WO2023046158A1 - Azaquinolinone compound and medical use thereof - Google Patents

Azaquinolinone compound and medical use thereof 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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French (fr)
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

Provided are an azaquinolinone compound, an isomer, a solvate, a deuterated derivative or a pharmaceutically acceptable salt of the compound. In addition, also provided are a drug using the compound, the isomer, the solvate, the deuterated derivative and the salt thereof as active ingredients, and the use thereof in the preparation of a drug for diseases associated with PARP-1, such as cancer.

Description

氮杂喹啉酮类化合物及其医药用途Azaquinolinone compounds and their medicinal uses 技术领域technical field
本发明涉及一类氮杂喹啉酮类化合物、异构体、溶剂合物、氘代衍生物或该化合物的药学上可接受的盐类和以该化合物或其盐类为活性成分的药物，及其作为PARP1抑制剂在治疗癌症中的用途。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.
背景技术Background technique
PARP是一种广泛存在于真核细胞的多功能蛋白质翻译后修饰酶。在哺乳动物细胞内，PARP家族拥有17个成员，而参与DNA损伤修复过程的成员只有PARP1、PARP2和PARP33个，其中PARP1是参与DNA修复过程的主要成员，而PARP2和PARP3则参与较少。PARP is a multifunctional protein post-translational modification enzyme widely present in eukaryotic cells. In mammalian 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.
而当PARP功能受损或被抑制时，DNA单链断裂持续存在，易导致复制叉的停顿和DNA双链断裂，于是出现受损的DNA复制物并逐步积累，最终可导致复制叉崩溃，细胞无法正常复制。When the PARP function is damaged or inhibited, 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可在癌症治疗过程中被激活以修复化疗药物诱导的DNA损伤并且通常会导致耐药性和持续的肿瘤生长。因此，PARP-1抑制剂可作为化疗药物增强剂与DNA损伤性化疗药物联合使用，在部分肿瘤类型中还能够作为单药使用。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.
除了PARP能够修复损伤DNA之外，细胞内的另外一套修复系统，如抑癌基因BRCA1/2所介导的同源重组途径，可以修复DNA损伤、维持染色体的稳定。恰恰有部分卵巢癌、输卵管癌、原发性腹膜癌等生殖细胞系肿瘤患者携带BRCA1/2突变基因，也就是说存在BRCA1/2缺陷，相应的也就缺乏代偿机制，PARP功能受损或被抑制时，肿瘤细胞也就无法修复DNA损伤，最终导致细胞死亡。In addition to the ability of PARP to repair damaged DNA, another set of repair systems in cells, such as the homologous recombination pathway mediated by the tumor suppressor gene BRCA1/2, can repair DNA damage and maintain chromosome stability. Just some patients with ovarian cancer, fallopian tube cancer, primary peritoneal cancer and other germ cell tumors carry BRCA1/2 mutation gene, that is to say, there is BRCA1/2 deficiency, and the corresponding lack of compensation mechanism, PARP function impairment or When inhibited, tumor cells are unable to repair DNA damage, eventually leading to cell death.
PARP抑制剂在同源重组缺陷癌症患者中已经表现出了优异的临床疗效，然而无论是单药使用还是联合疗法，血液学毒性和其他毒性都限制了这类药物的应用。近期文献表明，这部分不良反应可能来源于已上市PARP抑制剂对于PARP2的抑制，而PARP2并非疗效所必须。因此，设计了选择性抑制剂，旨在克服已有PARP抑制剂的副作用，构建下一代PARP抑制剂非常必要。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家族酶的抑制已被用作使互补DNA修复途径失活而选择性杀伤癌细胞的策略。许多临床前和临床研究已经表明，BRCA1或BRCA2(参与同源重组(HR)而修复双股DNA断裂 (DSB)的关键肿瘤抑制蛋白)的有害改变的肿瘤细胞对DNA修复酶的PARP家族的小分子抑制剂选择性敏感。此类肿瘤的同源重组修复(HRR)途径不足，并且其存活取决于PARP酶的功能。尽管PARP抑制剂疗法主要靶向BRCA突变的癌症，但是PARP抑制剂已在非BRCA突变型肿瘤中进行了临床测试，这些肿瘤表现出同源重组缺陷(HRD)。Inhibition of PARP family enzymes has been used as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have shown that tumor cells with deleterious alterations of BRCA1 or BRCA2 (key tumor suppressor proteins involved in homologous recombination (HR) to repair double-stranded DNA breaks (DSBs)) have a small response to the PARP family of DNA repair enzymes. Molecular inhibitors are selectively sensitive. Such tumors are deficient in the homologous recombination repair (HRR) pathway, and their survival depends on the function of the PARP enzyme. Although PARP inhibitor therapy primarily targets BRCA-mutated cancers, PARP inhibitors have been clinically tested in non-BRCA-mutated tumors that exhibit homologous recombination deficiency (HRD).
与其他临床PARP1/2抑制剂相比，对PARP1选择性提高的PARP抑制剂可提高临床疗效和降低副作用。对PARP1的选择性强抑制将导致PARP1捕获在DNA上，这借由使S期中的复制叉坍塌而导致DNA双股断裂(DSB)。PARP1-DNA捕获后选择性具有HRD的肿瘤细胞的有效。Compared with other clinical PARP1/2 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. Effectiveness of PARP1-DNA capture selectively in tumor cells with HRD.
因此，对于有效且安全的PARP抑制剂存在未满足的医学需求。特别是对PARP1具有选择性抑制剂。Therefore, there is an unmet medical need for effective and safe PARP inhibitors. In particular, it is a selective inhibitor of PARP1.
发明内容Contents of the invention
申请人发现，本文所述的氮杂喹啉酮令人惊讶地具有PARP抑制活性，因此可用于治疗其中PARP功能具有病理学意义的疾病和病症。此外，本文所述的氮杂喹啉酮对PARP1的选择性比具他PARP家族成员(如PARP2、PARP3、PARP5a和PARP6)出人意料地高。此外本文所述的氮杂喹啉酮具有低hERG活性。Applicants have discovered that 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.
本发明的第一个目的是提供式(Ⅰ)化合物：The first object of the present invention is to provide formula (I) compound:
Figure PCTCN2022121293-appb-000001
Figure PCTCN2022121293-appb-000001
异构体、溶剂合物、氘代衍生物及其药学上可接受的盐；Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof;
其中：in:
R独立地选自为氢、氘、卤素、氰基、C 1-10烷基； R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
R 1为C 1-10烷基、C 3-10环烷基，并可被氘任意取代； R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
R 2为独立地选自氢、卤素、C 1-10烷基、卤代C 1-10烷氧基； R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
R 3为独立地选自氢、卤素、C 1-10烷基、C 3-10环烷基、C 1-10烷氧基，这些基团可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自NR 7或CR 5； X is independently selected from NR 7 or CR 5 ;
X 1独立地选自N或CR 4； X 1 is independently selected from N or CR 4 ;
X 2独立地选自CR 10、CHR 10、N或NR 9； X 2 is independently selected from CR 10 , CHR 10 , N or NR 9 ;
X 3独立地选自N或CR 6； X 3 is independently selected from N or CR 6 ;
R 4、R 5为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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 6为氢、氘、卤素、氰基、C 1-10烷基； R is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
Figure PCTCN2022121293-appb-000002
为3-12元单杂环、螺杂环、并杂环，杂原子为2-4个氮原子、氧原子、硫原子，杂环可被R 7、R 8任意取代；
Figure PCTCN2022121293-appb-000002
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、R 8独立地选自氢、C 1-3烷基，R 7、R 8与其相连的碳原子可形成3-6元碳环或4-6烷杂环，杂原子为氧、硫、氮原子； 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为氢、氘、卤素、氰基、C 1-10烷基； R 9 is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
R 10为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自0、1、2或3。n is independently selected from 0, 1, 2 or 3.
异构体、溶剂合物、氘代衍生物及其药学上可接受的盐；Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof;
优选的，所述的化合物具有式(Ⅱ)结构：Preferably, the compound has the structure of formula (II):
Figure PCTCN2022121293-appb-000003
Figure PCTCN2022121293-appb-000003
异构体、溶剂合物、氘代衍生物及其药学上可接受的盐；Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof;
其中：in:
R独立地选自为氢、氘、卤素、氰基、C 1-10烷基； R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
R 1为C 1-10烷基、C 3-10环烷基，并可被氘任意取代； R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
R 2为独立地选自氢、卤素、C 1-10烷基、卤代C 1-10烷氧基； R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
R 3为独立地选自氢、卤素、C 1-10烷基、C 3-10环烷基、C 1-10烷氧基，这些基团可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自N或CR 4； X 1 is independently selected from N or CR 4 ;
X独立地选自N或CR 5； X is independently selected from N or CR 5 ;
R 4、R 5为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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;
哌嗪环可被R 7、R 8任意取代； The piperazine ring can be optionally substituted by R 7 and R 8 ;
R 7、R 8独立地选自氢、C 1-3烷基，R 7、R 8与其相连的碳原子可形成3-6元碳环或4-6杂环，杂原子为氧、硫、氮原子； 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独立地选自0、1、2或3。n is independently selected from 0, 1, 2 or 3.
