A quinoline protein degradation agent, and a preparation method and application thereof

Abstract

The application discloses a quinoxaline protein degrading agent and a preparation method and application thereof. Through a special molecular design strategy, a PROTAC (protein hydrolysis targeting chimera) molecule with high efficient target PARP1 protein degradation capacity is constructed. Compared with a traditional PARP1-PROTAC degrading agent, the technology significantly improves the protein degradation selectivity by optimizing the connecting arm structure and ligand spatial orientation, effectively overcomes the drug resistance existing in the clinical application of the traditional PARP1-PROTAC degrading agent, and the degrading agent is not easy to cause off-target effects. Compared with traditional drugs, such as Olaparib (AZD2281) and Saruparib (AZD5305), the degrading agent has the advantages of lower toxicity, high drug delivery efficiency and good clinical effect.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a quinoxaline-based protein degrading agent, its preparation method, and its application. Background Technology

[0002] Currently marketed PARP1 inhibitors, due to their DNA capture mechanism, can cause numerous problems such as high cytotoxicity and innate immunity, potentially limiting their application in non-tumor diseases. However, the unique degradation mechanism based on Proteolysis Targeting Chimera (PROTAC) technology is widely used in drug design. PROTACs are bifunctional molecules composed of three parts: a target protein ligand (POI), responsible for binding to the target protein; an E3 ubiquitin ligase recruiter, responsible for recruiting the E3 ubiquitin ligase; and a linker strand, which connects the two parts. Figure 1 As shown, PROTACs work by bringing the target protein closer to an E3 ubiquitin ligase, causing the target protein to be ubiquitinated and subsequently degraded by the proteasome. This technology can target "undruggable" proteins that are difficult for traditional drugs to act on.

[0003] To date, several PARP1 degrading agents based on PROTAC technology have been reported. Chaoguo Cao et al. designed and synthesized a PARP1-PROTAC degrading agent using existing olaparib as a small molecule targeting PARP1 protein and thalidomide as an E3 ubiquitin ligand. Among them, SKS-575 effectively induced the degradation of PARP1 protein, and in PARP1-positive tumor cell lines, Dmax > 95%. In 2021, Zheng et al. proposed the concept of dual-target degradation, using some natural amino acids with three reaction sites, such as tyrosine and serine, to design and synthesize a series of dual-target PROTAC molecules. These molecules can not only simultaneously degrade two targets but also absorb the advantages of both PROTAC and dual-target drugs, achieving therapeutic effects similar to bispecific receptors while relatively retaining the advantages of small molecule drugs.

[0004] Besides serving as a tumor target, PARP1 is overactivated in response to genotoxic stress associated with various pathological conditions (such as ischemia-reperfusion and neurodegenerative diseases). Traditional inhibitors are unsuitable for treating these non-tumor disease models due to their cumulative damage, high cytotoxicity, and innate immunity. Therefore, the PROTAC molecules of PARP1 inhibitors are of great significance for the treatment of non-tumor diseases. Wang et al. synthesized a PROTAC inhibitor of Rucaparib, iRucaparib-AP6, which effectively degraded PARP1 protein in a myocardial ischemia model, protecting cardiomyocytes from energy crises and cell death caused by DNA damage.

[0005] In recent years, CRBN ligands have become important players in the field of E3 ligands. They have played a crucial role not only in the design and synthesis of PROTACs but also in the design of molecular glue degraders, making them indispensable in both PROTACs and molecular glues. Currently, the application of CRBN ligands in this field is mainly focused on immunomodulatory inhibitors, such as lenalidomide, thalidomide, and pomalidomide. However, these compounds have some drawbacks, such as easy racemization and easy degradation by neosubstrate. Therefore, researchers have been continuously striving to develop novel CRBN ligands.

[0006] As a rapidly developing field of pharmaceuticals, targeted protein degraders include molecular colloids and heterologous bifunctional degraders such as PROTACs, which utilize endogenous protein degradation processes to target previously "untreatable" proteins. Molecular colloids and PROTACs differ in properties, but both achieve protein degradation through E3 ligases. Among them, CRBN-based PROTACs have advantages in oral absorption, and several CRBN-based PROTACs have entered clinical trials, including ARV-110 and ARV-471, the latter of which has entered phase III clinical trials. Summary of the Invention

[0007] In view of this, the present invention provides a quinoxaline-based protein degrader, its preparation method, and its application. This quinoxaline-based protein degrader can efficiently degrade PAPR1 protein while inhibiting PAPR1 enzyme activity, solving problems such as off-target effects, drug resistance, severe side effects, and poor clinical efficacy due to low drug delivery efficiency caused by insufficient selectivity.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0009] First aspect of the invention

[0010] Quinoxaline compounds having the structure shown in formula (a) or its stereoisomers, geometric isomers, tautomers, isosteres, or pharmaceutically acceptable salts thereof:

[0011]

[0012] Wherein, R is selected from hydrogen atom, halogen, hydroxyl, C1-C6 straight-chain alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C4 hydroxyalkyl, nitro, cyano or amino;

[0013] It can be a single bond or a double bond, provided that the chemical bond requirements of X and C are met;

[0014] X is selected from CH2, NH, CH, N atoms, oxygen atoms, or sulfur atoms;

[0015] Y is selected from CH2, NH, or oxygen atom;

[0016] Z is selected from either carbon or nitrogen atoms;

[0017] n is any integer greater than or equal to 0.

[0018] This invention utilizes an innovative molecular design strategy to construct a quinoxaline-based protein degrader with highly efficient targeting of PARP1 protein degradation, as shown in formula (a). Compared to traditional PARP1-PROTAC degraders, this invention's degrader significantly improves protein degradation selectivity by optimizing the linker arm structure and ligand spatial orientation, effectively overcoming the drug resistance issues present in the clinical application of traditional PARP1-PROTAC degraders, and exhibiting lower toxicity, thus possessing greater clinical value.

[0019] In some embodiments, the quinoxaline compounds of the present invention have the structure shown in formula (I):

[0020]

[0021] In formula (Ⅰ):

[0022] R is selected from hydrogen atom, halogen, hydroxyl group, C1-C6 straight-chain alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C4 hydroxyalkyl, nitro, cyano or amino;

[0023] It can be a single bond or a double bond, provided that the chemical bond requirements of the C atom and X atom at both ends are met.

