Piperazine derivatives and their use in medicine

Abstract

The present application relates to piperazine compounds and compositions thereof and uses thereof in the preparation of anti-tumor drugs. The piperazine compounds of the present application can selectively inhibit PARP7, thereby treating cancer.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a piperazine derivative or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof and its medical use. BACKGROUND

[0002] ADP-ribosylation is a post-translational modification process of proteins, which involves the insertion of single or multiple ADP-ribose groups into amino acid residues of proteins. ADP-ribosylation is a reversible process, which is involved in physiological regulation of cell signal transduction, DNA damage repair, transcription, gene expression regulation and apoptosis. ADP-ribose is derived from the redox cofactor: Nicotinamide adenine dinucleotide (NAD+), and the enzyme mediating the insertion of ADP-ribose modification is ADP-ribosylation enzyme. In this physiological reaction regulation, the N-glycosidic bond of NAD+ connecting ADP-ribose molecule and nicotinamide group is cleaved, and then it is captured into a bond with the corresponding amino acid residues of the target protein. ADP-ribosylation enzymes can carry out two types of modification: mono-ADP-ribosylation and poly-ADP-ribosylation. When DNA is damaged or cells are under stress, PARP is activated, leading to an increase in the amount of poly-ADP-ribose and a decrease in the amount of NAD+. For more than a decade, it has been believed that PARP1 is the only poly-ADP-ribose polymerase in mammalian cells, and therefore the most studied enzyme. To date, scientists have identified 17 different PARPs. MonoPARPs account for the majority of the PARP family and mediate important biological functions and various stress responses, such as: unfolded protein response, NF-κB signaling, antiviral response and cytokine signaling.

[0003] 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (PARP-7) is one of the members of the MonoPARP family, whose expression is regulated by TCDD-activated aryl hydrocarbon receptor (AHR), which is a ligand-activated transcription factor that mediates the toxic activity of many environmental xenobiotics. AHR upregulates the expression of PARP-7, which inhibits the activity of TBK1 by interacting with it and ADP-ribosylating it, leading to downregulation of IFN-I (type I interferon) response, and thus to inhibition of the body's antiviral and tumor immune response. Therefore, selective inhibition of PARP7 can regulate the body's antiviral and tumor immune response. SUMMARY

[0004] One or more embodiments of the present application provide a selective PARP7 inhibitor or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, and a medical use thereof, for example, an anticancer use.

[0005] One or more embodiments of the present application provide a compound, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof:

[0006]

[0007] A compound according to the present application, or a pharmaceutically acceptable salt, stereoisomer or deuterated form thereof, wherein the compound is:

[0008]

[0009] One or more embodiments of the present application provide a pharmaceutical composition comprising the above-mentioned compound, pharmaceutically acceptable salt, stereoisomer or deuterated form thereof and one or more pharmaceutically acceptable carriers and / or excipients.

[0010] One or more embodiments of the present application provide a use of the pharmaceutical composition of the present application or the above-mentioned compound, pharmaceutically acceptable salt, stereoisomer or deuterated form thereof in the preparation of a medicament for treating and / or preventing cancer.

[0011] One or more embodiments of the present application provide a preparation method of the above-mentioned compound, comprising the following steps:

[0012]

[0013] Compound 3 and compound 4 are reacted in a reaction solvent under the condition of a basic reagent at 50-120℃ to prepare compound 1.

[0014] According to the preparation method of the present application, the reaction solvent is selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane or ethyl acetate; and the basic reagent is selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium phosphate, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropyl ethylamine or pyridine.

[0015] According to the preparation method of the present application, the reaction is carried out at 70-110℃, preferably at 80-100℃, for example, at 90℃.

[0016] According to the preparation method described in the present application, the molar ratio of compound 3 to compound 4 is 1:0.9 to 1:1.2, preferably 1:1.

[0017] According to the preparation method described in the present application, the mass-volume ratio (g / mL) of compound 3 to the reaction solvent is 0.050:1 to 0.060:1, preferably 0.055:1.

