WO2023046158A1 - Composé d'azaquinolinone et son utilisation médicale - Google Patents

Composé d'azaquinolinone et son utilisation médicale Download PDF

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WO2023046158A1
WO2023046158A1 PCT/CN2022/121293 CN2022121293W WO2023046158A1 WO 2023046158 A1 WO2023046158 A1 WO 2023046158A1 CN 2022121293 W CN2022121293 W CN 2022121293W WO 2023046158 A1 WO2023046158 A1 WO 2023046158A1
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methyl
oxo
naphthyridin
ethyl
carboxamide
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PCT/CN2022/121293
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Chinese (zh)
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张文燕
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张文燕
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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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of azaquinolinone compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts of the compounds and medicines with the compounds or their salts as active ingredients. and its use as a PARP1 inhibitor in the treatment of cancer.
  • PARP is a multifunctional protein post-translational modification enzyme widely present in eukaryotic cells.
  • the PARP family has 17 members, and only PARP1, PARP2, and PARP33 are involved in the DNA damage repair process, of which PARP1 is the main member involved in the DNA repair process, while PARP2 and PARP3 are less involved.
  • DNA single-strand breaks persist, which can easily lead to the pause of the replication fork and DNA double-strand breaks, so that damaged DNA replicas appear and gradually accumulate, which can eventually lead to the collapse of the replication fork, and the cell Unable to copy normally.
  • PARP1 is activated during cancer therapy to repair chemotherapeutic drug-induced DNA damage and often leads to drug resistance and persistent tumor growth. Therefore, PARP-1 inhibitors can be used as chemotherapeutic drug enhancers in combination with DNA-damaging chemotherapeutic drugs, and can also be used as a single drug in some tumor types.
  • PARP inhibitors have shown excellent clinical efficacy in patients with homologous recombination-deficient cancers, however, hematological and other toxicities limit the application of these drugs, whether used alone or in combination. Recent literature shows that this part of adverse reactions may be due to the inhibition of PARP2 by marketed PARP inhibitors, and PARP2 is not necessary for the efficacy. Therefore, it is necessary to design selective inhibitors to overcome the side effects of existing PARP inhibitors, and to construct next-generation PARP inhibitors.
  • PARP inhibitors with increased PARP1 selectivity can improve clinical efficacy and reduce side effects.
  • Selective strong inhibition of PARP1 will result in the trapping of PARP1 on DNA, which leads to DNA double-strand breaks (DSBs) by collapsing replication forks in S phase.
  • the azaquinolones described herein surprisingly possess PARP inhibitory activity and are therefore useful in the treatment of diseases and conditions in which PARP function is pathologically significant. Furthermore, the azaquinolones described herein are surprisingly selective for PARP1 over other PARP family members such as PARP2, PARP3, PARP5a and PARP6. In addition, the azaquinolones described herein have low hERG activity.
  • the first object of the present invention is to provide formula (I) compound:
  • R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl
  • R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
  • R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
  • R 3 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, these groups can be replaced by deuterium, halogen, C 1-10 alkoxy , C 3-10 cycloalkyl is optionally substituted;
  • X is independently selected from NR 7 or CR 5 ;
  • X 1 is independently selected from N or CR 4 ;
  • X 2 is independently selected from CR 10 , CHR 10 , N or NR 9 ;
  • X 3 is independently selected from N or CR 6 ;
  • R 4 and R 5 are hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl can be optionally deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl replace;
  • R is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl
  • heterocycle It is a 3-12 membered monoheterocycle, a spiroheterocycle, and a heterocycle, and the heteroatoms are 2-4 nitrogen atoms, oxygen atoms, and sulfur atoms, and the heterocycle can be optionally substituted by R 7 and R 8 ;
  • R 7 and R 8 are independently selected from hydrogen, C 1-3 alkyl, and the carbon atoms connected to R 7 and R 8 can form a 3-6 membered carbocyclic or 4-6 alkane heterocyclic ring, and the heteroatoms are oxygen and sulfur ,Nitrogen atom;
  • R 9 is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl
  • R 10 is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl can be optionally substituted by deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
  • n is independently selected from 0, 1, 2 or 3.
  • the compound has the structure of formula (II):
  • R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl
  • R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
  • R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
  • R 3 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, these groups can be replaced by deuterium, halogen, C 1-10 alkoxy , C 3-10 cycloalkyl is optionally substituted;
  • X 1 is independently selected from N or CR 4 ;
  • X is independently selected from N or CR 5 ;
  • R 4 and R 5 are hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl can be optionally deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl replace;
  • the piperazine ring can be optionally substituted by R 7 and R 8 ;
  • R 7 and R 8 are independently selected from hydrogen, C 1-3 alkyl, and the carbon atoms connected to R 7 and R 8 can form a 3-6-membered carbocyclic ring or a 4-6 heterocyclic ring, and the heteroatoms are oxygen, sulfur, Nitrogen atom;
  • n is independently selected from 0, 1, 2 or 3.