更具体地，式(Ⅱ)结构的化合物包括但不限于下列结构：More specifically, compounds of formula (II) include but are not limited to the following structures:
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)-6-(二氟甲基)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) -6-(difluoromethyl)pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)-6-(三氟甲基)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) -6-(trifluoromethyl)pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl -d 3 ) pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N-(methyl- d3 ) pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N-methylpyridine- 2-formamide;
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-6-methyl-N -(methyl-d 3 )pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-chloro-N-(methyl -d 3 ) pyridine-2-carboxamide;
6-氟-N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazine- 1-yl) pyridine-2-carboxamide;
N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) Pyridine-2-carboxamide;
6-甲基-N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Methyl-N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazine -1-yl) pyridine-2-carboxamide;
6-氟-N-甲基-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺；6-fluoro-N-methyl-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridine -2-formamide;
5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl -d 3 ) pyridine-2-carboxamide;
5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶 -2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-(methyl -d 3 ) pyridine-2-carboxamide;
(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N-methylpyridine-2-carboxamide;
(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺；(S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N,6-lutidine-2-carboxamide;
(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- 6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
(R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
(R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-3-methylpiperazine-1- Base)-N-(methyl-d 3 )pyridine-2-carboxamide;
(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)- N-methylpyridine-2-carboxamide;
(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )-3-methylpiperazine-1- Base)-N-(methyl-d 3 )pyridine-2-carboxamide;
(R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(R)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N-methylpyridine-2-carboxamide;
(R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
5-((2S，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-((2S,5S)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide;
5-((2S，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-((2S,5S)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
5-((2R，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-((2R,5R)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide;
5-((2R，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-((2R,5R)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
5-((2S，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-((2S,5R)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide;
5-((2S，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-((2S,5R)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
5-((2R，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-((2R,5S)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
S-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； S-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-2-methylpiperazin-1-yl) -N-(methyl-d 3 )pyridine-2-carboxamide;
或S-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺； or S-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-2-methylpiperazin-1-yl )-N-methylpyridine-2-carboxamide;
优选地，所述的化合物具有式(Ⅲ)结构：Preferably, the compound has the structure of formula (III):
Figure PCTCN2022121293-appb-000004
Figure PCTCN2022121293-appb-000004
异构体、溶剂合物、氘代衍生物及其药学上可接受的盐；Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof;
其中：in:
R独立地选自为氢、氘、卤素、氰基、C 1-10烷基； R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
R 1为C 1-10烷基、C 3-10环烷基，并可被氘任意取代； R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
R 2为独立地选自氢、卤素、C 1-10烷基、卤代C 1-10烷氧基； R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
R 3为独立地选自氢、卤素、C 1-10烷基、C 3-10环烷基、C 1-10烷氧基，这些基团可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自N或CR 5； X is independently selected from N or CR 5 ;
X 1独立地选自N或CR 4； X 1 is independently selected from N or CR 4 ;
X 2独立地选自NR 9或CHR 10； X 2 is independently selected from NR 9 or CHR 10 ;
R 4、R 5为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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 6为氢、氘、卤素、氰基、C 1-10烷基； R is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
哌嗪环可被R 7、R 8任意取代； The piperazine ring can be optionally substituted by R 7 and R 8 ;
R 7、R 8独立地选自氢、C 1-3烷基，R 7、R 8与其相连的碳原子可形成3-6元碳环或4-6杂环，杂原子为氧、硫、氮原子； 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为氢、氘、卤素、氰基、C 1-10烷基； R 9 is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
R 10为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自0、1、2或3。n is independently selected from 0, 1, 2 or 3.
更具体地，式(Ⅲ)结构的化合物包括但不限于下列结构：More specifically, compounds of formula (III) include but are not limited to the following structures:
5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide;
6-氯-5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((7-ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methyl Pyridine-2-carboxamide;
5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺；5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N,6- Lutidine-2-carboxamide;
5-(4-((2-乙基-3-氧代-1,2-二氢-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-3-oxo-1,2-dihydro-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-乙基-3-氧代-1,2-二氢-喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-(4-((2-Ethyl-3-oxo-1,2-dihydro-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpyridine-2 - Formamide;
5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide;
5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-N-methyl Pyridine-2-carboxamide;
或5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-甲基-N,6-二甲基吡啶-2-甲酰胺；or 5-(4-((3-ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-methan Base-N,6-dimethylpyridine-2-carboxamide;
其中：in:
专业术语Terminology
术语“烷基”是指链中具有1至12个碳原子的直链或支链的烷基，烷基的实例包括甲基(Me)、乙基(Et)、正丙基、异丙基、丁基、异丁基、仲丁基、叔丁基(t-Bu)、戊基，异戊基、叔戊基、己基，异己基、以及根据本领域普通技术人员和文本所提供的教导认为是相当于上述实例中的任何一种基团。The term "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.
术语“烷氧基”是指键接氧原子的如上定义的烷基。烷氧基经由氧原子连接到母体结构。The term "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.
术语“烯基”指由至少两个碳原子和至少一个碳碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基等。优选C 2-10烯基，优选C 2-6烯基，最优选C 2-4烯基，最佳为乙烯基。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烷氧基、烷基氨基、卤素、羟基、环烷基、杂环烷基、杂环烷氧基。 The term "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. Preferably 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.
术语“氨基”是指-NH 2基团或单或二烷基氨基。 The term "amino" refers to a -NH2 group or a mono- or dialkylamino group.
术语环烷基是指饱和和部分饱和的，单环的、稠合多环的、桥连多环的或爆多环的碳环，每个碳原子具有3至12个环原子数。环烷基的说明性实例包括以下的适当键合部分形式的实体：The term 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:
Figure PCTCN2022121293-appb-000005
Figure PCTCN2022121293-appb-000005
术语“杂芳基”是指单环的、稠合双环的或稠合多环的芳组杂环(环结构具有选自碳原子和至多四个选自氮、氧和硫的杂原子的环原子)，每个杂环具有3至12个环原子。杂芳基的说明性实例包括以下的以适当键合部分形式的实体：The term "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. Illustrative examples of heteroaryl groups include the following entities in the form of appropriate bonding moieties:
Figure PCTCN2022121293-appb-000006
Figure PCTCN2022121293-appb-000006
术语“芳基”是指含C5-C20的单环的、稠合双环的或稠合多环的芳组环，不含杂原子氮、氧、硫等，通常的芳香基团包括但不限于，源自苯的残基、取代的苯、萘、蒽、联苯等。The term "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.
术语“杂环”是指饱和或部分不饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳。优选包括3至12个环原子，其中1～4个杂原子，更优选的杂环烷基环包含3至10个环原子，更优选的杂环烷基环包含5至6个环原子。单环杂环烷基的非限制性实例包含吡咯烷基、哌啶基、吗啉基四氢呋喃基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。杂环可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、卤代烷基、烷氧基、烷基氨基、卤素、羟基、氨基、氧代基、烷氨基、环烷基、杂环烷基、杂环烷氧基、羟烷基、羧基或羧酸酯基。The term "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. Preferably, 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.
术语“卤素”表示氯、氟、溴或碘。术语“卤代”代表氯代，氟代，溴代或碘代。术语“卤代烷基”是指如上所定义的烷基，其被一个或多个卤原子取代。The term "halogen" means chlorine, fluorine, bromine or iodine. The term "halo" represents chloro, fluoro, bromo or iodo. The term "haloalkyl" refers to an alkyl group as defined above, which is substituted with one or more halogen atoms.
第二方面，本发明提供了式(Ⅰ)结构、式(Ⅱ)结构或式(Ⅲ)结构的化合物、异构体、氘代衍生物的制备方法，具体见实施例。In the second aspect, 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.
在本发明所提供的实施方案中，本发明的化合物如含有碱性基团，则可与酸成盐，采用本领域技术人员所熟知的方法可以制备本发明化合物的盐。In the embodiments provided by the present invention, if the compound of the present invention 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.
常见酸盐有有机酸盐、无机酸盐等。通常，比较常用的有机酸盐有枸橼酸盐、富马酸盐、草酸盐、苹果酸盐、乳酸盐、磺酸盐(例如樟脑磺酸盐、对甲苯磺酸盐、甲磺酸盐等)等；无机酸盐有氢卤酸盐、硫酸盐、磷酸盐、硝酸盐等。例如，与低级烷基磺酸，如甲磺酸，三氟甲磺酸等可形成甲磺酸盐、三氟甲磺酸盐；与芳基磺酸，如苯磺酸或对甲苯磺酸等可形成对甲苯磺酸盐、苯磺酸盐；与有机羧酸，如乙酸，富马酸，酒石酸，草酸，马来酸，苹果酸， 琥珀酸或柠檬酸等可形成相应的盐；与氨基酸，如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨酸盐；与无机酸，如氢卤酸(如氢氟酸、氢溴酸、氢碘酸、氢氯酸)，硝酸，碳酸，硫酸或磷酸等也可形成相应的盐。Common salts include organic acid salts and inorganic acid salts. Usually, the more commonly used 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. For example, with lower alkylsulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, etc., can form mesylate, trifluoromethanesulfonate; with 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.
