents

PARP-1 enzyme activity assay kit was purchased from BPS Bioscience.

2. Experimental method

The compound sample was dissolved in DMSO to prepare a 10mM mother solution, and then the compound was added to the screening system. The detection concentration range of the compound was 0.1nM-10μM, and the compound was diluted according to a 3-fold gradient, and two replicate holes were made for each concentration. Take out the 96-well plate that has been pre-coated with histone, and add the following enzyme reaction system and different concentrations of inhibitors to each well, including: 50 μL of reaction buffer (Tris*HCl, pH 8.0), NAD ⁺ , biotin-labeled activation DNA, PARP-1 enzyme and inhibitor; after reacting at room temperature for 1 hour, add 50 μL of avidin-labeled HRP to each well and react for 30 minutes; then add 100 μL of HRP substrate, and detect chemiluminescence on a SpectraMax M instrument value.

The inhibition rate of PARP1 enzyme activity was calculated as (Lu control-Lu treatment/Lu control)×100%. The concentration required for 50% inhibition of PARP1 enzymatic activity ( _IC50 ) was calculated using Prism GraphPad software using a normalized dose-response fit for non-linear regression.

In this experiment, the marketed PARP1 inhibitor olaparib was selected as the positive control.

3. Experimental results

The specific results are shown in Table 2.

Table 2. Enzyme inhibitory activity data of compounds on PARP1

As shown in Table 2, some compounds of the present invention not only have strong inhibitory activity on PARP7, but also have strong inhibitory activity on PARP1.

Example 7: Anti-proliferation activity of compounds on tumor cells

1. Experimental process

a. A group of cancer cell lines cultured to the logarithmic growth phase is spread to a 96-well plate at a pre-specified density in a medium containing fetal bovine serum;

b. Cells were treated with compound or vehicle (DMSO) after 24 hours, and day 0 plates were collected for analysis;

c. After the drug application, place the 96-well plate in a 37°C, 4.5% _CO2 incubator and incubate it. After 6 days, add 20 μL of 1.0% MTT thiazole blue solution to each well;

d. Continue to place it in a constant temperature incubator, and after 4 hours, suck away the supernatant culture solution, add 150 μL DMSO to each well, and mix well on a decolorization shaker until the crystals dissolve;

e. Measure the absorbance at 570nm with a multi-functional microplate reader, and calculate the IC ₅₀ value according to the improved Koech method: lgIC ₅₀ =Xm-I[P-(3-Pm-Pn)/4].

2. Experimental results

The specific results are shown in Table 3.

Table 3. Proliferation inhibitory activity of test compounds on tumor cells

Note: "+++" means IC ₅₀ <0.1 μM; "++" means IC ₅₀ ≥0.1 μM and <1.0 μM.

As shown in Table 3, compounds I-A-20, I-A-23, I-A-39 and I-B-1 of the present invention have strong inhibitory effects on the proliferation of various tumor cells.

Example 8: Pharmacokinetic study of compounds in mice

Experimental process: four test compounds (RBN-2397, I-A-8, I-A-20 and I-A-25) were selected, and 6 male ICR mice were selected for each compound, and 3 were orally administered (10mg/kg) , 3 intravenous injections (1mg/kg), collected respectively 0 minutes, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8 hours blood samples, centrifuged (3000 RPM/5 minutes), the collected supernatant was analyzed by LC-MS-MS, and the results were analyzed by winnonlin software. The specific results are shown in Table 4.

Table 4. Pharmacokinetic data of test compounds in ICR mice

IV: Indicates intravenous injection, PO: Indicates intragastric administration.

As shown in Table 4, compounds I-A-8, I-A-20 and I-A-25 of the present invention have good pharmacokinetic properties in ICR mice.

Embodiment 9: Study on the pharmacodynamics of compounds in mice

1. Balb/c mouse allograft CT26 tumor model experiment

CT26 cells (colon cancer cells) were inoculated subcutaneously in the right flank of BALB/c mice to develop tumors. Four days after tumor inoculation, 30 mice with tumor sizes ranging from 55 to 75 mm ³ (average tumor size 63 mm ³ ) were selected and randomly divided into 5 groups of 6 mice based on their tumor volume. On the second day after random grouping (the day of random grouping was defined as the 0th day), the drug was administered with vehicle (0.5% sodium carboxymethyl cellulose, ), compound RBN-2397 (100 mg/kg, 2 days per day) respectively. times, administered by intragastric administration for 14 consecutive days), compound IA-20 (respectively 25mg/kg, 50mg/kg, 100mg/kg, twice a day, administered by intragastric administration for 14 consecutive days), and during the administration period Tumor size was measured three times a week. The entire study was terminated on the 14th day, and the drug efficacy results are shown in Figure 1.

