Pyridazinone compounds and preparation methods, pharmaceutical compositions and applications thereof

Abstract

The present invention discloses a class of pyridazinone compounds and a preparation method, a pharmaceutical composition and an application thereof. The structure of the pyridazinone compound is as shown in formula (I), and the pyridazinone compound comprises an isomer thereof, a pharmaceutically acceptable salt or a mixture thereof. The pyridazinone compound has excellent pharmacokinetic properties in vivo, has a highly effective inhibitory effect on PARP7 and a variety of tumor cells, can be used to prepare anti-tumor drugs that can exert efficacy at both the molecular level and the cellular level, can also promote the release of immune factors, and especially has excellent anti-tumor activity in vivo; in addition, the preparation method of the pyridazinone compound is simple and easy.

Description

Technical Field

[0001] The present invention relates to a class of pyridazinone compounds and a preparation method, a pharmaceutical composition and application thereof, and in particular to a class of pyridazinone compounds with anti-tumor activity and a preparation method, a pharmaceutical composition and application thereof. Background Art

[0002] Studies have shown that most PARP family members in the human body exhibit monoADP ribosyltransferase activity. The MonoPARP protein family is closely related to the development of cancer, inflammation, and neurodegenerative diseases. PARP7 is a member of the monoPARP protein family. It is a new negative regulator of nucleic acid sensors in cells and is overexpressed in tumors. Since cancer cells can use PARP-7 to inhibit interferon signals and "hide" from the immune system, many cancer cells rely on PARP-7 to survive. Studies have found that inhibiting PARP7 can restore interferon signaling in cells, 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 have shown persistent tumor growth inhibition.

[0003] Currently, no PARP-7 inhibitor has been approved for marketing. RBN-2397 developed by Ribon is the first compound with strong inhibitory activity and selectivity against PARP-7. In the xenograft tumor model of NCI-H1373 cells (human lung cancer adenocarcinoma cells), RBN-2397 has a significant anti-tumor effect at a dose of ≥30 mg / kg when taken orally once a day, and it is dose-dependent. It has entered Phase I clinical studies (NCT04053673). However, RBN-2397 has a high clearance rate in the body, resulting in great defects in in vivo exposure and oral bioavailability. Its efficacy in animals shows that it is difficult for a single administration of RBN-2397 to have an anti-tumor effect. It must be combined with a CYP450 inhibitor to reduce its clearance rate in order to work. Summary of the invention

[0004] Purpose of the invention: In view of the shortcomings of existing compounds such as poor pharmacokinetics and difficulty in exerting effects as a single drug, the present invention aims to provide a class of pyridazinone compounds with excellent anti-tumor activity and pharmacokinetic properties, as well as a preparation method, a pharmaceutical composition and application thereof.

[0005] Technical solution: As the first aspect of the present invention, the pyridazinone compound of the present invention has a structure of formula (I), and the pyridazinone compound includes its isomers, pharmaceutically acceptable salts or mixtures thereof:

[0006]

[0007] in:

[0008] m is selected from 0, 1, 2 or 3;

[0009] R 1 Selected from hydrogen, halogen, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, methylthio, methylsulfonyl, carbamoyl;

[0010] R 2 or R 3 are independently selected from hydrogen, C1-C6 alkyl, substituted C3-C6 cycloalkyl or heterocycloalkyl, cyano, trifluoromethyl, or R 2 and R 3 Together with the connected carbon atom, it forms a C3-C6 cycloalkyl group; the substituent of the C3-C6 cycloalkyl group is selected from hydrogen, methyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetylamino, hydroxyl, acetoxy, carboxyl or methoxycarbonyl, and the substituent is one or more;

[0011] R 4 is selected from substituted aryl, substituted heteroaryl or substituted 1,3-benzodioxanyl, wherein the substituent of the heteroaryl or 1,3-benzodioxanyl is selected from hydrogen, halogen, cyano, trifluoromethyl, 2,2-difluoroethyl, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, methoxy, amino, methylamino, dimethylamino, acetylamino, carboxyl, methoxycarbonyl or nitro, and the substituent is one or more;

[0012] A 1 Selected from -NH-, -O-, -S- or -N(CH3)-;

[0013] A 2 Selected from Among them, n 1 and n 2 Each independently selected from 0, 1 or 2;

[0014] R 5 is selected from hydrogen, halogen, methyl, trifluoromethyl, cyano, hydroxy, methoxy, amino, methylamino, dimethylamino, diethylamino or acetamido, R 5 for one or more;

[0015] A 3 Selected from Among them, X 1 represents -O-, -NH- or

[0016] A 4 Selected from Among them, X 2and X 3 are independently selected from N or CH, R 6 , R 7 or R 8 Each is independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxy, methoxy, amino, methylamino, dimethylamino, acetylamino, carboxyl or methoxycarbonyl.

[0017] Preferably, in the structure of the pyridazinone compound:

[0018] m is selected from 0 or 1;

[0019] R 1 is selected from halogen, cyano or trifluoromethyl;

[0020] R 2 or R 3 are independently selected from hydrogen, methyl or trifluoromethyl; when R 2 and R 3 Different from R 2 and R 3 The connected carbon atoms are in racemic, R or S configuration;

[0021] R 4 Selected from Among them, Y 1 or Y 2 are independently selected from CH or N, R 9 , R 10 are independently selected from trifluoromethyl, methyl, fluorine, chlorine, bromine, cyano, methoxy, methanesulfonyl, 2,2-difluoroethyl or 4-trifluoromethylphenyl, R 9 or R 10 for one or more;

[0022] A 1 Selected from -NH-;

[0023] A 2 Selected from

[0024] A 3 Selected from

[0025] A 4 Selected from

[0026] Further preferably, in the structure of the pyridazinone compound:

[0027] m is 0.

[0028] Further preferably, in the structure of the pyridazinone compound:

[0029] R 1 is trifluoromethyl, R2 is hydrogen, R 3 is methyl, and R 3 The attached carbon atoms are in S configuration.

[0030] Further preferably, in the structure of the pyridazinone compound:

[0031] A 2 Selected from A 3 for A 4 for

[0032] Further preferably, in the structure of the pyridazinone compound:

[0033] R 4 Selected from

[0034] More specifically, the pyridazinone compound is any of the following compounds:

[0035]

[0036]

[0037]

[0038]

[0039]

[0040] The pharmaceutically acceptable salt of the above-mentioned pyridazinone compound is a salt formed by the pyridazinone compound and an acid, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.

[0041] As the second aspect of the present invention, the preparation method of the pyridazinone compound is any of the following methods:

[0042] (1) When R 1 is selected from trifluoromethyl, cyano or halogen, R 2 is hydrogen, R 3 is selected from methyl or hydrogen, and R 3 The connected methyl group is in S configuration, or R 2 and R 3 To form a cyclopropyl group, R 4 for A 1 Represents -NH-, A 2 for n 1 or 2 Each independently represents 0 or 1, A 3 for A 4 for The preparation method of the target compound IA is as follows:

[0043]

[0044]

[0045] 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, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably acetonitrile; the acid-binding agent is sodium carbonate, potassium carbonate, triethylamine or N,N-diisopropylethylamine (DIPEA), preferably DIPEA.

[0046] Compound V is prepared from compound IV by dissolving IV in a solvent and adding an acid for reaction. The reaction solvent is dichloromethane, tetrahydrofuran or 1,4-dioxane, preferably dichloromethane; the acid used is an ethyl acetate solution saturated with hydrogen chloride, a 1,4-dioxane solution saturated with hydrogen chloride or trifluoroacetic acid, preferably trifluoroacetic acid.