第三方面，本发明提供利用本发明式(I)结构、式(Ⅱ)结构或式(Ⅲ)结构的化合物、异构体、溶剂合物、氘代衍生物或其药学上可接受的盐或溶剂合物为活性成分的药物。在上述药物中还可以含有一种或多种药学上可接受的载体，所述载体包括药学领域的常规稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等，必要时还可以加入香味剂、甜味剂等。本发明药物可以制成片剂、粉剂、粒剂、胶囊、口服液及注射用药等多种形式，上述各剂型的药物均可以按照药学领域的常规方法制备。In a third aspect, 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.
第四方面，本发明提供式(I)结构、式(Ⅱ)结构或式(Ⅲ)结构的化合物、异构体、溶剂合物、氘代衍生物或其药学上可接受的盐，提供治疗与PARP1有关肿瘤药物中的用途，该癌细胞选自乳癌、卵巢癌、胰脏癌、前列腺癌、血液癌、胃肠道癌、肺癌中的任一项。In the fourth aspect, 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.
附图说明Description of drawings
图1为实施例中的化合物的结构通式。Fig. 1 is the general structural formula of the compound in the embodiment.
具体实施方式Detailed ways
下面结合具体实施例，对本发明作进一步详细的阐述，下述实施例不用于限制本发明，仅用于说明本发明。以下实施例中所使用的实验方法如无特殊说明，实施例中未注明具体条件的实验方法，通常按照常规条件，下述实施例中所使用的材料、试剂等，如无特殊说明，均可从商业途径得到。The present invention will be described in further detail below in conjunction with specific examples. The following examples are not intended to limit the present invention, but are only used to illustrate the present invention. The experimental methods used in the following examples, if there is no special instructions, the experimental methods that do not indicate the specific conditions in the examples, generally according to the conventional conditions, the materials, reagents, etc. used in the following examples, if there are no special instructions, all Commercially available.
实施例1、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 1, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000007
Figure PCTCN2022121293-appb-000007
步骤1：6-甲酰基-5-硝基-吡啶-3-甲酸乙酯Step 1: Ethyl 6-formyl-5-nitro-pyridine-3-carboxylate
Figure PCTCN2022121293-appb-000008
Figure PCTCN2022121293-appb-000008
将6-甲基-5-硝基烟酸乙酯(20g，95.2mmol)和二氧化硒16g在1,4-二六环100ml中的混合物在110℃下搅拌20h。将反应混合物冷却至室温，通过硅藻土垫过滤并将硅藻土用乙酸乙酯洗涤。将合并的滤液浓缩，并将所得残余物借由硅胶柱层析法(洗脱梯度为己烷中的0％至70％乙酸乙酯)进行纯化。得到呈棕色油状物17.50g。A mixture of ethyl 6-methyl-5-nitronicotinate (20 g, 95.2 mmol) and 16 g of selenium dioxide in 100 ml of 1,4-dihexane was stirred at 110° C. for 20 h. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the celite was washed with ethyl acetate. The combined filtrates were concentrated and the resulting residue was purified by silica gel column chromatography (elution gradient 0% to 70% ethyl acetate in hexane). This gave 17.50 g of a brown oil.
ESI MS m/z：225.04[M+1] +。 ESI MS m/z: 225.04 [M+1] + .
步骤2：(E)-6-(2-(乙氧羰基)丁基-1-烯-1-基)-5-硝基吡啶-3-甲酸乙酯(E/Z异构的混合物)Step 2: Ethyl (E)-6-(2-(ethoxycarbonyl)butyl-1-en-1-yl)-5-nitropyridine-3-carboxylate (mixture of E/Z isomers)
Figure PCTCN2022121293-appb-000009
Figure PCTCN2022121293-appb-000009
在0℃下，用加料漏斗向氢化钠(60％)9.6g在无水四氢呋喃(100ml)中的搅拌溶液中滴加乙基-(二乙氧基磷酰基)丁酸脂60.8g以给出灰色的混合物。将所得混合物在0℃下搅拌10分钟，加温至室温搅拌50分钟。将反应混合物冷却至-20℃，然后向该冷却的反应混合物中缓慢添加6-甲酰基-5-硝基-吡啶-3-甲酸乙酯22.5g在100ml四氢呋喃中的溶液。将混合物用饱和氯化铵溶液淬灭，用乙酸乙酯萃取。将合并的有机层经硫酸钠干燥，过滤并浓缩以给出粗产物。将所得残余物借由硅胶层析法(洗脱梯度为己烷中的0％至70％乙酸乙酯)进行纯化。将产物级分在减压下浓缩至干燥以得到目标物22.6g(E/Z异构的1:1混合物)。At 0°C, 60.8 g of ethyl-(diethoxyphosphoryl) butyrate was added dropwise to a stirred solution of 9.6 g of sodium hydride (60%) in anhydrous tetrahydrofuran (100 ml) using an addition funnel to give Gray mixture. The resulting mixture was stirred at 0°C for 10 minutes, warmed to room temperature and stirred for 50 minutes. The reaction mixture was cooled to -20°C, and then a solution of 22.5 g of ethyl 6-formyl-5-nitro-pyridine-3-carboxylate in 100 ml of tetrahydrofuran was slowly added to the cooled reaction mixture. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give crude product. The resulting residue was purified by silica gel chromatography (elution gradient 0% to 70% ethyl acetate in hexane). The product fractions were concentrated to dryness under reduced pressure to give target 22.6 g (1:1 mixture of E/Z isomers).
ESI MS m/z：323.13[M+1] +。 ESI MS m/z: 323.13 [M+1] + .
步骤3：7-乙基-6-氧代-7,8-二氢-5H-1,5-萘啶-3-羧酸乙酯Step 3: Ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate
Figure PCTCN2022121293-appb-000010
Figure PCTCN2022121293-appb-000010
将步骤2产物7.5g、Pd/C(10％)2.5g在乙醇100ml中的混合物脱气，用H 2充满，并将反应在室温下在H 2气氛搅拌过夜。将混合物通过硅藻土垫过滤并将硅藻土用乙酸乙酯洗涤。浓缩后，并在真空下干燥得到目标物4.8g。 A mixture of 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.
ESI MS m/z：249.12[M+1] +。 ESI MS m/z: 249.12 [M+1] + .
步骤4：7-乙基-6-氧代-5H-1,5-萘啶-3-羧酸乙酯Step 4: Ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate
Figure PCTCN2022121293-appb-000011
Figure PCTCN2022121293-appb-000011
将步骤3中间体4.2g，溶解于1,4-二氧六环40ml中，添加DDQ 4.3g并将混合物在回流下搅拌3小时。在减压下除去溶剂，添加饱和碳酸氢钠溶液并将残余物在室温下搅拌1小时。将固体过滤出，用水随后10ml二乙醚洗涤。将所得固体在真空下干燥得到呈淡棕色固体3.6g。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.
ESI MS m/z：247.10[M+1] +。 ESI MS m/z: 247.10 [M+1] + .
步骤5：3-乙基-7-(羟甲基)-1H-1,5-萘啶-2-酮Step 5: 3-Ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one
Figure PCTCN2022121293-appb-000012
Figure PCTCN2022121293-appb-000012
在0℃下，将氢化铝锂2g加至四氢呋喃30ml中，然后加入步骤4中间体3.4g，将所得混合物在60℃下搅拌2.0小时。将反应混合物先加5ml乙酸乙酯，滴加适量水淬灭，过滤固体，乙醚洗涤，固体柱层析，在真空下干燥以得到中间体2.3g。At 0°C, 2 g of lithium aluminum hydride was added to 30 ml of tetrahydrofuran, and then 3.4 g of the intermediate in Step 4 was added, and the resulting mixture was stirred at 60°C for 2.0 hours. The reaction mixture was firstly added with 5ml of ethyl acetate, quenched by adding an appropriate amount of water dropwise, the solid was filtered, washed with ether, subjected to solid column chromatography, and dried under vacuum to obtain 2.3 g of the intermediate.
ESI MS m/z：205.09[M+1] +。 ESI MS m/z: 205.09 [M+1] + .
步骤6：5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 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
将二氯亚砜2ml滴加至步骤5中间体2.5g、0.1ml N,N-二甲基甲酰胺在二氯甲烷30ml，室温搅拌3小时，将反应混合物浓缩至干，得到3-乙基-7-(氯甲基)-1,5-萘啶-2(1H)-酮，将3-乙基-7-(氯甲基)-1,5-萘啶-2(1H)-酮、二异丙基乙胺3ml，碘化钾0.2g，N-(甲基-d 3)-5-(哌嗪-1-基)吡啶酰胺2g溶解于乙腈50ml，80℃搅拌2小时，浓缩至干，加入碳酸氢钠水溶液搅拌，乙酸乙酯萃取，水洗，干燥，过滤，残余物柱层析，得到目的物2.3g。 Add 2ml of thionyl chloride dropwise to 2.5g of the intermediate in step 5, 0.1ml of N,N-dimethylformamide in 30ml of dichloromethane, stir at room temperature for 3 hours, and concentrate the reaction mixture to dryness to obtain 3-ethyl -7-(chloromethyl)-1,5-naphthyridin-2(1H)-one, 3-ethyl-7-(chloromethyl)-1,5-naphthyridin-2(1H)-one , 3ml of diisopropylethylamine, 0.2g of potassium iodide, 2g of N-(methyl-d 3 )-5-(piperazin-1-yl)pyridinamide dissolved in 50ml of acetonitrile, stirred at 80°C for 2 hours, and concentrated to dryness , added aqueous sodium bicarbonate solution and stirred, extracted with ethyl acetate, washed with water, dried, filtered, and the residue was subjected to column chromatography to obtain 2.3 g of the target compound.
