WO2023046149A1 - Quinoxaline compound and medicinal use thereof - Google Patents

Quinoxaline compound and medicinal use thereof Download PDF

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WO2023046149A1
WO2023046149A1 PCT/CN2022/121260 CN2022121260W WO2023046149A1 WO 2023046149 A1 WO2023046149 A1 WO 2023046149A1 CN 2022121260 W CN2022121260 W CN 2022121260W WO 2023046149 A1 WO2023046149 A1 WO 2023046149A1
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methyl
quinoxalin
oxo
pyridine
piperazin
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PCT/CN2022/121260
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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
    • 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

Definitions

  • the present invention relates to a class of quinoxaline compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts of the compounds and drugs 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 PARP3 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 quinoxalines described herein surprisingly possess PARP inhibitory activity and are therefore useful in the treatment of diseases and conditions in which PARP function is of pathological significance. Furthermore, the quinoxaline compounds described herein are surprisingly selective for PARP1 over other PARP family members such as PARP2, PARP3, PARP5a and PARP6. In addition, the quinoxalines described herein have advantageously low hERG activity.
  • the first object of the present invention is to provide formula (I) compound:
  • R is hydrogen, 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, C 1-10 alkoxy, and can be optionally substituted by halogen, C 1-C3 alkyl, C 1-10 alkoxy, deuterium;
  • 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;
  • R 4 is hydrogen, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl, which can be optionally substituted by deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
  • R 5 is hydrogen, C 1-10 alkyl, and the carbon atom connected to R 5 has 2 substituents, it can form a 3-6 membered ring with the carbon atom connected to it;
  • n is independently selected from 0, 1, 2 or 3;
  • compounds of formula (I) 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. C2-10 alkenyl is preferred, C2-6 alkenyl is preferred, C2-4 alkenyl is most preferred, vinyl is most preferred. 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 heterocyclic ring (the ring structure has carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur ring 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 the usual aromatic groups include, but Without limitation, residues derived from benzene, substituted benzenes, naphthalene, anthracene, biphenyl, and the like.
  • 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), see 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.
  • Corresponding salts can also be formed with inorganic acids, such as hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid.
  • the present invention provides a drug using the compound, isomer, solvate, deuterated derivative or pharmaceutically acceptable salt or solvate thereof of the formula (I) structure of the present invention as an active ingredient.
  • One or more pharmaceutically acceptable carriers may also be contained in the above-mentioned drugs, and the carriers include conventional diluents in the pharmaceutical field, 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 in the above 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) for use in drugs for treating tumors related to PARP1, and these tumors are selected from Any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.
  • step 1 intermediate Add 5g of step 1 intermediate, 5.96g of piperazine-1-carboxylate tert-butyl ester into 60ml of 1,4-dioxane, add 18g of cesium carbonate, add 1.25g of Ruphos Pd G3 under nitrogen protection, and add 1.25g of Ruphos Pd G3 under nitrogen protection.
  • the reaction was stirred overnight at 80°C. After the reaction was completed, 50 ml of water was added to quench the reaction, passed through diatomaceous earth, and washed with 40 ml of 1,4-dioxane. The filtrate was collected and concentrated under reduced pressure to remove 1,4-dioxane.
  • step 2 Add 5.3g of the intermediate of step 2 into 10ml of tetrahydrofuran, dissolve 0.59g of sodium hydroxide in 10ml of water and add to the system, and react at room temperature for 4 hours. After completion of the reaction, THF was removed by concentration under reduced pressure. Adjust the pH to 2 with concentrated hydrochloric acid, extract three times with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter with suction, and concentrate to dryness under reduced pressure to obtain 4.9 g of the target compound.
  • step 3 middle 1.23 g of deuterated methylamine hydrochloride into 15 ml of ethyl acetate.
  • the reactant was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure to dryness, and obtained 4.2 g of the product.
  • Xphos Pd G2 (1.121g, 1.43mmol) was added to step 3 intermediate 7.7g and (tributyltin base)methanol 10.0g in 1,4-dioxane 120ml solution, and the reaction mixture was stirred at 90°C for 4 Hour. The solvent was removed in vacuo, 80 ml of diethyl ether was added, stirred for 30 min, and the solid was washed with 50 ml of diethyl ether to obtain 3.2 g of white solid.
  • Step 1 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl- d2 )piperazin-1-yl)picolinate ester
  • Step 2 5-(4-((2-Ethyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl) Pyridinamide
  • Xphos Pd G2 (1.121g, 1.43mmol) was added to 7-bromo-3-methyl-8-fluoro-1H-quinoxalin-2-one 0.1g and (tributyltin base)methanol 0.138g at 1,4 - in 5 ml of dioxane, the reaction mixture was stirred at 90° C. for 4 hours. The solvent was removed in vacuo, 10 ml of diethyl ether was added, stirred for 30 min, and the solid was washed with 10 ml of diethyl ether to obtain 0.12 g of a white solid.
  • step 1 Ammonia (7N ammonia in methanol solution) 10.3ml was added to step 1 intermediate 0.5g was added to a 50ml round bottom flask, sealed and stirred at room temperature for 24 hours to obtain 200mg of pure product. The filtrate was concentrated in vacuo, and the resulting white solid was slurried in 4 ml of methanol, and filtered to obtain 237 mg of the desired compound.
  • Method 1 Dissolve the compound sample in DMSO, prepare a 10mM stock solution, and then add the compound to the screening system.
  • the detection concentration range of the compound is 0.1nM-10 ⁇ M. Dilute according to a 3-fold gradient, and make two replicate wells for each concentration.
  • the experimental results were converted into the activity percentage, the drug concentration was taken as the abscissa, and the enzyme activity percentage 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 value.
  • 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 of buffer (50 mM Tris, 2 mM magnesium chloride, pH 8.0) were added to each well, and then 5 ⁇ L of test compounds or solvent controls at different concentrations were added.
  • 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 (pH7.9), 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.
  • 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.
  • Example 70 has a higher inhibitory effect or capture ability on PARP1 than AZD-9574.
  • 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 AZD-9574.
  • + indicates IC50 value at 500nM
  • ++ indicates IC50 value at 30nM
  • +++ indicates IC50 value at 5nM.
  • Embodiment 118 rat pharmacokinetic test of the 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 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 10 minutes 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 70 to rats was greater than that of AZD-9574.

Abstract

Disclosed in the present invention are a quinoxaline compound, an isomer, a solvate, a deuterated derivative, or a pharmaceutically acceptable salt of the compound. R1, R2, R3, R4, R5, and n are defined in detail in the description. In addition, also disclosed in the present invention are a drug which uses the compound, the isomer, the solvate, the deuterated derivative, and the salt of the compound as active ingredients, and a use thereof in the treatment of diseases related to PARP-1, such as cancer.

Description

喹喔啉类化合物及其医药用途Quinoxaline compounds and their medicinal uses 技术领域technical field
本发明涉及一类喹喔啉类化合物、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 quinoxaline compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts of the compounds and drugs with the compounds or their salts as active ingredients, and Its use as a PARP1 inhibitor in the treatment of cancer.
发明背景Background of the invention
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PARP3 3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 PARP3 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，本文所述的喹喔啉令人惊讶地具有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，本文所述的喹喔啉化合物对PARP1的选择性比其它PARP家族成员(如PARP2、PARP3、PARP5a和PARP6)出人意料地高。此外本文所述的喹喔啉类化合物具有有利的低hERG活性。Applicants have discovered that the quinoxalines described herein surprisingly possess PARP inhibitory activity and are therefore useful in the treatment of diseases and conditions in which PARP function is of pathological significance. Furthermore, the quinoxaline compounds described herein are surprisingly selective for PARP1 over other PARP family members such as PARP2, PARP3, PARP5a and PARP6. In addition, the quinoxalines described herein have advantageously 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 PCTCN2022121260-appb-000001
Figure PCTCN2022121260-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 1为氢、C 1-10烷基、C 3-10环烷基，并可被氘任意取代； R is hydrogen, 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、C 1-10烷氧基，并可被卤素、C1-C3烷基、C 1-10烷氧基、氘任意取代； R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 1-10 alkoxy, and can be optionally substituted by halogen, C 1-C3 alkyl, C 1-10 alkoxy, deuterium;
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;
R 4为氢、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 is hydrogen, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl, which can be optionally substituted by deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
R 5为氢、C 1-10烷基、与R 5相连的碳原子连有2个取代基时，可与其相连的碳原子形成3-6元环； When R 5 is hydrogen, C 1-10 alkyl, and the carbon atom connected to R 5 has 2 substituents, it can form a 3-6 membered ring with the carbon atom connected to it;
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(Ⅰ)结构的化合物包括但不限于下列结构：More specifically, compounds of formula (I) include but are not limited to the following structures:
5-(4-((2-乙基-3-氧代-4H-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-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridine-2 - Formamide;
6-乙基-5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-ethyl-5-(4-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-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-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )-6- (Trifluoromethyl)pyridine-2-carboxamide;
5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-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-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )-6- (Difluoromethyl)pyridine-2-carboxamide;
5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-chloro-N-(methyl-d 3 ) pyridine-2-carboxamide;
N-(甲基-d 3)5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) Pyridine-2-carboxamide;
6-氯-N-(甲基-d 3)5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-chloro-N-(methyl-d 3 )5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl) pyridine-2-carboxamide;
6-氯-N-(甲基-d 3)-5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Chloro-N-(methyl-d 3 )-5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine -1-yl) pyridine-2-carboxamide;
N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2 - Formamide;
6-氯-N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Chloro-N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide;
6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-3,4-dihydroquinoxalin-6-yl)methyl)piperazine -1-yl) pyridine-2-carboxamide;
6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-乙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-ethyl-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide;
5-(4-((2-(1,1-二氟乙基)-3-氧代-4H-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-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((2-(2,2-二氟乙基)-3-氧代-4H-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-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((2-(2,2-二氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro- N-(methyl-d 3 )pyridine-2-carboxamide;
5-(4-((2-(2-氟乙基)-3-氧代-4H-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-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
6-氟-5-(4-((2-(2-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide;
N-(甲基-d 3)-5-(4-((3-氧代-2-(2,2,2-三氟乙基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl)methyl) Piperazin-1-yl)pyridine-2-carboxamide;
6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-(2,2,2-三氟乙基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl ) methyl) piperazin-1-yl) pyridine-2-carboxamide;
6-氟-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide;
6-甲基-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Methyl-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine-1- Base) pyridine-2-carboxamide;
N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2 - Formamide;
6-氟-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine- 1-yl) pyridine-2-carboxamide;
6-氟-N-甲基-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine -2-formamide;
N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl) Pyridine-2-carboxamide;
6-氟-5-(4-((2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl- d3 ) pyridine-2-carboxamide;
5-(4-((2-异丙基-3-氧代-4H-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-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridine- 2-formamide;
5-(4-((2-环丙基-3-氧代-4H-喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-cyclopropyl-3-oxo-4H-oxolin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-环丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl- d3 ) pyridine-2-carboxamide;
5-(4-((2-环丙基-3-氧代-4H-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-cyclopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridine- 2-formamide;
6-氟-N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2- Formamide;
6-甲基-N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Methyl-N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2 - Formamide;
N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2-carboxamide;
6-氟-N-(甲基-d3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d3)-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine- 2-formamide;
6-氟-N-甲基-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-methyl-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)pyridine-2-carboxamide ;
6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶酰胺； 5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridineamide ;
5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl- d3 ) pyridine-2-carboxamide;
6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基-d2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl-d2)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide;
6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)-N-methyl Pyridine-2-carboxamide;
5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide;
6-(二氟甲基)-5-(4-(2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-(Difluoromethyl)-5-(4-(2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)pyridine-2-carboxamide ;
6-甲基-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-methyl-5-(4-((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine -2-formamide;
5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
6-氯-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((2-乙基-5-氟-3-氧代-4H-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-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl -d 3 ) pyridine-2-carboxamide;
5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
6-氯-5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide;
5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-氟吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-6-fluoropyridine-2 - Formamide;
5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)-6-methylpyridine -2-formamide;
5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-6-methylpyridine- 2-formamide;
6-氯-5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d3)吡啶-2-甲酰胺；5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl Base-d3) pyridine-2-carboxamide;
5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide;
(R)-6-氟-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-6-fluoro-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
(S)-6-氟-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-6-fluoro-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
(R)-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
(S)-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-(1,1-二氟乙基)-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-(1,1-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- 6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-N -(methyl-d 3 )pyridine-2-carboxamide;
6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-N -Methylpyridine-2-carboxamide;
6-氯-5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3) 吡啶-2-甲酰胺； 6-chloro-5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-乙基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide;
5-(4-((2-乙基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-( Methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-乙基-5-甲基-3-氧代-4H-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-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
6-(二氟甲基)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-(Difluoromethyl)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -N-(methyl-d 3 )pyridine-2-carboxamide;
6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine- 2-formamide;
6-氯-5-(4-((2-甲基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((2-methyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
N-(乙基-2,2,2-d 3)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(ethyl-2,2,2-d 3 )-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl ) methyl) piperazin-1-yl) pyridine-2-carboxamide;
N-(乙基-2,2,2-d 3)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺； N-(ethyl-2,2,2-d 3 )-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl) Piperazin-1-yl)-6-methylpyridine-2-carboxamide;
5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide;
6-氟-5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
4-氯-5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 4-Chloro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridine-2- Formamide;
6-氯-5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-Chloro-5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl-d 3 ) pyridine-2-carboxamide;
6-氟-5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2- 甲酰胺； 6-fluoro-5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
5-(4-((2-(二氟甲基)-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-(Difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide;
5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
6-氟-5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide;
6-氟-5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide;
5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-( Methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide;
5-(4-((2-环丙基-5-氟-3-氧代-4H-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-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
5-(4-((2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N -(methyl-d 3 )pyridine-2-carboxamide;
6-氟-5-(4-((2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N- (Methyl-d 3 )pyridine-2-carboxamide;
6-(二氟甲基)-5-(4-(2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-(Difluoromethyl)-5-(4-(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl )-N-(methyl-d 3 )pyridine-2-carboxamide;
6-(二氟甲基)-5-(4-(2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-(Difluoromethyl)-5-(4-(2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N -(methyl-d 3 )pyridine-2-carboxamide;
(S)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(S)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide;
(S)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
(S)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(S)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide;
(S)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺；(S)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl) -N,6-lutidine-2-carboxamide;
(S)-6-氟-N-甲基-5-(2-甲基-4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺；(S)-6-fluoro-N-methyl-5-(2-methyl-4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine -1-yl) pyridine-2-carboxamide;
(S)-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl) -6-fluoro-N-(methyl-d 3 )pyridine-2-carboxamide;
(S)-5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl )-6-fluoro-N-(methyl-d 3 )pyridine-2-carboxamide;
(S)-5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-甲基吡啶-2-甲酰胺；(S)-5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl )-6-fluoro-N-methylpyridine-2-carboxamide;
(R)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
或(R)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；Or (R)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine -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;
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C2-10烯基，优选C2-6烯基，最优选C2-4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. C2-10 alkenyl is preferred, C2-6 alkenyl is preferred, C2-4 alkenyl is most preferred, vinyl is most preferred. 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-NH2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 PCTCN2022121260-appb-000002
Figure PCTCN2022121260-appb-000002
Figure PCTCN2022121260-appb-000003
Figure PCTCN2022121260-appb-000003
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 heterocyclic ring (the ring structure has carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur ring 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 PCTCN2022121260-appb-000004
Figure PCTCN2022121260-appb-000004
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 the usual aromatic groups include, but Without limitation, residues derived from benzene, substituted benzenes, naphthalene, anthracene, biphenyl, and the like.
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), see 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. Corresponding salts can also be formed with inorganic acids, such as hydrohalic acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid or phosphoric acid.
第三方面，本发明提供利用本发明式(I)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 a drug using the compound, isomer, solvate, deuterated derivative or pharmaceutically acceptable salt or solvate thereof of the formula (I) structure of the present invention as an active ingredient. One or more pharmaceutically acceptable carriers may also be contained in the above-mentioned drugs, and the carriers include conventional diluents in the pharmaceutical field, 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 in the above 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，这些肿瘤选自乳癌、卵巢癌、胰脏癌、前列腺癌、血液癌、胃肠道癌、和肺癌中的任一项。In the fourth aspect, the present invention provides compounds, isomers, solvates, deuterated derivatives or pharmaceutically acceptable salts thereof with the structure of formula (I) for use in drugs for treating tumors related to PARP1, and these tumors are selected from Any one of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, and lung cancer.
具体实施方式Detailed ways
下面通过实施例来说明本发明的可实施性，本领域的技术人员应当理解，根据现有技术的教导，对相应的技术特征进行修改或替换，仍然属于本发明要求保护的范围The implementability of the present invention is illustrated by the following examples. Those skilled in the art should understand that, according to the teachings of the prior art, modifying or replacing the corresponding technical features still belongs to the scope of the present invention.