[0047] Compound VII is prepared from compound V by dissolving V and VI in a solvent and adding an acid-binding agent to carry out a substitution reaction. The reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-dioxane; the acid-binding agent is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA.

[0048] Compound VIII is prepared from compound VII by dissolving VII in a solvent and adding a catalyst for catalytic hydrogenation. The reaction solvent is tetrahydrofuran, methanol, ethanol or a mixed solvent of any two, preferably methanol; the catalyst is palladium hydroxide or palladium carbon, preferably palladium carbon.

[0049] Compound X is prepared from compound VIII by dissolving VIII in a solvent, adding a condensing agent, and then adding a base and compound IX to carry out a condensation reaction to obtain the compound. The solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N'-dimethylformamide; the condensing agent is selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 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 benzotriazole-1-yl-oxytripyrrolidino hexafluorophosphate (PyBop), preferably EDCI; the base is triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate or DIPEA, preferably DIPEA.

[0050] The target compound I-A is prepared from compound X by dissolving X in a solvent and adding an acid for reaction. The solvent is tetrahydrofuran, acetonitrile or dichloromethane, preferably dichloromethane; the acid is hydrochloric acid or trifluoroacetic acid or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.

[0051] (2) When R 1 is selected from trifluoromethyl, cyano or halogen, R 2 is hydrogen, R 3 is selected from methyl or hydrogen, and R 3 The connected methyl group is in S configuration, or R 2 and R 3 To form a cyclopropyl group, R 4 for A 1 -NH-, A 2 for n 1 or 2 are each independently selected from 0 or 1, A 3 for A 4 for The preparation method of the target compound IB is as follows:

[0052]

[0053] Compound XII is prepared from compound VIII by dissolving VIII in a solvent, adding a condensing agent, and then adding a base and compound XI to carry out a condensation reaction to obtain the compound. The solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane or acetonitrile, preferably N,N'-dimethylformamide; the condensing agent is selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 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-oxytripyrrolidino hexafluorophosphate (PyBop), preferably EDCI; the base is triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate or DIPEA, preferably DIPEA.

[0054] The target compound I-B is prepared from compound XII by dissolving XII in a solvent and adding an acid for reaction. The solvent is tetrahydrofuran, acetonitrile or dichloromethane, preferably dichloromethane; the acid is hydrochloric acid or trifluoroacetic acid or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.

[0055] (3) When R 1 represents trifluoromethyl, cyano or halogen, R 2 is hydrogen, R 3 is selected from methyl or hydrogen, and R 3 The connected methyl group is in S configuration, or R 2 and R 3 To form a cyclopropyl group, R 4 for A 1 -NH-, A 2 for A 3 for A 4 for The preparation method of the target compound IC is as follows:

[0056]

[0057] Compound XIV is prepared from compound XIII by dissolving XIII in a solvent, adding a base, and then adding compound III to react. The reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N-dimethylformamide; the base is sodium hydride, sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably sodium hydride.

[0058] Compound XV is prepared from compound XIV by dissolving XIV in a solvent and adding an aqueous solution of a base to hydrolyze the compound. The reaction solvent is tetrahydrofuran, methanol, acetonitrile or a mixed solvent of any two, preferably a mixed solvent of tetrahydrofuran and methanol; the base is sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide.

[0059] Compound XVI is prepared from compound XV by dissolving XV in a solvent, adding a condensing agent, and then adding a base and compound IX to carry out a condensation reaction to obtain the compound. The solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N-dimethylformamide; the condensing agent is selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 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), benzotriazole-1-yl-oxytripyrrolidino hexafluorophosphate (PyBop), preferably EDCI; the base is triethylamine, sodium carbonate, potassium carbonate or DIPEA, preferably DIPEA.

[0060] Compound XVII is prepared from compound XVI by dissolving XVI in a solvent and adding an acid for reaction. The solvent is dichloromethane, tetrahydrofuran or 1,4-dioxane, preferably dichloromethane; the acid is hydrochloric acid, trifluoroacetic acid or sulfuric acid, preferably trifluoroacetic acid.

[0061] Compound XVIII is prepared from compound XVII by dissolving XVII and compound VI in a solvent and adding a base for substitution reaction. The reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-dioxane; the base is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA.

[0062] Compound I-C is prepared from compound XVIII by dissolving XVIII in a solvent and adding an acid for reaction. The solvent is tetrahydrofuran, acetonitrile or dichloromethane, preferably dichloromethane; the acid is hydrochloric acid or trifluoroacetic acid or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.

[0063] (4) When m = 0, R 1 is selected from trifluoromethyl, cyano or halogen, R 2 is hydrogen, R 3 is methyl, R 4 for A 1 -NH-, A 2 for n 1 or 2 are each independently selected from 0 or 1, A 3 for A 4 for The preparation method of the target compound ID is as follows:

[0064]

[0065]

[0066] Compound XXI can be prepared from compound XX by dissolving XX in a solvent, adding a condensing agent, and then adding a base and compound XX to carry out a condensation reaction. The solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N-dimethylformamide; the condensing agent is selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 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), benzotriazole-1-yl-oxytripyrrolidino hexafluorophosphate (PyBop), preferably EDCI; the base is triethylamine, sodium carbonate, potassium carbonate or DIPEA, preferably DIPEA.

[0067] Compound XXII is prepared from compound XXI by dissolving XXI in a solvent and adding an aqueous solution of a base to hydrolyze the compound. The reaction solvent is tetrahydrofuran, methanol, acetonitrile or a mixed solvent of any two, preferably a mixed solvent of tetrahydrofuran and methanol; the base is sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide.

[0068] Compound XXIII is prepared from compound XXII by dissolving XXII in a solvent, adding a condensing agent, and then adding N,O-dimethylhydroxylamine hydrochloride to carry out a condensation reaction to obtain the compound. The solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N-dimethylformamide; the condensing agent is selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 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 hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidino (PyBop), preferably CDI.

[0069] Compound XXIV is prepared from compound XXIII by dissolving XXIII in a solvent and adding methylmagnesium bromide at low temperature to react. The reaction solvent is anhydrous tetrahydrofuran, anhydrous ether, anhydrous dichloromethane or anhydrous dioxane, preferably anhydrous tetrahydrofuran.

[0070] Compound XXV is prepared from compound XXIV by dissolving XXIV in a solvent, adding an ammonia source and a catalyst for reaction. The solvent is methanol, ethanol, tetrahydrofuran or a mixed solvent of any two, preferably methanol, the ammonia source is ammonium formate or ammonium acetate, preferably ammonium formate, and the catalyst is preferably dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer.

[0071] Compound XXVI is prepared from compound XXV by dissolving XXV and compound VI in a solvent and adding a base for substitution reaction. The reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-dioxane; the base is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA.

[0072] The target compound I-D is prepared from compound XXVI by dissolving XXVI in a solvent and adding an acid for reaction. The solvent is tetrahydrofuran, acetonitrile, dichloromethane or a mixed solvent of any two, preferably dichloromethane; the acid is hydrochloric acid or trifluoroacetic acid or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.

[0073] Among them, m, Y 1 , Y 2 , R 7 , R 8 , R 9 , R 10The definition is as described above; Boc is tert-butyloxycarbonyl; P is (trimethylsilyl)ethoxymethyl (SEM) or p-methoxybenzyl (PMB);

[0074] The corresponding acid is reacted with the compound (I) prepared by the above method to form a salt, thereby obtaining a pharmaceutically acceptable salt of the pyridazinone compound.