1H NMR(400MHz,DMSO-d 6)δ11.86(1H,s),8.42-8.40(1H,m),8.38-8.36(1H,m),8.27(1H,d),7.83(1H,d),7.76-7.75(1H,m),7.64-7.62(1H,m),7.41-7.37(1H,m),3.66(2H,s),3.39-3.33(4H,m)2.59-2.53(6H,m),1.18(3H,t). 1 H NMR (400MHz,DMSO-d 6 )δ11.86(1H,s),8.42-8.40(1H,m),8.38-8.36(1H,m),8.27(1H,d),7.83(1H,d ),7.76-7.75(1H,m),7.64-7.62(1H,m),7.41-7.37(1H,m),3.66(2H,s),3.39-3.33(4H,m)2.59-2.53(6H, m), 1.18(3H,t).
ESI MS m/z：410.23[M+1] +。 ESI MS m/z: 410.23 [M+1] + .
实施例2、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)-6-(二氟甲基)吡啶-2-甲酰胺 Example 2, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 )-6-(Difluoromethyl)pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000013
Figure PCTCN2022121293-appb-000013
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：460.23[M+1] +。 ESI MS m/z: 460.23 [M+1] + .
实施例3、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)-6-(三氟甲基)吡啶-2-甲酰胺 Example 3, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 )-6-(trifluoromethyl)pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000014
Figure PCTCN2022121293-appb-000014
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：478.22[M+1] +。 ESI MS m/z: 478.22 [M+1] + .
实施例4、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 4, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N -(Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000015
Figure PCTCN2022121293-appb-000015
参考实施例1方法制备。Prepared with reference to the method of Example 1.
1H NMR(400MHz,DMSO-d 6)δ11.85(1H,s),8.32-8.49(2H,m),7.86(1H,d),7.76(1H,s),7.64(1H,s),7.58(1H,dd),3.66(2H,s),3.19(4H,br s),2.58(4H,br d)2.55(2H,m,与溶剂DMSO峰重叠),1.19(3H,t). 1 H NMR (400MHz,DMSO-d 6 )δ11.85(1H,s),8.32-8.49(2H,m),7.86(1H,d),7.76(1H,s),7.64(1H,s), 7.58(1H,dd),3.66(2H,s),3.19(4H,br s),2.58(4H,br d)2.55(2H,m, overlapping with solvent DMSO peak),1.19(3H,t).
ESI MS m/z：428.22[M+1] +。 ESI MS m/z: 428.22 [M+1] + .
实施例5、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 5, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000016
Figure PCTCN2022121293-appb-000016
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：428.22[M+1 ]+。 ESI MS m/z: 428.22 [M+1 ]+ .
实施例6、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 6, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N- (Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000017
Figure PCTCN2022121293-appb-000017
参考实施例1方法制备。Prepared with reference to the method of Example 1.
1H NMR(400MHz,DMSO-d 6)δ11.83(s,1H),8.40(d,1H),8.35-8.32(s,1H),8.26(d,1H),7.83(d,1H),7.76-7.75(m,1H),7.64-7.62(m,1H),7.38(dd,1H),3.36-3.34(m,overlapped with water 4H),2.61-2.52(m,6H),1.19(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.83(s,1H),8.40(d,1H),8.35-8.32(s,1H),8.26(d,1H),7.83(d,1H), 7.76-7.75(m,1H),7.64-7.62(m,1H),7.38(dd,1H),3.36-3.34(m,overlapped with water 4H),2.61-2.52(m,6H),1.19(t, 3H).
ESI MS m/z：412.24[M+1] +。 ESI MS m/z: 412.24 [M+1] + .
实施例7、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2- 甲酰胺 Example 7, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N- Pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000018
Figure PCTCN2022121293-appb-000018
参考实施例1方法制备。Prepared with reference to the method of Example 1.
1H NMR(400MHz,DMSO-d 6)δ11.84(s,1H),8.41-8.37(m,2H),8.26(d,1H),7.82(d,1H),7.76-7.74(m,1H),7.63-7.61(m,1H),7.38(d,1H),3.36-3.32(m,overlapped with water 4H),2.78(s,3H),2.58-2.52(m,6H),1.18(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.84(s,1H),8.41-8.37(m,2H),8.26(d,1H),7.82(d,1H),7.76-7.74(m,1H ),7.63-7.61(m,1H),7.38(d,1H),3.36-3.32(m,overlapped with water 4H),2.78(s,3H),2.58-2.52(m,6H),1.18(t, 3H).
ESI MS m/z：409.22[M+1 ]+。 ESI MS m/z: 409.22 [M+1 ]+ .
实施例8、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 8, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-6- Methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000019
Figure PCTCN2022121293-appb-000019
参考实施例1方法制备。Prepared with reference to the method of Example 1.
1H NMR(400MHz,DMSO-d 6)δ11.84(s,1H),8.41(d,1H),8.38(bs,1H),7.79(d,1H),7.75(s,1H),7.64-7.61(m,1H),7.48(d,1H),3.00-2.90(m,4H),2.65–2.52(m,6H),2.48(s,3H),1.18(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.84(s,1H),8.41(d,1H),8.38(bs,1H),7.79(d,1H),7.75(s,1H),7.64- 7.61(m,1H),7.48(d,1H),3.00-2.90(m,4H),2.65–2.52(m,6H),2.48(s,3H),1.18(t,3H).
ESI MS m/z：426.22[M+1 ]+。 ESI MS m/z: 426.22 [M+1 ]+ .
实施例9、5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶-2-甲酰胺 Example 9, 5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-chloro-N -(Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000020
Figure PCTCN2022121293-appb-000020
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：444.19[M+1] +。 ESI MS m/z: 444.19 [M+1] + .
实施例10、6-氟-N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 10, 6-fluoro-N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl ) piperazin-1-yl) pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000021
Figure PCTCN2022121293-appb-000021
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：414.21[M+1] +。 ESI MS m/z: 414.21 [M+1] + .
实施例11、N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 11, N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazine- 1-yl)pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000022
Figure PCTCN2022121293-appb-000022
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：396.21[M+1] +。 ESI MS m/z: 396.21 [M+1] + .
实施例12、6-甲基-N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 12, 6-methyl-N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methanol Base) piperazin-1-yl) pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000023
Figure PCTCN2022121293-appb-000023
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：410.23[M+1] +。 ESI MS m/z: 410.23 [M+1] + .
实施例13、6-氟-N-甲基-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺Example 13, 6-fluoro-N-methyl-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazine-1 -yl)pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000024
Figure PCTCN2022121293-appb-000024
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：411.19[M+1] +。 ESI MS m/z: 411.19 [M+1] + .
实施例14、5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 14, 5-(4-((3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000025
Figure PCTCN2022121293-appb-000025
参考实施例1方法制备。Prepared with reference to the method of Example 1.
1H NMR(400MHz,DMSO-d 6)δ11.60-12.11(1H,m),8.75(1H,s),8.41(1H,br d),8.29(1H,br d,),7.77-7.88(1H,m),7.76(s,1H),7.42(1H,br dd),7.34(1H,s),3.75(2H,br s),3.38(4H,br s)2.66(4H,br s),2.54(2H,m),1.18(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.60-12.11(1H,m),8.75(1H,s),8.41(1H,br d),8.29(1H,br d,),7.77-7.88( 1H,m),7.76(s,1H),7.42(1H,br dd),7.34(1H,s),3.75(2H,br s),3.38(4H,br s),2.66(4H,br s), 2.54(2H,m),1.18(t,3H).
ESI MS m/z：410.23[M+1] +。 ESI MS m/z: 410.23 [M+1] + .
实施例15、5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 15, 5-(4-((3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N -(Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000026
Figure PCTCN2022121293-appb-000026
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：428.22[M+1 ]+。 ESI MS m/z: 428.22 [M+1 ]+ .
实施例16、5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶-2-甲酰胺 Example 16, 5-(4-((3-ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-chloro-N -(Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000027
Figure PCTCN2022121293-appb-000027
参考实施例1方法制备。Prepared with reference to the method of Example 1.
1H NMR(400MHz,DMSO-d 6)δ11.94(1H,s),8.74(1H,s),8.43(1H,br d,),7.95(1H,d),7.81(1H,s),7.68(1H,s),7.33(1H,s),3.72(2H,br s),3.15(4H,br s)2.65(4H,br s),2.54(2H,m与溶剂DMSO峰重叠),1.18(t,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.94(1H,s),8.74(1H,s),8.43(1H,br d,),7.95(1H,d),7.81(1H,s), 7.68 (1H, s), 7.33 (1H, s), 3.72 (2H, br s), 3.15 (4H, br s), 2.65 (4H, br s), 2.54 (2H, m overlapped with solvent DMSO peak), 1.18 (t,3H).
