WO2023143236A1 - 2h-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用 - Google Patents

2h-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用 Download PDF

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WO2023143236A1
WO2023143236A1 PCT/CN2023/072562 CN2023072562W WO2023143236A1 WO 2023143236 A1 WO2023143236 A1 WO 2023143236A1 CN 2023072562 W CN2023072562 W CN 2023072562W WO 2023143236 A1 WO2023143236 A1 WO 2023143236A1
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indazole
carboxamide
trifluoromethyl
pyrimidin
piperazin
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PCT/CN2023/072562
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English (en)
French (fr)
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徐云根
郝海平
邹毅
古宏峰
许文博
严文昕
汪勇
杨解平
黄磊
王洪
苏宇佩
朱启华
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中国药科大学
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Priority claimed from CN202210094416.9A external-priority patent/CN116535395A/zh
Priority claimed from CN202210814374.1A external-priority patent/CN117430587A/zh
Application filed by 中国药科大学 filed Critical 中国药科大学
Publication of WO2023143236A1 publication Critical patent/WO2023143236A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a class of 2H-indazole-7-carboxamide compounds, a preparation method, a pharmaceutical composition and applications, in particular to a class of 2H-indazole-7-carboxamides which are PARP7 inhibitors and have antitumor activity Compounds, preparation methods, pharmaceutical compositions and applications.
  • PARP7 a member of the monoPARP protein family, is a novel negative regulator of nucleic acid sensors in cells and is overexpressed in a variety of tumor cells. Because cancer cells can use PARP-7 to suppress interferon signaling, making it "hide” from the immune system, many cancer cells rely on PARP-7 for survival. The study found that inhibiting PARP7 can restore intracellular interferon signaling, restore the body's innate and adaptive immunity, and thereby inhibit the growth of cancer cells. In cancer models such as lung cancer and colorectal cancer, PARP7 inhibitors showed durable tumor growth inhibition.
  • RBN-2397 developed by Ribon is the first compound with strong inhibitory activity and selectivity for PARP-7, and it has entered clinical phase I research (NCT04053673).
  • RBN-2397 has a high in vivo clearance rate, resulting in low in vivo exposure and oral bioavailability, and its drug efficacy in animals shows that it is difficult to achieve an anti-tumor effect with a single administration of RBN-2397, which must be combined with CYP450 inhibitors are used in combination to slow down their clearance to be effective.
  • Purpose of the invention Aiming at the shortcomings of the existing compounds such as poor pharmacokinetic properties and difficulty in exerting single-drug effects, the present invention aims to provide a class of 2H-indazole-7- Formamide compound, preparation method, pharmaceutical composition and application.
  • the 2H-indazole-7-carboxamide compound of the present invention has the structure of formula (I), and the compound includes its isomers, pharmaceutically acceptable salts or Their mixture: in:
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0 or 1;
  • R is selected from hydrogen or halogen
  • R 2 or R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl or heterocycloalkyl, cyano, halogen, difluoromethyl, trifluoromethyl , or R 2 and R 3 form a C 3 -C 6 cycloalkyl group together with the connected carbon atoms; the substituents of the C 3 -C 6 cycloalkyl group are selected from hydrogen, methyl, trifluoromethyl, 2, 2-Difluoroethyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetamido, hydroxyl, acetoxy, carboxyl or methoxycarbonyl, the substituent is one or more;
  • a 1 is selected from -NH-, -O-, -CH 2 -, C 3 ⁇ C 6 cycloalkyl or heterocycloalkyl or 5-10 membered aromatic ring or heteroaryl ring; wherein, the C 3 ⁇ C Any position of 6- cycloalkyl or heterocycloalkyl or 5-10 membered aromatic ring or heteroaryl ring is replaced by one or more The following group substitutions: hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, difluoromethylsulfonyl, trifluoromethyl, trifluoromethylsulfonyl, methylsulfonyl, cyano, hydroxyl, Amino, methylamino, dimethylamino, diethylamino, acetamido, formamido, nitro, methoxy or ethoxy;
  • R 5 , R 6 or R 7 are independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, methylamino, dimethylamino, acetamido, carboxyl or methoxy carbonyl;
  • R is selected from aryl, heteroaryl or 1,3-benzodioxanyl substituted at any position by one or more of the following groups: hydrogen, halogen, cyano, trifluoromethyl, 2,2, -Difluoroethyl, C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, aryl, C 1 to C 6 alkoxy, hydroxyl, methoxy, amino, methylamino, di Methylamino, acetylamino, carboxyl, methoxycarbonyl or nitro.
  • n is selected from 0, 1 or 2;
  • R is selected from hydrogen or fluorine
  • R 2 or R 3 are independently selected from hydrogen, methyl, fluorine or ethyl; when R 2 and R 3 are different, the carbon atom connected to R 2 and R 3 is racemic configuration, R configuration or S structure;
  • a 1 is selected from -NH-, -CH 2 -, wherein, X 1 , X 2 or X 3 are each independently selected from CH or N, and R 8 is selected from one or more of hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl, difluoromethanesulfonate Acyl, trifluoromethyl, trifluoromethanesulfonyl, methanesulfonyl, cyano, hydroxyl, amino, methylamino, dimethylamino, diethylamino, acetamido, formamido, nitro, methoxy, or ethyl Oxygen;
  • R4 is selected from Wherein, Y1 and Y2 independently represent CH or N, and R9 is selected from one or more hydrogen, trifluoromethyl, C3 - C6 cycloalkyl, aryl, methyl, fluorine, chlorine, Bromo, cyano, methoxy, methanesulfonyl, 2,2-difluoroethyl or 4-trifluoromethylphenyl.
  • R 2 or R 3 are independently selected from hydrogen or methyl, and when R 2 and R 3 are different, the carbon atom connected to R 2 and R 3 is in a racemic configuration;
  • a 1 is selected from -CH 2 -,
  • R4 is selected from
  • 2H-indazole-7-carboxamide compounds are selected from any of the following compounds:
  • the pharmaceutically acceptable salt of the above-mentioned 2H-indazole-7-carboxamide compound is a salt formed by the above-mentioned compound and an acid, and the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzene Sulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or arginine Wei acid.
  • compound IV is prepared from compound II by dissolving II and III in a solvent and adding an acid-binding agent for substitution reaction.
  • the reaction solvent is N,N-dimethylformamide (DMF), N,N-dimethylacetamide, tetrahydrofuran (THF), 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably DMF;
  • the acid-binding agent is sodium carbonate, potassium carbonate, triethylamine or N,N-diisopropylethylamine (DIPEA), preferably potassium carbonate.
  • Compound V is prepared from compound IV by dissolving IV in a solvent and adding an aqueous alkali solution to carry out hydrolysis reaction.
  • the reaction solvent is THF, methanol, ethanol, acetonitrile or a mixed solvent of any two, preferably a mixed solvent of THF and methanol;
  • the base is sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide.
  • Compound IA is prepared from compound V by dissolving V in a solvent, adding a condensing agent, adding a base and compound VI is obtained by condensation reaction.
  • the solvent is dichloromethane, THF, DMF, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably DMF;
  • the condensing agent is selected from N,N'-carbonyldiimidazole (CDI), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBT), N,N'-dicyclohexylcarbodiimide (DCC) , N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N