Test the drug effect of compound I-A-25 (being respectively 12.5mg/kg, 50mg/kg, 100mg/kg, every day 2 times, continuous 14 days gavage administration) with the same method, the results are shown in Figure 2.

It can be seen from Fig. 1 and Fig. 2 that the compounds I-A-20 and I-A-25 of the present invention have obvious anti-tumor activity on mouse colon cancer. Compared with the positive drug RBN-2397, the compounds I-A-20 and I-A-25 of the present invention can exert better anti-tumor effects at lower doses.

2. Subcutaneous xenografting of NCI-H1373 tumor model in CB17 SCID mice

NCI-H1373 cells (human lung cancer adenocarcinoma cells) were subcutaneously inoculated on the right flank of SCID CB17 mice to develop tumors. After 5 days of tumor growth, mice with tumors ranging from 100 to 188 mm ³ were randomized into treatment groups with an average tumor volume of 181 mm ³ . On the second day after randomization (the day of randomization was defined as day 0), treatment was initiated and administered by intragastric administration of vehicle (50% Labrasol) or compound RBN-2397 (30 mg/kg) or compound IA-20 (30 mg/kg ) treatment, once a day for 21 days. Tumor size was measured every three days during the dosing period. The entire study was terminated on day 21, and the drug efficacy results are shown in Figure 3.

It can be seen from Figure 3 that the compound I-A-20 of the present invention has obvious anti-tumor effect on mouse lung adenocarcinoma, which is better than the positive drug RBN-2397.

3. MDA-MB-231 tumor model experiment of subcutaneous xenograft in NSG mice

MDA-MB-231 cells (human breast cancer cells) were subcutaneously inoculated on the right flank of NSG mice to develop tumors. Four days after tumor inoculation, 24 mice with tumor sizes ranging from 50 to 100 ^mm3 were selected and randomly divided into 4 groups of 6 mice based on their tumor volume. On the second day after random grouping (the day of random grouping was defined as the 0th day), the drug was administered with vehicle (0.5% sodium carboxymethylcellulose, gavage), olaparib (50 mg/kg, Once a day, intraperitoneal injection), RBN-2397 (30mg/kg, once a day, intragastric administration), compound IB-1 (12.5mg/kg, once a day, intragastric administration), continuous administration for 27 days. Tumors were measured every three days during the dosing period. The entire study was terminated on day 27, and the drug efficacy results are shown in Figure 4.

It can be seen from Figure 4 that in the MDA-MB-231 triple-negative breast cancer mouse xenograft tumor model, the compound IB-1 of the present invention has a good anti-tumor effect, and is far superior to the positive drug RBN-2397.

Claims

A 2H-indazole-7-carboxamide compound is characterized in that it has a structure of formula (I), and said compound includes its isomers, pharmaceutically acceptable salts or mixtures thereof:

in:

n is selected from 0, 1, 2, 3 or 4;

m is selected from 0 or 1;

R is selected from hydrogen or halogen;

R 2 or R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl or heterocycloalkyl, cyano, halogen, difluoromethyl, trifluoromethyl , or R 2 and R 3 form a C 3 -C 6 cycloalkyl group together with the connected carbon atoms; the substituents of the C 3 -C 6 cycloalkyl group are selected from hydrogen, methyl, trifluoromethyl, 2, 2-Difluoroethyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetamido, hydroxyl, acetoxy, carboxyl or methoxycarbonyl, the substituent is one or more;

A 1 is selected from -NH-, -O-, -CH 2 -, C 3 ~C 6 cycloalkyl or heterocycloalkyl or 5-10 membered aromatic ring or heteroaryl ring; wherein, the C 3 ~C Any position of 6- cycloalkyl or heterocycloalkyl or 5-10 membered aromatic ring or heteroaryl ring is substituted by one or more of the following groups: hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethane Difluoromethanesulfonyl, trifluoromethyl, trifluoromethanesulfonyl, methanesulfonyl, cyano, hydroxyl, amino, methylamino, dimethylamino, diethylamino, acetylamino, formamido, nitro , methoxy or ethoxy;

A 2 from Wherein, R 5 , R 6 or R 7 are independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, methylamino, dimethylamino, acetamido, carboxyl or methoxy carbonyl;

R 4 is selected from aryl, heteroaryl or 1,3-benzodioxanyl substituted at any position by one or more of the following groups: hydrogen, halogen, cyano, trifluoromethyl, 2,2- Difluoroethyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, C 1 -C 6 alkoxy, hydroxyl, methoxy, amino, methylamino, dimethyl Amino, acetamido, carboxy, methoxycarbonyl or nitro.
2H-indazole-7-carboxamides according to claim 1, characterized in that, in the structure:

n is selected from 0, 1 or 2;