ESI MS m/z：444.19[M+1] +。 ESI MS m/z: 444.19 [M+1] + .
实施例17、(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 17, (S)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazine-1 -yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000028
Figure PCTCN2022121293-appb-000028
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：421.23[M+1] +。 ESI MS m/z: 421.23 [M+1] + .
实施例18、(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 18, (S)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazine-1 -yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000029
Figure PCTCN2022121293-appb-000029
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：424.25[M+1] + ESI MS m/z: 424.25[M+1] +
实施例19、(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺Example 19, (S)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazine-1 -yl)-N,6-dimethylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000030
Figure PCTCN2022121293-appb-000030
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：435.24[M+1] +。 ESI MS m/z: 435.24 [M+1] + .
实施例20、(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 20, (S)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazine-1 -yl)-6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000031
Figure PCTCN2022121293-appb-000031
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：438.26[M+1] +。 ESI MS m/z: 438.26 [M+1] + .
实施例21、(R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 21, (R)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazine-1 -yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000032
Figure PCTCN2022121293-appb-000032
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：424.25[M+1] + ESI MS m/z: 424.25[M+1] +
实施例22、(R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 22, (R)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-3-methylpiper Azin-1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000033
Figure PCTCN2022121293-appb-000033
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：426.26[M+1] +。 ESI MS m/z: 426.26 [M+1] + .
实施例23、(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 23, (S)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazine-1 -yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000034
Figure PCTCN2022121293-appb-000034
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：421.23[M+1] +。 ESI MS m/z: 421.23 [M+1] + .
实施例24、(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 24, (S)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazine-1 -yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000035
Figure PCTCN2022121293-appb-000035
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：424.25[M+1] + ESI MS m/z: 424.25[M+1] +
实施例25、(S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 25, (S)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-3-methylpiper Azin-1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000036
Figure PCTCN2022121293-appb-000036
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：426.26[M+1] +。 ESI MS m/z: 426.26 [M+1] + .
实施例26、(R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 26, (R)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazine-1 -yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000037
Figure PCTCN2022121293-appb-000037
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：421.23[M+1] +。 ESI MS m/z: 421.23 [M+1] + .
实施例27、(R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 27, (R)-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazine-1 -yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000038
Figure PCTCN2022121293-appb-000038
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：424.25[M+1] +。 ESI MS m/z: 424.25 [M+1] + .
实施例28、5-((2S，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 28, 5-((2S,5S)-4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethyl (Piperazin-1-yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000039
Figure PCTCN2022121293-appb-000039
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：434.24[M+1] +。 ESI MS m/z: 434.24 [M+1] + .
实施例29、5-((2S，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 29, 5-((2S,5S)-4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethyl Basepiperazin-1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000040
Figure PCTCN2022121293-appb-000040
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：438.26[M+1] +。 ESI MS m/z: 438.26 [M+1] + .
实施例30、5-((2R，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 30, 5-((2R,5R)-4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethyl (Piperazin-1-yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000041
Figure PCTCN2022121293-appb-000041
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：435.24[M+1] +。 ESI MS m/z: 435.24 [M+1] + .
实施例31、5-((2R，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 31, 5-((2R,5R)-4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethyl Basepiperazin-1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000042
Figure PCTCN2022121293-appb-000042
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：438.26[M+1] +。 ESI MS m/z: 438.26 [M+1] + .
实施例32、5-((2S，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 32, 5-((2S,5R)-4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethyl (Piperazin-1-yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000043
Figure PCTCN2022121293-appb-000043
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：435.54[M+1] +。 ESI MS m/z: 435.54 [M+1] + .
实施例33、5-((2S，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 33, 5-((2S,5R)-4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethyl Basepiperazin-1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000044
Figure PCTCN2022121293-appb-000044
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：438.26[M+1] +。 ESI MS m/z: 438.26 [M+1] + .
实施例34、5-((2R，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 34, 5-((2R,5S)-4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethyl Basepiperazin-1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000045
Figure PCTCN2022121293-appb-000045
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：438.26[M+1] +。 ESI MS m/z: 438.26 [M+1] + .
实施例35、S-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 35, S-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )-2-methylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000046
Figure PCTCN2022121293-appb-000046
参考实施例1方法制备。Prepared with reference to the method of Example 1.
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),8.43-8.39(m,1H),8.37-8.32(m,1H),8.18(d,1H),7.82(d,1H),7.73(s,1H),7.66-7.64(m,1H),7.34-7.28(m,1H),4.24-4.17(m,1H),3.62-3.54(m,1H),3.11-3.03(m,1H),2.95-2.88(m,1H),2.72-2.68(m,1H),2.58–2.50(m,2H),2.36-2.28(m,1H),2.25-2.19(m,1H),1.18(t,3H),1.12(d,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.88(s,1H),8.43-8.39(m,1H),8.37-8.32(m,1H),8.18(d,1H),7.82(d,1H ),7.73(s,1H),7.66-7.64(m,1H),7.34-7.28(m,1H),4.24-4.17(m,1H),3.62-3.54(m,1H),3.11-3.03(m ,1H),2.95-2.88(m,1H),2.72-2.68(m,1H),2.58–2.50(m,2H),2.36-2.28(m,1H),2.25-2.19(m,1H),1.18 (t,3H),1.12(d,3H).
ESI MS m/z：426.26[M+1] +。 ESI MS m/z: 426.26 [M+1] + .
实施例36、S-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺 Example 36, S-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )-2-methylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000047
Figure PCTCN2022121293-appb-000047
参考实施例1方法制备。Prepared with reference to the method of Example 1.
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),8.42-8.39(m,1H),8.37-8.33(m,1H),8.19(d,1H),7.81(d,1H),7.74(s,1H),7.67-7.64(m,1H),7.34-7.29(m,1H),4.25-4.17(m,1H),3.61-3.55(m,1H),3.11-3.03(m,1H),2.95-2.89(m,1H),2.77(d,3H),2.73-2.68(m,1H),2.57–2.51(m,2H),2.36-2.29(m,1H),2.26-2.18(m,1H),1.17(t,3H),1.11(d,3H). 1 H NMR (400MHz,DMSO-d 6 )δ11.88(s,1H),8.42-8.39(m,1H),8.37-8.33(m,1H),8.19(d,1H),7.81(d,1H ),7.74(s,1H),7.67-7.64(m,1H),7.34-7.29(m,1H),4.25-4.17(m,1H),3.61-3.55(m,1H),3.11-3.03(m ,1H),2.95-2.89(m,1H),2.77(d,3H),2.73-2.68(m,1H),2.57–2.51(m,2H),2.36-2.29(m,1H),2.26-2.18 (m,1H),1.17(t,3H),1.11(d,3H).
ESI MS m/z：423.24[M+1] +。 ESI MS m/z: 423.24 [M+1] + .
实施例37、5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 37, 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
Figure PCTCN2022121293-appb-000048
Figure PCTCN2022121293-appb-000048
步骤1：7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-羧酸乙酯Step 1: Ethyl 7-ethyl-6-oxo-7,8-dihydro-1,5-naphthyridine-3-carboxylate
Figure PCTCN2022121293-appb-000049
Figure PCTCN2022121293-appb-000049
将实施例1步骤2产物7.0g、Pd/C(10％)2g在乙醇100ml中的混合物脱气，用氢气充满，并将反应在室温下在H 2气氛搅拌过夜。将混合物通过硅藻土垫过滤并将硅藻土用乙酸乙酯洗涤。浓缩后，并在真空下干燥得到目标物4.1g。 A mixture of 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.
ESI MS m/z：249.12[M+1] +。 ESI MS m/z: 249.12 [M+1] + .
步骤2：3-乙基-7-(羟甲基)-3,4-二氢-1H-1,5-萘啶-2-酮Step 2: 3-Ethyl-7-(hydroxymethyl)-3,4-dihydro-1H-1,5-naphthyridin-2-one
Figure PCTCN2022121293-appb-000050
Figure PCTCN2022121293-appb-000050
在0℃下经45min的时间段在氮气下，将氢化铝锂2g加至四氢呋喃50ml中，然后加入步骤1中间体1.5g，将所得混合物在0℃下搅拌2.0小时。将反应混合物先加5ml乙酸乙酯，滴加适量水淬灭，过滤除去固体，乙醚洗涤，滤液干燥(无水硫酸钠)，过滤，滤液浓缩得到固体，用乙醚洗涤，在真空下干燥以得到中间体0.8g。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. Add 5ml of ethyl acetate to the reaction mixture, quench it by adding an appropriate amount of water dropwise, remove the solid by filtration, wash with ether, dry the filtrate (anhydrous sodium sulfate), filter, concentrate the filtrate to obtain a solid, wash with ether, and dry under vacuum to obtain Intermediate 0.8g.
ESI MS m/z：207.11[M+1] +。 ESI MS m/z: 207.11 [M+1] + .