[0018] According to the preparation method described in the present application, the molar ratio of compound 3 to the basic reagent is 1:3 to 1:5, preferably 1:4.

[0019] According to the preparation method described in the present application, the method comprises: reacting compound 3-1 and compound 4 in a reaction solvent at 50-120°C under the condition of a basic reagent to prepare compound 1-1.

[0020]

[0021] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0022] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of a compound of the present application which retains the biological effectiveness and properties of the free acid or the free base, and which is obtained by reaction of the free acid with a non-toxic inorganic or organic base, or the free base with a non-toxic inorganic or organic acid.

[0023] "Pharmaceutical composition" refers to a mixture of one or more compounds described in the present application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein the "other chemical components" refer to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic or active agents.

[0024] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of an administered compound.

[0025] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders and disintegrating agents.

[0026] "Stereoisomer" refers to isomers that have the same molecular formula but different structures resulting from the spatial arrangement of atoms.

[0027] Experiments show that the piperazine compounds of the present application can selectively inhibit PARP7, thereby treating cancer, such as lung cancer. DETAILED DESCRIPTION

[0028] The following examples illustrate the technical solutions of the present application, but the protection scope of the present application includes but is not limited to the following.

[0029] Unless otherwise specified in the examples, the reaction temperature is room temperature, and the optimum reaction temperature at room temperature is 20-30°C.

[0030] MPLC: medium pressure liquid chromatography.

[0031] Intermediate 1

[0032] 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0033] 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0034]

[0035]

[0036] First step:

[0037] 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0038] 4,5-dibromo-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0039] To a solution of 4,5-dibromo-2,3-dihydropyridazin-3-one (1a, 50 g, 196.94 mmol, 1.0 equiv) in N,N-dimethylformamide (500 mL) was added sodium hydride (11.82 g, 295.41 mmol, 1.5 equiv, 60%) in batches at 0-10°C, followed by 1-(chloromethyl)-4-methoxybenzene (46.06 g, 294.11 mmol, 1.49 equiv) at 0°C. After the addition was completed, the reaction solution was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was slowly poured into a 1.0 L ice water mixture to quench, and extracted with dichloromethane (2 x 500 mL). The organic layers were combined and concentrated. The solid was washed with methanol (500 mL x 2) to obtain 1b as a yellow solid (48.4 g, yield 66%).

[0040] LC-MS m / z (ESI) = 375.00 [M+1].

[0041] Second step:

[0042] 4-Bromo-5-methoxy-2-(4-methoxybenzyl)pyridazine-3(2H)-one (1c)

[0043] 4-bromo-5-methoxy-2-(4-methoxybenzyl)pyridazin-3(2H)-one

[0044] 1b (48.4 g, 129.40 mmol, 1.0 equiv) and potassium hydroxide (21.78 g, 388.30 mmol, 3.00 equiv) were dissolved in methanol (417 mL), and the reaction mixture was stirred at room temperature for 2 h. The resulting reaction mixture was concentrated to 80 mL and filtered to obtain a crude product. The resulting filter cake was slurried in water (160 mL) for 1 h and filtered to obtain 1c, a white solid (38.72 g, 92% yield).

[0045] LC-MS m / z(ESI)=326.30[M+1].

[0046] Step 3:

[0047] 5-Methoxy-2-(4-Methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (1d)

[0048] 5-methoxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0049] Weigh 1c (14 g, 43.04 mmol, 1.0 equiv) and CuI (4.10 g, 21.52 mmol, 0.50 equiv) into a 250 mL reaction flask, dissolve in N-methylpyrrolidone (72 mL), then slowly add methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (16.4 mL, 129.11 mmol, 3.0 equiv). After addition, stir the reaction mixture in a 100 °C oil bath for 3 h. After the reaction is complete, quench the reaction mixture with 90 mL of water. Extract the resulting solution with dichloromethane (3 × 60 mL). Combine the organic layers, dry over anhydrous sodium sulfate, concentrate under vacuum, and purify the residue by column chromatography (petroleum ether: ethyl acetate = 1:1) to give 1d, a white solid (12.1 g, 89% yield).