[0075] As a third aspect of the present invention, the pharmaceutical composition comprises any of the above-mentioned pyridazinone compounds and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier can be added to prepare a common pharmaceutical preparation, such as a tablet, capsule, syrup, suspension or injection, and the preparation can be added with common pharmaceutical excipients such as flavors, sweeteners, liquid / solid fillers, diluents, etc.

[0076] As the fourth aspect of the present invention, the pyridazinone compounds and pharmaceutical compositions thereof can be prepared as PARP7 inhibitor drugs for treating tumors, specifically treating lung squamous cell carcinoma, colon cancer, breast cancer and other cancers.

[0077] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0078] (1) This type of pyridazinone compound has excellent in vivo pharmacokinetic properties, with significantly improved half-life, in vivo exposure and bioavailability, and has significant drug-making advantages;

[0079] (2) This class of pyridazinone compounds has excellent in vivo pharmacodynamic properties, and can achieve better tumor inhibitory activity at a lower dose; and can also promote the release of immune factors, and can achieve significant therapeutic effects when used alone without the need for combined medication;

[0080] (3) This class of pyridazinone compounds can effectively inhibit PARP7 enzyme activity, and the enzyme inhibition IC 50 The optimal value is less than 0.1μM, reaching the nanomolar concentration level; and it has an inhibitory effect on a variety of tumor cells. The tumor cell inhibition IC 50 The optimal value is less than 0.05 μM, reaching the nanomolar concentration level;

[0081] (4) The pyridazinone compounds and pharmaceutical compositions thereof are widely used and can be prepared as anti-tumor drugs; the drugs can exert their efficacy at both the molecular and cellular levels, and in particular have more excellent in vivo pharmacokinetic and pharmacodynamic properties;

[0082] (5) The preparation method of the compound is simple and easy. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] Figure 1 The compound promotes the release of interferon;

[0084] Figure 2 The in vivo antitumor effect of the compound. DETAILED DESCRIPTION

[0085] The technical solution of the present invention is further described below in conjunction with embodiments.

[0086] Example 1: Synthesis of (S)-4-trifluoromethyl-5-((1-(3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)-one (IA-1)

[0087] Synthesis of (S)-1-(2-((tert-Butyloxycarbonyl)amino)propyl)azetidine-3-carboxylic acid benzyl ester (IV-1)

[0088] Benzyl azetidine-3-carboxylate (II-1) (16.0 g, 83.7 mmol) was dissolved in 70 mL of acetonitrile, and (S)-(1-bromopropyl-2-yl)carbamic acid tert-butyl ester (III-1) (21.9 g, 92.0 mmol) and DIPEA (32.4 g, 251.1 mmol) were added, and the temperature was raised to 80 °C for 2 hours. The reaction was monitored by thin layer chromatography (V petroleum ether: V ethyl acetate = 1:1), 200 mL of water was added, and ethyl acetate (100 mL × 3) was used for extraction. 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 = 3:1) to obtain 25.4 g of colorless oil (IV-1), with a yield of 87.0%. ESI-MS [M+H] + 349.2; 1 H NMR(300MHz,DMSO-d6)δ7.40-7.30(m,5H),5.14(s,2H),3.65-3.50(m,3H),3.40- 3.30(m,3H),2.45(dd,J1=6Hz,J2=1.8Hz,2H),1.44(s,9H),1.08(d,J=6.6Hz,3H).

[0089] Synthesis of (S)-1-(2-aminopropyl)azetidine-3-carboxylic acid benzyl ester (V-1)

[0090] Compound IV-1 (6.9 g, 20.0 mmol) was dissolved in 30 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 0.5 hours. The reaction was monitored by thin layer chromatography (V dichloromethane: V methanol = 15:1). The solvent was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane (50 mL × 7), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 4.40 g of a light yellow oil (V-1), with a yield of 88.7%. ESI-MS [M+H] + 249.2.

[0091] Synthesis of (S)-1-(2-((6-oxo-5-trifluoromethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)azetidine-3-carboxylic acid benzyl ester (VII-1)

[0092] Compound V-1 (2.2 g, 9.0 mmol) was dissolved in 10 mL 1,4-dioxane, 5-chloro-4-trifluoromethyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-3(2H)-one (VI-1) (3.3 g, 10.0 mmol) and DIPEA (3.5 g, 27.0 mmol) were added, and the mixture was heated to 90°C for 2 hours. The reaction was monitored by TLC (V petroleum ether: V ethyl acetate = 1:1). 40 mL of water was added, and the mixture was extracted with ethyl acetate (20 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 = 3:1) to obtain 4.1 g of colorless oil (VII-1), with a yield of 83.7%. ESI-MS [M+H] + 541.2; 1 HNMR(300MHz,DMSO-d6)δ7.61(s,1H),7.38-7.32(m,5H),6.15(m,1H),5.37(dd,J1=14.1Hz,J2=9.9Hz,2H),5.14(s,2 H),3.74-3.55(m,5H),3.45-3.35(m,3H),2.72-2.54(m,2H),1.23(d,J=6.6Hz,3H),0.99-0.91(m,2H),-0.01(s,9H).

[0093] Synthesis of (S)-1-(2-((6-oxo-5-trifluoromethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)azetidine-3-carboxylic acid (VIII-1)

[0094] Compound VII-1 (4.0 g, 7.4 mmol) was dissolved in 20 mL of anhydrous methanol, and 500 mg of palladium carbon was added. After the reaction system was replaced with hydrogen, the reaction was allowed to proceed at room temperature for 30 minutes. The reaction was complete as monitored by thin layer chromatography (V dichloromethane: V methanol = 15:1). The filter cake was washed with 10 mL of methanol and dried to obtain 3.2 g of a white solid (VIII-1), with a yield of 96.1%. ESI-MS [M+H] + 451.2; 1 H NMR(300MHz,DMSO-d6)δ11.4(s,1H,-COOH),7.62(s,1H,Ar-H),6.45-6.35(m,1 H,-NH-),5.37(dd,J1=14.1Hz,J2=9.9Hz,2H,-Ar-CH2-O-),3.74-3.55(m,5H,- CH2-CH2-,-CH-),3.45-3.35(m,3H,-CH2-,-CH-),2.72-2.54(m,2H,-CH2-),1. 23(d,J=6.6Hz,3H,-CH3),0.99-0.91(m,2H,-Si-CH2-),-0.01(s,9H,-(CH3)3).

[0095] Synthesis of (S)-4-trifluoromethyl-5-((1-(3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)propan-2-amino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (X-1)

[0096] Compound VIII-1 (480.0 mg, 1.1 mmol) was dissolved in 5 mL of dichloromethane, and 1-hydroxybenzotriazole (HOBt, 180.0 mg, 1.3 mmol) and EDCI (210.0 mg, 1.3 mmol) were added respectively. After reacting at room temperature for 0.5 hours, 2-(piperazine-1-yl)-5-trifluoromethylpyrimidine (IX-1) (280.0 mg, 1.2 mmol) and DIPEA (430.0 mg, 3.3 mmol) were added in sequence. The reaction was continued at room temperature for 1 hour. The reaction was completed by monitoring by thin layer chromatography (V dichloromethane: V methanol = 15:1). 10 mL of water was added, and dichloromethane (5 mL × 3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride aqueous 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 obtain 560.0 mg of a white solid (X-1) with a yield of 76.6%. ESI-MS [M+H] + 665.2; 1H NMR(300MHz,DMSO-d6)δ8.73(s,2H),8.00(s,1H),6.65-6.55(m,1H),5.21(s,2H),4.20-4.00(m,1H),3.83-3.74(m,4H), 3.66-3.45(m,8H),3.28-3.13(m,5H),1.24(t,J=7.2Hz,1H),1.18(d,J=6.3Hz,3H),0.84(t,J=8.1Hz,2H),-0.04(s,9H).