步骤3：5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 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
将二氯亚砜2ml滴加至步骤2中间体0.6g、0.1ml N,N-二甲基甲酰胺在二氯甲烷30ml，室温搅拌3小时，将反应混合物浓缩至干，得到3-乙基-7-(氯甲基)-3,4-二氢-1H-1,5-萘啶-2-酮，将3-乙基-7-(氯甲基)-3,4-二氢-1,5-萘啶-2(1H)-酮、二异丙基乙胺3ml，N-(甲基-d 3)-5-(哌嗪-1-基)吡啶酰胺2g溶解于乙腈50ml，80℃搅拌2小时，浓缩至干，加入碳酸氢钠水溶液搅拌，乙酸乙酯萃取，水洗，干燥，过滤，残余物柱层析，得到目的物0.3g。 Add 2ml of thionyl chloride dropwise to 0.6g of the intermediate in step 2, 0.1ml of N,N-dimethylformamide in 30ml of dichloromethane, stir at room temperature for 3 hours, and concentrate the reaction mixture to dryness to obtain 3-ethyl -7-(chloromethyl)-3,4-dihydro-1H-1,5-naphthyridin-2-one, 3-ethyl-7-(chloromethyl)-3,4-dihydro- 1,5-Naphthyridin-2(1H)-one, 3ml of diisopropylethylamine, 2g of N-(methyl-d 3 )-5-(piperazin-1-yl)pyridinamide dissolved in 50ml of acetonitrile, Stir at 80°C for 2 hours, concentrate to dryness, add aqueous sodium bicarbonate solution and stir, extract with ethyl acetate, wash with water, dry, filter, and the residue is column chromatographed to obtain 0.3 g of the target compound.
ESI MS m/z：412.25[M+1] +。 ESI MS m/z: 412.25 [M+1] + .
实施例38、5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 38, 5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-Methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000051
Figure PCTCN2022121293-appb-000051
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：426.26[M+1] +。 ESI MS m/z: 426.26 [M+1] + .
实施例39、6-氯-5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 39, 6-chloro-5-(4-((7-ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1 -yl)-6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000052
Figure PCTCN2022121293-appb-000052
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：446.21[M+1] +。 ESI MS m/z: 446.21 [M+1] + .
实施例40、5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 40, 5-(4-((7-ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000053
Figure PCTCN2022121293-appb-000053
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：409.23[M+1] +。 ESI MS m/z: 409.23 [M+1] + .
实施例41、5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺Example 41, 5-(4-((7-ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- N,6-Lutidine-2-carboxamide
Figure PCTCN2022121293-appb-000054
Figure PCTCN2022121293-appb-000054
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：423.24[M+1] +。 ESI MS m/z: 423.24 [M+1] + .
实施例42、5-(4-((2-乙基-3-氧代-1,2-二氢-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 42, 5-(4-((2-Ethyl-3-oxo-1,2-dihydro-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000055
Figure PCTCN2022121293-appb-000055
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：412.25[M+1] +。 ESI MS m/z: 412.25 [M+1] + .
实施例43、5-(4-((2-乙基-3-氧代-1,2-二氢-喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 43, 5-(4-((2-Ethyl-3-oxo-1,2-dihydro-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-methyl Pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000056
Figure PCTCN2022121293-appb-000056
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：409.23[M+1] +。 ESI MS m/z: 409.23 [M+1] + .
实施例44、5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 44, 5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000057
Figure PCTCN2022121293-appb-000057
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：412.25[M+1] +。 ESI MS m/z: 412.25 [M+1] + .
实施例45、5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 45, 5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)- 6-Methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121293-appb-000058
Figure PCTCN2022121293-appb-000058
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：426.26[M+1] +。 ESI MS m/z: 426.26 [M+1] + .
实施例46、5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 46, 5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)- N-methylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000059
Figure PCTCN2022121293-appb-000059
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：409.23[M+1] +。 ESI MS m/z: 409.23 [M+1] + .
实施例47、5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-甲基-N,6-二甲基吡啶-2-甲酰胺Example 47, 5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)- 6-Methyl-N,6-dimethylpyridine-2-carboxamide
Figure PCTCN2022121293-appb-000060
Figure PCTCN2022121293-appb-000060
参考实施例37方法制备。Prepared with reference to the method of Example 37.
ESI MS m/z：423.24[M+1] +。 ESI MS m/z: 423.24 [M+1] + .
实施例48、化合物对PARP的抑制作用Example 48, the inhibitory effect of the compound on PARP
方法1：将化合物(结构通式见图1)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。实验结果换算成活性百分率，将药物浓度作为横坐标，各浓度对应酶活性百分率作为纵坐标，描绘量效曲线，使用GRAPHPAD PRISM 5做非线性回归，计算得到受试化合物对PARP-1酶抑制的IC 50值。具体操作步骤如下： 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-10μM. 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:
在96孔板中测试目标化合物对PARP-1酶的抑制活性。各孔预涂稀释在100uL PBS缓冲液(10mM磷酸二氢钠，10mM磷酸氢二钠，150mM氯化钠，pH 7.4)中的组蛋白(20ug/mL)，4℃下培养过夜。之后，每孔加入稀释在30uL缓冲液(50mM Tris，2mM氯化镁，pH 8.0)中的100μM的NAD+，25uM生物素化的NAD+和200nM sDNA，然后加入不同浓度的5μL受试化合物或溶剂对照。30℃下每孔加入20uL(5ng)PARP-1，1h后加入50uL HRP，培养30min后再加100μL缓冲液(0.1M H 2O 2柠檬酸盐缓冲液，pH 5.4)终止反应，在SpectraMax M5仪器上检测化学发光值。按下列公式计算酶活性百分率： 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 μM 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 μL of test compound or solvent control at different concentrations. Add 20uL (5ng) PARP-1 to each well at 30°C, add 50uL HRP after 1h, add 100μL buffer (0.1M H 2 O 2 citrate buffer, pH 5.4) after incubation for 30min to terminate the reaction, and use the SpectraMax M5 instrument Chemiluminescence values were detected. Calculate the percentage of enzyme activity according to the following formula:
酶活性百分率(％)＝(OD值给药孔-OD值本底)/(OD值对照孔-OD值本底)×100％PARP1/2trappingEnzyme activity percentage (%)=(OD value administration well-OD value background)/(OD value control well-OD value background)×100%PARP1/2trapping
方法2：实验方案Method 2: Experimental Protocol
Assay buffer成分：10mM磷酸盐缓冲液(pH 7.9)，50mM NaCl，1mM EDTA，0.05％Brij-35，1mM DTT。Assay buffer composition: 10mM phosphate buffer (pH 7.9), 50mM NaCl, 1mM EDTA, 0.05% Brij-35, 1mM DTT.
化合物准备：通过DMSO溶解化合物，并且梯度稀释。使用assay buffer将化合物稀释到测试浓度，震板仪震荡15min。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.
酶准备：使用assay buffer将PARP1/PARP2酶稀释为4X，同时加入GST-TB。将准备好的酶加入到实验板中，4μL每孔。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 μL per well.
DSB DNA准备：使用assay buffer将DSB DNA稀释为4X，每孔4μL加入到实验板中。待测化合物每孔4μL加入到实验板中，与酶等在室温培养箱共同孵育1小时。DSB DNA preparation: use assay buffer to dilute DSB DNA to 4X, and add 4 μL per well to the experimental plate. Add 4 μL 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准备：使用assay buffer将NAD稀释为4X，每孔4μL加入到实验板中，室温孵育10分钟。NAD preparation: Dilute NAD to 4X with assay buffer, add 4 μL per well to the experimental plate, and incubate at room temperature for 10 minutes.
检测：通过Envision2105读取最终数值。Detection: read the final value by Envision2105.
实验结果见表1。The experimental results are shown in Table 1.
表1受试化合物在酶水平对PARP-1IC 50值 Table 1 test compound at the enzyme level to PARP-1 IC 50 value
Figure PCTCN2022121293-appb-000061
Figure PCTCN2022121293-appb-000061
Figure PCTCN2022121293-appb-000062
Figure PCTCN2022121293-appb-000062
注：+表示IC 50值在50nM下。 Note: + indicates IC50 value at 50nM.
实施例1化合物较AZD-5305对PARP1有较高的抑制作用或捕获能力。Compared with AZD-5305, the compound of Example 1 has a higher inhibitory effect or capture ability on PARP1.
实施例49、化合物对人肿瘤细胞的增殖抑制作用Example 49, Compound's Proliferation Inhibitory Effect on Human Tumor Cells
细胞准备：DLD-1BRCA2(-/-)、UWB1.289、UWB1.289BRCA1+、MDA-MB-43，细胞通过ATCC推荐培养基进行培养。Cell preparation: DLD-1BRCA2(-/-), UWB1.289, UWB1.289BRCA1+, MDA-MB-43, cells were cultured in the medium recommended by ATCC.
化合物准备：通过DMSO溶解化合物，并且梯度稀释。通过ECHO转移40nL化合物到实验板中。Compound preparation: Compounds were dissolved in DMSO and serially diluted. Transfer 40 nL of compound to the assay plate by ECHO.