实施例1、5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 1, 5-(4-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000005
Figure PCTCN2022121260-appb-000005
步骤1、4-(1-甲氧基-1-氧代丁烷-2-基)氨基)-3-硝基苯甲酸乙酯Step 1. Ethyl 4-(1-methoxy-1-oxobutan-2-yl)amino)-3-nitrobenzoate
Figure PCTCN2022121260-appb-000006
Figure PCTCN2022121260-appb-000006
将10g原料4-氟-3-硝基-苯甲酸甲酯，8.49g(s)-2-氨基丁酸甲酯盐酸盐，19.47g二异丙基乙胺加入到40ml甲醇溶液中，体系呈橘黄色，室温下搅拌。反应完毕后，除去甲醇，用二氯甲烷和水萃取体系3次，饱和氯化钠溶液洗涤3次，合并有机相，用无水硫酸钠干燥后抽滤，浓缩滤液，得黄色油状物。Add 10g raw material 4-fluoro-3-nitro-benzoic acid methyl ester, 8.49g (s)-2-aminobutyric acid methyl ester hydrochloride, 19.47g diisopropylethylamine to 40ml methanol solution, the system It was orange and stirred at room temperature. After the reaction was complete, methanol was removed, the system was extracted with dichloromethane and water three times, washed three times with saturated sodium chloride solution, the organic phases were combined, dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain a yellow oil.
步骤2、3-氨基-4-((1-甲氧基-1-氧代丁烷-2-基)氨基)苯甲酸乙酯Step 2. Ethyl 3-amino-4-((1-methoxy-1-oxobutan-2-yl)amino)benzoate
Figure PCTCN2022121260-appb-000007
Figure PCTCN2022121260-appb-000007
将15.65g步骤1原料溶于150ml甲醇中，加入150ml水，55.19g连二亚硫酸钠，升温至 60℃搅拌，体系呈浅黄色。反应完毕后，加300ml冰水搅拌30min，抽滤得浅黄色固体。Dissolve 15.65g of the raw material of Step 1 in 150ml of methanol, add 150ml of water, 55.19g of sodium dithionite, and stir at 60°C, the system turns light yellow. After the reaction was completed, add 300 ml of ice water and stir for 30 min, and filter with suction to obtain a light yellow solid.
ESI MS m/z：311.12[M+1] + ESI MS m/z: 311.12[M+1] +
步骤3、2-乙基-3-氧代-2,4-二氢-1H-喹喔啉-6-羧酸乙酯Step 3, 2-Ethyl-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylic acid ethyl ester
Figure PCTCN2022121260-appb-000008
Figure PCTCN2022121260-appb-000008
将7g步骤2原料溶于60ml水中，并加入60ml水和6.4g高碘酸钠，升温至80℃搅拌，体系逐渐变为棕黄色。反应完毕后向体系中加入180ml冰水搅拌30分钟，抽滤得棕黄色固体5g。Dissolve 7g of the raw material in step 2 in 60ml of water, add 60ml of water and 6.4g of sodium periodate, heat up to 80°C and stir, the system gradually turns brown. After the reaction was completed, 180 ml of ice water was added to the system, stirred for 30 minutes, and 5 g of a brownish-yellow solid was obtained by suction filtration.
ESI MS m/z：247.10[M+1] + ESI MS m/z: 247.10[M+1] +
步骤4、3-乙基-7-(羟甲基)-1H-喹喔啉-2-酮Step 4, 3-ethyl-7-(hydroxymethyl)-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000009
Figure PCTCN2022121260-appb-000009
在0℃下及氮气保护下，将氢化铝锂2g加至四氢呋喃30ml中，然后加入步骤3中间体4g，将所得混合物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，在真空下干燥得到中间体3.3g。At 0°C and under nitrogen protection, 2 g of lithium aluminum hydride was added to 30 ml of tetrahydrofuran, and then 4 g of the intermediate in step 3 was added, and the resulting mixture was stirred at 60° C. for 2.0 hours. Add 5ml of ethyl acetate to the reaction mixture, dropwise add an appropriate amount of water to quench, filter the solid, wash with ether, perform solid column chromatography, and dry under vacuum to obtain 3.3g of the intermediate.
ESI MS m/z：205.09[M+1] + ESI MS m/z: 205.09[M+1] +
步骤5、5-(4-((2-乙基-3-氧代-3,4-二氢喹啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶酰胺 Step 5, 5-(4-((2-ethyl-3-oxo-3,4-dihydroquinolin-6-yl)methyl)piperazin-1-yl)-N-(methyl- d 3 ) Pyridinamide
将二氯亚砜2ml滴加至步骤4中间体2.0g、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7-(氯甲基)-3-乙基喹啉-2(1H)-酮，将7-(氯甲基)-3-乙基喹啉-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2.1g。 Add 2 ml of thionyl chloride dropwise to 2.0 g of the intermediate in step 4, 0.1 ml of N,N-dimethylformamide in 30 ml of dichloromethane, stir at room temperature for 3 hours, and concentrate the reaction mixture to dryness to obtain 7-(chloro Methyl)-3-ethylquinolin-2(1H)-one, 7-(chloromethyl)-3-ethylquinolin-2(1H)-one, diisopropylethylamine 3ml, N -(Methyl-d 3 )-5-(piperazin-1-yl)pyridineamide 2g was dissolved in 50ml of acetonitrile, stirred at 80°C for 2 hours, concentrated to dryness, stirred with aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with water , dried, filtered, and the residue was subjected to column chromatography to obtain 2.1 g of the target compound.
1H NMR(400MHz,DMSO-d 6)δ12.25(1H,bs),8.37(1H,s),8.27(1H,d),7.83(1H,d),7.69(1H,d),7.41-7.37(1H,m),7.30–7.23(2H,m),3.62(2H,s),3.37-3.30(overlapped with water 4H,m),2.80(2H,q),2.58-2.53(4H,m),1.22(3H,t). 1 H NMR (400MHz,DMSO-d 6 )δ12.25(1H,bs),8.37(1H,s),8.27(1H,d),7.83(1H,d),7.69(1H,d),7.41- 7.37(1H,m),7.30–7.23(2H,m),3.62(2H,s),3.37-3.30(overlapped with water 4H,m),2.80(2H,q),2.58-2.53(4H,m) ,1.22(3H,t).
ESI MS m/z：410.23[M+1] + ESI MS m/z: 410.23[M+1] +
实施例2、6-乙基-5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 2, 6-ethyl-5-(4-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000010
Figure PCTCN2022121260-appb-000010
参考实施例12方法制备。Prepared with reference to the method of Example 12.
ESI MS m/z：438.26[M+1] + ESI MS m/z: 438.26[M+1] +
实施例3、5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-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-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )-6-(trifluoromethyl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000011
Figure PCTCN2022121260-appb-000011
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-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)-6-(二氟甲基)吡啶-2-甲酰胺 Example 4, 5-(4-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )-6-(difluoromethyl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000012
Figure PCTCN2022121260-appb-000012
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5、5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 5, 5-(4-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl base-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000013
Figure PCTCN2022121260-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：428.22[M+1] + ESI MS m/z: 428.22[M+1] +
实施例6、5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 6, 5-(4-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000014
Figure PCTCN2022121260-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：424.25[M+1] + ESI MS m/z: 424.25[M+1] +
实施例7、5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶-2-甲酰胺 Example 7, 5-(4-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-chloro-N-(form base-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000015
Figure PCTCN2022121260-appb-000015
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：443.19[M+1] + ESI MS m/z: 443.19[M+1] +
实施例8、N-(甲基-d 3)5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 8, N-(methyl-d 3 )5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000016
Figure PCTCN2022121260-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：450.19[M+1] + ESI MS m/z: 450.19[M+1] +
实施例9、6-氯-N-(甲基-d 3)5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 9, 6-chloro-N-(methyl-d 3 ) 5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl ) piperazin-1-yl) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000017
Figure PCTCN2022121260-appb-000017
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：484.15[M+1] + ESI MS m/z: 484.15[M+1] +
实施例10、6-氯-N-(甲基-d 3)-5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 10, 6-chloro-N-(methyl-d 3 )-5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl Base) piperazin-1-yl) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000018
Figure PCTCN2022121260-appb-000018
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：468.18[M+1] + ESI MS m/z: 468.18[M+1] +
实施例11、N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 11, N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000019
Figure PCTCN2022121260-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)δ12.16(1H,bs),8.36(1H,s),8.26(1H,d),7.83(1H,d),7.67(d,1H),7.41-7.35(m,1H),7.29–7.20(m,2H),3.60(s,2H),3.37-3.31(m,overlapped with water 4H),2.75(2H,t),2.57-2.52(4H,m),1.77–1.66(2H,m),0.96(3H,t)； 1 H NMR (400MHz,DMSO-d 6 )δ12.16(1H,bs),8.36(1H,s),8.26(1H,d),7.83(1H,d),7.67(d,1H),7.41- 7.35(m,1H),7.29–7.20(m,2H),3.60(s,2H),3.37-3.31(m,overlapped with water 4H),2.75(2H,t),2.57-2.52(4H,m) ,1.77–1.66(2H,m),0.96(3H,t);
ESI MS m/z：424.25[M+1] + ESI MS m/z: 424.25[M+1] +
实施例12、6-氯-N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 12, 6-chloro-N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl)piperazine -1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000020
Figure PCTCN2022121260-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：458.21[M+1] + ESI MS m/z: 458.21[M+1] +
实施例13、6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 13, 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-3,4-dihydroquinoxalin-6-yl)methyl Base) piperazin-1-yl) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000021
Figure PCTCN2022121260-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：442.24[M+1] + ESI MS m/z: 442.24[M+1] +
实施例14、6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-乙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 14, 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-ethyl-4H-quinoxalin-6-yl)methyl)piperazine -1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000022
Figure PCTCN2022121260-appb-000022
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)δ1.22(3H,t),2.61-2.54(4H,m),2.80(2H,q),3.21-3.14(4H,m),3.62(2H,s),7.29-7.22(2H,m),7.60-7.54(1H,m),7.69(1H,d),7.85(1H,d),8.36(1H,s),12.25(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ1.22(3H,t),2.61-2.54(4H,m),2.80(2H,q),3.21-3.14(4H,m),3.62(2H,s ),7.29-7.22(2H,m),7.60-7.54(1H,m),7.69(1H,d),7.85(1H,d),8.36(1H,s),12.25(1H,s);
ESI MS m/z：446.21[M+1] + ESI MS m/z: 446.21[M+1] +
实施例15、5-(4-((2-(1,1-二氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 15, 5-(4-((2-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000023
Figure PCTCN2022121260-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：446.21[M+1] + ESI MS m/z: 446.21[M+1] +
实施例16、5-(4-((2-(2,2-二氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 16, 5-(4-((2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000024
Figure PCTCN2022121260-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：446.21[M+1] + ESI MS m/z: 446.21[M+1] +
实施例17、5-(4-((2-(2,2-二氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 17, 5-(4-((2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- 6-fluoro-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000025
Figure PCTCN2022121260-appb-000025
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：464.20[M+1] + ESI MS m/z: 464.20[M+1] +
实施例18、5-(4-((2-(2-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 18, 5-(4-((2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000026
Figure PCTCN2022121260-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19、6-氟-5-(4-((2-(2-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 19, 6-fluoro-5-(4-((2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000027
Figure PCTCN2022121260-appb-000027
参考实施例1方法制备。Prepared with reference to the method of Example 1.
ESI MS m/z：446.21[M+1] + ESI MS m/z: 446.21[M+1] +
实施例20、N-(甲基-d 3)-5-(4-((3-氧代-2-(2,2,2-三氟乙基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 20, N-(methyl-d 3 )-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl )methyl)piperazin-1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000028
Figure PCTCN2022121260-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：464.20[M+1] + ESI MS m/z: 464.20[M+1] +
实施例21、6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-(2,2,2-三氟乙基)-4H-喹喔啉-6-基)甲 基)哌嗪-1-基)吡啶-2-甲酰胺 Example 21, 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxaline -6-yl)methyl)piperazin-1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000029
Figure PCTCN2022121260-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：482.19[M+1] + ESI MS m/z: 482.19[M+1] +
实施22、6-氟-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Implementation 22, 6-fluoro-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000030
Figure PCTCN2022121260-appb-000030
步骤1、5-溴-6-氟吡啶甲酸甲酯Step 1, methyl 5-bromo-6-fluoropicolinate
Figure PCTCN2022121260-appb-000031
Figure PCTCN2022121260-appb-000031
在氮气保护下，将5g原料5-溴哌啶酸甲酯，15g二氟化银加入到50ml无水乙腈中，室温反应6小时。反应完毕，过硅藻土除去不溶物，用60ml乙腈洗涤固体，收集滤液，减压浓缩干，将残留物用二氯甲烷50ml溶解，用饱和食盐水洗涤3次。然后用无水硫酸钠干燥有机层，抽滤，旋干得白色固体产物5g。Under nitrogen protection, 5 g of raw material 5-bromopiperidine methyl ester and 15 g of silver difluoride were added to 50 ml of anhydrous acetonitrile, and reacted at room temperature for 6 hours. After the reaction was completed, the insoluble matter was removed through diatomaceous earth, the solid was washed with 60 ml of acetonitrile, the filtrate was collected, concentrated to dryness under reduced pressure, the residue was dissolved in 50 ml of dichloromethane, and washed 3 times with saturated brine. Then the organic layer was dried with anhydrous sodium sulfate, filtered with suction, and spin-dried to obtain 5 g of a white solid product.
1H NMR(400MHz,DMSO-d 6)δ3.89(3H,s),7.92(1H,dd),8.50(1H,dd)； 1 H NMR (400MHz,DMSO-d 6 )δ3.89(3H,s),7.92(1H,dd),8.50(1H,dd);
步骤2、4-(2-氟-6-(甲氧羰基)吡啶-3-基)哌嗪-1-羧酸叔丁酯Step 2, tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate
Figure PCTCN2022121260-appb-000032
Figure PCTCN2022121260-appb-000032
将5g步骤1中间体，5.96g哌嗪-1-羧酸叔丁酯加入60ml 1，4-二氧六环中，加入18g碳酸铯，在氮气保护下加入1.25g Ruphos Pd G3,在氮气保护下80℃搅拌反应过夜。反应完毕后，加入50ml水淬灭反应，过硅藻土，并用1，4-二氧六环40ml洗涤，收集滤液，减压浓缩除去1，4-二氧六环。将剩余滤液用乙酸乙酯萃取3次，合并有机相。无水硫酸钠干燥后抽滤，减压浓缩干获得粗产物，过柱纯化，用石油醚、乙酸乙酯体系洗脱，获得黄色固体产物5.3g。Add 5g of step 1 intermediate, 5.96g of piperazine-1-carboxylate tert-butyl ester into 60ml of 1,4-dioxane, add 18g of cesium carbonate, add 1.25g of Ruphos Pd G3 under nitrogen protection, and add 1.25g of Ruphos Pd G3 under nitrogen protection. The reaction was stirred overnight at 80°C. After the reaction was completed, 50 ml of water was added to quench the reaction, passed through diatomaceous earth, and washed with 40 ml of 1,4-dioxane. The filtrate was collected and concentrated under reduced pressure to remove 1,4-dioxane. The remaining filtrate was extracted 3 times with ethyl acetate, and the organic phases were combined. After drying with anhydrous sodium sulfate, it was filtered with suction, concentrated to dryness under reduced pressure to obtain a crude product, which was purified by column and eluted with petroleum ether and ethyl acetate to obtain 5.3 g of a yellow solid product.
1HNMR(400MHz,DMSO-d 6)δ1.44(9H,s),3.22–3.15(4H,m),3.52–3.45(4H,m),3.83(3H,s),7.55(1H,dd),7.93(1H,dd)； 1 HNMR (400MHz, DMSO-d 6 ) δ1.44(9H,s),3.22–3.15(4H,m),3.52–3.45(4H,m),3.83(3H,s),7.55(1H,dd) ,7.93(1H,dd);
步骤3、5-(4-(叔丁氧羰基)哌嗪-1-基)-6-氟吡啶-2-甲酸Step 3, 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluoropyridine-2-carboxylic acid
Figure PCTCN2022121260-appb-000033
Figure PCTCN2022121260-appb-000033
将5.3g步骤2中间体加入10ml四氢呋喃中，将0.59g氢氧化钠溶于10ml水中加入体系中，室温反应4小时。反应完毕后，减压浓缩除去THF。用浓盐酸调节PH至2，用乙酸乙酯萃取3次，合并有机层，无水硫酸钠干燥，抽滤，减压浓缩干，获得目的物4.9g。Add 5.3g of the intermediate of step 2 into 10ml of tetrahydrofuran, dissolve 0.59g of sodium hydroxide in 10ml of water and add to the system, and react at room temperature for 4 hours. After completion of the reaction, THF was removed by concentration under reduced pressure. Adjust the pH to 2 with concentrated hydrochloric acid, extract three times with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter with suction, and concentrate to dryness under reduced pressure to obtain 4.9 g of the target compound.