[0050] LC-MS m / z(ESI)=315.10[M+1].

[0051] Step 4:

[0052] 5-Hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazine-3(2H)-one (1e)

[0053] 5-hydroxy-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0054] To a solution of 1d (12.1 g, 38.52 mmol, 1.0 equiv) in N,N-dimethylformamide (60 mL) was added trimethylsilyl iodide (9.97 g, 50.07 mmol, 1.3 equiv) dropwise at room temperature. The resulting reaction solution was stirred at 85 °C for 20 h. After the reaction was completed, the reaction mixture was quenched by adding 60 mL of water, followed by extracting the resulting solution with dichloromethane (3 x 60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to give 1e as a white solid (10.4 g, 90% yield).

[0055] LC-MS m / z (ESI) = 301.07 [M+1].

[0056] Fifth step:

[0057] 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0058] 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0059] To a solution of compound 1e (10.4 g, 34.66 mmol, 1.0 equiv) in N,N-dimethylformamide (52 mL) was slowly added oxalyl chloride (8.79 g, 69.32 mmol, 2.0 equiv) at 0 °C. After the addition, the reaction mixture was stirred at room temperature for 8 h. After the reaction was completed, the reaction solution was quenched by adding 550 mL of water. The mixture was filtered to give intermediate 1 as a white solid (11.04 g, 99%).

[0060] LC-MS m / z (ESI) = 319.68 [M+1].

[0061] Intermediate 2

[0062] (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2- yl)methoxy)propan-2-amine (Intermediate 2)

[0063] (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)m ethoxy)propan-2-amine

[0064]

[0065] First step:

[0066] 5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (2b)

[0067] ethyl-5-(4-methoxybenzyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

[0068] Weighed 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (2a, 5.0 g, 24 mmol, 1.0 equiv), p-methoxybenzyl bromide (4.2 mL, 28.8 mmol, 1.2 equiv) were dissolved in N,N-dimethylformamide (50 mL), sodium hydride (1.15 g, 28.8 mmol, 1.2 equiv) was added slowly under ice-bath, after addition, the reaction was carried out at room temperature for 3 h. After the reaction was completed, water was added to quench the reaction, ethyl acetate was used to extract the reaction mixture, anhydrous sodium sulfate was used to dry the organic phase, and the organic phase was rotary evaporated. The crude product was purified by flash column chromatography (dichloromethane:methanol = 20:1) to obtain 2b as a white solid (7.5 g, yield 92%).

[0069] 1 H NMR (400 MHz, DMSO-d6): δ 7.33-7.23 (m, 2H), 7.14 (s, 1H), 6.94-

[0070] 6.87 (m, 2H), 4.62 (s, 2H), 4.50-4.38 (m, 2H), 4.28 (q, 2H), 3.76-3.69 (m, 5H), 1.29 (t, 3H).

[0071] LC-MS m / z (ESI) = 330.10 [M+1].

[0072] Second step:

[0073] (5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methanol (2c)

[0074] (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine

[0075] Weighed 2b (4.1 g, 12.5 mmol, 1.0 equiv) dissolved in tetrahydrofuran (100 mL). Nitrogen protection, slowly added lithium aluminum hydride tetrahydrofuran solution (50 mL, 50 mmol, 4.0 equiv) dropwise under ice bath. After dropwise, 70°C for 10 min. The reaction was complete, cooled to room temperature, quenched in an ice water bath, suction filtered, and the filtrate was rotary evaporated. The crude product was purified by flash column chromatography (dichloromethane:methanol = 10:1) to give 2c as a yellow solid (2.45 g, yield 71%).

[0076] LC-MS m / z (ESI) = 274.10 [M+1].