[0097] Synthesis of (S)-4-trifluoromethyl-5-((1-(3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)azetidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)-one (IA-1)

[0098] Compound X-1 (531,2 mg, 0.8 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 hours. The reaction was monitored by thin layer chromatography (V dichloromethane: V methanol = 15:1). The solvent was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8. 10 mL of water was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with a saturated aqueous 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 dichloromethane: V methanol = 40:1) to obtain 332.4 mg of a white solid (IA-1) with a yield of 77.8%. ESI-MS [M+H] + 535.2; 1 H NMR(300MHz,DMSO-d6)δ12.50(s,1H),8.73(s,2H),7.90(s,1H),6.49-6.35(m,1H) ,4.10-3.90(m,1H),3.92-3.72(m,4H),3.62-3.42(m,11H),1.16(d,J=6.3Hz,3H).

[0099] Referring to the preparation method of Example 1, the following compound was prepared:

[0100]

[0101]

[0102] Example 18: Synthesis of 4-trifluoromethyl-5-((((S)-1-((S)-3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl))propan-2-yl)amino)pyridazin-3(2H)-one (IA-18)

[0103] Synthesis of Benzyl 1-((S)-2-((tert-Butyloxycarbonyl)amino)propyl)pyrrolidine-3-carboxylate (IV-2)

[0104] Dissolve pyrrolidine-3-carboxylic acid benzyl ester (II-2) (17.2g, 83.7mmol) in 70mL acetonitrile, add compound III-1 (21.9g, 92.0mmol) and DIPEA (32.4g, 251.1mmol), and heat to 80℃ for 2 hours. Monitor the reaction by thin layer chromatography (V petroleum ether: V ethyl acetate = 1:1), add 200mL water, extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate. The crude product is purified by silica gel column chromatography (V petroleum ether: V ethyl acetate = 3:1) to obtain 25.4g colorless oil (IV-2), with a yield of 83.8%. ESI-MS [M+H] + 363.2.

[0105] Synthesis of Benzyl 1-((S)-2-Aminopropyl)pyrrolidine-3-carboxylate (V-2)

[0106] Compound IV-2 (7.2 g, 19.9 mmol) was dissolved in 30 mL of dichloromethane, and 20 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 0.5 hours. The reaction was monitored by thin layer chromatography (V dichloromethane: V methanol = 15:1). The solvent was evaporated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 7-8. Dichloromethane (50 mL × 5) was added for extraction, and the organic phases were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 4.4 g of a light yellow oil (V-2), with a yield of 84.6%. ESI-MS [M+H] + 263.2.

[0107] Synthesis of 1-((S)-2-((6-oxo-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)pyrrolidine-3-carboxylic acid benzyl ester (VII-3) Compound V-2 (2.4 g, 9.0 mmol) was dissolved in 10 mL 1,4-dioxane, compound VI-1 (3.3 g, 10.0 mmol) and DIPEA (3.5 g, 27.0 mmol) were added, the temperature was raised to 90°C for 2 hours, and the reaction was complete by monitoring by thin layer chromatography (V petroleum ether: V ethyl acetate = 1:1). 40 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride aqueous 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 = 3:1) to obtain 4.2 g of colorless oil (VII-3), with a yield of 84.4%. ESI-MS [M+H] + 555.3.

[0108] Synthesis of 1-((S)-2-((6-oxo-5-trifluoromethyl-1-((2-trimethylsilylethoxy)methyl)-1,6-dihydropyridazin-4-yl)amino)propyl)pyrrolidine-3-carboxylic acid (VIII-3)

[0109] Compound VII-3 (4.1 g, 7.4 mmol) was dissolved in 20 mL of anhydrous methanol, and 500 mg of palladium carbon was added. After the reaction system was replaced with hydrogen, the reaction was allowed to proceed at room temperature for 30 minutes. The reaction was complete as monitored by thin layer chromatography (V dichloromethane: V methanol = 15:1). The filter cake was washed with 10 mL of methanol and dried to obtain 3.2 g of a white solid (VIII-3), with a yield of 93.3%. ESI-MS [M+H] + 465.2.

[0110] Synthesis of 4-trifluoromethyl-5-((2S)-1-(3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)-2-((2-trimethylsilylethoxy)methyl)pyridazin-3(2H)-one (X-18)

[0111] Compound VIII-3 (139.2 mg, 0.3 mmol) and compound IX-1 (70.0 mg, 0.3 mmol) were used as raw materials, and the preparation process was similar to compound X-1 to obtain 129.0 mg of a white solid (X-18), with a yield of 63.5%. ESI-MS: [M+H] + 679.3.

[0112] Synthesis of 4-trifluoromethyl-5-((((S)-1-((S)-3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)pyrrolidin-1-yl))propan-2-yl)amino)pyridazin-3(2H)-one (IA-18)

[0113] Compound X-18 (88.0 mg, 0.13 mmol) was used as the raw material, and the preparation process was similar to compound IA-1 to obtain 50.0 mg of a white solid (IA-18) with a yield of 70.4%. ESI-MS [M+H] + 549.2; 1 H NMR (300MHz, DMSO-d6) δ12.32(s,1H),8.71(s,2H),7.53(s,1H),6.19(t,J=1.8Hz,1H),4.50-4.40(m,1 H), 4.10-4.05 (m, 2H), 3.81-3.70 (m, 4H), 3.67-3.60 (m, 4H), 1.92-1.22 (m, 11H), 1.22 (d, J = 6.3Hz, 3H).

[0114] Referring to the preparation method of Example 18, the following compound was prepared:

[0115]

[0116] Example 25: Synthesis of (S)-5-((1-(3-(4-(2,2-difluorobenzo[d][1,3]dioxin-5-yl)piperazine-1-carbonyl)azetidin-1-yl)propan-2-yl)amino)-4-trifluoromethylpyridazin-3(2H)-one (IB-1)

[0117] Compound X-25 (113.0 mg, 0.17 mmol) was used as the raw material, and the preparation process was similar to compound IA-1 to obtain 80.0 mg of a white solid (IB-1) with a yield of 86.5%. ESI-MS [M+H] + 545.2; 1H NMR (400MHz, DMSO-d6) δ12.46(s,1H),7.89(s,1H),7.22(d,J=8.8Hz,1H),7.09(d,J=2.4Hz,1H),6.70(dd,J1=8.8Hz,J2=2.4Hz,1H),6.45-6.35( m,1H),4.00-3.90(m,1H),3.65-3.45(m,4H),3.45-3.35(m,3H),3.26-3 .18(m,2H),3.10-3.00(m,4H),2.65-2.54(m,2H),1.12(d,J=6.3Hz,3H).

[0118] Example 26: Synthesis of (S)-4-trifluoromethyl-5-((1-(3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrrol-1-yl)propan-2-yl)amino)pyridazin-3(2H)-one (IC-1)

[0119] Synthesis of (S)-1-(2-(tert-Butyloxycarbonylamino)propyl)-1H-pyrrole-3-carboxylic acid methyl ester (XIV-1)

[0120] 1H-pyrrole-3-carboxylic acid methyl ester (XIII-1) (1.3g, 10.3mmol) was dissolved in 5mL of anhydrous DMF, sodium hydride (0.8g, 20.0mmol) was added under ice bath, after addition, the mixture was heated to room temperature and stirred for 1 hour, then compound III-1 (3.6g, 15.0mmol) was added under ice bath, after addition, the mixture was heated to 50°C and reacted for 6 hours. The reaction was monitored to be complete by thin layer chromatography (V petroleum ether: V acetone = 8:1). 10mL of ice water was added to quench the reaction, and ethyl acetate (20mL×3) was used for extraction. 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 column chromatography (V petroleum ether: V acetone = 11:1) to obtain 2.4g of white solid (XIV-1), with a yield of 82.8%. ESI-MS [M+H] + 283.1; 1 H NMR (300MHz, CDCl3) δ7.23 (t, J = 2.1 Hz, 1H), 6.55 (d, J = 2.1 Hz, 2H), 4.49 (d, J = 6.9 Hz, 1H), 3.92 (m, 2H), 3.77 (s, 3H), 1.41 (s, 9H), 1.07 (d, J = 6.9 Hz, 3H).