1HNMR(400MHz,DMSO-d 6)δ1.42(9H,s),3.20-3.11(4H,m),3.53-3.44(4H,m),7.53(1H,dd),7.90(1H,d),12.98(1H,s)； 1 HNMR (400MHz,DMSO-d 6 )δ1.42(9H,s),3.20-3.11(4H,m),3.53-3.44(4H,m),7.53(1H,dd),7.90(1H,d) ,12.98(1H,s);
步骤4、4-(2-氟-6-((甲基-d 3)氨甲酰基)吡啶-3-基)哌嗪-1-羧酸叔丁酯 Step 4, tert-butyl 4-(2-fluoro-6-((methyl-d 3 )carbamoyl)pyridin-3-yl)piperazine-1-carboxylate
Figure PCTCN2022121260-appb-000034
Figure PCTCN2022121260-appb-000034
将4.9g步骤3中间，1.23g氘代甲胺盐酸盐加入15ml乙酸乙酯中。加入22.5g丙基磷酸酐50％乙酸乙酯溶液，4.5g二异丙基乙胺，室温搅拌反应3小时。反应完毕后，将反应物用饱和食盐水洗涤3次，无水硫酸钠干燥后抽滤，减压浓缩干，得产物4.2g。Add 4.9 g of step 3 middle, 1.23 g of deuterated methylamine hydrochloride into 15 ml of ethyl acetate. Add 22.5 g of 50% ethyl acetate solution of propyl phosphoric anhydride and 4.5 g of diisopropylethylamine, and stir at room temperature for 3 hours. After the reaction was completed, the reactant was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure to dryness, and obtained 4.2 g of the product.
步骤5、6-氟-N-(甲基-d3)-5-(哌嗪-1-基)吡啶酰胺Step 5, 6-fluoro-N-(methyl-d3)-5-(piperazin-1-yl)pyridineamide
Figure PCTCN2022121260-appb-000035
Figure PCTCN2022121260-appb-000035
将2g步骤3中间，加入10ml 10M盐酸乙醇溶液，室温搅拌反应2小时。反应完毕。将反应体系减压浓缩干。获得黄色固体产物6-氟-N-(甲基-d3)-5-(哌嗪-1-基)吡啶酰胺二盐酸盐1.1g。Add 10ml of 10M hydrochloric acid ethanol solution to 2g of the middle of step 3, and stir at room temperature for 2 hours. The reaction is complete. The reaction system was concentrated to dryness under reduced pressure. 1.1 g of 6-fluoro-N-(methyl-d3)-5-(piperazin-1-yl)pyridineamide dihydrochloride was obtained as a yellow solid product.
步骤6、5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Step 6, 5-(4-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide
将7-(溴甲基)-3-甲基喹啉-2(1H)-酮0.10g、二异丙基乙胺0.5ml，步骤5中间体0.2g溶解于乙腈10ml，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0.12g。Dissolve 0.10g of 7-(bromomethyl)-3-methylquinolin-2(1H)-one, 0.5ml of diisopropylethylamine, 0.2g of the intermediate in step 5 in 10ml of acetonitrile, and stir at 80°C for 2 hours , 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 0.12 g of the target compound.
1H NMR(400MHz,DMSO-d 6)δ2.39(3H,s),2.60-2.54(4H,m),3.21-3.14(4H,m),3.62(2H,s),7.28-7.22(2H,m),7.60-7.54(1H,m),7.66(1H,d),7.84(1H,dd),8.36(1H,s),12.26(1H,bs)； 1 H NMR (400MHz,DMSO-d 6 )δ2.39(3H,s),2.60-2.54(4H,m),3.21-3.14(4H,m),3.62(2H,s),7.28-7.22(2H ,m),7.60-7.54(1H,m),7.66(1H,d),7.84(1H,dd),8.36(1H,s),12.26(1H,bs);
ESI MS m/z：414.21[M+1] + ESI MS m/z: 414.21[M+1] +
实施例23、6-甲基-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 23, 6-methyl-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piper Azin-1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000036
Figure PCTCN2022121260-appb-000036
参考实施例1方法合成。Synthesized with reference to Example 1 method.
1H NMR(400MHz,DMSO-d 6)δ12.26(1H,s),8.38(1H,bs),7.82-7.77(1H,m),7.68-7.64(1H,m),7.51-7.46(1H,m),7.29-7.22(2H,m),3.64(2H,s),2.99-2.93(4H,m),2.62-2.55(4H,m),2.50(3H,overlapped with DMSO,s),2.40(3H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ12.26(1H,s),8.38(1H,bs),7.82-7.77(1H,m),7.68-7.64(1H,m),7.51-7.46(1H ,m),7.29-7.22(2H,m),3.64(2H,s),2.99-2.93(4H,m),2.62-2.55(4H,m),2.50(3H,overlapped with DMSO,s),2.40 (3H,s);
ESI MS m/z：410.23[M+1] + ESI MS m/z: 410.23[M+1] +
实施例24、N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 24, N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000037
Figure PCTCN2022121260-appb-000037
参考实施例1方法合成。Synthesized with reference to Example 1 method.
1H NMR(400MHz,DMSO-d 6)δ12.34(1H,bs),8.37(1H,bs),8.27-8.23(1H,m),7.84-7.80(1H,m),7.67-7.63(1H,m),7.40-7.36(1H,m),7.34-7.24(2H,m),3.61(2H,s),3.38-3.30(4H,m),2.64-2.54(4H,m),2.38(3H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ12.34(1H,bs),8.37(1H,bs),8.27-8.23(1H,m),7.84-7.80(1H,m),7.67-7.63(1H ,m),7.40-7.36(1H,m),7.34-7.24(2H,m),3.61(2H,s),3.38-3.30(4H,m),2.64-2.54(4H,m),2.38(3H ,s);
ESI MS m/z：396.21[M+1] + ESI MS m/z: 396.21[M+1] +
实施例25、6-氟-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺 Example 25, 6-fluoro-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 ) piperazin-1-yl) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000038
Figure PCTCN2022121260-appb-000038
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：416.22[M+1] + ESI MS m/z: 416.22[M+1] +
实施例26、6-氟-N-甲基-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡 啶-2-甲酰胺 Example 26, 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine-1 -yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000039
Figure PCTCN2022121260-appb-000039
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：413.20[M+1] + ESI MS m/z: 413.20[M+1] +
实施例27、N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺 Example 27, N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine- 1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000040
Figure PCTCN2022121260-appb-000040
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：398.23[M+1] + ESI MS m/z: 398.23[M+1] +
实施例28、6-氟-5-(4-((2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 28, 6-fluoro-5-(4-((2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000041
Figure PCTCN2022121260-appb-000041
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：442.24[M+1] + ESI MS m/z: 442.24[M+1] +
实施例29、5-(4-((2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 29, 5-(4-((2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000042
Figure PCTCN2022121260-appb-000042
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：438.26[M+1] + ESI MS m/z: 438.26[M+1] +
实施例30、5-(4-((2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3) 吡啶-2-甲酰胺 Example 30, 5-(4-((2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000043
Figure PCTCN2022121260-appb-000043
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：424.253[M+1] + ESI MS m/z: 424.253[M+1] +
实施例31、5-(4-((2-环丙基-3-氧代-4H-喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 31, 5-(4-((2-cyclopropyl-3-oxo-4H-oxolin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl base-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000044
Figure PCTCN2022121260-appb-000044
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：440.22[M+1] + ESI MS m/z: 440.22[M+1] +
实施例32、5-(4-((2-环丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 32, 5-(4-((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000045
Figure PCTCN2022121260-appb-000045
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：436.25[M+1] + ESI MS m/z: 436.25[M+1] +
实施例33、5-(4-((2-环丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 33, 5-(4-((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000046
Figure PCTCN2022121260-appb-000046
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：422.23[M+1] + ESI MS m/z: 422.23[M+1] +
实施例34、6-氟-N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 34, 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) Pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000047
Figure PCTCN2022121260-appb-000047
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：400.19[M+1] + ESI MS m/z: 400.19[M+1] +
实施例35、6-甲基-N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 35, 6-methyl-N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000048
Figure PCTCN2022121260-appb-000048
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：396.21[M+1] + ESI MS m/z: 396.21[M+1] +
实施例36、N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 36, N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2- Formamide
Figure PCTCN2022121260-appb-000049
Figure PCTCN2022121260-appb-000049
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：382.20[M+1] + ESI MS m/z: 382.20[M+1] +
实施例37、6-氟-N-(甲基-d3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺 Example 37, 6-fluoro-N-(methyl-d3)-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine-1- base) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000050
Figure PCTCN2022121260-appb-000050
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：402.20[M+1] + ESI MS m/z: 402.20[M+1] +
实施例38、6-氟-N-甲基-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺 Example 38, 6-fluoro-N-methyl-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine- 2-formamide
Figure PCTCN2022121260-appb-000051
Figure PCTCN2022121260-appb-000051
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：399.18[M+1] + ESI MS m/z: 399.18[M+1] +
实施例39、6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 39, 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000052
Figure PCTCN2022121260-appb-000052
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：430.20[M+1] + ESI MS m/z: 430.20[M+1] +
实施例40、5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶酰胺 Example 40, 5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridinamide
Figure PCTCN2022121260-appb-000053
Figure PCTCN2022121260-appb-000053
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：412.21[M+1] + ESI MS m/z: 412.21[M+1] +
实施例42、5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 42, 5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000054
Figure PCTCN2022121260-appb-000054
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：426.23[M+1] + ESI MS m/z: 426.23[M+1] +
实施例42、6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基-d2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 42, 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl-d2)piperazin-1-yl)-N -(Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000055
Figure PCTCN2022121260-appb-000055
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：432.21[M+1] + ESI MS m/z: 432.21[M+1] +
实施例43、6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺 Example 43, 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)- N-methylpyridine-2-carboxamide
Figure PCTCN2022121260-appb-000056
Figure PCTCN2022121260-appb-000056
参考实施例1方法合成。Synthesized with reference to Example 1 method.
ESI MS m/z：429.19[M+1] + ESI MS m/z: 429.19[M+1] +
实施例44、5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 44, 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000057
Figure PCTCN2022121260-appb-000057
步骤1、2-((4-溴-3-氟-2-硝基苯基)氨基)丁酸甲酯Step 1. Methyl 2-((4-bromo-3-fluoro-2-nitrophenyl)amino)butanoate
Figure PCTCN2022121260-appb-000058
Figure PCTCN2022121260-appb-000058
将二异丙基乙胺165ml缓慢加入到1-溴-2,4-二氟-3-硝基苯37.4g和甲基-2-氨基丁酸甲酯盐酸24.3g的N,N-二甲基甲酰胺350ml搅拌溶液中，搅拌8小时。用水稀释后，用乙酸乙酯萃取，减压浓缩产物得到2-(4-溴-3-氟-2-硝基-苯氨基)丁酸甲酯23.6g。Slowly add 165ml of diisopropylethylamine to 37.4g of 1-bromo-2,4-difluoro-3-nitrobenzene and 24.3g of methyl-2-aminobutyric acid methyl hydrochloride in N,N-dimethyl 350ml of methyl formamide stirring solution, stirring for 8 hours. After dilution with water, it was extracted with ethyl acetate, and the product was concentrated under reduced pressure to obtain 23.6 g of methyl 2-(4-bromo-3-fluoro-2-nitro-phenylamino)butyrate.
ESI MS m/z：335.0[M+1] + ESI MS m/z: 335.0[M+1] +
步骤2、7-溴-3-乙基-8-氟-3，4-二氢-1H-喹喔啉-2-酮Step 2, 7-bromo-3-ethyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000059
Figure PCTCN2022121260-appb-000059
将保险粉和2-(4-溴-3-氟-2-硝基-苯氨基)丁酸甲酯12.5克加入甲醇100mL混合物中。在室温下搅拌2h，固体过滤，用甲醇洗涤。真空下除去溶剂，用乙酸乙酯稀释，用碳酸盐氢钠水溶液碱化。分离有机层，用水冲洗，用硫酸钠干燥，浓缩得到粗产物。固体加入100ml甲醇，搅拌10分钟，过滤得到目的物8.8g。Sodium hydrosulfite and 12.5 g of methyl 2-(4-bromo-3-fluoro-2-nitro-phenylamino)butyrate were added to a mixture of 100 mL of methanol. Stirring at room temperature for 2h, the solid was filtered and washed with methanol. The solvent was removed in vacuo, diluted with ethyl acetate, and basified with aqueous sodium bicarbonate. The organic layer was separated, washed with water, dried over sodium sulfate, and concentrated to give crude product. Add 100ml of methanol to the solid, stir for 10 minutes, and filter to obtain 8.8g of the target compound.
步骤3、7-溴-3-乙基-8-氟-1H-喹喔啉-2-酮Step 3, 7-bromo-3-ethyl-8-fluoro-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000060
Figure PCTCN2022121260-appb-000060
将DDQ 10g加入到步骤2中间体8.6g在二氯甲烷200ml中，室温搅拌2小时。除去溶剂，固体中加入150mL甲醇，搅拌30分钟。固体过滤，用30mL甲醇洗涤，加入50毫升水，然后缓慢加入60ml碳酸氢钠后，混合物室温搅拌过夜，停止搅拌，过滤固体，用水洗涤，得到目的物4.5g。Add 10 g of DDQ to 8.6 g of the intermediate in step 2 in 200 ml of dichloromethane, and stir at room temperature for 2 hours. The solvent was removed, 150 mL of methanol was added to the solid, and the mixture was stirred for 30 minutes. The solid was filtered, washed with 30 mL of methanol, 50 mL of water was added, and then 60 mL of sodium bicarbonate was slowly added. The mixture was stirred overnight at room temperature, and the stirring was stopped. The solid was filtered and washed with water to obtain 4.5 g of the target compound.
步骤4、3-乙基-8-氟-7-羟甲基-1H-喹喔啉-2-酮Step 4. 3-Ethyl-8-fluoro-7-hydroxymethyl-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000061
Figure PCTCN2022121260-appb-000061
将Xphos Pd G2(1.121g,1.43mmol)加入到步骤3中间体7.7g和(三丁基锡基)甲醇10.0g在1,4-二氧六环120ml溶液中，将反应混合物在90℃下搅拌4小时。真空除去溶剂，加入80ml乙醚，搅拌30min，固体用50ml乙醚洗涤，得到白色固体3.2g。Xphos Pd G2 (1.121g, 1.43mmol) was added to step 3 intermediate 7.7g and (tributyltin base)methanol 10.0g in 1,4-dioxane 120ml solution, and the reaction mixture was stirred at 90°C for 4 Hour. The solvent was removed in vacuo, 80 ml of diethyl ether was added, stirred for 30 min, and the solid was washed with 50 ml of diethyl ether to obtain 3.2 g of white solid.
1H NMR(400MHz,DMSO-d 6)δ1.21(3H,t),2.81(2H,q)。4.64(2H,br d),5.39(1H,t),7.32(1H,br t),7.55(1H,d),12.41(1H,br s)； 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.21 (3H, t), 2.81 (2H, q). 4.64(2H,br d),5.39(1H,t),7.32(1H,br t),7.55(1H,d),12.41(1H,br s);
ESI MS m/z：223.08[M+1] + ESI MS m/z: 223.08[M+1] +
步骤5、3-乙基-8-氟-7-溴甲基-1H-喹喔啉-2-酮Step 5, 3-Ethyl-8-fluoro-7-bromomethyl-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000062
Figure PCTCN2022121260-appb-000062
将1.0g中间体3加入到4ml HCl中，升温至80℃搅拌，3小时后反应完成，加入冰水中，加二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，得目的物0.5g。Add 1.0 g of intermediate 3 to 4 ml of HCl, raise the temperature to 80°C and stir. After 3 hours, the reaction is complete. Add to ice water, extract with dichloromethane, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 0.5 g of the target product.
步骤6、5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶酰胺 Step 6, 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl- N-(methyl-d 3 )pyridinamide
将二异丙基乙胺20.90ml、步骤5中间体5g和6-甲基-N-(甲基-d3)-5-(哌嗪-1-基)吡啶酰胺盐酸盐7.0g，加入到乙腈20mL中，反应混合物在60℃下，搅拌2小时，反应完成，析出固体，过滤，加入乙腈洗涤，滤去固体，用碳酸酸钠水洗涤，再用水洗，过滤得到目的物7.6g。Diisopropylethylamine 20.90ml, step 5 intermediate 5g and 6-methyl-N-(methyl-d3)-5-(piperazin-1-yl)pyridinamide hydrochloride 7.0g were added to In 20 mL of acetonitrile, the reaction mixture was stirred at 60°C for 2 hours. After the reaction was complete, a solid precipitated out, filtered, added acetonitrile to wash, filtered off the solid, washed with sodium carbonate water, washed with water, and filtered to obtain 7.6 g of the target compound.