  • compound I-B is prepared from compound I-A by dissolving I-A in a solvent and adding a fluorinated reagent for reaction.
  • the reaction solvent is acetic acid, acetonitrile, THF and a mixed solvent of acetonitrile and acetic acid, preferably a mixed solvent of acetic acid and acetonitrile
  • the fluorinated reagent is 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2 ] Octane bis(tetrafluoroborate).
  • the pharmaceutical composition comprises the above-mentioned 2H-indazole-7-carboxamide compound and a pharmaceutically acceptable carrier.
  • 2H-indazole-7-carboxamide compounds can be added with pharmaceutically acceptable carriers to make common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions or injections, and the preparations can be added with spices, sweeteners, Common pharmaceutical excipients such as liquid/solid fillers and diluents.
  • the above-mentioned 2H-indazole-7-carboxamide compounds and their pharmaceutical compositions can be prepared as PARP7 inhibitor antitumor drugs; more specifically, they can be prepared for the treatment of lung squamous adenocarcinoma, Drugs for colon cancer, breast cancer and other cancers.
  • the present invention has the following significant advantages:
  • This type of compound has excellent in vivo pharmacokinetic properties, and its half-life, in vivo exposure and bioavailability have all been significantly improved, and it has significant advantages as a drug;
  • This type of compound has excellent in vivo pharmacodynamic properties, and a lower dose can achieve better tumor suppression activity, especially for colon cancer, lung adenocarcinoma, and triple-negative breast cancer with a high degree of malignancy. inhibitory effect;
  • This type of compound can effectively inhibit the enzyme activity of PARP7, with an optimal IC 50 value of less than 50nM, reaching the nanomolar concentration level; it can also effectively inhibit the enzyme activity of PARP1, with an optimal inhibitory IC 50 value of less than 0.5nM, reaching the picomolar concentration level ; And it has a significant inhibitory effect on the proliferation of various tumor cells, and the IC 50 value for inhibiting the proliferation of tumor cells is optimally less than 0.1 ⁇ M, reaching the nanomolar concentration level;
  • This type of compound and its pharmaceutical composition are widely used and can be prepared as anti-tumor drugs; the drugs can exert drug effects at the molecular level, cellular level and animal level, especially have better pharmacokinetics in vivo pharmacological and pharmacodynamic properties;
  • Fig. 1 is the anti-colon cancer result of compound I-A-20 of the present invention in mice for 14 days;
  • Fig. 2 is the anti-colon cancer result of compound I-A-25 of the present invention for 14 days in mice;
  • Fig. 3 is the anti-lung adenocarcinoma result of compound I-A-20 of the present invention for 21 days in mice;
  • Fig. 4 is the anti-triple-negative breast cancer result of compound I-B-1 of the present invention in mice for 27 days.
  • 10X PBS preparation Weigh 720mg KH 2 PO 4 , 45g NaCl and 5.311g Na 2 HPO 4 12H 2 O and dissolve them in 500mL deionized water, adjust the pH of the system to 7.4, and sterilize at 121°C for 30 minutes. After cooling, place it at 4°C for later use.
  • 1X PBS preparation Dilute 10X PBS 10 times with deionized water, that is, add 1 part of 10X PBS to 9 parts of deionized water to dilute.
  • Wash buffer preparation 1X PBS containing 0.05% Tween-20.
  • 1X PARP buffer preparation (Prepare now) Use deionized water to dilute 10X PARP buffer 10 times, and place it on ice for later use.
  • the compound to be tested was diluted to the desired concentration with 100% DMSO, and then diluted 10 times with 1X PARP buffer to prepare a 10X compound working solution.
  • % Enzyme Activity (RLU(Sample)-RLU(Blank))/(RLU(Pos.Ctrl)-RLU(Blank)) ⁇ 100%;
  • Enzyme inhibition rate 1-% Enzyme Activity
  • PARP-1 enzyme activity assay kit was purchased from BPS Bioscience.
  • the compound sample was dissolved in DMSO to prepare a 10mM mother solution, and then the compound was added to the screening system.
  • the detection concentration range of the compound was 0.1nM-10 ⁇ M, and the compound was diluted according to a 3-fold gradient, and two replicate holes were made for each concentration.
  • reaction buffer Tris*HCl, pH 8.0
  • NAD + biotin-labeled activation DNA
  • PARP-1 enzyme and inhibitor after reacting at room temperature for 1 hour, add 50 ⁇ L of avidin-labeled HRP to each well and react for 30 minutes; then add 100 ⁇ L of HRP substrate, and detect chemiluminescence on a SpectraMax M instrument value.
  • the inhibition rate of PARP1 enzyme activity was calculated as (Lu control-Lu treatment/Lu control) ⁇ 100%.
  • concentration required for 50% inhibition of PARP1 enzymatic activity ( IC50 ) was calculated using Prism GraphPad software using a normalized dose-response fit for non-linear regression.
  • a group of cancer cell lines cultured to the logarithmic growth phase is spread to a 96-well plate at a pre-specified density in a medium containing fetal bovine serum;
  • compounds I-A-20, I-A-23, I-A-39 and I-B-1 of the present invention have strong inhibitory effects on the proliferation of various tumor cells.
  • mice were selected for each compound, and 3 were orally administered (10mg/kg) , 3 intravenous injections (1mg/kg), collected respectively 0 minutes, 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8 hours blood samples, centrifuged (3000 RPM/5 minutes), the collected supernatant was analyzed by LC-MS-MS, and the results were analyzed by winnonlin software. The specific results are shown in Table 4.
  • compounds I-A-8, I-A-20 and I-A-25 of the present invention have good pharmacokinetic properties in ICR mice.
  • Embodiment 9 Study on the pharmacodynamics of compounds in mice
  • CT26 cells colon cancer cells
  • mice with tumor sizes ranging from 55 to 75 mm 3 (average tumor size 63 mm 3 ) were selected and randomly divided into 5 groups of 6 mice based on their tumor volume.
  • the drug was administered with vehicle (0.5% sodium carboxymethyl cellulose, ), compound RBN-2397 (100 mg/kg, 2 days per day) respectively.
  • the compounds I-A-20 and I-A-25 of the present invention have obvious anti-tumor activity on mouse colon cancer. Compared with the positive drug RBN-2397, the compounds I-A-20 and I-A-25 of the present invention can exert better anti-tumor effects at lower doses.
  • NCI-H1373 cells human lung cancer adenocarcinoma cells
  • mice with tumors ranging from 100 to 188 mm 3 were randomized into treatment groups with an average tumor volume of 181 mm 3 .
  • day 0 the day of randomization was defined as day 0
  • treatment was initiated and administered by intragastric administration of vehicle (50% Labrasol) or compound RBN-2397 (30 mg/kg) or compound IA-20 (30 mg/kg ) treatment, once a day for 21 days. Tumor size was measured every three days during the dosing period. The entire study was terminated on day 21, and the drug efficacy results are shown in Figure 3.
  • MDA-MB-231 cells human breast cancer cells
  • 24 mice with tumor sizes ranging from 50 to 100 mm3 were selected and randomly divided into 4 groups of 6 mice based on their tumor volume.
  • the drug was administered with vehicle (0.5% sodium carboxymethylcellulose, gavage), olaparib (50 mg/kg, Once a day, intraperitoneal injection), RBN-2397 (30mg/kg, once a day, intragastric administration), compound IB-1 (12.5mg/kg, once a day, intragastric administration), continuous administration for 27 days. Tumors were measured every three days during the dosing period. The entire study was terminated on day 27, and the drug efficacy results are shown in Figure 4.
  • the compound IB-1 of the present invention has a good anti-tumor effect, and is far superior to the positive drug RBN-2397.