[0121] Synthesis of (S)-1-(2-(tert-Butyloxycarbonylamino)propyl)-1H-pyrrole-3-carboxylic acid (XV-1)

[0122] Compound XIV-1 (2.4 g, 8.5 mmol) was dissolved in 20 mL of a mixed solvent of tetrahydrofuran and methanol (V tetrahydrofuran: V methanol = 1:1), and then a solution obtained by dissolving lithium hydroxide monohydrate (1.8 g, 42.5 mmol) in 4 mL of water was added to the above reaction solution, and the temperature was raised to 60°C for 12 hours. The reaction was complete as monitored by thin layer chromatography (V petroleum ether: V ethyl acetate = 4:1), 20 mL of water was added, and ethyl acetate (20 mL × 2) was used for extraction. The aqueous phase was collected, and the pH was adjusted to 5-6 with 2 mol / L dilute hydrochloric acid, and ethyl acetate (20 mL × 3) was used for extraction. The organic phases were combined, washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 1.9 g of a white solid (XV-1) with a yield of 83.4%. ESI-MS [M+H] + 269.1; 1 H NMR (300MHz, DMSO-d6) δ11.65(s,1H),7.30(t,J=2.1Hz,1H),6.86(d,J=10.8Hz,1H),6.71(t ,J=2.4Hz,1H),6.32(t,J=2.1Hz,1H),3.96-3.66(m,3H),1.33(s,9H),0.98(d,J=6.6Hz,3H).

[0123] Synthesis of tert-butyl (S)-(1-(3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrrol-1-yl)propan-2-yl)carbamate (XVI-1)

[0124] Compound XV-1 (1.0 g, 3.9 mmol) was dissolved in 6 mL of dichloromethane, HATU (1.6 g, 4.3 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Compound IX-1 (1.0 g, 4.3 mmol) and DIPEA (1.0 g, 7.80 mmol) were then added in sequence, and the mixture was reacted at room temperature for 30 minutes. The reaction was monitored by thin layer chromatography (V petroleum ether: V ethyl acetate = 1:1), 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. 1.4 g of white solid (XVI-1) was obtained by column chromatography (V petroleum ether: V ethyl acetate = 3:1), and the yield was 74.5%. ESI-MS [M+H] + 483.2; 1H NMR (300MHz, DMSO-d6) δ8.71(s,2H),7.14(t,J=2.1Hz,1H),6.90(d,J=10.8Hz,1H),6.73(t, J=2.4Hz,1H),6.25(t,J=2.1Hz,1H),3.94-3.66(m,11H),1.33(s,9H),0.98(d,J=6.6Hz,3H).

[0125] Synthesis of (S)-(1-(3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrrol-1-yl)propan-2-yl)amino (XVII-1)

[0126] Compound XVI-1 (1.4 g, 2.9 mmol) was dissolved in 5 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 15 minutes. The reaction was completed by monitoring with thin layer chromatography (V dichloromethane: V methanol = 5:1). The solvent was evaporated under reduced pressure, and a saturated sodium bicarbonate solution was added to adjust the pH of the system to 7-8. The mixture was extracted with dichloromethane (20 mL × 5). The organic phases were combined, washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 0.9 g of a light yellow solid (XVII-1) with a yield of 90.9%. ESI-MS [M+H] + 383.2; 1 H NMR (300MHz, DMSO-d6) δ8.74(s,2H),7.21(t,J=2.1Hz,1H),6.81(t,J=2.4Hz,1H),6.27(t,J=2.1Hz,1H),3.94-3.66(m,11H),0.98(d,J=6.6Hz,3H).

[0127] Synthesis of (S)-4-trifluoromethyl-5-((1-(3-(4-(5-trifluoromethyl)pyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrrol-1-yl)propan-2-yl)amino)-2-((2-trimethylsilylethoxy)methyl)pyridazin-3(2H)-one (XVIII-1)

[0128] Compound VI-1 (1.0 g, 3.2 mmol) was dissolved in 6 mL 1,4-dioxane, compound XVII-1 (1.1 g, 2.9 mmol) and DIPEA (1.1 g, 8.6 mmol) were added, the temperature was raised to 90 °C for 2 hours, and the reaction was monitored by thin layer chromatography (V petroleum ether: V ethyl acetate = 1:1) until the reaction was complete. 20 mL of water was added, and ethyl acetate (10 mL × 3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V petroleum ether: V ethyl acetate = 3:1) to obtain 1.5 g of a white solid (XVIII-1), with a yield of 69.4%. ESI-MS [M+H] + 675.2; 1 H NMR (300MHz, DMSO-d6) δ8.74(s,2H),7.63(s,1H),7.14(t,J=2.1Hz,1H),6.75(t,J= 2.7Hz,1H),6.73-6.66(m,1H),6.21-6.17(m,1H),5.18-5.10(m,2H),4.50-4.40(m, 1H),4.10-4.05(m,2H),3.88-3.80(m,4H),3.67-3.60(m,4H),3.53(t,J=8.1Hz,2H) ,1.24(d,J=6.3Hz,3H),1.18(t,J=7.2Hz,1H),0.81(t,J=8.1Hz,2H),-0.06(s,9H).

[0129] (S)-4-Trifluoromethyl-5-((1-(3-(4-(5-trifluoromethylpyrimidin-2-yl)piperazine-1-carbonyl)-1H-pyrrol-1-yl)propan-2-yl)amino)pyridazin-3(2H)-one (IC-1)

[0130] Compound XVIII-1 (674.0 mg, 1.0 mmol) was dissolved in 5 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 3 hours. The reaction was completed by TLC monitoring (V petroleum ether: V ethyl acetate = 1:4). The solvent was evaporated under reduced pressure, saturated sodium bicarbonate solution was added to adjust the pH to 7-8, 10 mL of water was added, and dichloromethane (10 mL × 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated and purified by column chromatography (V petroleum ether: V ethyl acetate = 1:1) to obtain 350.0 mg of a white solid (IC-1), with a yield of 64.3%. ESI-MS [M+H] + 544.2; 1H NMR (300MHz, DMSO-d6) δ12.37(s,1H),8.73(s,2H),7.90(s,1H),7.14(t,J=1.5Hz,1H),6.74(t,J=2.4Hz,1H),6.54-6.45(m,1 H),6.19(t,J=1.8Hz,1H),4.50-4.40(m,1H),4.10-4.05(m,2H),3.88-3.80(m,4H),3.67-3.60(m,4H),1.22(d,J=6.3Hz,3H).