1H NMR(400MHz,DMSO-d6)δ1.23(3H,t)，2.48(3H,s)，2.62(4H,br s)，2.76-2.88(5H,m)，2.95(4H,br s)，3.73(2H,s)，7.31(1H,t)，7.47(1H,d),7.56(1H,d),7.79(1H,d),8.41(1H,q),12.44(1H,s)1H NMR (400MHz, DMSO-d6) δ1.23(3H,t), 2.48(3H,s), 2.62(4H,br s), 2.76-2.88(5H,m), 2.95(4H,br s), 3.73(2H,s), 7.31(1H,t), 7.47(1H,d), 7.56(1H,d), 7.79(1H,d), 8.41(1H,q), 12.44(1H,s)
ESI MS m/z：442.24[M+1] + ESI MS m/z: 442.24[M+1] +
实施例45、6-(二氟甲基)-5-(4-(2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 45, 6-(difluoromethyl)-5-(4-(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine-1 -yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000063
Figure PCTCN2022121260-appb-000063
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(500MHz,DMSO-d 6)δ1.21(3H,t)，2.62(4H,br d)，2.75-2.83(2H,m)，2.97-3.02(4H,m),3.73(2H,s),7.03-7.26(1H,t),7.31(1H,br d),7.56(1H,br d),7.84(1H,d),8.08(1H,d),8.37(1H,q),12.44(1H,br d) 1 H NMR (500MHz, DMSO-d 6 ) δ1.21(3H,t), 2.62(4H,br d), 2.75-2.83(2H,m), 2.97-3.02(4H,m), 3.73(2H, s),7.03-7.26(1H,t),7.31(1H,br d),7.56(1H,br d),7.84(1H,d),8.08(1H,d),8.37(1H,q),12.44 (1H,br d)
ESI MS m/z：478.22[M+1] + ESI MS m/z: 478.22[M+1] +
实施例46、5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺 Example 46, 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)pyridine- 2-formamide
Figure PCTCN2022121260-appb-000064
Figure PCTCN2022121260-appb-000064
步骤1：5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶甲酸甲酯 Step 1: 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl- d2 )piperazin-1-yl)picolinate ester
Figure PCTCN2022121260-appb-000065
Figure PCTCN2022121260-appb-000065
将二异丙基乙胺0.5ml加入到7-(溴甲基-d2)-3-乙基-8-氟喹啉-2(1H)-酮680mg和5-(哌 嗪-1-基)甲基吡啶甲酸酯700mg的乙腈(5mL)的悬浮液中。反应混合物60℃下搅拌2小时，真空下除去溶剂，剩余物通过硅胶层析纯化，在二氯甲烷/甲醇(5：1)洗脱得到中间体516mg。Diisopropylethylamine 0.5ml was added to 7-(bromomethyl-d2)-3-ethyl-8-fluoroquinolin-2(1H)-one 680mg and 5-(piperazin-1-yl) A suspension of 700 mg of picolinate in acetonitrile (5 mL). The reaction mixture was stirred at 60°C for 2 hours, the solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with dichloromethane/methanol (5:1) to give intermediate 516 mg.
步骤2：5-(4-((2-乙基-5-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基-d2)哌嗪-1-基)吡啶酰胺Step 2: 5-(4-((2-Ethyl-5-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl-d2)piperazin-1-yl) Pyridinamide
将氨的甲醇(7N)溶液10mL加入步骤1中间体300mg中。将得到的悬浮液在50℃下搅拌24小时。用硅胶柱对所得残渣进行纯化，得到目的物167mg。10 mL of ammonia in methanol (7N) was added to 300 mg of the step 1 intermediate. The resulting suspension was stirred at 50°C for 24 hours. The resulting residue was purified with a silica gel column to obtain 167 mg of the desired compound.
1H NMR(400MHz,DMSO-d 6)δ1.24(3H,t),2.56-2.62(4H,m),2.81(2H,q),3.33-3.40(4H,m),7.26-7.34(2H,m),7.36(1H,dd),7.56(1H,d),7.75(1H,br d),7.84(1H,d),8.28(1H,d)，12.44(1H,br s) 1 H NMR (400MHz,DMSO-d 6 )δ1.24(3H,t),2.56-2.62(4H,m),2.81(2H,q),3.33-3.40(4H,m),7.26-7.34(2H ,m),7.36(1H,dd),7.56(1H,d),7.75(1H,br d),7.84(1H,d),8.28(1H,d),12.44(1H,br s)
ESI MS m/z：413.20[M+1] + ESI MS m/z: 413.20[M+1] +
实施例47、6-甲基-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺 Example 47, 6-methyl-5-(4-((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine-1 -yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000066
Figure PCTCN2022121260-appb-000066
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(500MHz,DMSO-d 6)δ1.23(3H,br t)，2.46-2.48(3H,m)，2.53-2.68(4H,m)，2.83(2H,q)，2.93(4H,br s)，7.31(1H,br t),7.39-7.50(2H,m),7.54(1H,br d),7.78(2H,br d),12.40(1H,br s) 1 H NMR (500MHz, DMSO-d 6 ) δ1.23(3H,br t), 2.46-2.48(3H,m), 2.53-2.68(4H,m), 2.83(2H,q), 2.93(4H, br s), 7.31 (1H, br t), 7.39-7.50 (2H, m), 7.54 (1H, br d), 7.78 (2H, br d), 12.40 (1H, br s)
ESI MS m/z：427.21[M+1] + ESI MS m/z: 427.21[M+1] +
实施例48、5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 48, 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000067
Figure PCTCN2022121260-appb-000067
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHz,DMSO-d 6)δ1.23(3H,t),2.58-2.64(4H,m),2.82(2H,q),3.15-3.20(4H,m),3.72(2H,s),7.28-7.33(1H,m),7.53-7.58(2H,m),7.83-7.86(1H,m),8.38-8.44(1H,m),12.46(1H,s) 1 H NMR (400MHz,DMSO-d 6 )δ1.23(3H,t),2.58-2.64(4H,m),2.82(2H,q),3.15-3.20(4H,m),3.72(2H,s ),7.28-7.33(1H,m),7.53-7.58(2H,m),7.83-7.86(1H,m),8.38-8.44(1H,m),12.46(1H,s)
ESI MS m/z：446.21[M+1] + ESI MS m/z: 446.21[M+1] +
实施例49、6-氯-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲 基-d 3)吡啶-2-甲酰胺 Example 49, 6-chloro-5-(4-((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000068
Figure PCTCN2022121260-appb-000068
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHz,DMSO-d 6)δ1.22(3H，t)2.57-2.65(4H,m),2.76-2.86(5H,m),3.05-3.15(4H,m),3.72(2H,s),7.29(1H,t),7.55(1H,d)。7.65(1H,d)，7.93(1H,d)，8.40-8.45(1H,m)，12.45(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ1.22(3H,t)2.57-2.65(4H,m),2.76-2.86(5H,m),3.05-3.15(4H,m),3.72(2H, s), 7.29(1H,t), 7.55(1H,d). 7.65(1H,d), 7.93(1H,d), 8.40-8.45(1H,m), 12.45(1H,s);
ESI MS m/z：462.18[M+1] + ESI MS m/z: 462.18[M+1] +
实施例50、5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 50, 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl base-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000069
Figure PCTCN2022121260-appb-000069
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHz,DMSO-d 6)δ1.21(3H,t),2.54-2.62(4H,m),2.76-2.86(2H,m),3.06-3.15(4H,m，合并为水峰),3.68(2H,s),7.28(1H,t),7.36(1H,dd),7.55(1H,d),7.82(1H,d),8.24(1H,d),8.36-8.42(1H,m),12.43(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ1.21(3H,t),2.54-2.62(4H,m),2.76-2.86(2H,m),3.06-3.15(4H,m, merged into water peak ),3.68(2H,s),7.28(1H,t),7.36(1H,dd),7.55(1H,d),7.82(1H,d),8.24(1H,d),8.36-8.42(1H, m),12.43(1H,s);
ESI MS m/z：428.22[M+1] + ESI MS m/z: 428.22[M+1] +
实施例51、5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 51, 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N -(Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000070
Figure PCTCN2022121260-appb-000070
向7-(溴甲基)-3,8-二甲基-1H-喹喔啉-2-酮185mg的悬浮液中加入氢溴酸，加入ACN(5ml)、6-氟-N-(甲基-d3)-5-(哌嗪-1-基)吡啶酰胺盐酸盐167mg和二异丙胺乙基0.5毫升，将反应混合物在70℃下搅拌1h，得到淡黄色悬浮液。将悬浮液冷却至室温，过滤收集固体，用乙腈洗涤3次并干燥，得到目的物85mg。Add hydrobromic acid to a suspension of 185 mg of 7-(bromomethyl)-3,8-dimethyl-1H-quinoxalin-2-one, add ACN (5 ml), 6-fluoro-N-(methyl Base-d3)-5-(piperazin-1-yl)pyridinamide hydrochloride 167mg and diisopropylaminoethyl 0.5ml, the reaction mixture was stirred at 70°C for 1h to obtain a light yellow suspension. The suspension was cooled to room temperature, and the solid was collected by filtration, washed 3 times with acetonitrile and dried to obtain 85 mg of the desired compound.
1HNMR(400MHz,DMSO-d 6)δ2.06(3H,brs),2.43(3H,brd),2.57(4H,brs),3.15(4H,brs),3.62 (2H,brs),7.24(1H,brd).7.43-7.67(2H,m),7.84(1H,brd),8.37(1H,brs),11.14-11.97(1H,m)； 1 H NMR (400MHz, DMSO-d 6 ) δ2.06 (3H, brs), 2.43 (3H, brd), 2.57 (4H, brs), 3.15 (4H, brs), 3.62 (2H, brs), 7.24 (1H ,brd).7.43-7.67(2H,m),7.84(1H,brd),8.37(1H,brs),11.14-11.97(1H,m);
ESI MS m/z：428.22[M+1] + ESI MS m/z: 428.22[M+1] +
实施例52、5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 52, 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000071
Figure PCTCN2022121260-appb-000071
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1HNMR(400MHz,DMSO-d 6)δ2.44(3H,s),2.56(3H,s),3.25-3.56(6Hm)3.87-4.01(2H,m),4.56(2Hbrs),7.47-7.71(3Hm),7.96(1H,brd),8.34(1H,brd),8.58(1H,brs),11.27(1H,brs),11.52-11.92(1H,m) 1 HNMR (400MHz,DMSO-d 6 )δ2.44(3H,s),2.56(3H,s),3.25-3.56(6Hm),3.87-4.01(2H,m),4.56(2Hbrs),7.47-7.71( 3Hm),7.96(1H,brd),8.34(1H,brd),8.58(1H,brs),11.27(1H,brs),11.52-11.92(1H,m)
ESI MS m/z：410.23[M+1] + ESI MS m/z: 410.23[M+1] +
实施例53、6-氯-5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 53, 6-chloro-5-(4-((2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N -(Methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000072
Figure PCTCN2022121260-appb-000072
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1HNMR(400MHz,DMSO-d 6)δ2.42(3H,s),2.41(3H,s),2.55-2.61(4H,m),3.06-3.10(4H,m),3.61(2H,s),7.25(1H,d),7.52(1H,d),7.66(1H,d),7.91(1H,d),8.42-8.45(1H,m),11.57(1H,s)； 1 HNMR(400MHz,DMSO-d 6 )δ2.42(3H,s),2.41(3H,s),2.55-2.61(4H,m),3.06-3.10(4H,m),3.61(2H,s) ,7.25(1H,d),7.52(1H,d),7.66(1H,d),7.91(1H,d),8.42-8.45(1H,m),11.57(1H,s);
ESI MS m/z：444.19[M+1] + ESI MS m/z: 444.19[M+1] +
实施例54、5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 54, 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000073
Figure PCTCN2022121260-appb-000073
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1HNMR(400MHz DMSO-d 6)δ2.41(3H,s),2.42(3H,s),2.47(3H,s),2.56-2.63(4H,m),2.88-2.94(4H,m),3.63(2H,s),7.25(1H,d),7.47(1H,d),7.52(1H,d),7.79(1H,d),8.38-8.44(1H,m),11.57(1H,s) 1 HNMR(400MHz DMSO-d 6 )δ2.41(3H,s),2.42(3H,s),2.47(3H,s),2.56-2.63(4H,m),2.88-2.94(4H,m), 3.63(2H,s),7.25(1H,d),7.47(1H,d),7.52(1H,d),7.79(1H,d),8.38-8.44(1H,m),11.57(1H,s)
ESI MS m/z：424.25[M+1] + ESI MS m/z: 424.25[M+1] +
实施例55、5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-氟吡啶-2-甲酰胺 Example 55, 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-6- Fluoropyridine-2-carboxamide
Figure PCTCN2022121260-appb-000074
Figure PCTCN2022121260-appb-000074
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1HNMR(400MHz,DMSO-d 6)δ2.41(3H,s),2.42(3H,s),2.56(4H,brs),3.14(4H,brs),7.22(1H,d),7.45(1H,brs),7.47-7.58(2H,m),7.77(1H,brs)7.85(1H,br d).11.16-11.70(1H,m): 1 HNMR (400MHz, DMSO-d 6 )δ2.41(3H,s),2.42(3H,s),2.56(4H,brs),3.14(4H,brs),7.22(1H,d),7.45(1H ,brs),7.47-7.58(2H,m),7.77(1H,brs),7.85(1H,br d).11.16-11.70(1H,m):
ESI MS m/z：413.20[M+1] + ESI MS m/z: 413.20[M+1] +
实施例56、5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺 Example 56, 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-6 -Methylpyridine-2-carboxamide
Figure PCTCN2022121260-appb-000075
Figure PCTCN2022121260-appb-000075
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1HNMR(400MHz DMSO-d 6)δ2.41(3H,s),2.45-2.48(3Hm),2.51-2.64(4Hm),2.92(4H,br s),7.28(1H,t),7.43-7.54(3H,m),7.76-7.83(2H,m),12.43(1H,br s)； 1 HNMR(400MHz DMSO-d 6 )δ2.41(3H,s),2.45-2.48(3Hm),2.51-2.64(4Hm),2.92(4H,br s),7.28(1H,t),7.43-7.54 (3H,m),7.76-7.83(2H,m),12.43(1H,br s);
ESI MS m/z：413.20[M+1] + ESI MS m/z: 413.20[M+1] +
实施例57、5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺 Example 57, 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-6- Pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000076
Figure PCTCN2022121260-appb-000076
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1HNMR(400MHzDMSO-d 6)δ2.42(3H,s)2.45(3H,s),2.49(3H,s).2.58(4H,br s),2.93(4H,brs),7.24(1H,br d).7.42(1H,brs),7.46(1H,brd).7.51(1H,brd),7.78(2H,brd),10.54-11.23(1H,m) 1 HNMR(400MHzDMSO-d 6 )δ2.42(3H,s)2.45(3H,s),2.49(3H,s).2.58(4H,br s),2.93(4H,brs),7.24(1H,br d).7.42(1H,brs),7.46(1H,brd).7.51(1H,brd),7.78(2H,brd),10.54-11.23(1H,m)
ESI MS m/z：409.22[M+1] + ESI MS m/z: 409.22[M+1] +
实施例58、6-氯-5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 58, 6-chloro-5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000077
Figure PCTCN2022121260-appb-000077
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1HNMR(400MHz,DMSO-d 6)δ1.22(3H,t),2.67(4H,brs),2.78-2.92(2H,m),3.14(4H,brs),7.45(1H,d).7.67(2H,dd).7.92(1H,d),8.41(1H,q),10.78-11.42(1H,m)； 1 HNMR (400MHz, DMSO-d 6 )δ1.22(3H,t),2.67(4H,brs),2.78-2.92(2H,m),3.14(4H,brs),7.45(1H,d).7.67 (2H,dd).7.92(1H,d),8.41(1H,q),10.78-11.42(1H,m);
ESI MS m/z：478.15[M+1] + ESI MS m/z: 478.15[M+1] +
实施例59、5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d3)吡啶-2-甲酰胺Example 59, 5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro- N-(Methyl-d3)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000078
Figure PCTCN2022121260-appb-000078
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1HNMR(400MHz,DMSO-d 6)δ1.23(3Ht)2.63(4Hbrs),2.84(2Hq),3.18(4H,brs),3.72(2Hs),7.42(1H,d).7.52-7.62(1H,m),7.70(1H,d).7.84(1H,d).8.39(1H,q)11.19-11.51(1H,m)； 1 HNMR (400MHz, DMSO-d 6 )δ1.23(3Ht)2.63(4Hbrs),2.84(2Hq),3.18(4H,brs),3.72(2Hs),7.42(1H,d).7.52-7.62(1H ,m),7.70(1H,d).7.84(1H,d).8.39(1H,q)11.19-11.51(1H,m);
ESI MS m/z：462.18[M+1] + ESI MS m/z: 462.18[M+1] +
实施例60、5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 60, 5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl base-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000079
Figure PCTCN2022121260-appb-000079
参考实施例44方法制备。Prepared with reference to the method of Example 44.
1H NMR(400MHz DMSO-d 6)δ1.23(3H,t),2.85(2H,q).3.24-3.37(8H,m,merged into water peak).4.41-4.62(2H,m),7.44(1H,dd),7.56(1H,br d),7.79-7.90(2H,m),8.33(1H,d),8.44(1H,br d),11.86-12.21(1H,m)； 1 H NMR (400MHz DMSO-d 6 )δ1.23(3H,t),2.85(2H,q).3.24-3.37(8H,m,merged into water peak).4.41-4.62(2H,m),7.44 (1H,dd),7.56(1H,br d),7.79-7.90(2H,m),8.33(1H,d),8.44(1H,br d),11.86-12.21(1H,m);
ESI MS m/z：444.199[M+1] + ESI MS m/z: 444.199[M+1] +
实施例61、5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲 基-d 3)吡啶-2-甲酰胺 Example 61, 5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000080
Figure PCTCN2022121260-appb-000080
将二异丙基乙胺0.5mL加入到6-甲基-N-(甲基-d3)-5-哌嗪-1-基吡啶-2-甲酰胺二盐酸盐480mg，和7-(溴甲基)-8-氯-3-乙基-1H-喹啉-2-酮480mg,乙腈5ml的搅拌悬浮液中，在70℃下搅拌2h，得到悬浮液。将混合物冷却至室温，过滤得固体，用水洗涤并干燥，得到目的物356mg。Add 0.5 mL of diisopropylethylamine to 480 mg of 6-methyl-N-(methyl-d3)-5-piperazin-1-ylpyridine-2-carboxamide dihydrochloride, and 7-(bromo Methyl)-8-chloro-3-ethyl-1H-quinolin-2-one 480mg, acetonitrile 5ml stirred suspension, stirred at 70°C for 2h to obtain a suspension. The mixture was cooled to room temperature and the solid was filtered, washed with water and dried to give 356 mg of the desired compound.