  • compounds of formula (II) include but are not limited to the following structures:
  • the compound has the structure of formula (III):
  • R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl
  • R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
  • R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
  • R 3 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, these groups can be replaced by deuterium, halogen, C 1-10 alkoxy , C 3-10 cycloalkyl is optionally substituted;
  • X is independently selected from N or CR 5 ;
  • X 1 is independently selected from N or CR 4 ;
  • X 2 is independently selected from NR 9 or CHR 10 ;
  • R 4 and R 5 are hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl can be optionally deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl replace;
  • R is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl
  • the piperazine ring can be optionally substituted by R 7 and R 8 ;
  • R 7 and R 8 are independently selected from hydrogen, C 1-3 alkyl, and the carbon atoms connected to R 7 and R 8 can form a 3-6-membered carbocyclic ring or a 4-6 heterocyclic ring, and the heteroatoms are oxygen, sulfur, Nitrogen atom;
  • R 9 is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl
  • R 10 is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl can be optionally substituted by deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
  • n is independently selected from 0, 1, 2 or 3.
  • compounds of formula (III) include but are not limited to the following structures:
  • alkyl refers to a linear or branched alkyl group having 1 to 12 carbon atoms in the chain, examples of the alkyl group include methyl (Me), ethyl (Et), n-propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl (t-Bu), pentyl, isopentyl, tert-amyl, hexyl, isohexyl, and according to the teachings provided by those of ordinary skill in the art and the text Considered to be equivalent to any of the groups in the above examples.
  • alkoxy refers to an alkyl group as defined above bonded to an oxygen atom.
  • the alkoxy group is attached to the parent structure through an oxygen atom.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, eg vinyl, 1-propenyl, 2-propenyl, and the like.
  • C 2-10 alkenyl preferably C 2-6 alkenyl, most preferably C 2-4 alkenyl, most preferably vinyl.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkoxy, alkylamino, halogen, hydroxy, cycloalkane group, heterocycloalkyl, heterocycloalkoxy.
  • amino refers to a -NH2 group or a mono- or dialkylamino group.
  • cycloalkyl refers to saturated and partially saturated, monocyclic, fused polycyclic, bridged polycyclic or exploded polycyclic carbocyclic rings having from 3 to 12 ring atoms per carbon atom.
  • Illustrative examples of cycloalkyl groups include the following entities in the form of appropriate bonding moieties:
  • heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic group heterocyclic ring (ring structure having rings selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur atoms), each heterocyclic ring has 3 to 12 ring atoms.
  • suitable bonding moieties include the following entities in the form of appropriate bonding moieties:
  • aryl refers to a C5-C20 monocyclic, fused bicyclic or fused polycyclic aromatic group ring, free of heteroatoms nitrogen, oxygen, sulfur, etc., and common aromatic groups include but are not limited to , derived from benzene residues, substituted benzenes, naphthalene, anthracene, biphenyl, etc.
  • heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O)m (wherein m is an integer of 0-2), and the remaining ring atoms are carbon.
  • the heterocycloalkyl ring contains 3 to 12 ring atoms, including 1 to 4 heteroatoms, more preferably the heterocycloalkyl ring contains 3 to 10 ring atoms, and more preferably the heterocycloalkyl ring contains 5 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, piperidinyl, morpholinyltetrahydrofuranyl, and the like.
  • Multicyclic heterocycloalkyls include spiro, fused and bridged heterocycloalkyls.
  • Heterocycles may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, haloalkyl, alkoxy, alkylamino, halogen, hydroxy , amino, oxo, alkylamino, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, hydroxyalkyl, carboxyl or carboxylate.
  • halogen means chlorine, fluorine, bromine or iodine.
  • halo represents chloro, fluoro, bromo or iodo.
  • haloalkyl refers to an alkyl group as defined above, which is substituted with one or more halogen atoms.
  • the present invention provides methods for preparing compounds, isomers, and deuterated derivatives of the formula (I), formula (II) or formula (III), see the examples for details.
  • the compound of the present invention if it contains a basic group, it can form a salt with an acid, and the salt of the compound of the present invention can be prepared by methods well known to those skilled in the art.