Abstract

本发明公开了一类2H-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用。该类化合物结构如式(I)，其包含其异构体、药学上可接受的盐或它们的混合物。该类化合物及其药物组合物在体内具有优异的药代动力学性质，具有显著的成药优势。对PARP7、PRAP1和多种肿瘤细胞均具有高效的抑制作用，制备的抗肿瘤药物在分子水平、细胞水平及动物水平上均可以发挥良好的药效，尤其是在体内对恶性较高的结肠癌、肺腺癌、三阴性乳腺癌也具有优异的抗肿瘤活性。此外化合物的制备方法简便易行。

Description

2H-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用 技术领域
本发明涉及一类2H-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用，尤其涉及一类作为PARP7抑制剂、具有抗肿瘤活性的2H-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用。
背景技术
研究表明人体大多数的PARP家族成员展现的是monoADP核糖转移酶活性。MonoPARP蛋白家族与癌症、炎症和神经退行性疾病的发展密切相关。PARP7是monoPARP蛋白家族的成员之一，它是一种新的细胞中核酸感应器的负调控因子，其在多种肿瘤细胞中过度表达。由于癌细胞可以借助PARP-7来抑制干扰素信号，而使其“躲藏”在免疫***之外，因此，许多癌细胞都依赖PARP-7而存活。研究发现，抑制PARP7可恢复细胞内的干扰素信号传导，恢复机体的先天和适应性免疫，进而抑制癌细胞的生长。在肺癌、结直肠癌等癌症模型中，PARP7抑制剂表现出持久的肿瘤生长抑制作用。
目前尚未有PARP-7抑制剂被批准上市，Ribon公司开发的RBN-2397是首个对PARP-7具有较强抑制活性和选择性的化合物，目前已进入临床I期研究(NCT04053673)。但是，RBN-2397的体内清除率高，导致在体内的暴露量和口服生物利用度低，且其在动物体内药效表明，单一给以RBN-2397很难起到抗肿瘤作用，其必须与CYP450抑制剂联用来降低其清除速度才能发挥作用。
发明内容
发明目的：针对现有化合物存在的药代动力学性质差、单药难以发挥作用等不足，本发明旨在提供一类抗肿瘤活性、药代动力学性质均优异的2H-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的2H-吲唑-7-甲酰胺类化合物具有式(I)的结构，所述化合物包含其异构体、药学上可接受的盐或它们的混合物：

其中：
n选自0、1、2、3或4；
m选自0或1；
R1选自氢或卤素；
R2或R3分别独立地选自氢、C1～C6烷基、取代的C3～C6环烷基或杂环烷基、氰基、卤素、二氟甲基、三氟甲基，或者R2和R3与所连碳原子一起形成C3～C6环烷基；所述C3～C6环烷基的取代基选自氢、甲基、三氟甲基、2,2-二氟乙基、甲氧基、卤素、氰基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、羟基、乙酰氧基、羧基或甲氧羰基，所述取代基为一个或多个；
A1选自-NH-、-O-、-CH2-、C3～C6环烷基或杂环烷基或者5-10元芳环或杂芳环；其中，所述C3～C6环烷基或杂环烷基或者5-10元芳环或杂芳环的任意位置被一个或多个以 下基团取代：氢、卤素、甲基、乙基、异丙基、二氟甲基、二氟甲磺酰基、三氟甲基、三氟甲磺酰基、甲磺酰基、氰基、羟基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、甲酰氨基、硝基、甲氧基或乙氧基；
A2选自：A2选自 其中，R5、R6或R7分别独立地选自氢、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基或甲氧羰基；
R4选自任意位置被一个或多个以下基团取代的芳基、杂芳基或1,3-苯并二噁烷基：氢、卤素、氰基、三氟甲基、2,2,-二氟乙基、C1～C6的烷基、C3～C6的环烷基、芳基、C1～C6的烷氧基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基、甲氧羰基或硝基。
优选，上述结构中：
n选自0、1或2；
R1选自氢或氟；
R2或R3分别独立地选自氢、甲基、氟或乙基；当R2和R3不同时，与R2和R3相连的碳原子为消旋构型、R构型或S构型；
A1选自-NH-、-CH2-、其中，X1、X2或X3各自独立地选自CH或N，R8选自一个或多个氢、卤素、甲基、乙基、异丙基、二氟甲基、二氟甲磺酰基、三氟甲基、三氟甲磺酰基、甲磺酰基、氰基、羟基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、甲酰氨基、硝基、甲氧基或乙氧基；
A2选自
R4选自其中，Y1和Y2分别独立地代表CH或N，R9选自一个或多个氢、三氟甲基、C3～C6的环烷基、芳基、甲基、氟、氯、溴、氰基、甲氧基、甲磺酰基、2,2-二氟乙基或4-三氟甲基苯基。
更优选，上述结构中：
R2或R3分别独立地选自氢或甲基，当R2和R3不同时，与R2和R3相连的碳原子为消旋构型；
A1选自-CH2-、
A2选自
更优选，上述结构中：
R4选自
更具体地，上述2H-吲唑-7-甲酰胺类化合物选自以下任一化合物：