1H NMR(400MHz，DMSO-d 6)δ1.23(3H,t),2.64(4H,br s),2.84(2H,m),2.94(4H,br s),3.38(3H,s,overlapped water peak),3.76(2H,s),7.46(2H,dd),7.72(1H,d),7.78(1H,d),8.41(1H,br d),11.59-1.99(1H,m)； 1 H NMR (400MHz, DMSO-d 6 )δ1.23(3H,t),2.64(4H,br s),2.84(2H,m),2.94(4H,br s),3.38(3H,s,overlapped water peak),3.76(2H,s),7.46(2H,dd),7.72(1H,d),7.78(1H,d),8.41(1H,br d),11.59-1.99(1H,m);
ESI MS m/z：458.21[M+1] + ESI MS m/z: 458.21[M+1] +
实施例62、63、(S/R)-6-氟-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 62, 63, (S/R)-6-fluoro-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxaline-6- Base) methyl) piperazin-1-yl) -N-(methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000081
Figure PCTCN2022121260-appb-000081
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHz,DMSO-d 6)δ1.53-1.72(3H,m),3.54-3.90(8H,m),4.56(2H,br s),5.78-6.21(1H,m),7.61-7.82(3H,m),7.86(1H,d),8.44(1H,brd),11.40-11.85(1H-m),12.79-13.13(1H,m)； 1 H NMR (400MHz,DMSO-d 6 )δ1.53-1.72(3H,m),3.54-3.90(8H,m),4.56(2H,br s),5.78-6.21(1H,m),7.61- 7.82(3H,m),7.86(1H,d),8.44(1H,brd),11.40-11.85(1H-m),12.79-13.13(1H,m);
ESI MS m/z：464.20[M+1] + ESI MS m/z: 464.20[M+1] +
实施例64、65、(R/S)-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 64, 65, (R/S)-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl )piperazin-1-yl)-6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000082
Figure PCTCN2022121260-appb-000082
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1HNMR(400MHz,DMSO-d 6)δ1.41-1.70(3H,m),2.49(3H,s),2.55-2.69(4H,m),,2.95(4H,br s),3.76(2H,s),5.84-6.22(1H,m),7.18-7.42(1H,m),7.48(1H,d),7.66(1H,d),7.79(1H,d),8.41(1H,br d),11.66-12.88(1H,m)； 1 HNMR(400MHz,DMSO-d 6 )δ1.41-1.70(3H,m),2.49(3H,s),2.55-2.69(4H,m),,2.95(4H,br s),3.76(2H, s),5.84-6.22(1H,m),7.18-7.42(1H,m),7.48(1H,d),7.66(1H,d),7.79(1H,d),8.41(1H,br d), 11.66-12.88(1H,m);
ESI MS m/z：460.23[M+1] + ESI MS m/z: 460.23[M+1] +
实施例66、5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 66, 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl base-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000083
Figure PCTCN2022121260-appb-000083
将二异丙基乙胺0.2mL、N-(甲基-d 3)-5-(哌嗪-1-基)吡啶酰胺二盐酸盐90.5mg和7-(溴甲基)-8-氯-3-甲基-1H-喹喔啉-2-酮88mg，加入到乙腈(4mL)的混合物中，在70℃下搅拌3h。浓缩混合物，柱层析得目的物85mg。 Diisopropylethylamine 0.2mL, N-(methyl-d 3 )-5-(piperazin-1-yl)pyridinamide dihydrochloride 90.5mg and 7-(bromomethyl)-8-chloro -88mg of 3-methyl-1H-quinoxalin-2-one was added to a mixture of acetonitrile (4mL), and stirred at 70°C for 3h. The mixture was concentrated and subjected to column chromatography to obtain 85 mg of the target compound.
ESI MS m/z：430.18[M+1] + ESI MS m/z: 430.18[M+1] +
实施例67、5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 67, 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000084
Figure PCTCN2022121260-appb-000084
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHz,DMSO-d 6)δ2.37-2.47(3H,m),2.64(4H,br s),3.14-3.23(4H,m) 1 H NMR (400MHz,DMSO-d 6 )δ2.37-2.47(3H,m),2.64(4H,br s),3.14-3.23(4H,m)
,3.75(2H,s),7.46(1H,d),7.58(1H,dd),7.67(1H,d),7.84(1H,d),8.41(1H,br d),10.72-12.11(1H,m)；,3.75(2H,s),7.46(1H,d),7.58(1H,dd),7.67(1H,d),7.84(1H,d),8.41(1H,br d),10.72-12.11(1H, m);
ESI MS m/z：448.17[M+1] + ESI MS m/z: 448.17[M+1] +
实施例68、5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 68, 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000085
Figure PCTCN2022121260-appb-000085
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
ESI MS m/z：444.19[M+1] + ESI MS m/z: 444.19[M+1] +
实施例69、5-(4-((2-(1,1-二氟乙基)-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺盐s Example 69, 5-(4-((2-(1,1-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine-1 -yl)-6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide salt s
Figure PCTCN2022121260-appb-000086
Figure PCTCN2022121260-appb-000086
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
ESI MS m/z：478.22[M+1] + ESI MS m/z: 478.22[M+1] +
实施例70、6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 70, 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000087
Figure PCTCN2022121260-appb-000087
步骤1、2-((4-溴-3-氟-2-硝基苯基)氨基)丙酸甲酯Step 1, Methyl 2-((4-bromo-3-fluoro-2-nitrophenyl)amino)propionate
Figure PCTCN2022121260-appb-000088
Figure PCTCN2022121260-appb-000088
将1.63g二异丙基乙胺缓慢加入1g 1-溴-2,4-二氟-3-硝基苯和0.65g丙氨酸甲酯盐酸盐在5ml N,N-二甲基甲酰胺的搅拌溶液中，室温下搅拌，用水稀释后，并用二氯甲烷萃取3次，合并有机相，用饱和食盐水洗3次，无水硫酸钠干燥，抽滤，并将滤液减压浓缩后通过硅胶柱层析，得到橙黄色油状物0.8g。Slowly add 1.63g of diisopropylethylamine to 1g of 1-bromo-2,4-difluoro-3-nitrobenzene and 0.65g of alanine methyl ester hydrochloride in 5ml of N,N-dimethylformamide Stirred solution in the solution, stirred at room temperature, diluted with water, extracted 3 times with dichloromethane, combined the organic phases, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated the filtrate under reduced pressure and passed through silica gel Through column chromatography, 0.8 g of orange-yellow oil was obtained.
1H NMR(400MHz,DMSO-d 6)δ7.69(1H,dd),7.27(1H,d),6.74(1H,dd),4.56-4.48(1H,m),3.69(3H,s),1.45(3H,d)； 1 H NMR (400MHz,DMSO-d 6 )δ7.69(1H,dd),7.27(1H,d),6.74(1H,dd),4.56-4.48(1H,m),3.69(3H,s), 1.45(3H,d);
步骤2、7-溴-3-甲基-8-氟-3，4-二氢-1H-喹喔啉-2-酮Step 2, 7-bromo-3-methyl-8-fluoro-3,4-dihydro-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000089
Figure PCTCN2022121260-appb-000089
在0℃冰浴条件下，将0.81g锌粉缓慢加入到0.5g步骤1中间体与0.83g氯化铵在8ml甲醇与0.2g水的搅拌溶液中，转至室温下搅拌。原料反应完后，将体系进行抽滤，并用甲醇在二氯甲烷中的20％的溶液冲洗滤饼，浓缩滤液，得到棕褐色固体，向固体中加入水，并用乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗3次，用无水硫酸钠干燥后抽滤，并将滤液减压浓缩，得到粗产物。向装有粗产物的单口瓶中加入1ml乙酸乙酯和1ml甲醇，并滴入2滴4N氯化氢的1,4-二氧六环，室温下搅拌1h后，减压浓缩后硅胶过柱得0.3g。Under the condition of ice bath at 0°C, slowly add 0.81g of zinc powder to the stirring solution of 0.5g of the intermediate of step 1 and 0.83g of ammonium chloride in 8ml of methanol and 0.2g of water, and stir at room temperature. After the reaction of the raw materials, the system was suction filtered, and the filter cake was washed with a 20% solution of methanol in dichloromethane, and the filtrate was concentrated to obtain a tan solid. Water was added to the solid, and extracted 3 times with ethyl acetate, and the combined The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and suction filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Add 1ml of ethyl acetate and 1ml of methanol to the one-necked bottle containing the crude product, and drop 2 drops of 4N hydrogen chloride in 1,4-dioxane, stir at room temperature for 1 hour, concentrate under reduced pressure and pass through the column on silica gel to obtain 0.3 g.
步骤3、7-溴-3-甲基-8-氟-1H-喹喔啉-2-酮Step 3, 7-bromo-3-methyl-8-fluoro-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000090
Figure PCTCN2022121260-appb-000090
将DDQ 1g加入到步骤2中间体0.3g在二氯甲烷10ml中，室温搅拌2小时。除去溶剂，固体中加入15mL甲醇，搅拌30分钟。固体过滤，用5mL甲醇洗涤，加入50毫升水，然后缓慢加入60ml碳酸氢钠后，混合物室温搅拌过夜，停止搅拌，过滤固体，用水洗涤，得到目的物0.2g。Add 1 g of DDQ to 0.3 g of the intermediate in step 2 in 10 ml of dichloromethane, and stir at room temperature for 2 hours. The solvent was removed, 15 mL of methanol was added to the solid, and stirred for 30 minutes. The solid was filtered, washed with 5 mL of methanol, 50 mL of water was added, and then 60 mL of sodium bicarbonate was slowly added. The mixture was stirred at room temperature overnight, and the stirring was stopped. The solid was filtered and washed with water to obtain 0.2 g of the target compound.
1H NMR(400MHz,DMSO-d 6)δ12.60(1H,s),7.54-7.46(2H,m),2.41(3H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ12.60(1H,s),7.54-7.46(2H,m),2.41(3H,s);
步骤4、3-甲基-8-氟-7-羟甲基-1H-喹喔啉-2-酮Step 4, 3-methyl-8-fluoro-7-hydroxymethyl-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000091
Figure PCTCN2022121260-appb-000091
将Xphos Pd G2(1.121g,1.43mmol)加入到7-溴-3-甲基-8-氟-1H-喹喔啉-2-酮0.1g和(三丁基锡基)甲醇0.138g在1,4-二氧六环5ml溶液中，将反应混合物在90℃下搅拌4小时。真空除去溶剂，加入10ml乙醚，搅拌30min，固体用10ml乙醚洗涤，得到白色固体0.12g。Xphos Pd G2 (1.121g, 1.43mmol) was added to 7-bromo-3-methyl-8-fluoro-1H-quinoxalin-2-one 0.1g and (tributyltin base)methanol 0.138g at 1,4 - in 5 ml of dioxane, the reaction mixture was stirred at 90° C. for 4 hours. The solvent was removed in vacuo, 10 ml of diethyl ether was added, stirred for 30 min, and the solid was washed with 10 ml of diethyl ether to obtain 0.12 g of a white solid.
1HNMR(400MHz,DMSO-d 6)δ12.41(1H,s),7.53-7.50(1H,m),7.35-7.30(1H,m),5.42-5.38(1H,m),4.63(2H,d),2.41(3H,s)； 1 HNMR (400MHz,DMSO-d 6 )δ12.41(1H,s),7.53-7.50(1H,m),7.35-7.30(1H,m),5.42-5.38(1H,m),4.63(2H, d),2.41(3H,s);
步骤5、3-甲基-8-氟-7-溴甲基-1H-喹喔啉-2-酮Step 5, 3-Methyl-8-fluoro-7-bromomethyl-1H-quinoxalin-2-one
8-氟-7-(羟甲基)-3-甲基-1H-喹啉喔-2-酮0.12g，5ml氢溴酸水溶液(48％)，80°反应3h，加入冰水，二氯甲烷萃取，干燥。过滤，浓缩得到白色固体0.26g。8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolinoxal-2-one 0.12g, 5ml hydrobromic acid aqueous solution (48%), react at 80° for 3h, add ice water, dichloro Extracted with methane and dried. Filtration and concentration gave 0.26 g of a white solid.
步骤6、6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Step 6, 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N -(Methyl-d 3 )pyridine-2-carboxamide
加入步骤5中间体0.26g、6-氟-N-(甲基-d 3)-5-(哌嗪-1-基)吡啶酰胺二盐酸盐0.24g、乙腈10ml于烧瓶中，在室温下加二异丙基乙胺0.2ml，并在70℃下搅拌4h。减压除去溶剂，剩余物柱层析得产物0.3g。 Add 0.26g of the intermediate in Step 5, 0.24g of 6-fluoro-N-(methyl-d 3 )-5-(piperazin-1-yl)pyridinamide dihydrochloride, and 10ml of acetonitrile into the flask, and at room temperature Add 0.2ml of diisopropylethylamine, and stir at 70°C for 4h. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to obtain 0.3 g of the product.
1HNMR(400MHz DMSO-d 6)δ2.42(s,3H),2.64-2.54(m,4H),3.21-3.12(m,4H),3.70(s,2H),7.32-7.25(m,1H),7.59-7.49(m,2H),7.84(d,1H),8.36(s,1H),12.45(bs,1H)； 1 HNMR(400MHz DMSO-d 6 )δ2.42(s,3H),2.64-2.54(m,4H),3.21-3.12(m,4H),3.70(s,2H),7.32-7.25(m,1H ),7.59-7.49(m,2H),7.84(d,1H),8.36(s,1H),12.45(bs,1H);
ESI MS m/z：432.20[M+1] + ESI MS m/z: 432.20[M+1] +
实施例71、6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 71, 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine-1- base)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000092
Figure PCTCN2022121260-appb-000092
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1HNMR(400MHz DMSO-d 6)δ2.42(s,3H),2.63-2.54(m,4H),3.21-3.14(m,4H),7.31-7.25(m,1H),7.58-7.48(m,2H),7.84(d,1H),8.36(s,1H),12.44(bs,1H)； 1 HNMR(400MHz DMSO-d 6 )δ2.42(s,3H),2.63-2.54(m,4H),3.21-3.14(m,4H),7.31-7.25(m,1H),7.58-7.48(m ,2H),7.84(d,1H),8.36(s,1H),12.44(bs,1H);
ESI MS m/z：434.21[M+1] + ESI MS m/z: 434.21[M+1] +
实施例72、6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺 Example 72, 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine-1- Base) -N-methylpyridine-2-carboxamide
Figure PCTCN2022121260-appb-000093
Figure PCTCN2022121260-appb-000093
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
ESI MS m/z：431.19[M+1] + ESI MS m/z: 431.19[M+1] +
实施例73、6-氯-5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 73, 6-chloro-5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000094
Figure PCTCN2022121260-appb-000094
将二氯亚砜2ml滴加至中间体8-氟-7-(羟甲基)-3-甲氧基喹喔啉-2(1H)-酮1.5g、0.1ml N,N-二甲基甲酰胺在二氯甲烷20ml，室温搅拌3小时，将反应混合物浓缩至干，得到7-(氯甲基)-8-氟-3-甲氧基喹喔啉-2(1H)-酮。将7-(氯甲基)-8-氟-3-甲氧基喹喔啉-2(1H)-酮、二异丙基乙胺2.5ml，6-氯-N-(甲基-d3)-5-(哌嗪-1-基)吡啶酰胺1.5g溶解于乙腈25ml，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1.6g。Add 2ml of thionyl chloride dropwise to 1.5g of intermediate 8-fluoro-7-(hydroxymethyl)-3-methoxyquinoxalin-2(1H)-one, 0.1ml of N,N-dimethyl Formamide was dissolved in 20 ml of dichloromethane, stirred at room temperature for 3 hours, and the reaction mixture was concentrated to dryness to obtain 7-(chloromethyl)-8-fluoro-3-methoxyquinoxalin-2(1H)-one. 7-(Chloromethyl)-8-fluoro-3-methoxyquinoxalin-2(1H)-one, 2.5ml of diisopropylethylamine, 6-chloro-N-(methyl-d3) -1.5 g of 5-(piperazin-1-yl)pyridine amide was dissolved in 25 ml of acetonitrile, stirred at 80°C for 2 hours, concentrated to dryness, added with aqueous sodium bicarbonate solution and stirred, extracted with ethyl acetate, washed with water, dried, filtered, and the residue By column chromatography, 1.6 g of the target compound was obtained.