[0024] X is selected from CH2, NH, CH, N atoms, oxygen atoms, or sulfur atoms;

[0025] Y is selected from CH2, NH, or oxygen atom;

[0026] Z is selected from either carbon or nitrogen atoms.

[0027] In some embodiments, the quinoxaline compounds of the present invention have the structure shown in formula (II):

[0028]

[0029] In formula (II):

[0030] R is selected from hydrogen atom, halogen, hydroxyl group, C1-C6 straight-chain alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C4 hydroxyalkyl, nitro, cyano or amino;

[0031] It can be a single bond or a double bond, provided that the chemical bonds connected at both ends and X are satisfied;

[0032] X is selected from CH2, NH, CH, N atoms, oxygen atoms, or sulfur atoms;

[0033] Y is selected from CH2, NH, or oxygen atom;

[0034] Z is selected from carbon or nitrogen atoms.

[0035] The quinoxaline compounds or pharmaceutically acceptable salts thereof described in this invention, as well as formulations made from said compounds or salts and pharmaceutically acceptable carriers, all have the effect of targeting the degradation of PARP1 protein. In some embodiments, these compounds or salts thereof and their formulations can also inhibit the enzymatic catalytic activity of PARP1.

[0036] In a specific embodiment of the present invention, when X and Z are both N and Y is NH in the quinoxaline compound represented by formula (a), it is any of the compounds shown in Table 1:

[0037] Table 1. Compound Numbers and Structures

[0038]

[0039]

[0040]

[0041]

[0042] In some embodiments, when Z is N in the quinoxaline compound shown in formula (a), it is a compound obtained by replacing the N at position 1 of the quinoxaline in any of the compounds shown in Table 1 with an oxygen, sulfur, or carbon atom.

[0043] The present invention also provides a method for preparing the quinoxaline compounds, comprising:

[0044] Compound H-7 and compound H-11 were subjected to a condensation reaction to obtain the compound shown in formula (I);

[0045]

[0046] R is selected from hydrogen atom, halogen, hydroxyl, C1-C6 straight-chain alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C4 hydroxyalkyl, nitro, cyano or amino.

[0047] In some embodiments, the solvent for the condensation reaction is selected from any one or a combination of two or more of ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, tetrahydrofuran / ethyl acetate, and tetrahydrofuran / N,N-dimethylformamide.

[0048] In some embodiments, the condensing agent for the condensation reaction is selected from any one or any combination of two or more of the following: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), carbonyl diimidazole (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), carbonyl diimidazole / 1-hydroxybenzotriazole, and carbonyl diimidazole / N-hydroxysuccinimide.

[0049] The base for the condensation reaction is selected from one or a mixture of two or more of the following: methylamine, ethylamine, triethylamine, diisopropylethylamine, aniline, dimethylaniline, tetramethylguanidine, 1,8-diazabicycloundec-7-ene (DBU), 4-dimethylaminopyridine, and pyridine.

[0050] In some embodiments, the condensation reaction is carried out under the following conditions: stirring at room temperature for 2 to 8 hours, preferably stirring at room temperature for 2 to 5 hours, and more preferably stirring at room temperature for 2 to 3 hours.

[0051] In some implementations, X and Z are both N, and Y is NH. The compound H-7 is a double bond, specifically compound H-7-1. Taking compound H-7-1 as an example, the preparation method of compound H-7 is described in detail below. Compound H-7-1 is prepared by the following method:

[0052] S1. The compound shown in Formula III (or the compound obtained by replacing the amino group of Formula III with a nucleophilic group containing C, O or S) and the compound shown in Formula IV (or the compound of IV by replacing the nitro group with a group containing C or O) undergo a nucleophilic substitution reaction to obtain compound H-1. Compound H-1 undergoes a hydrogenation reduction reaction followed by nitro cyclization to obtain compound H-2.

[0053] S2 and compound H-2 were subjected to aromatization, reduction and halogenation reactions in sequence to obtain compound H-5;

[0054] S3,4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride undergoes a substitution reaction with compound H-5 after the Boc protecting group is removed, to give compound H-6; compound H-6 is hydrolyzed to give compound H-7-1.

[0055]

[0056] Wherein, R is selected from hydrogen atom, halogen, hydroxyl, C1-C6 straight-chain alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C4 hydroxyalkyl, nitro, cyano or amino.

[0057] The preparation of compounds other than H-7-1 in the H-7 compound group is the same as that of H-7-1 above, and will not be repeated here.

[0058] In some specific embodiments, step S2 includes:

[0059] Compound H-2 undergoes an aromatization reaction to yield compound H-3;

[0060] Compound H-3 was reduced to give compound H-4; compound H-4 was halogenated to give H-5.

[0061]

[0062] Wherein, X is N, Y is NH, and R is selected from the groups described above.

[0063] In some embodiments, the compound H-11 is prepared by the following method:

[0064] The compounds S4, V and VI undergo nucleophilic substitution to give compound H-8; compound H-8 is hydrolyzed to give compound H-9.

[0065] S5. Compound H-9 and 3-amino-2,6-piperidinidone hydrochloride were subjected to a condensation reaction to remove the Boc protecting group, yielding compound H-11.

[0066]

[0067] In the compound represented by Formula V of this invention, a Boc protecting group is used to protect the amino group at the C4 position. Other protecting groups besides the Boc protecting group are also feasible, such as benzyl, benzyloxycarbonyl, acetyl, propionyl, etc. The benzyl and benzyloxycarbonyl protecting groups can be removed by hydrogenation, while the acetyl and propionyl groups can be removed by hydrolysis or other conditions.

[0068] In some implementations, in step S4, the nucleophilic substitution reaction is carried out in the presence of cesium carbonate.

[0069] In some embodiments, the present invention does not have special limitations on the reagents used in the hydrolysis reaction in step S4; any reagent capable of hydrolyzing compound H-8 to obtain compound H-9 is acceptable, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. In some embodiments, lithium hydroxide is used as the reagent in the hydrolysis reaction.