[0131] Example 27: Synthesis of 4-trifluoromethyl-5-((1-(1-(1-(5-trifluoromethylpyrimidin-2-yl)piperidine-4-carbonyl)azetidin-3-yl)propan-2-yl)amino)pyridazin-3(2H)-one (ID-1)

[0132] Synthesis of methyl 2-(1-(1-(5-trifluoromethylpyrimidin-2-yl)piperidine-4-carbonyl)azetidin-3-yl)acetate (XXI-1)

[0133] 1-(5-trifluoromethylpyrimidin-2-yl)piperidine-4-carboxylic acid (XIX-1) (1.1 g, 4.0 mmol) was dissolved in 5 mL of dichloromethane, HATU (1.7 g, 4.4 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Methyl 2-(azetidin-3-yl)acetate (XX-1) (0.5 g, 4.0 mmol) and DIPEA (1.0 g, 8.0 mmol) were added. After addition, the mixture was reacted at room temperature for 30 minutes. The reaction was completed by TLC monitoring (V petroleum ether: V ethyl acetate = 3:1). 10 mL of water was added, and the mixture was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V petroleum ether: V ethyl acetate = 1:1) to obtain 1.5 g of a white solid (XXI-1) with a yield of 97.1%. ESI-MS [M+H] + 387.2; 1 HNMR (300MHz, CDCl3) δ8.45 (s, 2H), 4.82 (dt, J1 = 13.5Hz, J2 = 3.9Hz, 2H), 4.38 (t, J = 8.4Hz, 1H), 4.16 (t, J = 9.6Hz, 1H),3.95-3.87(m,1H),3.69(s,3H),3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70(m,4H).

[0134] Synthesis of 2-(1-(1-(5-trifluoromethylpyrimidin-2-yl)piperidine-4-carbonyl)azetidin-3-yl)acetic acid (XXII-1)

[0135] Compound XXI-1 (1.5 g, 3.8 mmol) was dissolved in 5 mL of tetrahydrofuran, and 5 mL of methanol was added, followed by 2 mL of 5 mol / L sodium hydroxide aqueous solution. After addition, the mixture was reacted at room temperature for 1 hour. The reaction was complete after monitoring by thin layer chromatography (V petroleum ether: V ethyl acetate = 1:1). 20 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The pH of the aqueous layer was adjusted to 4 with dilute hydrochloric acid, and a white solid was precipitated. The filter cake was washed with 5 mL of water, and the filter cake was collected and dried under vacuum to obtain 1.2 g of a white solid (XXII-1), with a yield of 83.5%. ESI-MS [M+H] + 373.2; 1 HNMR(300MHz, CDCl3)δ8.45(s,2H),4.82(dt,J1=13.5Hz,J2=3.9Hz,2H),4.38(t,J=8.4Hz,1H),4.16(t,J= 9.6Hz,1H),3.95-3.87(m,1H),3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70(m,4H).

[0136] Synthesis of N-methoxy-N-methyl-2-(1-(1-(5-trifluoromethylpyrimidin-2-yl)piperidine-4-carbonyl)azetidin-3-yl)acetamide (XXIII-1)

[0137] Compound XXII-1 (1.5 g, 4.0 mmol) was dissolved in 6 mL of dichloromethane, and CDI (1.0 g, 6.0 mmol) and dimethylhydroxylamine hydrochloride (1.2 g, 12.0 mmol) were added in sequence. After addition, the mixture was reacted at room temperature for 1 hour. The reaction was complete after monitoring by thin layer chromatography (V dichloromethane: V methanol = 15:1). 10 mL of water was added, and dichloromethane (8 mL × 3) was extracted. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V petroleum ether: V ethyl acetate = 1:1) to obtain 1.2 g of a white solid (XXIII-1), with a yield of 69.9%. ESI-MS [M+H] + 416.2; 1HNMR(300MHz, CDCl3)δ8.45(s,2H),4.82(dt,J1=13.5Hz,J2=3.9Hz,2H),4.38(t,J=8.4Hz,1H),4.16(t,J=9.6Hz,1H),3 .95-3.87(m,1H),3.69(s,3H),3.06-2.95(m,3H),2.72(s,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70(m,4H).

[0138] Synthesis of 1-(1-(1-(5-trifluoromethylpyrimidin-2-yl)piperidine-4-carbonyl)azetidin-3-yl)propan-2-one (XXIV-1)

[0139] Compound XXIII-1 (0.8 g, 2.0 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, and methylmagnesium bromide (1 mol / L, 4.0 mL) was added at -15 °C. After addition, the mixture was kept warm for 4 hours. The reaction was complete under TLC monitoring (V dichloromethane: V methanol = 15:1). 10 mL of water was added to quench the reaction, and the mixture was stirred at room temperature for 15 minutes. The mixture was extracted with ethyl acetate (8 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V petroleum ether: V ethyl acetate = 1:1) to obtain 450.0 mg of a white solid (XXIV-1) with a yield of 60.8%. ESI-MS [M+H] + 371.2; 1 HNMR (300MHz, CDCl3) δ8.45 (s, 2H), 4.82 (dt, J1 = 13.5Hz, J2 = 3.9Hz, 2H), 4.38 (t, J = 8.4Hz, 1H), 4.16 (t, J = 9.6Hz, 1H),3.95-3.87(m,1H),3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),2.20(s,3H),1.80-1.70(m,4H).

[0140] Synthesis of (3-(2-aminopropyl)azetidin-1-yl)(1-(5-trifluoromethylpyrimidin-2-yl)piperidin-4-yl)methanone (XXV-1)

[0141] Compound XXIV-1 (0.5 g, 1.4 mmol) was dissolved in 5 mL of methanol, and ammonium formate (0.4 g, 7.0 mmol) and dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer (43.0 mg, 0.07 mmol) were added in sequence. After addition, the temperature was raised to 70°C for reaction for 3 hours. The reaction was complete under thin layer chromatography monitoring (V dichloromethane: V methanol = 10:1). The mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, 2 mol / L hydrochloric acid was added to adjust the pH to 1-2, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate (5 mL × 2), the aqueous layer was adjusted to pH 8-9 with 5 mol / L sodium hydroxide aqueous solution, and extracted again with ethyl acetate (10 mL × 5), the organic layers were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V dichloromethane: V methanol = 10:1) to obtain 370.0 mg of a white solid (XXV-1) with a yield of 71.3%. ESI-MS [M+H] + 372.2; 1 HNMR(300MHz, DMSO-d6)δ8.70(s,2H),4.72(dt,J1=13.5Hz,J2=3.9Hz,2H),4.34(t,J=8.4Hz,1H),4.01-3.91(m,5H), 3.55-3.45(m,1H),3.15-2.95(m,3H),2.78-2.68(m,1H),1.80-1.65(m,3H),1.51-1.36(m,2H),1.11(d,J=6.3Hz,3H).

[0142] Synthesis of 4-trifluoromethyl-5-((1-(1-(1-(5-trifluoromethylpyrimidin-2-yl)piperidin-4-carbonyl)azetidin-3-yl)propan-2-amino)-2-((2-trimethylsilylethoxy)methyl)pyridazin-3(2H)-one (XXVI-1)

[0143] Compound XXV-1 (372.0 mg, 1.0 mmol) was dissolved in 4 mL of 1,4-dioxane, compound VI-1 (350.0 mg, 1.1 mmol) was added, and then DIPEA (388.0 mg, 3.0 mmol) was added. After addition, the temperature was raised to 90°C for reaction for 3 hours. TLC monitoring (V dichloromethane: V methanol = 15:1) showed that the reaction was complete. Cooled to room temperature, 10 mL of water was added, and extracted with ethyl acetate (8 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V dichloromethane: V methanol = 70:1) to obtain 370.0 mg of a white solid (XXVI-1), with a yield of 56.7%. ESI-MS [M+H] + 654.3;1 H NMR(300MHz,DMSO-d6)δ8.73(s,2H),8.00(s,1H),6.59(s,1H),5.21(s,2H),4.00(m,1H),3.83-3.74(m,4H),3.66- 3.45(m,9H),3.28-3.13(m,5H),1.24(t,J=7.2Hz,1H),1.18(d,J=6.3Hz,3H),0.81(t,J=8.1Hz,2H),-0.06(s,9H).