1H NMR(400MHZ,DMSO-d 6)δ2.57-2.66(4H,m),3.06-3.14(4H,m),3.70(2H,s),3.96(3H,s),7.21-7.30(m,1H),7.36(d,1H),7.65(d,1H),7.92(d,1H),8.43(d,1H),12.46(s,1H)； 1 H NMR (400MHZ,DMSO-d 6 )δ2.57-2.66(4H,m),3.06-3.14(4H,m),3.70(2H,s),3.96(3H,s),7.21-7.30(m ,1H),7.36(d,1H),7.65(d,1H),7.92(d,1H),8.43(d,1H),12.46(s,1H);
ESI MS m/z：464.16[M+1] + ESI MS m/z: 464.16[M+1] +
实施例74、5-(4-((2-乙基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 74, 5-(4-((2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methanol Base-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000095
Figure PCTCN2022121260-appb-000095
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHZ,DMSO-d 6)δ1.21(3H,t),2.43(3H,s),2.51(3H,s),5.54-2.58(4H,m),2.73-2.86(2H,m),2.87-2.93(4H,m),3.63(2H,s),7.24(1H,d),7.46(1H,d),7.53(1H,d),7.77(1H,d),8.38(1H,d),11.52(1H,s)； 1 H NMR (400MHZ,DMSO-d 6 )δ1.21(3H,t),2.43(3H,s),2.51(3H,s),5.54-2.58(4H,m),2.73-2.86(2H,m ),2.87-2.93(4H,m),3.63(2H,s),7.24(1H,d),7.46(1H,d),7.53(1H,d),7.77(1H,d),8.38(1H, d),11.52(1H,s);
ESI MS m/z：438.26[M+1] + ESI MS m/z: 438.26[M+1] +
实施例75、5-(4-((2-乙基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 75, 5-(4-((2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000096
Figure PCTCN2022121260-appb-000096
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1HNMR(400MHZ,DMSO-d 6)δ1.20(3H,t),2.41(3H,s),2.49-2.59(4H,m),2.70-2.81(5H,m),3.08-3.16(4H,m),3.59(2H,s),7.22(1H,d),7.47-7.60(2H,m),7.82(1H,dd),8.37(1H,d),11.52(1H,s)； 1 HNMR (400MHZ,DMSO-d 6 )δ1.20(3H,t),2.41(3H,s),2.49-2.59(4H,m),2.70-2.81(5H,m),3.08-3.16(4H, m), 3.59(2H,s), 7.22(1H,d), 7.47-7.60(2H,m), 7.82(1H,dd), 8.37(1H,d), 11.52(1H,s);
ESI MS m/z：442.24[M+1] + ESI MS m/z: 442.24[M+1] +
实施例76、5-(4-((2-乙基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 76, 5-(4-((2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000097
Figure PCTCN2022121260-appb-000097
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHZ,DMSO-d 6)δ1.17-1.26(3H,m),2.42(3H,s),2.48-2.56(4H,m),2.70-2.81(2H,m),3.31-3.34(4H,m),3.60(2H,s),7.26(1H,d),7.39(1H,d),7.54(1H,d),7.83(1H,d),8.27(1H,s),8.36(1H,s).11.52(1H,s)； 1 H NMR (400MHZ,DMSO-d 6 )δ1.17-1.26(3H,m),2.42(3H,s),2.48-2.56(4H,m),2.70-2.81(2H,m),3.31-3.34 (4H,m),3.60(2H,s),7.26(1H,d),7.39(1H,d),7.54(1H,d),7.83(1H,d),8.27(1H,s),8.36( 1H,s).11.52(1H,s);
ESI MS m/z：424.25[M+1] + ESI MS m/z: 424.25[M+1] +
实施例77、6-(二氟甲基)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 77, 6-(difluoromethyl)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000098
Figure PCTCN2022121260-appb-000098
将二异丙胺0.52mL加入到3-甲基-8-氟-7-溴甲基-1H-喹喔啉-2-酮200mg和6-(二氟甲基)-5-(哌嗪-1-基)-N-(甲基-d3)吡啶酰胺二盐酸盐250.6mg和5ml乙腈的搅拌混合物中，得到的混合物在70℃下搅拌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84mg。Add 0.52 mL of diisopropylamine to 200 mg of 3-methyl-8-fluoro-7-bromomethyl-1H-quinoxalin-2-one and 6-(difluoromethyl)-5-(piperazine-1 In a stirred mixture of 250.6 mg of -yl)-N-(methyl-d3)pyridineamide dihydrochloride and 5 ml of acetonitrile, the resulting mixture was stirred at 70°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 84 mg of the target compound.
1H NMR(500MHz,DMSO-d 6)δ2.36(3H,s)，2.66(4H,brs)，3.03(4H,br d),3.71(2H,s),7.04-7.28(2H,m),7.41(1H,br d),7.85(1H,d),8.08(1H,d),8.39(1H,q),12.27-12.63(1H,m)； 1 H NMR (500MHz, DMSO-d 6 ) δ2.36(3H,s), 2.66(4H,brs), 3.03(4H,br d), 3.71(2H,s), 7.04-7.28(2H,m) ,7.41(1H,br d),7.85(1H,d),8.08(1H,d),8.39(1H,q),12.27-12.63(1H,m);
ESI MS m/z：464.20[M+1] + ESI MS m/z: 464.20[M+1] +
实施例78、6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺 Example 78, 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine-1- base) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000099
Figure PCTCN2022121260-appb-000099
步骤1、6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d2)哌嗪-1-基)吡啶甲酸甲酯Step 1, 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d2)piperazin-1-yl) Methyl picolinate
Figure PCTCN2022121260-appb-000100
Figure PCTCN2022121260-appb-000100
加入7-(溴甲基-d 2)-3-甲基-8-氟-1H-喹喔啉-2-酮的800mg、6-氟-5-(哌嗪-1-基)吡啶甲酸甲酯盐酸盐1200mg、乙腈25mL和二异丙基乙胺0.2ml，将反应混合物加热至70℃2小时。反应混合物冷却至室温，浓缩，纯化粗固体。得到目的物0.96g。 Add 800 mg of 7-(bromomethyl-d 2 )-3-methyl-8-fluoro-1H-quinoxalin-2-one, 6-fluoro-5-(piperazin-1-yl)picolinate 1200 mg of ester hydrochloride, 25 mL of acetonitrile and 0.2 ml of diisopropylethylamine, and the reaction mixture was heated to 70° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated and the crude solid was purified. 0.96 g of the target product was obtained.
ESI MS m/z：432.17[M+1] + ESI MS m/z: 432.17[M+1] +
步骤2、6-氟-5-(4-((5-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶酰胺 Step 2, 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl-d 2 )piperazine -1-yl)pyridineamide
氨水(7N氨水在甲醇溶液中)10.3ml加入到步骤1中间体0.5g加入到50ml的圆底烧瓶中，密封并在室温下搅拌24小时，得到200mg纯产品。真空浓缩滤液，得到的白色固体在4ml甲醇打浆，过滤获得目的物237mg。Ammonia (7N ammonia in methanol solution) 10.3ml was added to step 1 intermediate 0.5g was added to a 50ml round bottom flask, sealed and stirred at room temperature for 24 hours to obtain 200mg of pure product. The filtrate was concentrated in vacuo, and the resulting white solid was slurried in 4 ml of methanol, and filtered to obtain 237 mg of the desired compound.
1H NMR(500MHz,DMSO-d 6)δ2.43(3H,s),2.60(4H,br s),3.12-3.25(4H,m),7.28(1H,br t),7.44(1H,br s),7.48-7.56(2H,m),7.75(1H,br s),7.86(1H,br d),12.34(1H,br s)； 1 H NMR (500MHz,DMSO-d 6 )δ2.43(3H,s),2.60(4H,br s),3.12-3.25(4H,m),7.28(1H,br t),7.44(1H,br s),7.48-7.56(2H,m),7.75(1H,br s),7.86(1H,br d),12.34(1H,br s);
ESI MS m/z：417.12[M+1] + ESI MS m/z: 417.12[M+1] +
实施例79、6-氯-5-(4-((2-甲基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 79, 6-chloro-5-(4-((2-methyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000101
Figure PCTCN2022121260-appb-000101
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHz,DMSO-d 6)δ2.43(3H,s),2.59-2.65(4H,m),3.08-3.17(4H,m),3.71(2H,s),7.31(1H,t),7.52(1H,d),7.64(1H,d),7.92(1H,d),8.42-8.48(1H,m),12.46(1 H,s) 1 H NMR (400MHz,DMSO-d 6 )δ2.43(3H,s),2.59-2.65(4H,m),3.08-3.17(4H,m),3.71(2H,s),7.31(1H,t ),7.52(1H,d),7.64(1H,d),7.92(1H,d),8.42-8.48(1H,m),12.46(1H,s)
ESI MS m/z：448.17[M+1] + ESI MS m/z: 448.17[M+1] +
实施例80、5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 80, 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000102
Figure PCTCN2022121260-appb-000102
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHz,DMSO-d6)δ2.43(3H,s),2.48(3H,s),2.56-2.63(4H,m),2.92-2.97(4H,m),3.73(2H,s),7.31(1H,t),7.46(1H,d),7.53(1H,d),7.78(1H,d),8.39-8.45(1H,m),12.47(1H,s)； 1 H NMR(400MHz,DMSO-d6)δ2.43(3H,s),2.48(3H,s),2.56-2.63(4H,m),2.92-2.97(4H,m),3.73(2H,s) ,7.31(1H,t),7.46(1H,d),7.53(1H,d),7.78(1H,d),8.39-8.45(1H,m),12.47(1H,s);
ESI MS m/z：428.22[M+1] + ESI MS m/z: 428.22[M+1] +
实施例81、5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 81, 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl base-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000103
Figure PCTCN2022121260-appb-000103
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1HNMR(400MHz,DMSO-d 6)δ12.45(1H,bs),8.35(1H,bs),8.25(1H,d),7.82(1H,d),7.52(1H,d),7.39-7.35(1H,m),7.32-7.27(m,1H),3.69(2H,s),3.30(4H,overlapped with water m),2.61-2.53(4H,m),2.42(3H,s)； 1 H NMR (400MHz, DMSO-d 6 ) δ12.45 (1H, bs), 8.35 (1H, bs), 8.25 (1H, d), 7.82 (1H, d), 7.52 (1H, d), 7.39-7.35 (1H,m),7.32-7.27(m,1H),3.69(2H,s),3.30(4H,overlapped with water m),2.61-2.53(4H,m),2.42(3H,s);
ESI MS m/z：414.21[M+1] + ESI MS m/z: 414.21[M+1] +
实施例82、N-(乙基-2,2,2-d 3)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺 Example 82, N-(ethyl-2,2,2-d 3 )-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxaline -6-yl)methyl)piperazin-1-yl)pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000104
Figure PCTCN2022121260-appb-000104
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHZ,DMSO-d 6)δ2.40(3H,s),2.52-2.62(4H,m),3.17-3.27(4H,m),3.25(2H,q), 3.68(2H,s),7.27(1H,t),7.49-7.56(2H,m),7.82(1H,d),8.44(1H.d),12.46(1H,s)； 1 H NMR (400MHZ,DMSO-d 6 )δ2.40(3H,s),2.52-2.62(4H,m),3.17-3.27(4H,m),3.25(2H,q), 3.68(2H,s ),7.27(1H,t),7.49-7.56(2H,m),7.82(1H,d),8.44(1H.d),12.46(1H,s);
ESI MS m/z：446.21[M+1] + ESI MS m/z: 446.21[M+1] +
实施例83、N-(乙基-2,2,2-d 3)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺 Example 83, N-(ethyl-2,2,2-d 3 )-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl )methyl)piperazin-1-yl)-6-methylpyridine-2-carboxamide
Figure PCTCN2022121260-appb-000105
Figure PCTCN2022121260-appb-000105
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHZ,DMSO-d 6)δ2.42(3H,s),2.51(3H,s),2.55-2.62(4H,m),2.86-2.96(4H,m),3.31(2H,q),3.71(2H,s),7.26(1H,t),7.46(1H,d),7.51(1H,d),7.76(1H,d),8.40(1H,t),12.42(1H,s)； 1 H NMR (400MHZ,DMSO-d 6 )δ2.42(3H,s),2.51(3H,s),2.55-2.62(4H,m),2.86-2.96(4H,m),3.31(2H,q ),3.71(2H,s),7.26(1H,t),7.46(1H,d),7.51(1H,d),7.76(1H,d),8.40(1H,t),12.42(1H,s) ;
ESI MS m/z：442.24[M+1] + ESI MS m/z: 442.24[M+1] +
实施例84、5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 84, 5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- 6-Methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000106
Figure PCTCN2022121260-appb-000106
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHZ,DMSO-d 6)δ2.51(3H,s),2.57-2.64(4H,m),2.90-2.96(4H,m),3.76(2H,s),7.42(1H,t),7.46(1H,d),7.71(1H,d),7.78(1H,d),8.38-8.42(1H,m),13.21(1H,brs)； 1 H NMR (400MHZ,DMSO-d 6 )δ2.51(3H,s),2.57-2.64(4H,m),2.90-2.96(4H,m),3.76(2H,s),7.42(1H,t ),7.46(1H,d),7.71(1H,d),7.78(1H,d),8.38-8.42(1H,m),13.21(1H,brs);
ESI MS m/z：482.19[M+1] + ESI MS m/z: 482.19[M+1] +
实施例85、6-氟-5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 85, 6-fluoro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazine-1 -yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000107
Figure PCTCN2022121260-appb-000107
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHZ,DMSO-d 6)δ2.58-2.64(4H,m),3.13-3.22(4H,m),3.76(2H,s),7.38(1H,t),7.55(1H,dd),7.72(1H,d),7.83(1H,dd),8.38-8.43(1H,m),13.38(1H,brs)； 1 H NMR (400MHZ,DMSO-d 6 )δ2.58-2.64(4H,m),3.13-3.22(4H,m),3.76(2H,s),7.38(1H,t),7.55(1H,dd ),7.72(1H,d),7.83(1H,dd),8.38-8.43(1H,m),13.38(1H,brs);
ESI MS m/z：486.17[M+1] + ESI MS m/z: 486.17[M+1] +
实施例86、4-氯-5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基) -N-(甲基-d 3)吡啶-2-甲酰胺 Example 86, 4-chloro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazine-1 -yl) -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000108
Figure PCTCN2022121260-appb-000108
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHZ,DMSO-d 6)δ2.61-2.66(4H,m),3.08-3.14(4H,m),3.76(2H,s),7.41(1H,t),7.65(1H,d),7.73(1H,d),7.92(1H,d),8.41-8.43(1H,m),13.25(1H,brs)； 1 H NMR (400MHZ,DMSO-d 6 )δ2.61-2.66(4H,m),3.08-3.14(4H,m),3.76(2H,s),7.41(1H,t),7.65(1H,d ),7.73(1H,d),7.92(1H,d),8.41-8.43(1H,m),13.25(1H,brs);
ESI MS m/z：501.14[M+1] + ESI MS m/z: 501.14[M+1] +
实施例87、5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 87, 5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000109
Figure PCTCN2022121260-appb-000109
参考实施例44方法合成。Synthesized with reference to the method of Example 44.
1H NMR(400MHZ,DMSO-d 6)δ2.51-2.56(4H,m),3.26-3.35(4H,m),3.73(2H,s),7.31(1H,t),7.41(1H,dd),7.64(1H,d),7.82(1H,d),8.28(1H,d),8.37-8.41(1H,m)； 1 H NMR (400MHZ,DMSO-d 6 )δ2.51-2.56(4H,m),3.26-3.35(4H,m),3.73(2H,s),7.31(1H,t),7.41(1H,dd ),7.64(1H,d),7.82(1H,d),8.28(1H,d),8.37-8.41(1H,m);
ESI MS m/z：468.18[M+1] + ESI MS m/z: 468.18[M+1] +
实施例88、5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 88, 5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000110
Figure PCTCN2022121260-appb-000110
步骤1、4-溴-3-氟-苯-1,2-二胺Step 1. 4-bromo-3-fluoro-benzene-1,2-diamine
将保险粉20g加入到4-溴-3-氟-2-硝基苯胺7.3g、甲醇60ml。将混合物回流搅拌3小时。减压下除去溶剂。用水层用乙酸乙酯(3×50ml)萃取，水洗涤(100ml)，。有机层无水硫酸钠干燥，过滤，除溶剂，柱层析得到4-溴-3-氟-苯-1.2-二胺5.38g。Add 20 g of sodium hydrosulfite to 7.3 g of 4-bromo-3-fluoro-2-nitroaniline and 60 ml of methanol. The mixture was stirred at reflux for 3 hours. The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3 x 50ml), washed with water (100ml). The organic layer was dried over anhydrous sodium sulfate, filtered, the solvent was removed, and 5.38 g of 4-bromo-3-fluoro-benzene-1.2-diamine was obtained by column chromatography.
ESI MS m/z：204.97[M+1] + ESI MS m/z: 204.97[M+1] +
步骤2、7-溴-8-氟-1H-喹喔啉-2-酮Step 2, 7-bromo-8-fluoro-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000111
Figure PCTCN2022121260-appb-000111
将2-氧代乙酸乙酯3.2g加入到4-溴-3-氟-苯-1.2二胺2.2g的甲苯30ml中。得到的混合物在100℃下搅拌60分钟。溶剂在减压下除去，沉淀物经过滤收集，用乙酸乙酯洗涤5ml，真空干燥得到1.6g。3.2 g of ethyl 2-oxoacetate was added to 2.2 g of 4-bromo-3-fluoro-benzene-1.2diamine in 30 ml of toluene. The resulting mixture was stirred at 100°C for 60 minutes. The solvent was removed under reduced pressure and the precipitate was collected by filtration, washed with ethyl acetate (5ml) and dried in vacuo to give 1.6g.