[0070] In some embodiments, the removal of the protecting group Boc of compound H-10 in step S5 and the Boc protecting group of 4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylic acid tert-butyl hydrochloride in step S3 is carried out by using one or a combination of two or more of the following reagents: hydrochloric acid, trifluoroacetic acid, and acetyl chloride.

[0071] In a specific embodiment of the present invention, taking X and Z as both N and Y as NH as an example, the preparation method of the quinoxaline compound described in formula (I) is described in detail. The preparation method specifically includes:

[0072] First, the starting material methyl 4-fluoro-3-nitrobenzene (IV) undergoes a nucleophilic substitution reaction with an R-substituted 2-amino acid ester hydrochloride (III) in the presence of a basic catalyst to generate compound H-1. Catalytic hydrogenation reduction of the nitro group leads to cyclization, yielding compound H-2. Aromatization with DDQ gives compound H-3, followed by reduction of the ester group to an alcohol hydroxyl group with DIBAL-H to give compound H-4. Subsequent halogenation with hydrobromic acid yields compound H-5. Then, tert-butyl 4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylic acid hydrochloride is deprotected by the Boc protecting group. After substitution with compound H-5, compound H-6 is obtained, which is then hydrolyzed with lithium hydroxide to give compound H-7-1. Piperidin-4-ylcarbamate tert-butyl ester and methyl 5-fluoropyridine-2-carbamate undergo a nucleophilic substitution reaction in the presence of cesium carbonate to give compound H-8, which is then hydrolyzed with lithium hydroxide to give compound H-9. Compound H-9 is then condensed with 3-amino-2,6-piperidinedione hydrochloride to give compound H-10. Deoxygenation with trifluoroacetic acid yields compound H-11, which is then condensed with compound H-7-1 to give compound of general formula (I). The specific synthetic route is as follows:

[0073]

[0074]

[0075] In the compounds involved in the above synthetic route, X and Z are both N atoms, and Y is NH.

[0076] Furthermore, in a specific embodiment of the present invention, taking the compound of formula (II) where X and Z are both N, Y is NH, and R is -CH2CH3 as an example, the preparation method of the quinoxaline compound of formula (II) is described in detail. The preparation method specifically includes:

[0077] 4-Boc-aminomethylpiperidine and methyl 5-fluoropyridine-2-carboxylate undergo a nucleophilic substitution reaction in the presence of cesium carbonate to give compound H-12. Hydrolysis with lithium hydroxide yields compound H-13, which is then condensed with 3-amino-2,6-piperidinedione hydrochloride to give compound H-14. Deoxygenation with trifluoroacetic acid yields compound H-15, which is then condensed with compound H-7-1 to give compound (II). The specific synthetic route is as follows:

[0078]

[0079] In the preparation method of the compound of formula (I) or formula (II) of the present invention, when X is nitrogen, the starting material is the compound shown in formula III and formula IV. When X is a carbon, oxygen, or sulfur atom, the corresponding starting material is: the -NH2 in formula III is replaced with a nucleophilic group containing C, O, or S, such as -CH3, -OH, or -SH, to obtain the compound containing X. Compounds containing Y that can undergo nucleophilic substitution reactions with the compound containing X are all within the scope of protection of the present invention. Specifically, Y can be a carbon atom or an oxygen atom in addition to a N atom. When Y is a carbon atom or an oxygen atom, the corresponding starting material is: the compound obtained by replacing -NO2 in formula IV with -CHO or -OH, or it can be replaced with other groups that can undergo nucleophilic substitution reactions with the compound containing X as described above.

[0080] In another aspect of the present invention, a composition is provided comprising the compounds of formula (a), formula (I), formula (II), any of the compounds shown in Table 1, or their stereoisomers, geometric isomers, tautomers, isosteres, or pharmaceutically acceptable salts.

[0081] The pharmaceutical compositions of this invention may include, in addition to the quinoxaline compounds described herein, other PAPR1 protein degraders or PARP1 enzyme inhibitors. That is, the quinoxaline compounds of this invention can be used in combination with other PAPR1 protein degraders or PARP1 enzyme inhibitors.

[0082] The present invention also provides pharmaceutical preparations containing compounds of formula (a), formula (I) and / or formula (II), any compound shown in Table 1 or its stereoisomers, geometric isomers, tautomers, isosteres or pharmaceutically acceptable salts, and pharmaceutical preparations containing the compositions thereof.

[0083] In another aspect, the present invention provides the use of the quinoxaline compounds, the pharmaceutical compositions, or the pharmaceutical formulations described above as protein degrading agents for CRBN (Cereblon) E3 ubiquitin ligands.

[0084] In another aspect, the invention provides the use of the compounds of formula (I) and (II) or salts thereof, or compositions containing the compounds of formula (I) and (II) or salts thereof, as protein degrading agents for the preparation of CRBN (Cereblon) E3 ubiquitin ligands.

[0085] On the other hand, the present invention provides compounds of formula (a), formula (I) and / or formula (II) or salts thereof, or compositions containing compounds of formula (a), formula (I) and / or formula (II) or salts thereof, for use as pharmaceuticals. That is, the present invention provides pharmaceutical compositions containing compounds of formula (a), formula (I) and / or formula (II), any compound shown in Table 1, or stereoisomers, geometric isomers, tautomers, isosteres, or pharmaceutically acceptable salts thereof.

[0086] On the other hand, the present invention provides pharmaceutical formulations comprising quinoxaline compounds or pharmaceutical compositions as described above, and pharmaceutically acceptable excipients.

[0087] Pharmaceutically acceptable excipients include one or more of the following: fillers, diluents, lubricants, disintegrants, wetting agents, and binders.

[0088] Specifically, fillers include, but are not limited to, starch, microcrystalline cellulose, lactose, and dicalcium phosphate; lubricants include, but are not limited to, magnesium stearate, talc, and silica; disintegrants include, but are not limited to, dry starch, sodium carboxymethyl cellulose, and crospovidone; and binders include, but are not limited to, starch paste, methyl cellulose, hydroxypropyl cellulose, and gelatin.

[0089] In this invention, the pharmaceutical composition and pharmaceutically acceptable excipients are prepared into a pharmaceutical formulation according to methods commonly used in the art. The dosage form of the pharmaceutical formulation may be a powder, granules, tablets, capsules, pills, or paste, etc.