上述2H-吲唑-7-甲酰胺类化合物的药学上可接受的盐为上述化合物与酸形成的盐，所述酸选自盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸或阿魏酸。
作为本发明涉及的第二方面，上述2H-吲唑-7-甲酰胺类化合物的制备方法为：
(1)当R1为氢时，化合物I-A的制备方法如下：
具体地，由化合物II制备化合物IV，是将II和III溶于溶剂，加入缚酸剂进行取代反应得到。反应溶剂为N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺、四氢呋喃(THF)、1,4-二氧六环、乙二醇二甲醚或乙腈，优选DMF；缚酸剂为碳酸钠、碳酸钾、三乙胺或N,N-二异丙基乙胺(DIPEA)，优选碳酸钾。
由化合物IV制备化合物V，是将IV溶于溶剂，加入碱的水溶液进行水解反应得到。反应溶剂为THF、甲醇、乙醇、乙腈或任意两者的混合溶剂，优选THF与甲醇混合溶剂；碱为氢氧化钠、氢氧化锂或氢氧化钾，优选氢氧化钠。
由化合物V制备化合物I-A，是将V溶于溶剂，加入缩合剂，再加入碱和化合物 VI进行缩合反应得到。溶剂为二氯甲烷、THF、DMF、1,4-二氧六环、乙二醇二甲醚或乙腈，优选DMF；缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和1-羟基苯并***(HOBT)、N,N'-二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)或六氟磷酸苯并***-1-基-氧基三吡咯烷基(PyBop)，优选EDCI和HOBT；碱为三乙胺、碳酸钠、碳酸钾或DIPEA，优选DIPEA。
(2)当R1为氟时，化合物I-B的制备方法如下：
具体地，由化合物I-A制备化合物I-B，是将I-A溶于溶剂，加入氟代试剂反应得到。反应溶剂为乙酸、乙腈、THF以及乙腈和乙酸混合溶剂，优选乙酸和乙腈混合溶剂，所述氟代试剂为1-氯甲基-4-氟-1,4-重氮化双环[2.2.2]辛烷二(四氟硼酸盐)。
上述制备方法合成路线中m、n、A1、Y1、Y2、R2、R3、R6、R7、R9的定义如前所述；将相应的酸与以上方法制备的化合物(I)成盐，即得所述化合物的药学上可接受的盐。
作为本发明涉及的第三方面，药物组合物包含上述2H-吲唑-7-甲酰胺类化合物以及药学上可接受的载体。
上述2H-吲唑-7-甲酰胺类化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第三方面，上述2H-吲唑-7-甲酰胺类化合物及其药物组合物可制备为PARP7抑制剂类抗肿瘤药物；更具体地，可制备为治疗肺鳞腺癌、结肠癌、乳腺癌等癌症的的药物。
有益效果：与现有技术相比，本发明具有如下显著优点：
1、该类化合物具有优异的体内药代动力学性质，半衰期、体内暴露量及生物利用度均得到显著提升，具有显著的成药优势；
2、该类化合物具有优异的体内药效学性质，给予更低的剂量即可实现更优的肿瘤抑制活性，尤其是对恶性程度较高的结肠癌、肺腺癌、三阴性乳腺癌具有显著的抑制作用；
3、该类化合物可有效抑制PARP7酶活性，抑制IC50值最优小于50nM，达到纳摩尔浓度水平；还可有效抑制PARP1酶活性，抑制IC50值最优小于0.5nM，达到皮摩尔浓度水平；并且对多种肿瘤细胞的增殖均有显著的抑制作用，对肿瘤细胞抑制增殖的IC50值最优小于0.1μM，达到纳摩尔浓度水平；
4、该类化合物及其药物组合物应用广泛，可制备为抗肿瘤药物；所述药物在分子水平、细胞水平均及动物水平上均可以发挥药效，尤其是具有更优异的体内药代动力学和药效学性质；
5、化合物制备方法简便可行。
附图说明
图1为本发明的化合物I-A-20在小鼠体内14天的抗结肠癌结果；
图2为本发明的化合物I-A-25在小鼠体内14天的抗结肠癌结果；
图3为本发明的化合物I-A-20在小鼠体内21天的抗肺腺癌结果；
图4为本发明的化合物I-B-1在小鼠体内27天的抗三阴性乳腺癌结果。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1：2-(3-氧代-3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙基)-2H-吲唑-7-甲酰胺(I-A-1)的合成
3-(7-氨甲酰-2H-吲唑-2-基)丙酸乙酯(IV-1)的合成
将化合物1H-吲唑-7-甲酰胺(II)(161.2mg,1.0mmol)溶于DMF(3mL)中，再加入3-溴丙酸乙酯(III-1)(199.1mg,1.1mmol)和碳酸钾(414.0mg,3.0mmol)，90℃反应2小时，薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全，加入10mL水，乙酸乙酯(8mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝1:2)纯化得251.1mg黄色油状物(IV-1)，收率96.1％。ESI-MS[M+H]+262.1。
3-(7-氨甲酰-2H-吲唑-2-基)丙酸(V-1)的合成
将化合物IV-1(234.9mg,0.9mmol)溶于3mL四氢呋喃中，加入甲醇3mL，再加入5mol/L氢氧化钠水溶液2mL，加毕，室温反应1小时，薄层色谱监测(V石油醚：V乙酸乙酯＝1:1)反应完全。加水5mL，乙酸乙酯(6mL×2)萃取，水层用稀盐酸调pH至4，析出白色固体，抽滤，滤饼用5mL水洗涤，收集滤饼，真空干燥得白色固体(V-1)200.5mg，收率95.5％。ESI-MS[M+H]+234.1
4-叔丁基-1-(5-碘嘧啶-2-基)哌嗪甲酸酯(VI-1-1)的合成
将2-氯-5-碘嘧啶(7.2g,0.03mol)溶于25mL的N-甲基吡咯烷酮(NMP)，依次加入哌嗪-1-甲酸叔丁酯(5.6g,0.03mol)和碳酸钾(8.3g,0.06mol)，升温至80℃反应5小时。薄层色谱(V石油醚：V乙酸乙酯＝8:1)监测反应完全，加入100mL水，乙酸乙酯(30mL×4)萃取，合并有机相，并依次用饱和氯化钠溶液(40mL×3)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝15：1)纯化得10.6g黄色固体(VI-1-1)，收率90.6％。ESI-MS[M+H]+391.0
4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羧酸叔丁酯(VI-1-2)的合成
将4-叔丁基-1-(5-碘嘧啶-2-基)哌嗪甲酸酯(11.7g,0.03mol)溶于25mL NMP，加入碘化亚铜(1.2g,0.06mol)，氮气保护，于室温下缓慢滴加2,2-二氟-2-(氟磺酰基)乙酸甲酯(11.6g,0.06mol)，加毕，升温至100℃，反应8小时，薄层色谱(V石油醚：V二氯甲烷：V甲醇＝15:10:2)监测反应完全，加入100mL水，乙酸乙酯(40mL×4)萃取，合并有机相，分别用饱和氯化钠溶液(40mL×3)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，粗品通过硅胶柱层析(V二氯甲烷：V甲醇＝30:1)纯化得8.2g淡黄色固体(VI-1-2)，收率81％。ESI-MS[M+H]+333.2；1H NMR(300MHz,DMSO-d6)δ8.72(s,2H),3.87–3.77(m,4H),3.47–3.37(m,4H),1.47(s,9H).
2-(哌嗪-1-基)-5-三氟甲基嘧啶(VI-1)
将4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羧酸叔丁酯(3.3g,10.0mmol)溶于15mL二氯甲烷，并加入10mL三氟乙酸，室温下搅拌0.5小时后，薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全。浓缩，使用饱和碳酸氢钠水溶液将pH调至7～8，加入二氯甲烷15mL×5萃取，合并有机相，分别使用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩得白色固体(VI-1)2.1g，收率90.1％。ESI-MS[M+H]+233.1；1H NMR(300MHz, DMSO-d6)δ8.52(s,2H),3.87–3.77(m,4H),3.47–3.37(m,4H),1.75(s,1H).
2-(3-氧代-3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙基)-2H-吲唑-7-甲酰胺(I-A-1)的合成
将化合物V-1(186.6mg,0.8mmol)溶于4mL DMF中，依次加入HOBT(135.1mg,1.0mmol)和EDCI(165.1mg,1.0mmol)，室温反应0.5小时，再加入VI-1(186.4mg,0.8mmol)和DIPEA(387.1mg,3.0mmol)，室温反应3小时，薄层色谱监测(V石油醚：V乙酸乙酯＝1:1)反应完全。加水10mL，乙酸乙酯(8mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝1:2)纯化得白色固体(I-A-1)264.1mg，收率73.4％。ESI-MS[M+H]+448.2；1H NMR(300MHz,DMSO-d6)δ8.72(s,2H),8.63(s,1H),8.55(s,1H),8.01–7.92(m,2H),7.82(s,1H),7.21-7.14(m,1H),4.76(t,J＝6.7Hz,2H),3.86-3.73(m,4H),3.60-3.50(m,4H),3.17(t,J＝6.7Hz,2H).
参照化合物I-A-1的制备方法，制备得到以下化合物：