R is selected from hydrogen or fluorine;

R 2 or R 3 are independently selected from hydrogen, methyl, fluorine or ethyl; when R 2 and R 3 are different, the carbon atom connected to R 2 and R 3 is racemic configuration, R configuration or S structure;

A 1 is selected from -NH-, -CH 2 -, Wherein, X 1 , X 2 or X 3 are each independently selected from CH or N, and R 8 is selected from one or more of hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, difluoromethanesulfonate Acyl, trifluoromethyl, trifluoromethanesulfonyl, methanesulfonyl, cyano, hydroxyl, amino, methylamino, dimethylamino, diethylamino, acetamido, formamido, nitro, methoxy, or ethyl Oxygen;

A 2 from

R4 is selected from Wherein, Y 1 or Y 2 independently represent CH or N, and R 9 is selected from one or more hydrogen, trifluoromethyl, C 3 -C 6 cycloalkyl, aryl, methyl, fluorine, chlorine, Bromo, cyano, methoxy, methanesulfonyl, 2,2-difluoroethyl or 4-trifluoromethylphenyl.
2H-indazole-7-carboxamide compound according to claim 1 or 2, is characterized in that, in the described structure:

R 2 or R 3 are independently selected from hydrogen or methyl, and when R 2 and R 3 are different, the carbon atom connected to R 2 and R 3 is in a racemic configuration;

A 1 is selected from -CH 2 -,

A 2 from
2H-indazole-7-carboxamide compound according to claim 1 or 2, is characterized in that, in the described structure:

R4 is selected from
2H-indazole-7-carboxamide compound according to claim 1 or 2, is characterized in that, is selected from following any compound:

2-(3-oxo-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)propyl)-2H-indazole-7-carboxamide (I-A -1), 2-(3-(4-(5-cyanopyrimidin-2-yl)piperazin-1-yl)-3-oxopropyl)-2H-indazole-7-carboxamide (I-A -2),

2-(3-oxo-3-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)propyl)-2H-indazole-7-methyl Amide (I-A-3),

2-(3-(Methyl(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)-3-oxopropyl)-2H-indazole-7 -Formamide (I-A-4),

2-(3-(Methyl(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)amino)-3-oxopropyl)-2H-ind Azole-7-carboxamide (I-A-5),

2-(3-oxo-3-((1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)amino)propyl)-2H-indazole- 7-formamide (I-A-6),

2-(3-(4-(2,2-Difluorobenzo[d][1,3]dioxan-5-yl)piperazin-1-yl)-3-oxopropyl)-2H - indazole-7-carboxamide (IA-7),

2-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butyl)-2H-indazole-7-carboxamide (I-A -8),

2-(4-(4-(5-cyanopyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)-2H-indazole-7-carboxamide (I-A-9),

2-(4-oxo-4-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)butyl)-2H-indazole-7-methyl Amide (I-A-10),

2-4-(Methyl(1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)amino)-4-oxobutyl)-2H-indazole-7- Formamide (I-A-11),

2-(4-(Methyl(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)amino)-4-oxobutyl)-2H-ind Azole-7-carboxamide (I-A-12),

2-(4-oxo-4-((1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)amino)butyl)-2H-indazole- 7-formamide (I-A-13),

2-(4-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)-2H-indazole-7-carboxamide (I-A-14),

2-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-4-oxobutyl)-2H-indazole-7-carboxamide (I-A-15),

2-(4-oxo-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)butyl)-2H-indazole-7-carboxamide (I-A -16),

2-(4-oxo-4-(4-(5-(trifluoromethyl)pyrazin-2-yl)piperazin-1-yl)butyl)-2H-indazole-7-carboxamide ( I-A-17),

2-(4-(4-(2,2-Difluorobenzo[d][1,3]dioxan-5-yl)piperazin-1-yl)-4-oxobutyl)-2H - indazole-7-carboxamide (I-A-18),

(E)-2-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)but-2-en-1-yl)- 2H-indazole-7-carboxamide (I-A-19),

2-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pentyl)-2H-indazole-7-carboxamide (I-A -20),

2-(5-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)-5-oxopentyl)-2H-indazole-7-carboxamide (I-A-21),

2-(4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-22),

2-(3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-23),

2-(4-oxo-4-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]hept-6-yl)butyl )-2H-indazole-7-carboxamide (I-A-24),

2-(1-Oxo-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yl)-2H-indazole-7-metha Amide (I-A-25),