[0090] In addition, the pharmaceutical composition described in this invention can also be coated and can be formulated into sustained-release or controlled-release formulations.

[0091] The present invention also provides the use of the quinoxaline compounds, the pharmaceutical compositions, or the pharmaceutical formulations described herein in any of the following:

[0092] (1) Preparation of PARP1 enzyme inhibitors;

[0093] (2) Preparation of PAPR1 protein degrading agent;

[0094] (3) Prepare drugs for the prevention and / or treatment of tumors or other autoimmune diseases.

[0095] The tumor includes at least one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, stomach cancer, and liver cancer.

[0096] The other autoimmune-related diseases include at least one of the following: rash, pruritus, vitiligo, colitis, thyroiditis, hypophysitis, immune-mediated pneumonia, arthritis, myasthenia gravis, peripheral neuropathy, etc.

[0097] The condensing agents and combinations of condensing agents used in the condensation reaction of carboxylic acids and amines described in this invention include 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), carbonyl diimidazole (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), carbonyl diimidazole / 1-hydroxybenzotriazole, carbonyl diimidazole / N-hydroxysuccinimide, etc.

[0098] The solvent used in the condensation reaction of carboxylic acids and amines described in this invention is a single or mixed solvent such as ethyl acetate, tetrahydrofuran, tetrahydrofuran / ethyl acetate, or tetrahydrofuran / N,N-dimethylformamide.

[0099] This invention further provides a pharmaceutically acceptable salt form of a quinoxaline protein degrader. Experimental verification shows that, under stringent medical evaluation standards, the salt form is suitable for applications involving human and mammalian tissue contact, and its toxicological characteristics meet the following requirements: (1) no significant toxicity, irritation, sensitization, or other adverse reactions; (2) a good balance between therapeutic benefit and risk; and (3) pharmacokinetic parameters required for clinical drug development. The term "pharmaceuticalally acceptable salt" specifically refers to a stable ionic complex formed by the compound and a physiologically compatible acid, specifically covering inorganic acid salts (such as hydrochloride, sulfate, and phosphate) and organic acid salts (including but not limited to: methanesulfonate, ethanesulfonate, p-toluenesulfonate, oxalate, lactate, tartrate, maleate, malate, acetate, etc.).

[0100] This invention discloses a novel class of quinoxaline-based protein degraders based on CRBN (Cereblon) E3 ubiquitin ligands, which are PROTAC (proteolytic-targeting chimeras) molecules with highly efficient PARP1 protein degradation capabilities. Compared to traditional PARP1-PROTAC degraders, this technology significantly improves protein degradation selectivity by optimizing the linker arm structure and ligand spatial orientation, effectively overcoming the drug resistance issues present in the clinical application of traditional PARP1-PROTAC degraders. Furthermore, the novel quinoxaline-based protein degraders exhibit lower toxicity. They also demonstrate high drug delivery efficiency and greater clinical value. Attached Figure Description

[0101] Figure 1 The mechanism of action of PROTAC;

[0102] Figure 2 The activity of compounds JPP2 and JPP3 in breast cancer cells MX-1 was measured; AZD2281 was olaparib, and AZD5305 was saruparib.

[0103] Figure 3 The values ​​represent the degradation rates of PARP1 protein by compounds JPP2 and JPP3 at concentrations of 0.1 and 1 μM.

[0104] Figure 4 The values ​​represent the PARP protein inhibition rates of compounds JPP2 and JPP3 at concentrations of 0.1 and 1 μM. Detailed Implementation

[0105] This invention provides a quinoxaline-based protein degrading agent, its preparation method, and its application. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0106] In this article, expressions such as “including,” “having,” and “containing,” as well as their grammatical synonyms, should be understood as open expressions that are inclusive rather than exclusive. The option “composed of…” is also provided.

[0107] In addition to the publicly disclosed point values, the numerical ranges discussed in this article also cover all intermediate values ​​between any two endpoint values, including any numerical value between any two point values ​​and a small range within any two numerical ranges.

[0108] In this article, the compound of formula II is also referred to as the compound of formula (II), and the two refer to the same compound.

[0109] Unless otherwise specified, all experiments were conducted under standard conditions or conditions recommended by the manufacturer. Active pharmaceutical ingredients, excipients, reagents, and instruments used, unless otherwise specified, are commercially available products. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0110] The present invention is further illustrated below through specific embodiments. These embodiments are for illustrative purposes only and should not be construed as limiting the scope of protection of the present invention. The specific embodiments are illustrative and only demonstrate the specific compound preparation process in this class of compounds, reflecting the general synthetic idea and strategy of this class of compounds. Unless otherwise specified, the test materials used in the embodiments are all common commercial products and can be purchased from the market.

[0111] Example 1

[0112] Step 1: Preparation of methyl 4-((1-methoxy-1-oxobutane-2-yl)amino)-3-nitrobenzene

[0113] Methyl 4-fluoro-3-nitrobenzoate (3.98 g, 20 mmol, 1.0 eq), methyl 2-aminobutyrate hydrochloride (3.69 g, 24 mmol, 1.2 eq), and sodium bicarbonate (6.72 g, 80 mmol, 4.0 eq) were added to a 250 mL round-bottom flask, dissolved in 100 mL of THF, and stirred overnight at room temperature. After the reaction was complete, residual sodium bicarbonate solid was removed by filtration, and the mixture was washed with a small amount of THF. The filtrate was concentrated under reduced pressure for the next reaction. EI-MS (m / z): 297.1.1 [M+H] + ; 1 HNMR(400MHz, DMSO-d6)δ8.71–8.61(m,2H),7.99(dd,J=9.0,2.1Hz,1H),7.14(d,J=9.1Hz, 1H), 4.76–4.68 (m, 1H), 3.84 (s, 3H), 3.76 (s, 3H), 2.06–1.64 (m, 2H), 0.91 (t, J = 7.4Hz, 3H).