实施例2：3-氟-2-(5-氧代-5-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)戊基)-2H-吲唑-7-甲酰胺(I-B-1)的合成
将化合物I-A-20(475.0mg,1.0mmol)溶于乙酸(2mL)和乙腈(2mL)中，加入1-氯甲基-4-氟-1,4-重氮化双环[2.2.2]辛烷二(四氟硼酸盐)(531.4mg,1.5mmol)，90℃反应1小时，薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全，加入10mL水，乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝1:2)纯化得354.0mg白色固体(I-B-1)，收率71.7％。ESI-MS[M+H]+494.2。
1H NMR(300MHz,DMSO-d6)δ(ppm):8.72(s,2H),8.34(s,1H),8.01-7.97(m,1H),7.92(s,1H),7.89-7.85(m,1H),7.23-7.16(m,1H),4.45(t,J＝7.2Hz,2H),3.84–3.76(m,4H),3.56-3.48(m,4H),2.42(t,J＝7.4Hz,2H),2.00-1.90(m,2H),1.60-1.48(m,2H).
实施例3：2-(5-氧代-5-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)戊基)-2H-吲唑-7-甲酰胺(I-A-20)的合成
3-(7-氨甲酰-2H-吲唑-2-基)丁酸乙酯(IV-3)的合成
将化合物1H-吲唑-7-甲酰胺(II)(161.2g,1.0mol)溶于DMF(1.0L)中，再加入3-溴丁酸乙酯(III-3)(230.0g,1.1mol)，碳酸钾(414.0g,3.0mol)，于90℃反应约2小时，待薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全后，稍冷，抽滤，滤饼用300mL乙酸乙酯洗涤，收集滤液，减压蒸去大部分溶剂，向剩余物中加入1.0L水，用乙酸乙酯(1L×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，得261.5g黄色油状物(IV-3)，收率90.5％。
3-(7-氨甲酰-2H-吲唑-2-基)丁酸(V-3)的合成
将化合物IV-3(260.4g,0.9mol)置于3L三颈瓶中，加入四氢呋喃(800mL)和甲醇(800mL)，搅拌溶解，再加入5mol/L氢氧化钠水溶液(300mL)，加毕，室温反应1小时，薄层色谱监测(V石油醚：V乙酸乙酯＝1:1)反应完全后，减压浓缩，剩余物中加1L水，乙酸乙酯(600mL×2)萃取，水层用稀盐酸调pH至4，析出白色固体，抽滤，滤饼用水(800mL×2)洗涤，收集滤饼，真空干燥得白色固体(V-3)214.2g，收率91.1％。
2-(5-氧代-5-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)戊基)-2H-吲唑-7-甲酰胺(I-A-20)的合成
将化合物V-3(209.0g,0.8mol)溶于900mL DMF中，加入HATU(380.2g,1.0mol)，室温搅拌0.5小时，再加入VI-1(186.4g,0.8mol)和DIPEA(387.1g,3.0mol)，室温反应3小时，待薄层色谱监测(V石油醚：V乙酸乙酯＝1:1)反应完全，加水1.8L，室温搅拌0.5小时，析出白色固体，抽滤，滤饼用水(500mL×2)洗涤，收集滤饼，真空干燥得I-A-20粗品，粗品再加入600mL甲基叔丁基醚，室温搅拌30分钟，抽滤，滤饼用200mL甲基叔丁基醚洗涤，收集滤饼，真空干燥得白色固体(I-A-20)320.1g，收率84.2％。
实施例4：2-(1-氧代-1-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙-2-基)-2H-吲唑-7-甲酰胺(I-A-25)的合成
2-(7-氨基甲酰基-2H-吲唑-2-基)丙酸乙酯(IV-4)的合成
将化合物1H-吲唑-7-甲酰胺(II)(161.2g,1.0mol)溶于DMF(1.0L)中，再加入2-溴丙酸乙酯(III-4)(199.1g,1.1mol)，碳酸钾(414.0g,3.0mol)，于90℃反应约2小时，待薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全后，稍冷，抽滤，滤饼用乙酸乙酯(300mL×2)洗涤，合并滤液，减压蒸去大部分溶剂，向剩余物中加入1.0L水，用乙酸乙酯(800mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，得234.4g黄色油状物(IV-4)，收率89.7％。
2-(7-氨基甲酰基-2H-吲唑-2-基)丙酸(V-4)的合成
将化合物IV-4(230.0g,0.88mol)溶于800mL四氢呋喃中，加入甲醇800mL，再加入5mol/L氢氧化钠水溶液300mL，加毕，室温反应1小时，薄层色谱监测(V石油醚：V乙酸乙酯＝1:1)反应完全。加水1.5L，乙酸乙酯(600mL×2)萃取，水层用稀盐酸调pH至4，析出白色固体，抽滤，滤饼用1.5L水洗涤，收集滤饼，真空干燥得白色固体(V-4)196.6g，收率95.7％。
2-(1-氧代-1-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙-2-基)-2H-吲唑-7-甲酰胺(I-A-25)的合成
将化合物V-4(186.6g,0.8mol)溶于900mL DMF中，加入HATU(380.2g,1.0mol)，室温下搅拌反应0.5小时，再加入VI-1(186.4g,0.8mol)和DIPEA(387.1g,3.0mol)，室温搅拌反应约3小时，待薄层色谱监测(V石油醚：V乙酸乙酯＝1:1)反应完全后，加水1.8L，室温搅拌0.5小时，析出白色固体，抽滤，滤饼用水(500mL×2)洗涤，收集滤饼，真空干燥得I-A-25粗品。向粗品中加入600mL甲基叔丁基醚，室温搅拌1小时，抽滤，滤饼用甲基叔丁基醚(150mL×2)洗涤，收集滤饼，真空干燥得白色固体(I-A-25)300.2g，收率83.8％。
实施例5：化合物对PARP7酶的抑制活性
实验材料：PARP7 Chemiluminescent Assay Kit，BPS Bioscience；DMSO，国药，Nivo，PerkinElmer。
1、实验方法
(1)溶液与缓冲液的配置
10X PBS配制：分别称取720mg KH2PO4，45g NaCl和5.311g Na2HPO4·12H2O溶解在500mL去离子水中，将体系的pH调为7.4，在121℃下灭菌30分钟，冷却后放置于4℃备用。
1X PBS配制：将10X PBS用去离子水稀释10倍，即1份10X PBS加入9份去离子水稀释。
Wash buffer配制：1X PBS含有0.05％Tween-20。
1X PARP buffer配制：(现用现配)使用去离子水将10X PARP buffer进行10倍稀释，放置在冰上备用。
(2)化合物工作液浓度的配制
根据检测要求，将待测化合物用100％DMSO稀释至所需浓度，然后用1X PARP buffer进行10倍稀释，配制成10X的化合物工作液。
(3)实验步骤
a.实验前一天，冰上解冻5X histone mixture；
b.1X histone mixture配制，使用1X PBS将5X histone mixture配制成1X histone mixture；每孔取25μL 1X histone mixture到测试板中，在4℃下孵育过夜；
c.每孔取100μL Blocking buffer加入到测试板中，在25℃下孵育90分钟；
d.结束孵育后，甩干测试板中液体，重复洗板3次；
e.每孔取2.5μL的化合物工作液，按照实验排布图加入到测试板中；阳性对照孔中(Positive control)加入相应体积含有10％DMSO的1X PARP buffer，空白对照(Blank)中加入相应体积的1X PARP buffer；
f.酶完全溶解后，用1X PARP buffer将酶原液稀释到6ng/μL；
g.取10μL每孔酶溶液加入到测试孔板中，空白对照孔加入对应体积的1X PARP buffer，此时酶量为60ng每孔。注意：此步骤需要在冰上操作；
h.向测试板的各个孔中加入12.5μL master mixture(12.5μL master mixture包括1.25μL 10X PARP buffer，1.25μL Opti-PARP 10X Assay mixture和10μL水)；将测试板封膜置于25℃下孵育60分钟；
i.孵育结束后，甩干测试板中的液体，重复洗板3次；
j.将试剂盒中的Streptavidin-HRP用Blocking buffer溶液稀释50倍，每孔各25μL加入到测试板中，在25℃下孵育30分钟；
k.孵育结束后，甩干测试板中的液体，重复洗板3次；
l.按照1:1混合试剂盒中的ELISA ECL Substrate A和ELISA ECL Substrate B，向测试板中加入每孔50μL混合液，并且马上使用Nivo进行Luminescence检测，读取发光值(RLU)；
m.酶率计算：
％Enzyme Activity＝(RLU(Sample)-RLU(Blank))/(RLU(Pos.Ctrl)-RLU(Blank))×100％；
酶抑制率＝1-％Enzyme Activity；
使用Prism GraphPad软件进行IC50拟合。
2、实验结果
具体结果见表1。
表1.受试化合物对PARP7的酶抑制活性数据