选择合适细胞密度进行种板，40μL均匀加入实验板中，37℃培养箱中孵育7天。Select the appropriate cell density to seed the plate, add 40 μL evenly to the experimental plate, and incubate in a 37°C incubator for 7 days.
实验板于室温中放置30分钟，加入20μL检测试剂(Celltiter Glo assay kit)，室温孵育30分钟。The experimental plate was placed at room temperature for 30 minutes, 20 μL of detection reagent (Celltiter Glo assay kit) was added, and incubated at room temperature for 30 minutes.
检测：通过Envision2105读取最终数值。Detection: read the final value by Envision2105.
结果：实施例化合物对上述肿瘤细胞均具有显著的抑制作用，显著优于AZD-2281，也优于AZD-5305。Results: 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.
表2受试化合物对人肿瘤细胞的增殖抑制作用IC 50值 Table 2 IC50 value of the test compound on the proliferation inhibitory effect of human tumor cells
Figure PCTCN2022121293-appb-000063
Figure PCTCN2022121293-appb-000063
Figure PCTCN2022121293-appb-000064
Figure PCTCN2022121293-appb-000064
注：+表示IC 50值在30nM下。 Note: + indicates IC50 value at 30nM.
实施例50、本发明实施例化合物大鼠药代动力学试验Embodiment 50, rat pharmacokinetic test of embodiment compound of the present invention
1.试验目的1. Purpose of the test
考察雄性SD大鼠分别静脉和口服给予本发明实施例1后，血浆样品中本发明实施例1的药物浓度，计算该化合物的药代动力学参数。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.
2.材料和方法2. Materials and Methods
2.1动物试验2.1 Animal testing
2.2供试药2.2 Test drug
本发明实施例1，自制。Embodiment 1 of the present invention is self-made.
2.3给药制剂2.3 Administration preparation
静脉和口服给药溶液配制：Solution preparation for intravenous and oral administration:
称量5.383mg本发明实施例1化合物置于EP管中，之后加入DMSO 0.538mL、NMP0.538mL、Solutol 1.615mL和生理盐水8.075mL(比例为5:5:15:75,v/v/v/v)，涡旋超声使其充分溶解，最终实际浓度为0.500mg·mL-1的无色澄清溶液。Weigh 5.383mg of the compound of Example 1 of the present invention and place it in an EP tube, then add DMSO 0.538mL, NMP0.538mL, Solutol 1.615mL and normal saline 8.075mL (the ratio is 5:5:15:75, v/v/v /v), vortex and sonicate to fully dissolve, and the final actual concentration is a colorless and clear solution of 0.500mg·mL-1.
5.383mg×100％÷10.766mL＝0.500mg·mL -1 5.383mg×100%÷10.766mL＝0.500mg·mL -1
2.4实验动物2.4 Experimental animals
SD大鼠，购自斯贝福(北京)生物技术有限公司，实验动物生产许可证号：SCXK(京)2019-0010。该实验动物饲养于本实验室。大鼠信息见表3。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.
表3大鼠信息Table 3 Rat Information
Figure PCTCN2022121293-appb-000065
Figure PCTCN2022121293-appb-000065
2.5动物试验设计2.5 Design of animal experiments
大鼠试验，选择合格的健康SD大鼠6只，分成2组，每组3只，分别用于口服和静脉给药，于给药前0h，给药后0.0833(只适用于静脉)，0.25，0.5，1，2，4，6，8和24小时于大鼠眼眶静脉丛采集全血约0.25mL，置于含有EDTA-K2抗凝的离心管中，采集后即刻放置于碎冰中。0.5小时内在2000g条件下离心10min，分装全部血浆，置于另一干净离心管内。取血时注意2小时以内样品(含2小时)的实际取血时间应在理论取血时间±1分钟内，两小时后样品的实际取血时间应在理论取血时间±5分钟内，血浆样品运输条件为冰盒运输。大鼠试验条件见表4。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. When taking blood, note that the actual blood collection time for samples within 2 hours (including 2 hours) should be within ±1 minute of the theoretical blood collection time, and the actual blood collection time for samples after two hours should be within ±5 minutes of the theoretical blood collection time. Samples were transported in ice boxes. The experimental conditions of rats are shown in Table 4.
表4大鼠试验条件Table 4 Rat test conditions
Figure PCTCN2022121293-appb-000066
Figure PCTCN2022121293-appb-000066
注：M：Male，雄性；R：Rat，大鼠。Note: M: Male, male; R: Rat, rat.
根据相关SOP进行口服和静脉给药。Oral and intravenous administration according to relevant SOP.
2.6全血样品的收集2.6 Collection of whole blood samples
按照动物试验设计表中规定的时间点，给药后从SD大鼠眼眶静脉丛采集全血约0.25mL，置于含有EDTA-K2的1.5mL离心管中。收集到的全血在2000g，4℃条件下离心10min，分装全部血浆，置于另一干净离心管内，即刻置于-20℃冰箱保存，待测。According to the time points specified in the animal experiment design table, about 0.25 mL of whole blood was collected from the orbital venous plexus of SD rats after administration, and placed in a 1.5 mL centrifuge tube containing EDTA-K2. The collected whole blood was centrifuged at 2000g at 4°C for 10 minutes, all the plasma was divided into another clean centrifuge tube, and immediately stored in a -20°C refrigerator until testing.
3.试验结果3. Test results
试验结果见表5。The test results are shown in Table 5.
表5 SD大鼠单次口服给予后血浆中实施例1的药代动力学参数(5mg·kg -1,N＝3) Table 5 Pharmacokinetic parameters of Example 1 in SD rats after single oral administration (5 mg·kg -1 , N=3)
Figure PCTCN2022121293-appb-000067
Figure PCTCN2022121293-appb-000067
Figure PCTCN2022121293-appb-000068
Figure PCTCN2022121293-appb-000068
注：F％＝PO AUC 0～t_D_obs/Mean IV AUC 0～t_D_obs×100。 Note: F%=PO AUC 0～t_D_obs /Mean IV AUC 0～t_D_obs ×100.
结果：实施例1化合物大鼠口服给药暴露量大于AZD-5305，绝对生物利用度较AZD-5305更高。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.
最后应当说明的是，以上内容仅用以说明本发明的技术方案，而非对本发明保护范围的限制，本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换，均不脱离本发明技术方案的实质和范围。Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent replacements to the technical solution of the present invention by those skilled in the art will not depart from the present invention. The essence and scope of the technical solution of the invention.

Claims (14)

  1. 式(Ⅰ)结构化合物：Formula (I) structural compound:
    Figure PCTCN2022121293-appb-100001
    Figure PCTCN2022121293-appb-100001
    异构体、溶剂合物、氘代衍生物及其药学上可接受的盐；Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof;
    其中：in:
    R独立地选自为氢、氘、卤素、氰基、C 1-10烷基； R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
    R 1为C 1-10烷基、C 3-10环烷基，并可被氘任意取代； R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
    R 2为独立地选自氢、卤素、C 1-10烷基、卤代C 1-10烷氧基； R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
    R 3为独立地选自氢、卤素、C 1-10烷基、C 3-10环烷基、C 1-10烷氧基，这些基团可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自NR 7或CR 5； X is independently selected from NR 7 or CR 5 ;
    X 1独立地选自N或CR 4； X 1 is independently selected from N or CR 4 ;
    X 2独立地选自CR 10、CHR 10、N或NR 9； X 2 is independently selected from CR 10 , CHR 10 , N or NR 9 ;
    X 3独立地选自N或CR 6； X 3 is independently selected from N or CR 6 ;
    R 4、R 5为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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 6为氢、氘、卤素、氰基、C 1-10烷基； R is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
    Figure PCTCN2022121293-appb-100002
    为3-12元单杂环、螺杂环、并杂环，杂原子为2-4个氮原子、氧原子、硫原子，杂环可被R 7、R 8任意取代；
    Figure PCTCN2022121293-appb-100002
    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、R 8独立地选自氢、C 1-3烷基，R 7、R 8与其相连的碳原子可形成3-6元碳环或4-6烷杂环，杂原子为氧、硫、氮原子； 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为氢、氘、卤素、氰基、C 1-10烷基； R 9 is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
    R 10为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自0、1、2或3。n is independently selected from 0, 1, 2 or 3.
  2. 根据权利要求1所述的化合物，其特征在于，所述的化合物具有式(Ⅱ)结构：The compound according to claim 1, characterized in that, the compound has the structure of formula (II):
    Figure PCTCN2022121293-appb-100003
    Figure PCTCN2022121293-appb-100003
    异构体、溶剂合物、氘代衍生物及其药学上可接受的盐；Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof;
    其中：in:
    R独立地选自为氢、氘、卤素、氰基、C 1-10烷基； R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
    R 1为C 1-10烷基、C 3-10环烷基，并可被氘任意取代； R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
    R 2为独立地选自氢、卤素、C 1-10烷基、卤代C 1-10烷氧基； R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
    R 3为独立地选自氢、卤素、C 1-10烷基、C 3-10环烷基、C 1-10烷氧基，这些基团可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自N或CR 4； X 1 is independently selected from N or CR 4 ;
    X独立地选自N或CR 5； X is independently selected from N or CR 5 ;
    R 4、R 5为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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;
    哌嗪环可被R 7、R 8任意取代； The piperazine ring can be optionally substituted by R 7 and R 8 ;
    R 7、R 8独立地选自氢、C 1-3烷基，R 7、R 8与其相连的碳原子可形成3-6元碳环或4-6杂环，杂原子为氧、硫、氮原子； 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独立地选自0、1、2或3。n is independently selected from 0, 1, 2 or 3.