[0114] Step 2: Methyl 2-ethyl-3-oxo-1,2,3,4-tetrahydroquinoxalo-6-carboxylic acid

[0115] After concentrating the filtrate from step 1 under reduced pressure, 60 mL of methanol and a small amount of dichloromethane were added to dissolve it. Pd / C (600 mg) was then added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was complete, DCM / MeOH (10:1 v / v, 50 mL) was added and stirred for 2 hours. The mixture was filtered through a diatomaceous earth filter and washed multiple times with DCM / MeOH (10:1 v / v). The filtrate was concentrated under reduced pressure, and the residue was slurried with ethyl acetate to give a solid product (3.75 g, 80% yield). EI-MS (m / z): 235.1.1 [M+H] + ; 1HNMR(400MHz,DMSO-d6)δ10.39(s,1H),7.40(dd,J=8.3,1.9Hz,1H),7.32(d,J=1.9Hz,1H),6.89–6.81(m,1H ),6.70(d,J=8.3Hz,1H),3.89(td,J=5.5,1.8Hz,1H),3.75(s,3H),1.72–1.63(m,2H),0.91(t,J=7.4Hz,3H).

[0116] Step 3: Preparation of methyl 2-ethyl-3-oxo-3,4-dihydroquinoxal-6-carboxylic acid

[0117] In a 250 mL round-bottom flask, 1,4-dioxane (50 mL), methyl 2-ethyl-3-oxo-1,2,3,4-tetrahydroquinoxaloline-6-carboxylate (3.65 g, 15.5 mmol, 1.0 eq), and DDQ (3.86 g, 17 mmol, 1.1 eq) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (170 mL), and stirred at room temperature for 20 minutes. The mixture was filtered, the filter cake was washed with 50 mL of water, and dried to give a solid product (3.33 g, yield 92%). EI-MS (m / z): 233.1 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ12.45(s,1H),7.88(t,J=1.5Hz,1H),7.84–7.76(m ,2H),3.89(s,3H),2.84(qd,J=7.4,1.5Hz,2H),1.23(td,J=7.4,1.5Hz,3H).

[0118] Step 4: 3-Ethyl-7-(hydroxymethyl)quinoxaline-2(1H)-one

[0119] 2-Ethyl-3-oxo-3,4-dihydroquinoxal-6-carboxylic acid methyl ester (3.27 g, 14 mmol, 1.0 eq) was added to a 250 mL three-necked flask, along with ultra-dry THF (35 mL) under argon protection. When the system temperature dropped to 0 °C, DIBAL-H (28 mL) was slowly added dropwise using a constant-pressure dropping funnel. The mixture was stirred at 0 °C for 2 hours until the reaction was complete. The reaction was quenched with methanol (50 mL) and stirred at room temperature for 2 hours. DCM / MeOH = 10:1 (v / v, 100 mL) was added, and stirring continued for 2 hours. The mixture was filtered through a diatomaceous earth filter, and the filter cake was washed multiple times with DCM / MeOH = 10:1 (v / v). The mixture was concentrated under reduced pressure to give a solid product (1.7 g, yield 63%). EI-MS (m / z): 205.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ12.28(s,1H),7.66(d,J=8.2Hz,1H),7.27(d,J=1.7Hz,1H),7.18(dd,J=8.2,1 .8Hz,1H),5.38(t,J=5.7Hz,1H),4.58(d,J=5.7Hz,2H),2.79(q,J=7.4Hz,2H),1.22(t,J=7.4Hz,3H).

[0120] Step 5: 7-(bromomethyl)-3-ethylquinoxaline-2(1H)-one

[0121] 3-Ethyl-7-(hydroxymethyl)quinoxalin-2(1H)-one (1.6 g, 8.8 mmol, 1.0 eq) and 47 wt% HBr were added to a 50 mL round-bottom flask and stirred at 80 °C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was poured into 50 mL of ice water and stirred for 5 minutes, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was washed first with a small amount of water, then with a small amount of ethyl acetate, to obtain a brownish-yellow crude solid (1.37 g), which was used directly in the next step without purification.

[0122] Step 6: Methyl 5-((2-ethyl-3-oxo-3,4-dihydroquinoxalo-6-yl)methyl)piperazin-1-yl)pyridinecarboxylate

[0123] In a 50 mL round-bottom flask, add tert-butyl-4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (546 mg, 1.7 mmol, 1.0 eq), dichloromethane (5 mL), and hydrochloric acid / dioxane solution (1.7 mL, 4 M, 4.0 eq). Stir at room temperature for 3 hours. After the reaction is complete, add dichloromethane (10 mL) and concentrate under reduced pressure, repeating three times. Add 7-(bromomethyl)-3-ethylquinoxalin-2(1H)-one (460 mg, 1.7 mmol, 1.0 eq), acetonitrile (10 mL), and potassium carbonate (705 mg, 5.1 mmol, 3.0 eq) to the residue after reduced pressure concentration. Stir overnight at room temperature until the reaction is complete. The mixture was filtered, and the filter cake was washed with DCM / MeOH at a ratio of 10:1 (v / v). The residue was purified by rapid column chromatography (silica gel, DCM / MeOH = 20 / 1 to 10 / 1, v / v) to give a solid (514 mg, yield 74%). EI-MS (m / z): 408.2 [M+H] + ; 1HNMR (400MHz, CDCl3) δ8.34(d,J=2.9Hz,1H),8.00(d,J=8.8Hz,1H),7.79(d,J=8.2Hz,1H),7.49–7.28(m,2H),7.14(dd,J=8.8,2 .9Hz,1H),3.95(s,3H),3.71(d,J=16.9Hz,2H),3.40(t,J=5.0Hz,4H),3.00(q,J=7.4Hz,2H),2.66(s,4H),1.35(t,J=7.4Hz,3H).