[0077] Third step:

[0078] (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine

[0079] (S)-1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-amine

[0080] Into a 25 mL reaction bottle, added 2c (864 mg, 3.16 mmol, 1.0 equiv) dissolved in anhydrous N,N-dimethylformamide (18 mL). N2protection, sodium hydride (300 mg, 7.51 mmol, 2.5 eq) was added in batches at 0°C, after addition, continued to stir at the temperature for 30 min. Then, (S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide N,N-dimethylformamide solution (18 mL) was slowly added dropwise into the reaction system, keeping the temperature at 0°C during the dropwise process and continued to stir for 2 h. After the reaction was complete, the pH of the reaction system was adjusted to 3, and stirred at room temperature for 0.5 h. The reaction mixture was extracted with EA (3 x 120 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product, which was purified by column chromatography (dichloromethane:methanol = 40:1) to give intermediate 2 as a white solid (252 mg, yield 24%).

[0081] LC-MS m / z (ESI) = 331.50 [M+1].

[0082] Intermediate 3

[0083] (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0084] (S)-5-((1-((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0085]

[0086]

[0087] First step:

[0088] (S)-2-(4-methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0089] (S)-2-(4-methoxybenzyl)-5-((1-((5-(4-methoxybenzyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0090] Intermediate 2 (252 mg, 0.764 mmol, 1.0 eq) and Intermediate 1 (291.4 mg, 0.916 mmol, 1.1 equiv) were weighed in a 10 mL reaction flask and dissolved in N,N-dimethylformamide (3.0 mL). Then, N,N-diisopropylethylamine (0.5 mL, 3.06 mmol, 4.0 equiv) was added sequentially. The mixture was stirred at 100 °C for 4 h. After the reaction was complete, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 1:1.5) to give 3a as a white solid (359.8 mg, yield 77%).

[0091] LC-MS m / z (ESI) = 613.62 [M+1].

[0092] Step 2:

[0093] (S)-5-((1-(((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0094] (S)-5-((1-(((4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one

[0095] To a 10 mL reaction flask containing 3a (359.8 mg, 0.588 mmol, 1.0 equiv) was added trifluoroacetic acid (3.4 mL) and triflic acid (0.42 mL, 4.7 mmol, 8.0 equiv) sequentially. After addition, the reaction was stirred at 25 °C for 1 h. Subsequently, the reaction was stirred in a 70 °C oil bath. Upon completion of the reaction, the reaction was quenched by the addition of 15 mL of water. The resulting solution was extracted with ethyl acetate (3 x 15 mL). The pH of the organic layer was adjusted to 8-9 by potassium carbonate aqueous solution. The organic layers were combined and concentrated in vacuo. The residue was purified by MPLC (water / acetonitrile = 1:1) to give intermediate 3 as a white solid (48 mg, 22% yield).

[0096] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.81 (s, 2H), 7.90 (s, 1H), 6.28 (dd, 1H), 6.11 (s, 1H), 5.01 (s, 2H), 4.41 (d, 2H), 4.32 (t, 2H), 4.16 (t, 3H), 3.55-3.45 (m, 2H), 1.15 (d, 3H).

[0097] LC-MS m / z (ESI) = 373.1 [M+1].

[0098] Intermediate 4

[0099] 2-chloro-5-(2-fluorophenyl)pyrimidine

[0100] 2-chloro-5-(2-fluorophenyl)pyrimidine

[0101]

[0102] Intermediate 4a (1.93 g, 10 mmol, 1.0 equiv) was added to a mixture of toluene / water (50 mL / 2.5 mL), followed by 2-fluorobenzoic acid (1.68 g, 12 mmol, 1.2 equiv), Pd(dppf)Cl2(0.408 g, 0.5 mmol, 0.05 equiv), and cesium carbonate (9.78 g, 30 mmol, 3.0 equiv). After the addition was complete, the reaction was stirred at 80 °C for 5.0 h. After the reaction was complete, 30 mL of water was added to the reaction mixture, which was extracted with 3 x 40 mL of ethyl acetate (3 x 40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give intermediate 4 as a white solid (1.71 g, 82% yield).

[0103] LC-MS m / z (ESI) = 209.62 [M+1].