注：“+++”为IC50＜0.05μM；“++”为IC50≥0.05μM且＜0.5μM。
如表1所示，本发明的所有测试化合物对PARP7酶均表现出良好的抑制活性，IC50值均达到纳摩尔浓度水平。其中，化合物I-A-3、I-A-8～I-A-9、I-A-11～I-A-17、I-A-19～I-A-25、I-A-28～I-A-29、I-A-31～I-A-39、I-A-41～I-A-42、I-A-44、I-A-46～I-A-48、I-A-50～I-A-51和I-B-1抑制PARP7酶活性的IC50值均小于0.05μM。
实施例6：化合物对PARP1的酶抑制活性
1、实验试剂
PARP-1酶活分析试剂盒购自BPS Bioscience公司。
2、实验方法
将化合物样品用DMSO溶解，配制10mM母液，然后把化合物加到筛选体系中，化合物检测浓度范围是0.1nM～10μM，按照3倍梯度进行稀释，每个浓度做两个复孔。取出已经预包被组蛋白的96孔板，每孔加入以下酶反应体系及不同浓度的抑制剂，包括：50μL的反应缓冲液(Tris*HCl，pH 8.0)，NAD+，生物素标记的活化DNA，PARP-1酶及抑制剂；在室温下反应1小时以后，每孔中加入50μL亲和素标记的HRP，反应30分钟；再加入100μL的HRP底物，在SpectraMax M仪器上检测化学发光值。
PARP1酶活性的抑制率计算为(Lu对照-Lu处理/Lu对照)×100％。使用Prism GraphPad软件使用归一化的剂量反应拟合进行非线性回归，计算出对PARP1酶活性(IC50)抑制50％所需的浓度。
本实验选用已上市PARP1抑制剂奥拉帕尼为阳性对照。
3、实验结果
具体结果见表2。
表2.化合物对PARP1的酶抑制活性数据
如表2所示，本发明的部分化合物不仅对PARP7具有较强的抑制活性，对PARP1也具有较强的抑制活性。
实施例7：化合物对肿瘤细胞的增殖抑制活性
1、实验过程
a.将培养至对数生长期的一组癌细胞系以含胎牛血清的培养基中的预先指定密度涂铺至96孔板中；
b.细胞在24小时后用化合物或媒介(DMSO)，处理，并且收集第0天板用于分析；
c.施药后将96孔板放在37℃、4.5％CO2恒温培养箱中培养，6天后各孔加入20μL 1.0％的MTT噻唑蓝溶液；
d.继续放置于恒温培养箱中，4小时后用吸走上清培养液，每孔加入150μL DMSO，放在脱色摇床上混匀至结晶物溶解；
e.用多功能酶标仪测570nm处吸光度，按照改良寇式法计算IC50值：lgIC50＝Xm-I[P-(3-Pm-Pn)/4]。
2、实验结果
具体结果见表3。
表3.受试化合物对肿瘤细胞的增殖抑制活性

注：“+++”为IC50＜0.1μM；“++”为IC50≥0.1μM且＜1.0μM。
如表3所示，本发明的化合物I-A-20、I-A-23、I-A-39和I-B-1对多种肿瘤细胞的增殖均有较强的抑制作用。
实施例8：化合物的小鼠体内药代动力学研究
实验过程：选定四个受试化合物(RBN-2397、I-A-8、I-A-20和I-A-25)，对每个化合物选用雄性ICR小鼠6只，3只口服给药(10mg/kg)，3只静脉注射(1mg/kg),分别采集0分钟、2分钟、5分钟、10分钟、20分钟、30分钟、60分钟、2小时、4小时、6小时、8小时血样，离心(3000转/5分钟)，采集上清液使用LC-MS-MS进行分析，结果使用winnonlin软件进行分析，具体结果见表4。
表4.受试化合物在ICR小鼠体内的药代动力学数据

IV：表示静脉注射，PO：表示灌胃给药。
如表4所示，本发明的化合物I-A-8、I-A-20和I-A-25在ICR小鼠体内具有良好的药代动力学性质。
实施例9：化合物的小鼠体内药效研究
1、Balb/c小鼠同种移植CT26肿瘤模型实验
在BALB/c小鼠的右侧腹皮下接种CT26细胞(结肠癌细胞)以发展肿瘤。在肿瘤接种后四天，选择肿瘤尺寸在55～75mm3(平均肿瘤尺寸63mm3)范围内的30只小鼠并且基于其肿瘤体积，随机划分为5组，每组6只小鼠。在随机分组后的第二天(将随机分组当天定义为第0天)开始给药，分别用媒介物(0.5％羧甲基纤维素钠，)、化合物RBN-2397(100mg/kg，每天2次，连续14天灌胃给药)、化合物I-A-20(分别为25mg/kg，50mg/kg，100mg/kg，每天2次，连续14天灌胃给药)进行给药，在给药期间每周测量肿瘤尺寸三次。整个研究在第14天终止，其药效结果见图1。
用同样的方法测试化合物I-A-25(分别为12.5mg/kg，50mg/kg，100mg/kg，每天2次，连续14天灌胃给药)的药效，结果见图2.
由图1和图2可见，本发明的化合物I-A-20和I-A-25对小鼠结肠癌具有明显的抗肿瘤活性。相较于阳性药RBN-2397，本发明的化合物I-A-20和I-A-25在更低剂量即可发挥更优的抗肿瘤作用。
2、CB17 SCID小鼠皮下异种移植NCI-H1373肿瘤模型实验
在SCID CB17小鼠的右侧腹皮下接种NCI-H1373细胞(人肺癌腺癌细胞)以发展肿瘤。在肿瘤生长5天后，将具有100～188mm3肿瘤的小鼠随机分为治疗组，其中平均肿瘤体积为181mm3。在随机分组后第二天(将随机分组当天定义为第0天)开始治疗并通过灌胃媒介物(50％Labrasol)或化合物RBN-2397(30mg/kg)或化合物I-A-20(30mg/kg)治疗，一天一次持续21天。在给药期间每三天测量肿瘤尺寸1次。整个研究在第21天终止，其药效结果见图3。
由图3可见，本发明的化合物I-A-20对小鼠肺腺癌具有明显的抗肿瘤作用，且优于阳性药RBN-2397。
3、NSG小鼠皮下异种移植MDA-MB-231肿瘤模型实验
在NSG小鼠的右侧腹皮下接种MDA-MB-231细胞(人乳腺癌细胞)以发展肿瘤。在肿瘤接种后四天，选择肿瘤尺寸在50～100mm3范围内的24只小鼠并且基于其肿瘤体积，随机分为4组，每组6只小鼠。在随机分组后的第二天(将随机分组当天定义为第0天)开始给药，分别用媒介物(0.5％羧甲基纤维素钠，灌胃)、奥拉帕尼(50mg/kg，每天一次，腹腔注射)、RBN-2397(30mg/kg，每天一次，灌胃)、化合物I-B-1(12.5mg/kg，每天一次，灌胃)、连续给药27天。在给药期间每三天测量肿瘤一次。整个研究在第27天终止，其药效结果见图4。
由图4可知，在MDA-MB-231三阴性乳腺癌小鼠异种移植瘤模型中，本发明的化合物I-B-1具有良好的抗肿瘤效果，且远优于阳性药RBN-2397。