[0124] Step 7: 5-((2-ethyl-3-oxo-3,4-dihydroquinoxalo-6-yl)methyl)piperazin-1-yl)pyridinecarboxylic acid

[0125] In a 50 mL round-bottom flask, methyl 5-((2-ethyl-3-oxo-3,4-dihydroquinoxalo-6-yl)methyl)piperazin-1-yl)pyridinecarboxylate (490 mg, 1.2 mmol, 1.0 eq), THF / CH3OH / H2O (v,v,v = 3:2:1, 6 mL) and lithium hydroxide monohydrate (100 mg, 2.4 mmol, 2.0 eq) were added and stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the organic solvent. A small amount of water was added to the reaction flask, and the pH was adjusted to 4-5 with 10% citric acid. The mixture was stirred at room temperature for 10 minutes, and a solid precipitated. The solid product (388 mg, yield 83%) was obtained by filtration and washing the filter cake with a small amount of water. EI-MS (m / z): 394.2 [M+H] + ; 1 HNMR (400MHz, DMSO-d6) δ8.36(d,J=2.9Hz,1H),7.86(d,J=8.8Hz,1H),7.69(d,J=8.1Hz,1H),7.35(dd,J=8.9,2.9Hz,1H) ,7.30–7.21(m,2H),3.62(s,2H),3.41–3.37(m,4H),2.80(q,J=7.4Hz,2H),2.54(m,J=5.6Hz,4H),1.22(t,J=7.4Hz,3H).

[0126] Step 8: Methyl 5-(4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)pyridinecarboxylate

[0127] 1.92 g (1.2 mmol, 1.2 eq) of piperidine-4-ylcarbamate tert-butyl ester and methyl 5-fluoropyridine-2-carbamate (1.25 g, 8 mmol, 1.0 eq) were dissolved in DMSO (10 mL) in a 100 mL round-bottom flask. Cesium carbonate (0.78 g, 2.4 mmol, 0.3 eq) was added, and the mixture was stirred at 80 °C for 4 hours. The reaction mixture was cooled to room temperature. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (80 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 20 / 9, v / v) to give a product as a white solid (2.07 g, yield 77%). EI-MS (m / z): 336.2 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ8.36(d,J=2.9Hz,1H),7.85(d,J=8.8Hz,1H),7.32(dd,J =8.9,3.0Hz,1H),6.87(d,J=7.8Hz,1H),3.96–3.86(m,2H),3.80(s,3H),3.50(br s,1H),3.03–2.91(m,2H),1.87–1.74(m,2H),1.48–1.39(m,2H),1.39(s,9H).

[0128] Step 9: 5-(4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)pyridinecarboxylic acid

[0129] 2.0 g (5.96 mmol, 1.0 eq) of methyl 5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)pyridinecarboxylate was dissolved in a 100 mL round-bottom flask and dissolved in a mixed solvent of THF / CH3OH / H2O (20 mL, 2 / 1 / 1, v / v / v). Then, 0.5 g (11.92 mmol, 2.0 eq) of LiOH·H2O was added and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixed solvent was removed by vacuum distillation. A small amount of water was added to the round-bottom flask, and the pH was adjusted to 3-4 with 10% citric acid. A solid precipitated. The solid was filtered, washed, and dried to give a pale yellow solid (1.25 g, yield 65%). EI-MS (m / z): 322.2 [M+H] + ; 1HNMR (400MHz, CDCl3) δ8.22(d,J=2.9Hz,1H),8.03(d,J=8.8Hz,1H),7.23(dd,J=8.8,2.9Hz,1H),3.85(dt,J=13.5,3 .9Hz,2H),3.73(d,J=12.2Hz,1H),3.18–2.91(m,2H),2.18–1.98(m,2H),1.52(td,J=11.9,3.9Hz,2H),1.45(s,9H).

[0130] Step 10: 1-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)tert-butyl carbamate

[0131] 5-(4-((tert-Butoxycarbonyl)amino)piperidin-1-yl)pyridinecarboxylic acid (1.25 g, 4 mmol, 1.0 eq), 3-amino-2,6-piperidinidone hydrochloride (790 mg, 4.8 mmol, 1.2 eq), dichloromethane (40 mL), and HATU (1.82 g, 4.8 mmol, 1.2 eq) were sequentially added to a 100 mL round-bottom flask. After stirring for 3 min, TEA (1.7 mL, 12 mmol, 3.0 eq) was added. The mixture was stirred overnight at room temperature. The mixture was filtered, washed first with water and then with DCM. The residue was purified by rapid column chromatography (silica gel, DCM / MeOH = 5 / 1, v / v) to give a white solid (1.1 g). The remaining mother liquor was slurried to give 0.3 g of pure product. The products were combined to give a white solid (1.4 g, yield 85%). EI-MS (m / z): 432.2 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ10.85(s,1H),8.71(d,J=8.3Hz,1H),8.30(d,J=2.9Hz, 1H),7.84(d,J=8.8Hz,1H),7.40(dd,J=8.8,2.9Hz,1H),6.88(d,J=7.7Hz,1H),4. 81–4.64(m,1H),3.88(d,J=13.2Hz,2H),3.11–2.87(m,3H),2.86–2.71(m,1H),2. 54(m,1H),2.09–1.94(m,1H),1.88–1.70(d,2H),1.51–1.40(m,3H),1.39(s,9H).

[0132] Step 11: Compound JPP2: N-(2,6-dioxopiridine-3-yl)-5-(4-(5-(4-((2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide-1-yl)pyridineamide

[0133] In a 50 mL round-bottom flask, add tert-butyl 1-(6-((2,6-dioxadiazin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)carbamate (95 mg, 0.22 mmol, 1.1 eq) and DCM / TFA (4 mL, v / v = 3 / 1). Stir at room temperature for 1.5 hours. After the reaction is complete, add 1,2-dichloroethane (10 mL) and concentrate under reduced pressure. Repeat four times to remove residual trifluoroacetic acid. Dichloromethane (4 mL), 5-((2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarboxylic acid (79 mg, 0.2 mmol, 1.0 eq), Pybop (156 mg, 0.3 mmol, 1.5 eq), and triethylamine (101 mg, 1 mmol, 5.0 eq) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, washed with a small amount of DCM, and the residue was slurried with ethyl acetate to give the solid final product, compound JPP2 (19 mg, yield 13%). EI-MS (m / z): 707.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.30(d,J=8.3Hz,1H),8.25(d,J=2.8Hz,1H),8.02(t,J=7.3Hz,1H),7.84(d,J=8.8Hz,1H ),7.77–7.54(m,2H),7.39(dd,J=8.8,2.8Hz,1H),7.36–7.13(m,2H),6.96–6.69(m,2H),4.73(dt,J=12.8,6.7Hz ,1H),4.15–3.97(m,1H),3.89(d,J=12.6Hz,2H),3.60(s,2H),3.38(m,4H),2.95(m,3H),2.79(m,J=7.4Hz,2H),2 .74(m,1H),2.54(m,5H),2.00(m,2H),1.90–1.80(m,2H),1.71(d,1H),1.70–1.59(m,2H),1.21(t,J=7.4Hz,3H).