2-(2-(4-(2,2-Difluorobenzo[d][1,3]dioxan-5-yl)piperazin-1-yl)-2-oxoethyl)-2H - indazole-7-carboxamide (I-A-26),

2-(1-(4-(2,2-Difluorobenzo[d][1,3]dioxan-5-yl)piperazin-1-yl)-1-oxopropan-2-yl )-2H-indazole-7-carboxamide (I-A-27),

2-(2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2H-indazole-7-carboxamide (I-A -28),

2-(1-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)-1-oxopropan-2-yl)-2H-indazole-7-carboxamide (I-A- 29),

2-(1-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-1-oxopropan-2-yl)-2H-indazole-7-carboxamide (I-A-30 )

2-(1-fluoro-2-oxo-2-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-2H-indazole-7- Formamide (I-A-31),

2-(1-oxo-1-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)prop-2-yl)-2H-indazole-7-methan Amide (I-A-32),

2-(4-oxo-4-(6-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazabicyclo[3.1.1]hept-3-yl)butyl )-2H-indazole-7-carboxamide (I-A-33),

2-(1-oxo-1-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,6-diazacyclo[3.1.1]hept-6-yl)propane- 2-yl)-2H-indazole-7-carboxamide (I-A-34),

2-(1-oxo-1-(3-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]oct-8-yl)propane- 2-yl)-2H-indazole-7-carboxamide (I-A-35),

2-(1-oxo-1-(8-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]oct-3-yl)propane- 2-yl)-2H-indole Azole-7-carboxamide (IA-36),

2-(1-oxo-1-(8-(5-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazacyclo[3.2.1]oct-3-yl)propane- 2-yl)-2H-indazole-7-carboxamide (I-A-37),

2-(1-oxo-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butan-2-yl)-2H-indazole-7-methan Amide (I-A-38),

2-(4-fluoro-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A- 39),

2-(2-fluoro-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A- 40),

2-(6-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)pyridin-2-yl)methyl)-2H-indazole-7-carboxamide ( I-A-41),

2-(3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-42),

2-(4-fluoro-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A- 43),

2-(2-fluoro-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A- 44),

2-(3-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)piperazine-1-carbonyl)benzyl)-2H-indazole -7-formamide (I-A-45),

2-(3-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-46),

2-(3-(4-(5-bromopyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-47),

2-(3-(4-(5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-48),

2-(3-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)piperazine-1-carbonyl)-4-fluorobenzyl)- 2H-indazole-7-carboxamide (I-A-49),

2-(4-fluoro-3-(4-(5-fluoropyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-50),

2-(4-fluoro-3-(4-(trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-51),

2-(5-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)piperazine-1-carbonyl)-2-fluorobenzyl)- 2H-indazole-7-carboxamide (I-A-52),

2-(6-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)piperazine-1-carbonyl)pyridin-2-yl)methyl )-2H-indazole-7-carboxamide (I-A-53),

2-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-54),

2-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-2H-indazole-7-carboxamide (I-A-55),

3-fluoro-2-(5-oxo-5-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)pentyl)-2H-indazole-7- Formamide (I-B-1),

3-fluoro-2-(5-oxo-5-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)pentyl)-2H-indazole-7- Formamide (I-B-2),

3-fluoro-2-(4-oxo-4-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)butyl)-2H-indazole-7- Formamide (I-B-3),

3-fluoro-2-(5-(4-(5-methylpyrimidin-2-yl)piperazin-1-yl)-5-oxopentyl)-2H-indazole-7-carboxamide (I-B -4),

3-Fluoro-2-(1-oxo-1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)prop-2-yl)-2H-indazole -7-Carboxamide (I-B-5).
The 2H-indazole-7-carboxamide compound according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a salt formed by the compound and an acid, and the acid is 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, rich Malic acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid.
A preparation method of the 2H-indazole-7-carboxamide compound described in any one of claims 1 to 6, characterized in that it is selected from any of the following methods:

(1) When R is hydrogen, the preparation method of compound IA is as follows;

(2) When R is fluorine , the preparation method of compound IB is as follows:

Wherein, m, n, A 1 , Y 1 , Y 2 , R 2 , R 3 , R 6 , R 7 , and R 9 are as defined in any one of claims 1-5;

A pharmaceutically acceptable salt of the compound can be obtained by salting the corresponding acid with the compound (I) prepared by the above method.
A pharmaceutical composition, characterized by comprising the 2H-indazole-7-carboxamide compound according to any one of claims 1-6 and a pharmaceutically acceptable carrier.
A use of the 2H-indazole-7-carboxamide compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 8 in the preparation of PARP7 inhibitor drugs.
The use according to claim 9, characterized in that the drug is an antineoplastic drug.