[0144] Synthesis of 4-trifluoromethyl-5-((1-(1-(1-(5-trifluoromethylpyrimidin-2-yl)piperidin-4-carbonyl)azetidin-3-yl)propan-2-yl)amino)pyridazin-3(2H)-one (ID-1)

[0145] Compound XXVI-1 (327.0 mg, 0.5 mmol) was dissolved in 3 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 3 hours. The reaction was complete after monitoring by thin layer chromatography (V dichloromethane: V methanol = 15:1). The solvent was evaporated under reduced pressure, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7-8, 10 mL of water was added, and dichloromethane (10 mL × 3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (V petroleum ether: V ethyl acetate = 1:1) to obtain 230.0 mg of a white solid (ID-1), with a yield of 86.1%. ESI-MS [M+H] + 534.2; 1 H NMR(400MHz,DMSO-d6)δ12.48(s,1H),8.67(s,2H),7.92(s,1H),6.43-6.3 5(m,1H),4.70-4.60(m,2H),4.30-4.20(m,1H),4.05-3.95(m,1H),3.90-3 .82(m,1H),3.55-3.46(m,1H),3.10-3.00(m,2H),2.66-2.53(m,2H),2.03 -1.95(m,1H),1.82-1.65(m,3H),1.50-1.35(m,2H),1.17(d,J=6.3Hz,3H).

[0146] Example 28: Enzyme Inhibitory Activity of Compounds on PARP7

[0147] Experimental materials: PARP7 Chemiluminescent Assay Kit, BPS Bioscience; DMSO, Sinopharm, Nivo, PerkinElmer.

[0148] Experimental methods:

[0149] (1) Preparation of solutions and buffer solutions:

[0150] Preparation of 10X PBS: Weigh 720 mg KH2PO4, 45 g NaCl and 5.311 g Na2HPO4·12H2O respectively and dissolve them in 500 mL deionized water. Adjust the pH of the system to 7.4, sterilize at 121°C for 30 minutes, and place at 4°C for use after cooling.

[0151] Preparation of 1X PBS: Dilute 10X PBS 10 times with deionized water, that is, add 1 part 10X PBS to 9 parts deionized water.

[0152] Wash buffer preparation: 1X PBS containing 0.05% Tween-20.

[0153] Preparation of 1X PARP buffer: (Prepare immediately before use) Dilute 10X PARP buffer 10-fold with deionized water and place on ice for later use.

[0154] (2) Preparation of compound working solution concentration:

[0155] According to the detection requirements, the compound to be tested was diluted to the required concentration with 100% DMSO, and then diluted 10 times with 1X PARP buffer to prepare a 10X compound working solution.

[0156] (3) Experimental steps:

[0157] a. Thaw 5X histone mixture on ice one day before the experiment;

[0158] b. 1X histone mixture preparation: 1X histone mixture was prepared from 5X histone mixture using 1X PBS; 25 μL of 1X histone mixture was added to each well of the test plate and incubated overnight at 4°C;

[0159] c. Add 100 μL of Blocking buffer to each well of the test plate and incubate at 25°C for 90 minutes;

[0160] d. After the incubation, dry the liquid in the test plate and repeat the plate washing 3 times;

[0161] e. Take 2.5 μL of compound working solution from each well and add it to the test plate according to the experimental layout diagram; add the corresponding volume of 1X PARP buffer containing 10% DMSO to the positive control well (Positive control), and add the corresponding volume of 1X PARP buffer to the blank control (Blank);

[0162] f. After the enzyme is completely dissolved, dilute the enzyme stock solution to 6 ng / μL with 1X PARP buffer;

[0163] g. Take 10 μL of enzyme solution per well and add it to the test wells. Add the corresponding volume of 1X PARP buffer to the blank control wells. At this time, the enzyme amount is 60 ng per well. Note: This step needs to be performed on ice;

[0164] h. Add 12.5 μL of master mixture (12.5 μL of 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;

[0165] i. After the incubation, dry the liquid in the test plate and repeat the wash 3 times;

[0166] j. Dilute the Streptavidin-HRP in the kit 50 times with the Blocking buffer solution, add 25 μL to each well of the test plate, and incubate at 25°C for 30 minutes;

[0167] k. After the incubation is completed, the liquid in the test plate is dried and the plate is washed 3 times;

[0168] 1. Mix ELISA ECL Substrate A and ELISA ECL Substrate B in the kit in a 1:1 ratio, 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);

[0169] m. Enzyme rate calculation: % Enzyme Activity = (RLU (Sample) - RLU (Blank)) / (RLU (Pos.Ctrl) - RLU (Blank)) × 100%; Enzyme inhibition rate = 1-% Enzyme Activity. The specific results are shown in Table 1 below.

[0170] Table 1. Data on the inhibitory activity of the tested compounds on PARP7

[0171]

[0172] Note: “+++” means IC 50 <0.1μM; “++” is IC 50 ≥0.1μM and <0.5μM; “+” is IC 50 ≥0.5μM.

[0173] As shown in Table 1, all the tested compounds of the present invention showed good enzyme inhibition activity against PARP7, and the enzyme inhibition IC 50 The values ​​all reached the nanomolar concentration level. Among them, the enzyme inhibition IC values ​​of Examples 1, 3-7, 9-10, 13, 15-17, 20 and 25-27 were 50 The values ​​were all less than 0.1 μM.

[0174] Example 29: Antiproliferative activity of compounds against tumor cells

[0175] Experimental process:

[0176] a. A group of cancer cell lines cultured to the logarithmic growth phase are plated into a 96-well plate at a pre-specified density in a medium containing fetal bovine serum;

[0177] b. Cells were treated with compound or vehicle (DMSO) 24 hours later, and day 0 plates were harvested for analysis;

[0178] c. After application, the 96-well plate was placed in a 37°C, 4.5% CO2 constant temperature incubator, and 20 μL of 1.0% MTT thiazole blue solution was added to each well after 6 days;

[0179] d. Continue to place in a constant temperature incubator. After 4 hours, remove the supernatant culture medium by aspiration, add 150 μL DMSO to each well, and place on a decolorizing shaker to mix until the crystals dissolve;

[0180] e. Measure the absorbance at 570 nm using a multifunctional microplate reader and calculate the IC according to the modified Koch method 50 Value: lgIC 50 =Xm-I[P-(3-Pm-Pn) / 4]. The specific results are shown in Table 2 below.

[0181] Table 2. Antiproliferative activity data of the tested compounds on tumor cells

[0182] Cell lines <![CDATA[Example 1 (IC 50 )]]> <![CDATA[Example 26 (IC 50 )]]> NCI-H1373 +++ +++ HCC-827 ++ ++ SW-1990 + ++ SH-SY5Y ++ + CFPAC-1 ++ +++

[0183] Note: “+++” means IC 50 <0.05μM; “++” is IC 50≥0.05μM and <0.5μM; “+” is IC 50 ≥0.5μM).

[0184] The above data show that Example 1 (IA-1) and Example 26 (IC-1) of the present invention have good inhibitory effects on the proliferation of various tumor cells.

[0185] Example 30: Effect of Compounds on Promoting the Release of Interferon

[0186] In the presence of the STING agonist DMXAA, RAW264.7 cells were induced to interferon-β levels by PARP7 inhibitors. RAW264.7 cells grown to the logarithmic growth phase were plated in 96-well plates and incubated overnight at 37°C in a 5% CO2 incubator until adherence. The cells were co-treated with dose-titrated PARP7 inhibitors and 50 μg / mL DMXAA for 24 hours and the supernatant was collected and processed by ELISA (R&D, Mouse IFN--beta DuoSet Elisa) according to the kit instructions. The results are shown in Figure 1 .