[0134] Step 12: Methyl 5-(4-(((tert-Butoxycarbonylamino)methyl)piperidin-1-yl)pyridinecarboxylate

[0135] 2.06 g (piperidin-4-ylmethyl)carbamate tert-butyl ester (9.6 mmol, 1.2 eq) and methyl 5-fluoropyridine-2-carboxylate (1.25 g, 8 mmol, 1.0 eq) were dissolved in DMSO (10 mL) in a 100 mL round-bottom flask. Cesium carbonate (0.78 g, 2.4 mmol, 0.3 eq) was added, and the mixture was stirred at 80 °C for 4 hours. The reaction mixture was cooled to room temperature. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (80 mL × 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid column chromatography (silica gel, DCM / EA = 20 / 9, v / v) to give a product as a white solid (1.85 g, yield 66%). EI-MS (m / z): 350.2 [M+H] +1 HNMR (400MHz, DMSO-d6) δ8.35(d,J=2.9Hz,1H),7.84(d,J=8.8Hz,1H),7.31(dd,J=8.9,2.9Hz,1H),6.91(t,J=6.0H z,1H),3.96(d,J=12.8Hz,2H),3.79(s,3H),2.92–2.77(m,4H),1.75–1.57(m,3H),1.38(s,9H),1.22–1.17(m,2H).

[0136] Step 13: 5-(4-((((tert-Butoxycarbonyl)amino)methyl)piperidin-1-yl)pyridinecarboxylic acid

[0137] 1.72 g (4.92 mmol, 1.0 eq) of methyl 5-(4-(((tert-Butoxycarbonylamino)methyl)piperidin-1-yl)pyridinecarboxylate was dissolved in a 100 mL round-bottom flask and dissolved in a mixed solvent of THF / CH3OH / H2O (20 mL, 2 / 1 / 1, v / v / v). Then, LiOH·H2O (413 mg, 9.84 mmol, 2.0 eq) was added and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixed solvent was removed by vacuum distillation. A small amount of water was added to the round-bottom flask, and the pH was adjusted to 3-4 with 10% citric acid. No solid precipitated. The mixture was extracted three times with ethyl acetate (70 mL × 3), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a solid (1.43 g, yield 87%). EI-MS (m / z): 336.2 [M+H] + ; 1HNMR (400MHz, DMSO-d6) δ8.33(d,J=2.9Hz,1H),7.83(d,J=8.9Hz,1H),7.33(dd,J=8.9,2.9Hz,1H),6.90(t,J=5.9H z,1H),3.95(d,J=12.7Hz,2H),2.92–2.74(m,5H),1.78–1.62(m,2H),1.60(m,1H),1.38(s,9H),1.25–1.08(m,2H).

[0138] Step 14: ((1-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)tert-butyl carbamate

[0139] 5-(4-((((tert-Butoxycarbonyl)amino)methyl)piperidin-1-yl)pyridinecarboxylic acid (1 g, 3.1 mmol, 1.0 eq), 3-amino-2,6-piperidinidone hydrochloride (612 mg, 3.72 mmol, 1.2 eq), dichloromethane (30 mL), and HATU (1.41 g, 3.72 mmol, 1.2 eq) were added sequentially to a 100 mL round-bottom flask. After stirring for 3 min, TEA (1.3 mL, 9.3 mmol, 3.0 eq) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, washed with water and then with dichloromethane, and dried to obtain a solid (1.1 g). The remaining mother liquor was extracted and slurryed to obtain 0.3 g of pure product. The products were combined to give a white solid (1.4 g, yield 85%). EI-MS (m / z): 568.1 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ10.84(s,1H),8.70(d,J=8.3Hz,1H),8.30(d,J=2.9Hz,1H),7.8 3(d,J=8.8Hz,1H),7.39(dd,J=8.9,2.8Hz,1H),6.91(t,J=5.9Hz,1H),4.78–4.67(m,1H) ,3.93(d,J=12.8Hz,2H),2.90–2.73(m,5H),2.57–2.52(m,1H),2.25–2.08(m,1H),2.06– 1.95(m,1H),1.71(d,J=13.0Hz,2H),1.66–1.54(m,1H),1.38(s,9H),1.25–1.10(m,2H).

[0140] Step 15: Compound JPP3: N-(2,6-dioxopiridine-3-yl)-5-(4-((5-(4-((2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide)methyl)piperazin-1-yl)pyridineamide

[0141] In a 50 mL round-bottom flask, add ((1-(6-((2,6-dioxopiridine-3-yl)carbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)tert-butyl carbamate (99 mg, 0.22 mmol, 1.1 eq) and DCM / TFA (4 mL, v / v = 3 / 1). Stir at room temperature for 2 hours. After the reaction is complete, add 1,2-dichloroethane (10 mL) and concentrate under reduced pressure. Repeat four times to remove residual trifluoroacetic acid. Dichloromethane (4 mL), 5-((2-ethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarboxylic acid (79 mg, 0.2 mmol, 1.0 eq), Pybop (156 mg, 0.3 mmol, 1.5 eq) and triethylamine (101 mg, 1 mmol, 5.0 eq) were added and stirred overnight at room temperature. After the reaction was completed, the mixture was filtered, washed with a small amount of DCM, and the residue was slurried with ethyl acetate to give the solid final product, namely compound JPP3 (22 mg, yield 14%).

[0142] EI-MS (m / z): 721.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),10.86(s,1H),8.71(d,J=8.3Hz,1H),8.51(t,J=6.3Hz,1H),8.29(dd, J=6.0,2.8Hz,2H),7.84(dd,J=8.7,2.4Hz,2H),7.69(d,J=8.1Hz,1H),7.45–7.35(m,2H),7.28(s,1H),7.25 (d,J=8.0Hz,1H),4.80–4.68(m,1H),3.94(d,J=12.5Hz,2H),3.62(s,2H),3.42(s,1H),3.21(s,2H),2.91–2 .71(m,5H),2.62–2.52(m,5H),2.26–2.10(m,1H),2.07–1.95(m,1H),1.93–1.65(m,4H),1.33–1.15(m,5H).