  • Common salts include organic acid salts and inorganic acid salts.
  • organic acid salts are citrate, fumarate, oxalate, malate, lactate, sulfonate (such as camphorsulfonate, p-toluenesulfonate, methanesulfonic acid Salt, etc.); inorganic acid salts include hydrohalides, sulfates, phosphates, nitrates, etc.
  • lower alkylsulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, etc.
  • arylsulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid, etc.
  • It can form p-toluenesulfonate and benzenesulfonate; it can form corresponding salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; it can form corresponding salts with amino acids , such as glutamic acid or aspartic acid can form glutamate or aspartate; with inorganic acids, such as hydrohalic acid (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), Nitric acid, carbonic acid, sulfuric acid or phosphoric acid can also form corresponding salts.
  • organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid
  • amino acids such as glutamic acid or aspartic acid can form glutamate or aspartate
  • inorganic acids
  • the present invention provides compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts thereof using the structure of formula (I), structure of formula (II) or structure of formula (III) or solvates as the active ingredient.
  • One or more pharmaceutically acceptable carriers may also be contained in the above-mentioned drugs, and the carriers include conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption-promoting Agents, surfactants, adsorption carriers, lubricants, etc., and flavoring agents, sweeteners, etc. can also be added if necessary.
  • the medicine of the present invention can be made into various forms such as tablets, powders, granules, capsules, oral liquids and injections, and the medicines of the above-mentioned dosage forms can be prepared according to conventional methods in the field of pharmacy.
  • the present invention provides compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts thereof with the structure of formula (I), structure of formula (II) or structure of formula (III), providing treatment Use in tumor drugs related to PARP1, the cancer cells are selected from any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal tract cancer, and lung cancer.
  • Fig. 1 is the general structural formula of the compound in the embodiment.
  • step 2 product 7.5 g, Pd/C (10%) 2.5 g in ethanol 100 ml was degassed, flooded with H2 , and the reaction was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered through a pad of celite and the celite was washed with ethyl acetate. After concentration, it was dried under vacuum to obtain 4.8 g of the target compound.
  • Step 4 Ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate
  • step 3 intermediate 4.2g of the step 3 intermediate was dissolved in 40ml of 1,4-dioxane, 4.3g of DDQ was added and the mixture was stirred at reflux for 3 hours. The solvent was removed under reduced pressure, saturated sodium bicarbonate solution was added and the residue was stirred at room temperature for 1 hour. The solid was filtered off, washed with water followed by 10 ml diethyl ether. The resulting solid was dried under vacuum to give 3.6 g of a light brown solid.
  • Step 6 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl- d 3 ) Pyridine-2-carboxamide
  • Step 1 Ethyl 7-ethyl-6-oxo-7,8-dihydro-1,5-naphthyridine-3-carboxylate
  • Example 1 step 2 product 7.0 g, Pd/C (10%) 2 g in ethanol 100 ml was degassed, flooded with hydrogen, and the reaction was stirred at room temperature under H2 atmosphere overnight. The mixture was filtered through a pad of celite and the celite was washed with ethyl acetate. After concentration, it was dried under vacuum to obtain 4.1 g of the target compound.
  • Lithium aluminum hydride 2g was added to tetrahydrofuran 50ml under nitrogen at 0°C over a period of 45min, followed by 1.5g of the step 1 intermediate and the resulting mixture was stirred at 0°C for 2.0 hours.
  • Step 3 5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N -(Methyl-d 3 )pyridine-2-carboxamide
  • Method 1 Dissolve the sample of the compound (see Figure 1 for the general structure) in DMSO, prepare a 10mM mother solution, and then add the compound to the screening system.
  • the detection concentration range of the compound is 0.1nM-10 ⁇ M. Concentrations were repeated in duplicate.
  • the experimental results were converted into the percentage of activity, the drug concentration was taken as the abscissa, and the percentage of enzyme activity corresponding to each concentration was taken as the ordinate, and the dose-effect curve was drawn, and GRAPHPAD PRISM 5 was used for nonlinear regression to calculate the inhibitory effect of the test compound on the PARP-1 enzyme. IC50 values.
  • the specific operation steps are as follows:
  • the inhibitory activity of the target compound on PARP-1 enzyme was tested in a 96-well plate. Each well was pre-coated with histone (20 ug/mL) diluted in 100 uL of PBS buffer (10 mM sodium dihydrogen phosphate, 10 mM disodium hydrogen phosphate, 150 mM sodium chloride, pH 7.4), and incubated overnight at 4°C. Afterwards, 100 ⁇ M NAD+, 25 uM biotinylated NAD+ and 200 nM sDNA diluted in 30 uL buffer (50 mM Tris, 2 mM magnesium chloride, pH 8.0) were added to each well, followed by 5 ⁇ L of test compound or solvent control at different concentrations.
