WO2023143236A1 - Composé de 2h-indazole-7-formamide, procédé de préparation, composition pharmaceutique, et application - Google Patents

Composé de 2h-indazole-7-formamide, procédé de préparation, composition pharmaceutique, et application Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
indazole
carboxamide
trifluoromethyl
pyrimidin
piperazin
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PCT/CN2023/072562
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English (en)
Chinese (zh)
Inventor
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/fr

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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

L'invention divulgue un composé de 2H-indazole-7-formamide, un procédé de préparation, une composition pharmaceutique, et une application. La structure du composé est représentée par la formule (I), et comprend un isomère ou un sel pharmaceutiquement acceptable de celui-ci ou un mélange dudit isomère et dudit sel. Le composé et une composition pharmaceutique de celui-ci présentent d'excellentes propriétés pharmacocinétiques in vivo, et présentent des avantages remarquables en tant que médicament prêt à l'emploi. La présente invention a un effet inhibiteur hautement efficace sur PARP7, PRAP1, et une variété de cellules tumorales, un médicament antitumoral préparé peut obtenir un bon effet médicinal sur le niveau moléculaire, le niveau cellulaire et le niveau animal, et présente en particulier une excellente activité antitumorale in vivo contre un cancer du côlon relativement malin, un adénocarcinome pulmonaire et un cancer du sein triple négatif. De plus, le procédé de préparation du composé est simple et facile à mettre en œuvre.
PCT/CN2023/072562 2022-01-26 2023-01-17 Composé de 2h-indazole-7-formamide, procédé de préparation, composition pharmaceutique, et application WO2023143236A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202210094416.9A CN116535395A (zh) 2022-01-26 2022-01-26 2h-吲唑-7-甲酰胺类化合物、制备方法、药物组合物和应用
CN202210094416.9 2022-01-26
CN202210814374.1 2022-07-12
CN202210814374.1A CN117430587A (zh) 2022-07-12 2022-07-12 2h-吲唑-7-甲酰胺类parp7抑制剂和应用

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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)

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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 (fr) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Formes solides d'un inhibiteur de parp7
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 (fr) * 2019-04-29 2020-11-05 Ribon Therapeutics, Inc. Formes solides d'un inhibiteur de parp7
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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