[0143] Example 2: MX-1 activity assay in breast cancer cells

[0144] (1) The effects of PARP1 PROTAC degraders (compounds JPP2 and JPP3) on PARP1 protein and PARP1 activity (reaction to PAR) were investigated on human breast cancer cells.

[0145] After treating human breast cancer cells MX-1 with different concentrations of compounds for 24 hours, the cells were collected for Western blotting analysis. The results are shown in [Figure number missing]. Figure 2 .

[0146] The results showed that JPP2 and JPP3 compounds significantly reduced PARP1 protein levels, while small molecule inhibitors of PARP1, such as AZD2281 and AZD5305, had no effect on PARP1 protein levels. At the PARP1 activity level, JPP2 and JPP3 compounds significantly inhibited the catalytic activity of PARP1, resulting in a significant decrease in PARP1 levels, an effect consistent with that of small molecule PARP1 inhibitors.

[0147] The above results indicate that the PARP1-PROTAC degrader has biological activity in vitro, can degrade PARP1 protein, and inhibits the enzymatic catalytic activity of PARP1.

[0148] (2) PARP1 degraders JPP2 and JPP3 can significantly cause the degradation of PARP1 protein. The degradation rates of JPP2 at 0.1 and 1 μM concentrations were 66.36% and 93.68%, respectively, and the degradation rates of JPP3 at 0.1 and 1 μM concentrations were 73.97% and 27.89%, respectively. In contrast, PARP1 inhibitors AZD2281 and AZD5305 had no effect on the protein content of PARP1.

[0149] Meanwhile, JPP2 and JPP3, in addition to inducing PARP1 protein degradation, can function similarly to PARP1 inhibitors AZD2281 and AZD5305, significantly inhibiting intracellular PARP1 levels. Results are shown below. Figure 3 and Figure 4 .

[0150] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A quinoxaline compound, characterized in that, It is a compound with any of the following structures or a pharmaceutically acceptable salt thereof: JPP-2; JPP-3.

2. The method for preparing the quinoxaline compound according to claim 1, characterized in that, This includes condensing compounds H-7-1 and H-11 to obtain the compound shown in formula (I); Wherein, R is ethyl; Or it may involve a condensation reaction of compound H-7-1 and compound H-15 to obtain the compound shown in formula (I); 。 3. The preparation method according to claim 2, characterized in that, The solvent for the condensation reaction is selected from ethyl acetate, tetrahydrofuran, and... N,N -Dimethylformamide, tetrahydrofuran / ethyl acetate, tetrahydrofuran / N,N Any one or more of the following dimethylformamide solvents; The condensing agent for the condensation reaction is selected from 2-(7-azabenzotriazole)- N,N,N',N' -Tetramethylurea hexafluorophosphate, carbonyl diimidazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, carbonyl diimidazole / 1-hydroxybenzotriazole, carbonyl diimidazole / N- Any one or more of the hydroxysuccinimide condensing agents; The base for the condensation reaction is selected from any one or a mixture of two or more of the following: methylamine, ethylamine, triethylamine, diisopropylethylamine, aniline, dimethylaniline, tetramethylguanidine, 1,8-diazabicycloundec-7-ene (DBU), 4-dimethylaminopyridine, and pyridine. The conditions for the condensation reaction are: stirring at room temperature for 2 to 8 hours.

4. The preparation method according to claim 2 or 3, characterized in that, The compound H-7-1 was prepared by the following method: S1. React the compound shown in Formula III with the compound shown in Formula IV to obtain compound H-1. After hydrogenation reduction, compound H-1 undergoes nitro cyclization to obtain compound H-2. S2 and compound H-2 were subjected to aromatization, reduction and halogenation reactions in sequence to obtain compound H-5; S3,4-(6-methoxycarbonyl-2-pyridyl)piperazine-1-carboxylic acid tert-butyl ester hydrochloride undergoes a substitution reaction with compound H-5 after deprotection of the Boc group, to give compound H-6; compound H-6 is hydrolyzed to give compound H-7-1; ； ； ， ， ， ， ； Wherein, R is ethyl.

5. The preparation method according to claim 4, characterized in that, Step S2 includes: Compound H-2 undergoes an aromatization reaction to yield compound H-3; Compound H-3 was reduced to give compound H-4; compound H-4 was halogenated to give H-5. ， ； Where X is N and Y is NH; Wherein, R is ethyl.

6. The preparation method according to claim 2 or 3, characterized in that, Compound H-11 was prepared by the following method: The compounds S4, V and VI undergo nucleophilic substitution to give compound H-8; compound H-8 is hydrolyzed to give compound H-9. S5. Compound H-9 and 3-amino-2,6-piperidinidone hydrochloride were subjected to a condensation reaction to remove the Boc protecting group, yielding H-11. ； ； ， ， ， 。 7. A pharmaceutical composition, characterized in that, Including the quinoxaline compounds as described in claim 1.

8. A pharmaceutical preparation comprising the quinoxaline compound of claim 1, the quinoxaline compound prepared by any one of claims 2 to 6, or the pharmaceutical composition of claim 7, and pharmaceutically acceptable excipients.

9. The use of the quinoxaline compound of claim 1, the quinoxaline compound prepared by the preparation method of any one of claims 2 to 6, the pharmaceutical composition of claim 7, or the pharmaceutical formulation of claim 8 in any one of the following: (1) Preparation of PARP1 enzyme inhibitors; (2) Preparation of PAPR1 protein degrading agent.

10. The quinoxaline compound according to claim 9, characterized in that, The application To prepare drugs for the prevention and / or treatment of tumors or autoimmune diseases.

11. The application according to claim 10, characterized in that, The tumor includes at least one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, stomach cancer, and liver cancer; The autoimmune diseases mentioned include at least one of the following: rash, pruritus, vitiligo, colitis, thyroiditis, pituitary inflammation, immune pneumonia, arthritis, myasthenia gravis, and peripheral neuropathy.

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