ESI MS m/z：242.95[M+1] + ESI MS m/z: 242.95[M+1] +
步骤3、8-氟-7-(羟甲基)-1H-喹喔啉-2-酮Step 3, 8-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000112
Figure PCTCN2022121260-appb-000112
将氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯0.2g添加到(三丁烯基甲醇1.70g、7-溴-8-氟-1H-喹喔啉-2-酮1.5g和1,4-二氧六环(30mL)。混合物在氮气保护下、100℃下搅拌18小时后，用水洗涤，水层用乙酸乙酯(3×60ml)提取。有机层无水硫酸钠干燥，过滤，除溶剂，柱层析得到目的物520mg。Add 0.2 g of chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium to (1.70 g of tributenylmethanol, 7-bromo-8-fluoro- 1H-quinoxalin-2-one 1.5g and 1,4-dioxane (30mL). The mixture was stirred under nitrogen protection at 100°C for 18 hours, washed with water, and the aqueous layer was washed with ethyl acetate (3× 60ml) extraction. The organic layer was dried over anhydrous sodium sulfate, filtered, solvent removed, and column chromatography obtained 520 mg of the target compound.
ESI MS m/z：195.05[M+1] + ESI MS m/z: 195.05[M+1] +
步骤4、5-(4-((5-氟-3-氧代-4-H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶酰胺 Step 4, 5-(4-((5-fluoro-3-oxo-4-H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridinamide
将二氯亚砜0.5ml加入8-氟-7-(羟甲基)-1H-喹喔啉-2-酮320mg的二氯甲烷3mL溶液中。将得到的混合物在室温下搅拌1小时，在减压下去除溶剂。在NMP 3.0ml的混合物中加入二异丙胺0.5ml和N-(甲基-d 3)-5-哌嗪-1-基吡啶-2-甲酰胺280mg得到的混合物在80℃搅拌1小时，用水洗涤(100ml)，水层用乙酸乙酯提取。有机层无水硫酸钠干燥，过滤除溶剂，柱层析得到目的物234mg。 0.5 ml of thionyl chloride was added to a solution of 320 mg of 8-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one in 3 mL of dichloromethane. The resulting mixture was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. Add 0.5 ml of diisopropylamine and 280 mg of N-(methyl-d 3 )-5-piperazin-1-ylpyridine-2-carboxamide to a mixture of 3.0 ml of NMP and stir the resulting mixture at 80° C. for 1 hour, and water After washing (100ml), the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by filtration, and 234 mg of the target compound was obtained by column chromatography.
1H NMR(400MHz,DMSO-d 6)δ2.56-2.60(4H,m),3.29-3.33(4H,m),3.72(2H,s),7.31-7.43(2H,m),7.62(1H,d),7.81(1H,d),8.21(1H,s),8.26(1H,d),8.38-8.42(1H,m)； 1 H NMR (400MHz,DMSO-d 6 )δ2.56-2.60(4H,m),3.29-3.33(4H,m),3.72(2H,s),7.31-7.43(2H,m),7.62(1H ,d),7.81(1H,d),8.21(1H,s),8.26(1H,d),8.38-8.42(1H,m);
ESI MS m/z：400.19[M+1] + ESI MS m/z: 400.19[M+1] +
实施例89、6-氯-5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 89, 6-chloro-5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000113
Figure PCTCN2022121260-appb-000113
参考实施例88方法制备。Prepared with reference to the method of Example 88.
1H NMR(400MHz,DMSO-d 6)δ2.59-2.65(4H,m),3.08-3.13(4H,m),3.72(2H,s),7.34 (1H,dd),7.62(1H,d),7.64(1H,d),7.92(1H,d),8.21(1H,s),8.41-8.44(1H,m),12.57(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.59-2.65(4H,m),3.08-3.13(4H,m),3.72(2H,s),7.34(1H,dd),7.62(1H,d ),7.64(1H,d),7.92(1H,d),8.21(1H,s),8.41-8.44(1H,m),12.57(1H,s);
ESI MS m/z：434.15[M+1] + ESI MS m/z: 434.15[M+1] +
实施例90、5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 90, 5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl base-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000114
Figure PCTCN2022121260-appb-000114
参考实施例88方法制备。Prepared with reference to the method of Example 88.
1H NMR(400MHz,DMSO-d 6)δ2.47(3H,s),2.55-2.65(4H,s),2.93-2.98(4H,m),3.72(2H,s),7.31-7.39(1H,m),7.48(1H,d),7.62(1H,d),7.77(1H,d),,8.18(1H,s),8.39-8.44(1H,m),12.54(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.47(3H,s),2.55-2.65(4H,s),2.93-2.98(4H,m),3.72(2H,s),7.31-7.39(1H ,m),7.48(1H,d),7.62(1H,d),7.77(1H,d),,8.18(1H,s),8.39-8.44(1H,m),12.54(1H,s);
ESI MS m/z：414.21[M+1] + ESI MS m/z: 414.21[M+1] +
实施例91、6-氟-5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 91, 6-fluoro-5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000115
Figure PCTCN2022121260-appb-000115
参考实施例88方法制备。Prepared with reference to the method of Example 88.
ESI MS m/z：418.18[M+1] + ESI MS m/z: 418.18[M+1] +
实施例92、5-(4-((2-(二氟甲基)-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 92, 5-(4-((2-(difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- 6-Methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000116
Figure PCTCN2022121260-appb-000116
参考实施例88方法合成。Synthesize with reference to the method of Example 88.
1H NMR(400MHz,DMSO-d6)δ2.48(3H,s),2.61-2.65(4H,m),2.91-2.98(4H,m),3.75(2H,s),7.07(1H,t),7.38(1H,t),7.49(1H,d),7.71(1H,d),7.80(1H,d),8.41(1H,q),13.02(1H,s)； 1 H NMR(400MHz,DMSO-d6)δ2.48(3H,s),2.61-2.65(4H,m),2.91-2.98(4H,m),3.75(2H,s),7.07(1H,t) ,7.38(1H,t),7.49(1H,d),7.71(1H,d),7.80(1H,d),8.41(1H,q),13.02(1H,s);
ESI MS m/z：464.20[M+1] + ESI MS m/z: 464.20[M+1] +
实施例93、5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 93, 5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000117
Figure PCTCN2022121260-appb-000117
步骤1、4-溴-3-氟-苯-1,2-二胺Step 1. 4-bromo-3-fluoro-benzene-1,2-diamine
Figure PCTCN2022121260-appb-000118
Figure PCTCN2022121260-appb-000118
将保险粉8g加入到4-溴-3-氟-2-硝基苯胺3.0g，用甲醇30ml溶解。将得到的混合物回流5小时。用水稀释反应混合物，用乙酸乙酯萃取。用MgSO 4干燥有机层，过滤和蒸发得到4-溴-3-氟-苯-1,2-二胺2.4g。 Add 8 g of sodium hydrosulfite to 3.0 g of 4-bromo-3-fluoro-2-nitroaniline, and dissolve in 30 ml of methanol. The resulting mixture was refluxed for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 , filtered and evaporated to give 4-bromo-3-fluoro-benzene-1,2-diamine 2.4g.
1H NMR(400MHz,DMSO-d 6)δ4.66(2H,s),4.94(2H,s),6.31(1H,dd),6.55(1H,dd)； 1 H NMR (400MHz,DMSO-d 6 )δ4.66(2H,s),4.94(2H,s),6.31(1H,dd),6.55(1H,dd);
步骤2、7-溴-8-氟-3-甲氧基-1H-喹喔啉-2-酮Step 2, 7-bromo-8-fluoro-3-methoxy-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000119
Figure PCTCN2022121260-appb-000119
将2,2,2-三甲氧基乙酸甲酯2.4g，在室温下添加到4-溴-3-氟苯-1,2-二胺1.5g、三((三氟甲基)磺酰基)氧)镱0.45g的甲苯20ml溶液中。将得到的混合物在100℃下搅拌5h，减压去除溶剂。水洗，乙酸乙酯萃取，柱层析得到7-溴-8-氟-3-甲氧基-1H-喹喔啉-2-酮0.65g。Add 2.4 g of methyl 2,2,2-trimethoxyacetate to 1.5 g of 4-bromo-3-fluorobenzene-1,2-diamine, tris((trifluoromethyl)sulfonyl) Oxygen) ytterbium 0.45g in toluene 20ml solution. The resulting mixture was stirred at 100 °C for 5 h, and the solvent was removed under reduced pressure. Washing with water, extraction with ethyl acetate, and column chromatography gave 0.65 g of 7-bromo-8-fluoro-3-methoxy-1H-quinoxalin-2-one.
步骤3、8-氟-7-(羟甲基)3-甲氧基-1H-喹喔啉-2-酮Step 3, 8-fluoro-7-(hydroxymethyl) 3-methoxy-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000120
Figure PCTCN2022121260-appb-000120
将(三丁基锡基)甲醇1.6g、7-溴-8-氟-3-甲氧基喹喔啉-2(1H)-酮600.0mg和氯[(正丁基二(1-金刚烷基)膦)-2-(2-氨基联苯)]钯73mg加入到二氧六环20ml中，氮气保护下，将混合物在100℃下搅拌6小时，然后过滤，减压下浓缩除溶剂，对粗品柱层析进行纯化，干燥得到8-氟-7-(羟甲基)-3-甲氧基-1H-喹喔啉-2-酮254mg。(Tributyltin base)methanol 1.6g, 7-bromo-8-fluoro-3-methoxyquinoxalin-2(1H)-one 600.0mg and chloro[(n-butylbis(1-adamantyl) Phosphine)-2-(2-aminobiphenyl)]palladium 73mg was added to 20ml of dioxane, and under the protection of nitrogen, the mixture was stirred at 100°C for 6 hours, then filtered, concentrated under reduced pressure to remove the solvent, and the crude product Purified by column chromatography and dried to obtain 254 mg of 8-fluoro-7-(hydroxymethyl)-3-methoxy-1H-quinoxalin-2-one.
步骤4、7-氯甲基-8-氟-3-甲氧基-1H-喹喔啉-2-酮Step 4, 7-chloromethyl-8-fluoro-3-methoxy-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000121
Figure PCTCN2022121260-appb-000121
在室温下，将二氯亚砜8ml加入到步骤4中间体200.0mg的乙醚50ml溶液中。将得到的混合物在室温下搅拌8小时。除去溶剂，得到7-(氯甲基)-8-氟-3-甲氧基-1H-喹喔啉-2-酮178mg，该产品直接用于下一步。At room temperature, 8 ml of thionyl chloride was added to a solution of 200.0 mg of the intermediate in Step 4 in 50 ml of ether. The resulting mixture was stirred at room temperature for 8 hours. The solvent was removed to obtain 178 mg of 7-(chloromethyl)-8-fluoro-3-methoxy-1H-quinoxalin-2-one, which was directly used in the next step.
1H NMR(400MHz,DMSO-d 6)δ3.96(3H,s)，4.87(2H,s).7.27-7.42(2H,m)，12.60(1H,s) 1 H NMR (400MHz,DMSO-d 6 )δ3.96(3H,s), 4.87(2H,s).7.27-7.42(2H,m), 12.60(1H,s)
ESI MS m/z(ES +)[M+H] +＝243.03 ESI MS m/z(ES + )[M+H] + = 243.03
步骤5、5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Step 5, 5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(form base-d 3 ) pyridine-2-carboxamide
在室温下，在乙腈10ml中，加入步骤4中间体150mg，N-(甲基-d 3)-5-哌嗪-1-基吡啶-2-甲酰胺200mg，二异丙基乙胺0.5ml，混合物在60℃下搅拌6小时，减压去除溶剂。对粗产物用硅胶柱层析进行纯化，得到目的物163.0mg。 At room temperature, in 10ml of acetonitrile, add 150mg of the intermediate of step 4, 200mg of N-(methyl-d 3 )-5-piperazin-1-ylpyridine-2-carboxamide, 0.5ml of diisopropylethylamine , the mixture was stirred at 60 °C for 6 h, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 163.0 mg of the target compound.
1H NMR(400MHz,DMSO-d 6)δ2.52-2.58(4H,m)，3.18-3.44(4H,m)，3.65(2H,s)，3.94(3H,s)，7.11-7.27(1H,m),7.26-7.41(2H,m)，7.82(1H,d),8.24(1H,d)，8.38(1H,q),12.31(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.52-2.58(4H,m), 3.18-3.44(4H,m), 3.65(2H,s), 3.94(3H,s), 7.11-7.27(1H ,m), 7.26-7.41(2H,m), 7.82(1H,d), 8.24(1H,d), 8.38(1H,q), 12.31(1H,s);
ESI MS m/z：430.20[M+1] + ESI MS m/z: 430.20[M+1] +
实施例94、6-氟-5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 94, 6-fluoro-5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000122
Figure PCTCN2022121260-appb-000122
参考实施例93方法制备。Prepared with reference to the method of Example 93.
1H NMR(400MHz,DMSO-d 6)δ2.54-2.59(4H,m),3.10-3.18(4H,m),3.66(2H,s),3.95(3H,s),7.18-7.28(1H,m),7.35(1H,d),7.54(1H,dd),7.78-7.87(1H,m)，8.41(1H,d)，12.50(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.54-2.59(4H,m),3.10-3.18(4H,m),3.66(2H,s),3.95(3H,s),7.18-7.28(1H ,m), 7.35(1H,d), 7.54(1H,dd), 7.78-7.87(1H,m), 8.41(1H,d), 12.50(1H,s);
ESI MS m/z：448.19[M+1] + ESI MS m/z: 448.19[M+1] +
实施例95、5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 95, 5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methan Base-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000123
Figure PCTCN2022121260-appb-000123
参考实施例93方法制备。Prepared with reference to the method of Example 93.
1H NMR(400MHz,DMSO-d 6)δ2.49(3H s),2.57-2.63(4H,m),2.91-2.95(4H,m),3.68(2H,s),3.98(3H,s),7.26(1H,t),7.37(1H,d),7.46(1H,d),7.78(1H,d),8.44(1H,q),12.52(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.49(3H s),2.57-2.63(4H,m),2.91-2.95(4H,m),3.68(2H,s),3.98(3H,s) ,7.26(1H,t),7.37(1H,d),7.46(1H,d),7.78(1H,d),8.44(1H,q),12.52(1H,s);
ESI MS m/z：444.22[M+1] + ESI MS m/z: 444.22[M+1] +
实施例96、6-氟-5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 96, 6-fluoro-5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000124
Figure PCTCN2022121260-appb-000124
参考实施例93方法合成。Synthesized with reference to the method of Example 93.
1H NMR(400MHz,DMSO-d 6)1.23(6H,d),2.54-2.65(4H,m),3.13-3.24(4H,m),3.35-3.53(1H,m),3.72(2H,s),7.32(1H,t),7.51-7.57(2H,m),7.83(1H,d),8.37-8.41(1H,m),12.47(1H,br s)； 1 H NMR (400MHz,DMSO-d 6 )1.23(6H,d),2.54-2.65(4H,m),3.13-3.24(4H,m),3.35-3.53(1H,m),3.72(2H,s ),7.32(1H,t),7.51-7.57(2H,m),7.83(1H,d),8.37-8.41(1H,m),12.47(1H,br s);
ESI MS m/z：460.23[M+1] + ESI MS m/z: 460.23[M+1] +
实施例97、5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 97, 5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methanol Base-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000125
Figure PCTCN2022121260-appb-000125
参考实施例93方法合成。Synthesized with reference to the method of Example 93.
1H NMR(400MHz,DMSO-d 6)δ1.21(6H,d),2.45-2.47(3H,m),2.51-2.66(4H,m),2.93(4H,br s),3.37-3.51(1H,m),3.72(2H,s),7.28(1H,t),7.47(1H,d),7.55(1H,d),7.78(1H,d),8.38-8.45(1H,m),12.45(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ1.21(6H,d),2.45-2.47(3H,m),2.51-2.66(4H,m),2.93(4H,br s),3.37-3.51( 1H,m),3.72(2H,s),7.28(1H,t),7.47(1H,d),7.55(1H,d),7.78(1H,d),8.38-8.45(1H,m),12.45 (1H,s);
ESI MS m/z：456.25[M+1] + ESI MS m/z: 456.25[M+1] +
实施例98、5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 98, 5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000126
Figure PCTCN2022121260-appb-000126
参考实施例93方法合成。Synthesized with reference to the method of Example 93.
1H NMR(400MHz,DMSO-d 6)δ1.23(6H,d),2.51-2.60(4H,m),3.24 3.29(4H,m),3.373.51(1H,m),3.71(2H,s),7.32(1H,t),7.37(1H,dd),7.56(1H,d),7.83(1H,d),8.25(1H,d),8.37(1H,br d),12.45(1H,brs)； 1 H NMR (400MHz,DMSO-d 6 )δ1.23(6H,d),2.51-2.60(4H,m),3.24 3.29(4H,m),3.373.51(1H,m),3.71(2H, s),7.32(1H,t),7.37(1H,dd),7.56(1H,d),7.83(1H,d),8.25(1H,d),8.37(1H,br d),12.45(1H, brs);
ESI MS m/z：442.24[M+1] + ESI MS m/z: 442.24[M+1] +
实施例99、5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 99, 5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000127
Figure PCTCN2022121260-appb-000127
参考实施例93方法合成。Synthesized with reference to the method of Example 93.