Claims (10)

  1. 一种2H-吲唑-7-甲酰胺类化合物，其特征在于，具有式(I)的结构，所述化合物包含其异构体、药学上可接受的盐或它们的混合物：
    其中：
    n选自0、1、2、3或4；
    m选自0或1；
    R1选自氢或卤素；
    R2或R3分别独立地选自氢、C1～C6烷基、取代的C3～C6环烷基或杂环烷基、氰基、卤素、二氟甲基、三氟甲基，或者R2和R3与所连碳原子一起形成C3～C6环烷基；所述C3～C6环烷基的取代基选自氢、甲基、三氟甲基、2,2-二氟乙基、甲氧基、卤素、氰基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、羟基、乙酰氧基、羧基或甲氧羰基，所述取代基为一个或多个；
    A1选自-NH-、-O-、-CH2-、C3～C6环烷基或杂环烷基或者5-10元芳环或杂芳环；其中，所述C3～C6环烷基或杂环烷基或者5-10元芳环或杂芳环的任意位置被一个或多个以下基团取代：氢、卤素、甲基、乙基、异丙基、二氟甲基、二氟甲磺酰基、三氟甲基、三氟甲磺酰基、甲磺酰基、氰基、羟基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、甲酰氨基、硝基、甲氧基或乙氧基；
    A2选自 其中，R5、R6或R7分别独立地选自氢、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基或甲氧羰基；
    R4选自任意位置被一个或多个以下基团取代的芳基、杂芳基或1,3-苯并二噁烷基：氢、卤素、氰基、三氟甲基、2,2-二氟乙基、C1～C6的烷基、C3～C6的环烷基、芳基、C1～C6的烷氧基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基、甲氧羰基或硝基。
  2. 根据权利要求1所述的2H-吲唑-7-甲酰胺类化合物，其特征在于，所述结构中：
    n选自0、1或2；
    R1选自氢或氟；
    R2或R3分别独立地选自氢、甲基、氟或乙基；当R2和R3不同时，与R2和R3相连的碳原子为消旋构型、R构型或S构型；
    A1选自-NH-、-CH2-、其中，X1、X2或X3各自独立地选自CH或N，R8选自一个或多个氢、卤素、甲基、乙基、异丙基、二氟甲基、二氟甲磺酰基、三氟甲基、三氟甲磺酰基、甲磺酰基、氰基、羟基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、甲酰氨基、硝基、甲氧基或乙氧基；
    A2选自
    R4选自其中，Y1或Y2分别独立地代表CH或N，R9选自一个或多个氢、三氟甲基、C3～C6的环烷基、芳基、甲基、氟、氯、溴、氰基、甲氧基、甲磺酰基、2,2-二氟乙基或4-三氟甲基苯基。
  3. 根据权利要求1或2所述的2H-吲唑-7-甲酰胺类化合物，其特征在于，所述结构中：
    R2或R3分别独立地选自氢或甲基，当R2和R3不同时，与R2和R3相连的碳原子为消旋构型；
    A1选自-CH2-、
    A2选自
  4. 根据权利要求1或2所述的2H-吲唑-7-甲酰胺类化合物，其特征在于，所述结构中：
    R4选自
  5. 根据权利要求1或2所述的2H-吲唑-7-甲酰胺类化合物，其特征在于，选自以下任一化合物：
    2-(3-氧代-3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙基)-2H-吲唑-7-甲酰胺(I-A-1)，2-(3-(4-(5-氰基嘧啶-2-基)哌嗪-1-基)-3-氧代丙基)-2H-吲唑-7-甲酰胺(I-A-2)，
    2-(3-氧代-3-((1-(5-(三氟甲基)嘧啶-2-基)哌啶-4-基)氨基)丙基)-2H-吲唑-7-甲酰胺(I-A-3)，
    2-(3-(甲基(1-(5-(三氟甲基)嘧啶-2-基)哌啶-4-基)氨基)-3-氧代丙基)-2H-吲唑-7-甲酰胺(I-A-4)，
    2-(3-(甲基(1-(5-(三氟甲基)嘧啶-2-基)氮杂环丁烷-3-基)氨基)-3-氧代丙基)-2H-吲唑-7-甲酰胺(I-A-5)，
    2-(3-氧代-3-((1-(5-(三氟甲基)嘧啶-2-基)氮杂环丁烷-3-基)氨基)丙基)-2H-吲唑-7-甲酰胺(I-A-6)，
    2-(3-(4-(2,2-二氟苯并[d][1,3]二氧杂-5-基)哌嗪-1-基)-3-氧代丙基)-2H-吲唑-7-甲酰胺(I-A-7)，
    2-(4-氧代-4-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丁基)-2H-吲唑-7-甲酰胺(I-A-8)，
    2-(4-(4-(5-氰基嘧啶-2-基)哌嗪-1-基)-4-氧代丁基)-2H-吲唑-7-甲酰胺(I-A-9)，
    2-(4-氧代-4-((1-(5-(三氟甲基)嘧啶-2-基)哌啶-4-基)氨基)丁基)-2H-吲唑-7-甲酰胺(I-A-10)，
    2-4-(甲基(1-(5-(三氟甲基)嘧啶-2-基)哌啶-4-基)氨基)-4-氧代丁基)-2H-吲唑-7-甲酰胺(I-A-11)，
    2-(4-(甲基(1-(5-(三氟甲基)嘧啶-2-基)氮杂环丁烷-3-基)氨基)-4-氧代丁基)-2H-吲唑-7-甲酰胺(I-A-12)，
    2-(4-氧代-4-((1-(5-(三氟甲基)嘧啶-2-基)氮杂环丁烷-3-基)氨基)丁基)-2H-吲唑-7-甲酰胺(I-A-13)，
    2-(4-(4-(5-甲基嘧啶-2-基)哌嗪-1-基)-4-氧代丁基)-2H-吲唑-7-甲酰胺(I-A-14)，
    2-(4-(4-(5-氟嘧啶-2-基)哌嗪-1-基)-4-氧代丁基)-2H-吲唑-7-甲酰胺(I-A-15)，
    2-(4-氧代-4-(4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-基)丁基)-2H-吲唑-7-甲酰胺(I-A-16)，
    2-(4-氧代-4-(4-(5-(三氟甲基)吡嗪-2-基)哌嗪-1-基)丁基)-2H-吲唑-7-甲酰胺(I-A-17)，
    2-(4-(4-(2,2-二氟苯并[d][1,3]二氧杂-5-基)哌嗪-1-基)-4-氧代丁基)-2H-吲唑-7-甲酰胺(I-A-18)，
    (E)-2-(4-氧代-4-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丁-2-烯-1-基)-2H-吲唑-7-甲酰胺(I-A-19)，
    2-(5-氧代-5-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)戊基)-2H-吲唑-7-甲酰胺(I-A-20)，
    2-(5-(4-(5-甲基嘧啶-2-基)哌嗪-1-基)-5-氧代戊基)-2H-吲唑-7-甲酰胺(I-A-21)，
    2-(4-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-22)，
    2-(3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-23)，
    2-(4-氧代-4-(3-(5-(三氟甲基)嘧啶-2-基)-3,6-二氮杂双环[3.1.1]庚-6-基)丁基)-2H-吲唑-7-甲酰胺(I-A-24)，
    2-(1-氧代-1-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙-2-基)-2H-吲唑-7-甲酰胺(I-A-25)，
    2-(2-(4-(2,2-二氟苯并[d][1,3]二氧杂-5-基)哌嗪-1-基)-2-氧代乙基)-2H-吲唑-7-甲酰胺(I-A-26)，
    2-(1-(4-(2,2-二氟苯并[d][1,3]二氧杂-5-基)哌嗪-1-基)-1-氧代丙-2-基)-2H-吲唑-7-甲酰胺(I-A-27)，
    2-(2-氧代-2-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)乙基)-2H-吲唑-7-甲酰胺(I-A-28)，
    2-(1-(4-(5-甲基嘧啶-2-基)哌嗪-1-基)-1-氧代丙-2-基)-2H-吲唑-7-甲酰胺(I-A-29)，
    2-(1-(4-(5-氟嘧啶-2-基)哌嗪-1-基)-1-氧代丙-2-基)-2H-吲唑-7-甲酰胺(I-A-30)
    2-(1-氟-2-氧代-2-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)乙基)-2H-吲唑-7-甲酰胺(I-A-31)，
    2-(1-氧代-1-(4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-基)丙-2-基)-2H-吲唑-7-甲酰胺(I-A-32)，
    2-(4-氧代-4-(6-(5-(三氟甲基)嘧啶-2-基)-3,6-二氮杂双环[3.1.1]庚-3-基)丁基)-2H-吲唑-7-甲酰胺(I-A-33)，