[0187] Depend on Figure 1 It can be seen that the compound of the present invention can significantly promote the release of interferon β, and thus can be used for tumor immunotherapy, and the release amount is better than that of the positive drug RBN-2397.

[0188] Example 31: Pharmacokinetic study of the compound in rats

[0189] Experimental process: Six male SD rats were selected, three of which were orally administered (10 mg / kg) and three were intravenously injected (1 mg / kg). Blood samples were collected at 0 minutes, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, and 8 hours, respectively. The samples were centrifuged (3000 rpm / 5 minutes) and the supernatant was collected for analysis using LC-MS-MS. The results were analyzed using winnonlin software. The specific results are shown in Table 3 below.

[0190] Table 3. Pharmacokinetic data of the test compounds in SD rats

[0191]

[0192] IV: Intravenous injection, PO: Oral administration

[0193] The experimental results show that the compound of Example 1 (IA-1) of the present invention has good pharmacokinetic properties in SD rats. Compared with the positive drug RBN-2397, the compound of the present invention has a longer half-life, a larger in vivo exposure, and a better oral bioavailability.

[0194] Example 32: In vivo efficacy study of the compound in mice

[0195] BALB / c mice were inoculated subcutaneously with CT26 cells in the right flank to develop tumors. Four days after tumor inoculation, tumors with a size of 55-75 mm were selected. 3 (Average tumor size 63mm 3 ) and were randomly divided into 4 groups of 6 mice based on their tumor volume. Dosing began on the second day after randomization (the day of randomization was defined as day 0), and the vehicle (0.5% methylcellulose + 0.2% Tween 80), compound RBN-2397 (500 mg / kg, once a day, intragastric administration for 14 consecutive days), compound IA-1 (100 mg / kg, once a day, intragastric administration for 14 consecutive days), and compound IA-1 (50 mg / kg, twice a day, intragastric administration for 14 consecutive days) were used for administration. The tumor size was measured three times a week during the dosing period. The entire study was terminated on the 14th day, and its efficacy results are shown in Figure 2 .

[0196] Depend on Figure 2 It can be seen that the compound IA-1 of the present invention has obvious anti-tumor activity in mice. Compared with the positive drug RBN-2397, the compound IA-1 of the present invention can exert a better anti-tumor effect at a lower dose.

Claims

1. A pyridazinone compound, characterized in that Having the structure of formula (I), or a pharmaceutically acceptable salt thereof: in: m is selected from 0, 1, 2 or 3; R 1 Selected from hydrogen, halogen, cyano, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, methylthio, methylsulfonyl, carbamoyl; R 2 or R 3 are independently selected from hydrogen, C1-C6 alkyl, substituted C3-C6 cycloalkyl, cyano, trifluoromethyl, or R 2 and R 3 Together with the connected carbon atom, it forms a C3-C6 cycloalkyl group; the substituent of the substituted C3-C6 cycloalkyl group is selected from hydrogen, methyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetylamino, hydroxyl, acetoxy, carboxyl or methoxycarbonyl, and the substituent is one or more; R 4 Selected from Among them, Y 1 or Y 2 are independently selected from CH or N, R 9 , R 10 are independently selected from trifluoromethyl, methyl, fluorine, chlorine, bromine, cyano, methoxy, methanesulfonyl, 2,2-difluoroethyl or 4-trifluoromethylphenyl, R 9 or R 10 for one or more; A 1 Selected from -NH- or -N(CH3)-; A 2 Selected from Among them, n 1 and n 2 Each independently selected from 0, 1 or 2; R 5 is selected from hydrogen, halogen, methyl, trifluoromethyl, cyano, hydroxy, methoxy, amino, methylamino, dimethylamino, diethylamino or acetamido, R 5 for one or more; A 3 Selected from Among them, X 1 represents -O-, -NH- or A 4 Selected from Among them, X 2 and X 3 are independently selected from N or CH, R 6 , R 7 or R 8 Each is independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxy, methoxy, amino, methylamino, dimethylamino, acetylamino, carboxyl or methoxycarbonyl.

2. The pyridazinone compound according to claim 1, characterized in that In the structure: m is selected from 0 or 1; R 1 is selected from halogen, cyano or trifluoromethyl; R 2 or R 3 are independently selected from hydrogen, methyl or trifluoromethyl; when R 2 and R 3 Different from R 2 and R 3 The connected carbon atoms are in racemic, R or S configuration; A 1 Selected from -NH-; A 2 Selected from A 3 Selected from A 4 Selected from 3. The pyridazinone compound according to claim 1 or 2, characterized in that In the structure: m is 0.

4. The pyridazinone compound according to claim 1 or 2, characterized in that In the structure: R 1 is trifluoromethyl, R 2 is hydrogen, R 3 is methyl, and R 3 The attached carbon atoms are in S configuration.

5. The pyridazinone compound according to claim 1 or 2, characterized in that In the structure: A 2 Selected from A 3 for A 4 for 6. The pyridazinone compound according to claim 1 or 2, characterized in that In the structure: R 4 Selected from 7. The pyridazinone compound according to claim 1 or 2, characterized in that The pyridazinone compound is any of the following compounds:

8. The pyridazinone compound according to claim 1 or 2, characterized in that The pharmaceutically acceptable salt is a salt of the pyridazinone compound and an acid, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.

9. A method for preparing the pyridazinone compound according to any one of claims 1 to 8, characterized in that: The preparation method is any of the following methods: (1) When R 1 is selected from trifluoromethyl, cyano or halogen, R 2 is hydrogen, R 3 is selected from methyl or hydrogen, and R 3 The connected methyl group is in S configuration, or R 2 and R 3 To form a cyclopropyl group, R 4 for A 1 Represents -NH-, A 2 for n 1 or 2 Each independently represents 0 or 1, A 3 for A 4 for The preparation method of the target compound IA is as follows: (2) When R 1 is selected from trifluoromethyl, cyano or halogen, R 2 is hydrogen, R 3 is selected from methyl or hydrogen, and R 3 The connected methyl group is in S configuration, or R 2 and R 3 To form a cyclopropyl group, R 4 for A 1 -NH-, A 2 for n 1 or 2 are each independently selected from 0 or 1, A 3 for A 4 for The preparation method of the target compound IB is as follows: (3) When R 1 represents trifluoromethyl, cyano or halogen, R 2 is hydrogen, R 3 is selected from methyl or hydrogen, and R 3 The connected methyl group is in S configuration, or R 2 and R 3 To form a cyclopropyl group, R 4 for A 1 -NH-, A 2 for A 3 for A 4 for The preparation method of the target compound IC is as follows: (4) When m = 0, R 1 is selected from trifluoromethyl, cyano or halogen, R 2 is hydrogen, R 3 is methyl, R 4 for A 1 -NH-, A 2 for n 1 or 2 are each independently selected from 0 or 1, A 3 for A 4 for The preparation method of the target compound ID is as follows: Among them, m, Y 1 , Y 2 , R 7 , R 8 , R 9 , R 10 The definition is as described in any one of claims 1 to 7; Boc is tert-butyloxycarbonyl; P is (trimethylsilyl)ethoxymethyl or p-methoxybenzyl; The corresponding acid is reacted with the compound prepared by the above method to form a salt, thereby obtaining a pharmaceutically acceptable salt of the pyridazinone compound.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the pyridazinone compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

11. Use of the pyridazinone compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 10 in the preparation of PARP7 inhibitor drugs.

12. The use according to claim 11, characterized in that: The drug is an anti-tumor drug.

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