  • PBS buffer 10 mM sodium dihydrogen phosphate, 10 mM disodium hydrogen phosphate, 150 mM sodium chloride, pH 7.4
  • Enzyme activity percentage (OD value administration well-OD value background)/(OD value control well-OD value background) ⁇ 100%PARP1/2trapping
  • Assay buffer composition 10mM phosphate buffer (pH 7.9), 50mM NaCl, 1mM EDTA, 0.05% Brij-35, 1mM DTT.
  • Compound preparation Compounds were dissolved in DMSO and serially diluted. The compound was diluted to the test concentration with assay buffer, and shaken for 15 minutes with a shaking plate apparatus.
  • Enzyme preparation use assay buffer to dilute PARP1/PARP2 enzyme to 4X, and add GST-TB at the same time. Add the prepared enzyme to the experimental plate, 4 ⁇ L per well.
  • DSB DNA preparation use assay buffer to dilute DSB DNA to 4X, and add 4 ⁇ L per well to the experimental plate. Add 4 ⁇ L of the compound to be tested into the experimental plate, and incubate with the enzyme and the like in an incubator at room temperature for 1 hour.
  • NAD preparation Dilute NAD to 4X with assay buffer, add 4 ⁇ L per well to the experimental plate, and incubate at room temperature for 10 minutes.
  • the compound of Example 1 Compared with AZD-5305, the compound of Example 1 has a higher inhibitory effect or capture ability on PARP1.
  • DLD-1BRCA2(-/-), UWB1.289, UWB1.289BRCA1+, MDA-MB-43, cells were cultured in the medium recommended by ATCC.
  • Compound preparation Compounds were dissolved in DMSO and serially diluted. Transfer 40 nL of compound to the assay plate by ECHO.
  • the experimental plate was placed at room temperature for 30 minutes, 20 ⁇ L of detection reagent (Celltiter Glo assay kit) was added, and incubated at room temperature for 30 minutes.
  • detection reagent Celltiter Glo assay kit
  • the compounds of the examples have significant inhibitory effects on the above tumor cells, significantly better than AZD-2281, and also better than AZD-5305.
  • Embodiment 50 rat pharmacokinetic test of embodiment compound of the present invention
  • Example 1 of the present invention Investigate the drug concentration of Example 1 of the present invention in plasma samples after male SD rats were administered intravenously and orally respectively with Example 1 of the present invention, and calculate the pharmacokinetic parameters of the compound.
  • Embodiment 1 of the present invention is self-made.
  • SD rats were purchased from Sibeifu (Beijing) Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0010. The experimental animals were kept in this laboratory. See Table 3 for rat information.
  • Rat test select 6 qualified healthy SD rats, divide into 2 groups, 3 in each group, respectively for oral administration and intravenous administration, before administration 0h, after administration 0.0833 (only applicable to vein), 0.25 At 0.5, 1, 2, 4, 6, 8 and 24 hours, about 0.25 mL of whole blood was collected from the orbital venous plexus of rats, placed in a centrifuge tube containing EDTA-K2 anticoagulant, and placed in crushed ice immediately after collection. Centrifuge at 2000g for 10min within 0.5 hours, divide all the plasma, and place it in another clean centrifuge tube.
  • M Male, male
  • R Rat, rat.
  • F% PO AUC 0 ⁇ t_D_obs /Mean IV AUC 0 ⁇ t_D_obs ⁇ 100.
  • Results The oral exposure of the compound of Example 1 to rats was greater than that of AZD-5305, and the absolute bioavailability was higher than that of AZD-5305.

Abstract

L'invention concerne un composé d'azaquinolinone, un isomère, un solvate, un dérivé deutéré ou un sel pharmaceutiquement acceptable du composé. De plus, l'invention concerne également un médicament utilisant le composé, l'isomère, le solvate, le dérivé deutéré et le sel de celui-ci en tant que principes actifs, et l'utilisation de celui-ci dans la préparation d'un médicament contre des maladies associées à PARP-1, comme le cancer.
PCT/CN2022/121293 2021-09-26 2022-09-26 Composé d'azaquinolinone et son utilisation médicale WO2023046158A1 (fr)

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US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
WO2023227052A1 (fr) * 2022-05-25 2023-11-30 西藏海思科制药有限公司 Inhibiteur de parp dérivé bicyclique et son utilisation
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