[0104] Example 1

[0105] (S)-5-((1-((5-(5-(2-Fluorophenyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 1)

[0106] (S)-5-((1-((5-(5-(2-Fluorophenyl)pyrimidin-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazin-2-yl)methoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 1)

[0107]

[0108] Intermediate 3 (221 mg, 0.6 mmol, 1.0 equiv) and intermediate 4 (125 mg, 0.6 mmol, 1.0 equiv) were weighed into separate 10 mL reaction vials and dissolved in N,N- dimethylformamide (4.0 mL). To each mixture was added N,N-diisopropylethylamine (0.4 mL, 0.52 mmol, 4 equiv) and the reaction was stirred at 90 °C for 1 h. After the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was purified by MPLC (water / acetonitrile = 1:1) to give compound 1 as a white solid (176.4 mg, 54% yield).

[0109] LCMS m / z = 545.50 [M+l].

[0110] Biological test

[0111] 1. PARP enzyme biochemical test

[0112] The experiment adopts PARP1, TNKS1, TNKS2, PARP7 and PARP14 chemiluminescence detection kits (BPS, Cat No. 80551 / 80552 / 80573 / 80578 / 79729 / 80568) to detect the biochemical detection of PARP enzyme. The specific scheme is as follows: 1x histone mixture is added to a 96-well plate at 50ul per well, and incubated at 4 DEG C overnight. The next day, after washing with PBST, 200ul of blocking buffer was added to each well and incubated for 90min. After washing with PBST again, 5ul of inhibitor, 20ul of 1x PARP buffer and 25ul of streptavidin-HRP were added to each well, and incubated at room temperature for 30min. After washing with PBST, 100ul of Elisa ECL substrate A and B mixture was added to each well, and the chemiluminescence value was immediately read by an enzyme label instrument, and the IC 50 value was calculated.

[0113] The results show that the compound has significant biological inhibition activity on PARP7.

[0114] 2. NCI-H1373 cell proliferation inhibition test

[0115] Human lung adenocarcinoma cells NCI-H1373 (ATCC, CRL-5866 TM ) were cultured in RPMI-1640 medium containing 10% FBS and 1% double antibody at 37 DEG C in a cell incubator with 5% CO2. The logarithmic growth phase cells were counted and seeded in a 96-well plate at 1500 NCI-H1373 per well, and incubated in the incubator overnight. The next day, the test compound was prepared into a 10mM stock solution using DMSO, starting from the highest dose of 10uM, and 3-fold gradient dilution was carried out using RPMI-1640 medium, a total of 10 gradient concentrations, and 2 parallel holes were set in each hole. After 6 days of culture, 100ul of Cell Titer Blue working solution was added to each well, and the chemiluminescence reading was carried out on the enzyme label instrument. The IC 50 was calculated by using GraphPad Prism 7.0 software.

[0116] The results show that the compound has significant inhibition effect on NCI-H1373 cell proliferation.

[0117] The detailed description of the application is described in detail, and those skilled in the art should recognize that the above embodiments are exemplary and cannot be understood as limiting the application, and those skilled in the art can make several improvements and modifications to the application without departing from the principles of the application, and the technical solutions obtained by the improvements and modifications also fall within the protection scope of the claims of the application.

Claims

1. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound is selected from the following structures: 。 2. A pharmaceutical composition comprising the compound of claim 1 or a stereoisomer thereof and one or more pharmaceutically acceptable carriers and / or excipients.

3. Use of the compound of claim 1 or its pharmaceutically acceptable salt or stereoisomer, or the pharmaceutical composition of claim 2, in the preparation of a medicament for the treatment and / or prevention of PARP7-related cancers.

4. A method for preparing compound 1, comprising the following steps: Compound 3 and Compound 4 were reacted in a reaction solvent under alkaline conditions at 50-120 °C to prepare Compound 1. The reaction solvent was selected from acetonitrile, tetrahydrofuran, acetone, toluene, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, methyltetrahydrofuran, dichloromethane, or ethyl acetate. The alkaline reagent was selected from cesium carbonate, sodium carbonate, sodium acetate, sodium phosphate, sodium tert-butoxide, potassium tert-butoxide, magnesium tert-butoxide, potassium carbonate, potassium phosphate, potassium fluoride, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, or pyridine.

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