    2-(1-氧代-1-(3-(5-(三氟甲基)嘧啶-2-基)-3,6-二氮杂环[3.1.1]庚-6-基)丙-2-基)-2H-吲唑-7-甲酰胺(I-A-34)，
    2-(1-氧代-1-(3-(5-(三氟甲基)嘧啶-2-基)-3,8-二氮杂环[3.2.1]辛-8-基)丙-2-基)-2H-吲唑-7-甲酰胺(I-A-35)，
    2-(1-氧代-1-(8-(5-(三氟甲基)嘧啶-2-基)-3,8-二氮杂环[3.2.1]辛-3-基)丙-2-基)-2H-吲 唑-7-甲酰胺(I-A-36)，
    2-(1-氧代-1-(8-(5-(三氟甲基)嘧啶-2-基)-3,8-二氮杂环[3.2.1]辛-3-基)丙-2-基)-2H-吲唑-7-甲酰胺(I-A-37)，
    2-(1-氧代-1-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丁-2-基)-2H-吲唑-7-甲酰胺(I-A-38)，
    2-(4-氟-3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-39)，
    2-(2-氟-5-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-40)，
    2-(6-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)吡啶-2-基)甲基)-2H-吲唑-7-甲酰胺(I-A-41)，
    2-(3-(4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-42)，
    2-(4-氟-3-(4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-43)，
    2-(2-氟-5-(4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-44)，
    2-(3-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊-5-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-45)，
    2-(3-(4-(4-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-46)，
    2-(3-(4-(5-溴嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-47)，
    2-(3-(4-(5-氟嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-48)，
    2-(3-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊-5-基)哌嗪-1-羰基)-4-氟苄基)-2H-吲唑-7-甲酰胺(I-A-49)，
    2-(4-氟-3-(4-(5-氟嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-50)，
    2-(4-氟-3-(4-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-51)，
    2-(5-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊-5-基)哌嗪-1-羰基)-2-氟苄基)-2H-吲唑-7-甲酰胺(I-A-52)，
    2-(6-(4-(2,2-二氟苯并[d][1,3]二氧杂环戊-5-基)哌嗪-1-羰基)吡啶-2-基)甲基)-2H-吲唑-7-甲酰胺(I-A-53)，
    2-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-54)，
    2-(4-氟-3-(4-(嘧啶-2-基)哌嗪-1-羰基)苄基)-2H-吲唑-7-甲酰胺(I-A-55)，
    3-氟-2-(5-氧代-5-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)戊基)-2H-吲唑-7-甲酰胺(I-B-1)，
    3-氟-2-(5-氧代-5-(4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-基)戊基)-2H-吲唑-7-甲酰胺(I-B-2)，
    3-氟-2-(4-氧代-4-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丁基)-2H-吲唑-7-甲酰胺(I-B-3)，
    3-氟-2-(5-(4-(5-甲基嘧啶-2-基)哌嗪-1-基)-5-氧代戊基)-2H-吲唑-7-甲酰胺(I-B-4)，
    3-氟-2-(1-氧代-1-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-基)丙-2-基)-2H-吲唑-7-甲酰胺(I-B-5)。
  6. 根据权利要求1或2所述的2H-吲唑-7-甲酰胺类化合物，其特征在于，所述药学上可接受的盐为所述化合物与酸形成的盐，所述酸选自盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸或阿魏酸。
  7. 一种权利要求1～6任一所述的2H-吲唑-7-甲酰胺类化合物的制备方法，其特征在于，选自以下任一方法：
    (1)当R1为氢时，化合物I-A的制备方法如下；
    (2)当R1为氟时，化合物I-B的制备方法如下：
    其中，m、n、A1、Y1、Y2、R2、R3、R6、R7、R9的定义如权利要求1～5任一所述；
    将相应的酸与以上方法制备的化合物(I)成盐，即得所述化合物的药学上可接受的盐。
  8. 一种药物组合物，其特征在于，包含权利要求1～6任一所述的2H-吲唑-7-甲酰胺类化合物以及药学上可接受的载体。
  9. 一种权利要求1～6任一所述的2H-吲唑-7-甲酰胺类化合物或者权利要求8所述的药物组合物在制备PARP7抑制剂药物中的应用。
  10. 根据权利要求9所述的应用，其特征在于，所述药物为抗肿瘤药物。
PCT/CN2023/072562 2022-01-26 2023-01-17 2h-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用 WO2023143236A1 (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101415686A (zh) * 2006-04-03 2009-04-22 P.安杰莱蒂分子生物学研究所 作为聚(adp-核糖)聚合酶(parp)抑制剂的酰胺取代的吲唑和苯并***衍生物
CN109810098A (zh) * 2017-11-21 2019-05-28 中国药科大学 含有酞嗪-1(2h)-酮结构的parp-1和pi3k双靶点抑制剂
WO2020223229A1 (en) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Solid forms of a parp7 inhibitor
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
CN113045582A (zh) * 2021-02-05 2021-06-29 中国药科大学 Parp-1/pi3k双靶点抑制剂或其药学上可接受的盐及其制备方法与用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101415686A (zh) * 2006-04-03 2009-04-22 P.安杰莱蒂分子生物学研究所 作为聚(adp-核糖)聚合酶(parp)抑制剂的酰胺取代的吲唑和苯并***衍生物
CN109810098A (zh) * 2017-11-21 2019-05-28 中国药科大学 含有酞嗪-1(2h)-酮结构的parp-1和pi3k双靶点抑制剂
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2020223229A1 (en) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Solid forms of a parp7 inhibitor
CN113045582A (zh) * 2021-02-05 2021-06-29 中国药科大学 Parp-1/pi3k双靶点抑制剂或其药学上可接受的盐及其制备方法与用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof

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