  3. 根据权利要求2所述的化合物，其特征在于，所述的式(Ⅱ)化合物包括但不限于下列结构：The compound according to claim 2, characterized in that, the compound of formula (II) includes but is not limited to the following structures:
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)-6-(二氟甲基)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) -6-(difluoromethyl)pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)-6-(三氟甲基)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) -6-(trifluoromethyl)pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl -d 3 ) pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N-(methyl- d3 ) pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-N-methylpyridine- 2-formamide;
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl-d 2 )piperazin-1-yl)-6-methyl-N -(methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-chloro-N-(methyl -d 3 ) pyridine-2-carboxamide;
    6-氟-N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazine- 1-yl) pyridine-2-carboxamide;
    N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) Pyridine-2-carboxamide;
    6-甲基-N-(甲基-d 3)-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Methyl-N-(methyl-d 3 )-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazine -1-yl) pyridine-2-carboxamide;
    6-氟-N-甲基-5-(4-((7-甲基-6-氧代-5H-1,5-萘啶-3-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺；6-fluoro-N-methyl-5-(4-((7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridine -2-formamide;
    5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
    5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl -d 3 ) pyridine-2-carboxamide;
    5-(4-((3-乙基-2-氧代-1H-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-1H-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-chloro-N-(methyl -d 3 ) pyridine-2-carboxamide;
    (S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N-methylpyridine-2-carboxamide;
    (S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
    (S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺；(S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N,6-lutidine-2-carboxamide;
    (S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- 6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
    (R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
    (R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-3-methylpiperazine-1- Base)-N-(methyl-d 3 )pyridine-2-carboxamide;
    (S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)- N-methylpyridine-2-carboxamide;
    (S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-3-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-3-methylpiperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
    (S)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-3-甲基哌嗪-1-基)-N-(甲 基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-3-methylpiperazine-1- Base)-N-(methyl-d 3 )pyridine-2-carboxamide;
    (R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(R)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N-methylpyridine-2-carboxamide;
    (R)-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2-methylpiperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
    5-((2S，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-((2S,5S)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide;
    5-((2S，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-((2S,5S)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
    5-((2R，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-((2R,5R)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide;
    5-((2R，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-((2R,5R)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
    5-((2S，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-((2S,5R)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide;
    5-((2S，5R)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-((2S,5R)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
    5-((2R，5S)-4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基)-2,5-二甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-((2R,5S)-4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl)-2,5-dimethylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
    S-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； S-5-(4-((7-Ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-2-methylpiperazin-1-yl) -N-(methyl-d 3 )pyridine-2-carboxamide;
    或S-5-(4-((7-乙基-6-氧代-5H-1,5-萘啶-3-基)甲基-d 2)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺； or S-5-(4-((7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl- d 2 )-2-methylpiperazin-1-yl )-N-methylpyridine-2-carboxamide;
    异构体、溶剂合物、氘代衍生物及其药学上可接受的盐。Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof.
  4. 根据权利要求1所述的化合物，其特征在于，所述的化合物具有式(Ⅲ)结构：The compound according to claim 1, characterized in that, the compound has the structure of formula (III):
    Figure PCTCN2022121293-appb-100004
    Figure PCTCN2022121293-appb-100004
    异构体、溶剂合物、氘代衍生物及其药学上可接受的盐；Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof;
    其中：in:
    R独立地选自为氢、氘、卤素、氰基、C 1-10烷基； R is independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
    R 1为C 1-10烷基、C 3-10环烷基，并可被氘任意取代； R 1 is C 1-10 alkyl, C 3-10 cycloalkyl, and can be optionally substituted by deuterium;
    R 2为独立地选自氢、卤素、C 1-10烷基、卤代C 1-10烷氧基； R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, halogenated C 1-10 alkoxy;
    R 3为独立地选自氢、卤素、C 1-10烷基、C 3-10环烷基、C 1-10烷氧基，这些基团可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自N或CR 5； X is independently selected from N or CR 5 ;
    X 1独立地选自N或CR 4； X 1 is independently selected from N or CR 4 ;
    X 2独立地选自NR 9或CHR 10； X 2 is independently selected from NR 9 or CHR 10 ;
    R 4、R 5为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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 6为氢、氘、卤素、氰基、C 1-10烷基； R is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
    哌嗪环可被R 7、R 8任意取代； The piperazine ring can be optionally substituted by R 7 and R 8 ;
    R 7、R 8独立地选自氢、C 1-3烷基，R 7、R 8与其相连的碳原子可形成3-6元碳环或4-6杂环，杂原子为氧、硫、氮原子； 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为氢、氘、卤素、氰基、C 1-10烷基； R 9 is hydrogen, deuterium, halogen, cyano, C 1-10 alkyl;
    R 10为氢、氘、卤素、氰基、C 1-10烷基，C 1-10烷基可被氘、卤素、C 1-10烷氧基、C 3-10环烷基任意取代； 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独立地选自0、1、2或3。n is independently selected from 0, 1, 2 or 3.
  5. 根据权利要求4所述的化合物，其特征在于，所述的式(Ⅲ)化合物包括但不限于下列结构：The compound according to claim 4, wherein the compound of formula (III) includes but is not limited to the following structures:
    5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide;
    6-氯-5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((7-ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)- 6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methyl Pyridine-2-carboxamide;
    5-(4-((7-乙基-6-氧代-7,8-二氢-1,5-萘啶-3-基)甲基)哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺；5-(4-((7-Ethyl-6-oxo-7,8-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N,6- Lutidine-2-carboxamide;
    5-(4-((2-乙基-3-氧代-1,2-二氢-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-3-oxo-1,2-dihydro-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-乙基-3-氧代-1,2-二氢-喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-(4-((2-Ethyl-3-oxo-1,2-dihydro-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-methylpyridine-2 - Formamide;
    5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；5-(4-((3-Ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-N-methyl Pyridine-2-carboxamide;
    或5-(4-((3-乙基-2-氧代-3,4-二氢-1,6-萘啶-7-基)甲基)哌嗪-1-基)-6-甲基-N,6-二甲基吡啶-2-甲酰胺；or 5-(4-((3-ethyl-2-oxo-3,4-dihydro-1,6-naphthyridin-7-yl)methyl)piperazin-1-yl)-6-methan Base-N,6-dimethylpyridine-2-carboxamide;
    异构体、溶剂合物、氘代衍生物及其药学上可接受的盐。Isomers, solvates, deuterated derivatives and pharmaceutically acceptable salts thereof.
  6. 一种药物组合物，其包含权利要求1-5任意所述的化合物、异构体、氘代衍生物或其药学上可接受的盐。A pharmaceutical composition comprising the compound, isomer, deuterated derivative or pharmaceutically acceptable salt thereof according to any one of claims 1-5.
  7. 根据权利要求6所述的组合物，其进一步地包含药学上可接受的载体、赋性剂、稀释剂或它们的组合。The composition according to claim 6, further comprising a pharmaceutically acceptable carrier, excipient, diluent or a combination thereof.
  8. 根据权利要求7所述的药物组合物，用于在癌症的治疗中使用。The pharmaceutical composition according to claim 7, for use in the treatment of cancer.
  9. 根据权利要求8所述的药物组合物，其中所述癌症缺乏HR依赖性DNA DSB修复途径。The pharmaceutical composition according to claim 8, wherein the cancer lacks the HR-dependent DNA DSB repair pathway.
  10. 根据权利要求8所述的药物组合物，其中所述癌细胞具有BRCA1或BRCA2缺陷表现型。The pharmaceutical composition according to claim 8, wherein the cancer cells have a BRCA1 or BRCA2 deficient phenotype.
  11. 根据权利要求8所述的药物组合物，其中所述癌症对于编码HR依赖性DNA DSB修复途径的组分的基因中的突变系杂合的。The pharmaceutical composition of claim 8, wherein the cancer is heterozygous for mutations in genes encoding components of the HR-dependent DNA DSB repair pathway.
  12. 根据权利要求8所述的药物组合物，其中所述癌症对于BRCA1和/或BRCA2中的突变系杂合的。The pharmaceutical composition according to claim 8, wherein the cancer is heterozygous for mutations in BRCA1 and/or BRCA2.
  13. 根据权利要求8所述的药物组合物，其中该癌细胞包括但不限于乳癌、卵巢癌、胰脏癌、前列腺癌、血液癌、胃肠道癌和肺癌。The pharmaceutical composition according to claim 8, wherein the cancer cells include but not limited to breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.
  14. 根据权利要求8-13所述的药物组合物，在制备预防或者治疗与PARP-1有关疾病药物中的用途。Use of the pharmaceutical composition according to claims 8-13 in the preparation of drugs for preventing or treating diseases related to PARP-1.
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