1H NMR(400MHz,DMSO-d 6)δ1.05-1.12(4H,m),2.53-2.62(4H,m),2.72(1H,s),3.12-3.22(4H,m),3.68(2H,s),7.25(1H,t),7.44(1H,d),7.56(1H,dd),7.85(1H,d),8.38(1H,br d),12.45(1H,br s)； 1 H NMR (400MHz,DMSO-d 6 )δ1.05-1.12(4H,m),2.53-2.62(4H,m),2.72(1H,s),3.12-3.22(4H,m),3.68(2H ,s),7.25(1H,t),7.44(1H,d),7.56(1H,dd),7.85(1H,d),8.38(1H,br d),12.45(1H,br s);
ESI MS m/z：458.21[M+1] + ESI MS m/z: 458.21[M+1] +
实施例100、5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 100, 5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methan Base-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000128
Figure PCTCN2022121260-appb-000128
参考实施例93方法制备。Prepared with reference to the method of Example 93.
1H NMR(400MHz,DMSO-d 6)1.03-1.15(4H,m),2.46-2.49(3H,m),2.52-2.65(4H,m),2.65-2.75(1H,m),2.80(3H,d),2.94(4H,br s),3.71(2H,s),7.26(1H,t),7.40-7.50(2H,m),7.79(1H,d),8.37-8.44(1H,m),12.46(1H,s).； 19FNMR(471MHz,DMSO-d 6)-135.54(1F,s)； 1 H NMR (400MHz,DMSO-d 6 )1.03-1.15(4H,m),2.46-2.49(3H,m),2.52-2.65(4H,m),2.65-2.75(1H,m),2.80(3H ,d),2.94(4H,br s),3.71(2H,s),7.26(1H,t),7.40-7.50(2H,m),7.79(1H,d),8.37-8.44(1H,m) ,12.46(1H,s).; 19 FNMR(471MHz,DMSO-d 6 )-135.54(1F,s);
ESI MS m/z：454.24[M+1] + ESI MS m/z: 454.24[M+1] +
实施例101、5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 101, 5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000129
Figure PCTCN2022121260-appb-000129
参考实施例93方法制备。Prepared with reference to the method of Example 93.
1H NMR(400MHz,DMSO-d 6)δ1.04-1.15(4H,m),2.54-2.61(4H,m),2.64-2.80(2H,m),3.69(2H,s),7.26(1H,br t),7.39(1H,dd),7.41(1H,d),7.83(1H,d),8.26(1H,d),8.36-8.40(1H,m),12.39-12.51(1H,m)； 1 H NMR (400MHz,DMSO-d 6 )δ1.04-1.15(4H,m),2.54-2.61(4H,m),2.64-2.80(2H,m),3.69(2H,s),7.26(1H ,br t),7.39(1H,dd),7.41(1H,d),7.83(1H,d),8.26(1H,d),8.36-8.40(1H,m),12.39-12.51(1H,m) ;
ESI MS m/z：440.22[M+1] + ESI MS m/z: 440.22[M+1] +
实施例102、5-(4-((2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺 Example 102, 5-(4-((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6- Methyl-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000130
Figure PCTCN2022121260-appb-000130
步骤1、7-溴-3-甲氧基-8-甲基-1H-喹喔啉-2-酮Step 1, 7-bromo-3-methoxy-8-methyl-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000131
Figure PCTCN2022121260-appb-000131
将4-溴-3-甲基苯-1，2-二胺0.9g，2，2，2-三甲氧基乙酸甲酯1.4g，和三氟甲磺酸镱(III)0.540g，氮气保护，在100℃下搅拌，将混合物冷却至室温，过滤收集固体，用甲醇洗涤，干燥，得到7-溴-3-甲氧基-8-甲基-喹喔啉-2(1H)-酮1.8g。0.9g of 4-bromo-3-methylbenzene-1,2-diamine, 1.4g of methyl 2,2,2-trimethoxyacetate, and 0.540g of ytterbium (III) trifluoromethanesulfonate, nitrogen protection , stirred at 100 °C, the mixture was cooled to room temperature, the solid was collected by filtration, washed with methanol, and dried to give 7-bromo-3-methoxy-8-methyl-quinoxalin-2(1H)-one 1.8 g.
步骤2、7-(羟甲基)-3-甲氧基-8-甲基-1H-喹喔啉-2-酮Step 2, 7-(hydroxymethyl)-3-methoxy-8-methyl-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000132
Figure PCTCN2022121260-appb-000132
将(三丁基锡烷基)甲醇1.8g、7-溴-3-甲氧基-8-甲基-1H-喹喔啉-酮1.0g和Xphos Pd G20.452g加到100ml反应瓶中，再加入1，4-二氧六环30ml，在氮气保护下，在80℃下搅拌过夜，得到黑色混合物，减压除去溶剂，残余物硅胶柱上纯化然后将产物在10mL甲醇中打浆，过滤收集固体，干燥，得到目的物750mg。Add (tributylstannyl)methanol 1.8g, 7-bromo-3-methoxy-8-methyl-1H-quinoxalin-one 1.0g and Xphos Pd G20.452g to a 100ml reaction flask, then add 30ml of 1,4-dioxane was stirred overnight at 80°C under the protection of nitrogen to obtain a black mixture, the solvent was removed under reduced pressure, and the residue was purified on a silica gel column. Then the product was slurried in 10mL of methanol, and the solid was collected by filtration. After drying, 750 mg of the target compound was obtained.
1H NMR(400MHz,DMSO-d 6)δ2.31(3H,s),3.92-4.02(3H,m),4.57(2H,d),5.15(1H,t),7.28(1H,d),7.38(1H,d),11.58(1H,br s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.31(3H,s),3.92-4.02(3H,m),4.57(2H,d),5.15(1H,t),7.28(1H,d), 7.38(1H,d),11.58(1H,br s);
ESI MS m/z：211.08[M+1] + ESI MS m/z: 211.08[M+1] +
步骤3、7-(溴甲基)-3-甲氧基-8-甲基-1H-喹喔啉-2-酮Step 3, 7-(bromomethyl)-3-methoxy-8-methyl-1H-quinoxalin-2-one
Figure PCTCN2022121260-appb-000133
Figure PCTCN2022121260-appb-000133
将7-羟甲基-3-甲氧基-8-甲基-1H-喹喔啉-2-酮600mg和1，1，2，2-四溴-1，2-二氯乙烷180mg加到二氯甲烷20mL中，将混合物在室温下搅拌4h，减压除去溶剂，残余物悬浮在乙醚15ml中，过滤，固体用乙醚洗涤，固体悬浮用水洗涤，过滤，干燥，得到目的物0.42g。Add 600 mg of 7-hydroxymethyl-3-methoxy-8-methyl-1H-quinoxalin-2-one and 180 mg of 1,1,2,2-tetrabromo-1,2-dichloroethane Into 20 mL of dichloromethane, the mixture was stirred at room temperature for 4 h, the solvent was removed under reduced pressure, the residue was suspended in 15 ml of ether, filtered, the solid was washed with ether, the suspended solid was washed with water, filtered, and dried to obtain 0.42 g of the target compound.
ESI MS m/z：285.00[M+1] + ESI MS m/z: 285.00[M+1] +
步骤4、5-(4-((2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d3)吡啶酰胺Step 4, 5-(4-((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methan Base-N-(methyl-d3)pyridinamide
将6-甲基-N-(甲基-d 3)-5-(哌嗪-1-基)吡啶甲酰胺二盐酸盐250mg和7-(溴甲基)-3-甲氧基-8-甲基-1H-喹喔啉-2-酮258mg，加入乙腈5ml中，然后加入二异丙基乙胺0.6mL中，将混合物在70℃下搅拌2h，得到澄清溶液，将混合物冷却至室温，过滤收集固体，用乙腈、水洗涤，干燥，得目的物167mg。 250 mg of 6-methyl-N-(methyl-d 3 )-5-(piperazin-1-yl)pyridinecarboxamide dihydrochloride and 7-(bromomethyl)-3-methoxy-8 -Methyl-1H-quinoxalin-2-one 258mg was added to 5ml of acetonitrile, then added to 0.6mL of diisopropylethylamine, the mixture was stirred at 70°C for 2h to obtain a clear solution, and the mixture was cooled to room temperature , the solid was collected by filtration, washed with acetonitrile and water, and dried to obtain 167 mg of the target compound.
1H NMR(400MHz,DMSO-d 6)δ2.42(3H,s),2.48(3H,s),2.56(4H,br s),2.92(4H,br s),3.61(2H,s),3.94(3H,s),7.17(1H,d),7.36(1H,d),7.45(1H,d),7.77(1H,d),8.41(1H,q),11.57(1H,br s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.42(3H,s),2.48(3H,s),2.56(4H,br s),2.92(4H,br s),3.61(2H,s), 3.94(3H,s),7.17(1H,d),7.36(1H,d),7.45(1H,d),7.77(1H,d),8.41(1H,q),11.57(1H,br s);
ESI MS m/z：440.24[M+1] + ESI MS m/z: 440.24[M+1] +
实施例103、6-氟-5-(4-((2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 103, 6-fluoro-5-(4-((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl )-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000134
Figure PCTCN2022121260-appb-000134
参考实施例102方法合成。Synthesize with reference to the method of Example 102.
1H NMR(400MHz,DMSO-d 6)δ2.41(3H,s),2.54(4H,br s),3.15(4H,br s),3.57(2H,s),3.94(3H,s),7.16(1H,br d),7.34(1H,br d),7.51-7.61(1H,m),7.82(1H,br d),8.37(1H,br d),11.57(1H,s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.41(3H,s),2.54(4H,br s),3.15(4H,br s),3.57(2H,s),3.94(3H,s), 7.16(1H,br d),7.34(1H,br d),7.51-7.61(1H,m),7.82(1H,br d),8.37(1H,br d),11.57(1H,s);
ESI MS m/z：444.22[M+1] + ESI MS m/z: 444.22[M+1] +
实施例104、6-(二氟甲基)-5-(4-(2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 104, 6-(difluoromethyl)-5-(4-(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine -1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000135
Figure PCTCN2022121260-appb-000135
将6-(二氟甲基)-N-(甲基-d 3)-5-哌嗪-1-基吡啶-2-甲酰胺二盐酸盐167mg和7-(溴甲基)-3-甲氧基-8-甲基-1H-喹喔啉-2-酮160mg加入乙腈6ml中，混合物在70℃下搅拌2h，溶液澄清，将混合物冷却至室温得到悬浮液，过滤收集固体，用乙腈、水洗涤，干燥，得目的物142mg。 167 mg of 6-(difluoromethyl)-N-(methyl-d 3 )-5-piperazin-1-ylpyridine-2-carboxamide dihydrochloride and 7-(bromomethyl)-3- Add 160mg of methoxy-8-methyl-1H-quinoxalin-2-one into 6ml of acetonitrile, stir the mixture at 70°C for 2h, the solution is clear, cool the mixture to room temperature to obtain a suspension, collect the solid by filtration, and wash with acetonitrile , washed with water, and dried to obtain 142 mg of the target compound.
1H NMR(400MHz,DMSO-d 6)δ2.42(3H,s),2.58(4H,br s),2.96(4H,br s),3.61(2H,s),3.94(3H,s),6.93-7.27(2H,m),7.34(1H,d),7.84(1H,br d),8.07(1H,d),8.37(1H,br d),11.59(1H,br s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.42(3H,s),2.58(4H,br s),2.96(4H,br s),3.61(2H,s),3.94(3H,s), 6.93-7.27(2H,m),7.34(1H,d),7.84(1H,br d),8.07(1H,d),8.37(1H,br d),11.59(1H,br s);
ESI MS m/z：476.22[M+1] + ESI MS m/z: 476.22[M+1] +
实施例105、6-(二氟甲基)-5-(4-(2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基) -N-(甲基-d 3)吡啶-2-甲酰胺 Example 105, 6-(difluoromethyl)-5-(4-(2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine-1- base) -N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000136
Figure PCTCN2022121260-appb-000136
参考实施例102方法合成。Synthesize with reference to the method of Example 102.
1H NMR(400MHz,DMSO-d 6)δ2.41(3H,s),2.42(3H,s),2.61(4H,br s),2.97(4H,br d),3.62(2H,s),6.96-7.23(1H,m),7.24-7.28(1H,m),7.52(1H,d),7.86(1H,d),8.07(1H,d),8.37(1H,br d),11.53(1H,br s)； 1 H NMR (400MHz,DMSO-d 6 )δ2.41(3H,s),2.42(3H,s),2.61(4H,br s),2.97(4H,br d),3.62(2H,s), 6.96-7.23(1H,m),7.24-7.28(1H,m),7.52(1H,d),7.86(1H,d),8.07(1H,d),8.37(1H,br d),11.53(1H ,br s);
ESI MS m/z：460.23[M+1] + ESI MS m/z: 460.23[M+1] +
实施例106、(S)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 106, (S)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methanol (Piperazin-1-yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121260-appb-000137
Figure PCTCN2022121260-appb-000137
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：443.19[M+1] + ESI MS m/z: 443.19[M+1] +
实施例107、(S)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 107, (S)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methanol Basepiperazin-1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000138
Figure PCTCN2022121260-appb-000138
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：446.21[M+1] + ESI MS m/z: 446.21[M+1] +
实施例108、(S)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 108, (S)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121260-appb-000139
Figure PCTCN2022121260-appb-000139
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：425.20[M+1] + ESI MS m/z: 425.20[M+1] +
实施例109、(S)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺Example 109, (S)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-N,6-lutidine-2-carboxamide
Figure PCTCN2022121260-appb-000140
Figure PCTCN2022121260-appb-000140
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：439.22[M+1] + ESI MS m/z: 439.22[M+1] +
实施例110、(S)-6-氟-N-甲基-5-(2-甲基-4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺Example 110, (S)-6-fluoro-N-methyl-5-(2-methyl-4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methanol Base) piperazin-1-yl) pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000141
Figure PCTCN2022121260-appb-000141
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：425.20[M+1] + ESI MS m/z: 425.20[M+1] +
实施例111、(S)-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 111, (S)-5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-6-fluoro-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000142
Figure PCTCN2022121260-appb-000142
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：460.23[M+1] + ESI MS m/z: 460.23[M+1] +
实施例112、(S)-5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺 Example 112, (S)-5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine -1-yl)-6-fluoro-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000143
Figure PCTCN2022121260-appb-000143
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：472.23[M+1] + ESI MS m/z: 472.23[M+1] +
实施例113、(S)-5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-甲基吡啶-2-甲酰胺Example 113, (S)-5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine -1-yl)-6-fluoro-N-methylpyridine-2-carboxamide
Figure PCTCN2022121260-appb-000144
Figure PCTCN2022121260-appb-000144
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：469.21[M+1] + ESI MS m/z: 469.21[M+1] +
实施例114、(R)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺 Example 114, (R)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methanol Basepiperazin-1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide
Figure PCTCN2022121260-appb-000145
Figure PCTCN2022121260-appb-000145
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：446.21[M+1] + ESI MS m/z: 446.21[M+1] +
实施例115、(R)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺Example 115, (R)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methanol (Piperazin-1-yl)-N-methylpyridine-2-carboxamide
Figure PCTCN2022121260-appb-000146
Figure PCTCN2022121260-appb-000146
参考实施例44方法制备。Prepared with reference to the method of Example 44.
ESI MS m/z：443.19[M+1] + ESI MS m/z: 443.19[M+1] +
实施例116、化合物对PARP的抑制作用Example 116, the inhibitory effect of the compound on PARP
方法1：将化合物样品用DMSO溶解，配制10mM母液，然后把化合物加到筛选体系中，化合物检测浓度范围是0.1nM-10μM，按照3倍梯度进行稀释，每个浓度做两个复孔。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IC50值。具体操作步骤如下：Method 1: Dissolve the compound sample in DMSO, prepare a 10mM stock solution, and then add the compound to the screening system. The detection concentration range of the compound is 0.1nM-10μM. Dilute according to a 3-fold gradient, and make two replicate wells for each concentration. The experimental results were converted into the activity percentage, the drug concentration was taken as the abscissa, and the enzyme activity percentage 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 value. 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 of buffer (50 mM Tris, 2 mM magnesium chloride, pH 8.0) were added to each well, and then 5 μL of test compounds or solvent controls at different concentrations were added. 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(pH7.9),50mM NaCl,1mM EDTA,0.05％Brij-35,1mM DTTAssay buffer composition: 10mM phosphate buffer (pH7.9), 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。DSB DNA preparation: use assay buffer to dilute DSB DNA to 4X, and add 4 μL per well to the experimental plate.
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。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1The 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. IC 50 values of test compounds against PARP-1 at the enzyme level
Figure PCTCN2022121260-appb-000147
Figure PCTCN2022121260-appb-000147
Figure PCTCN2022121260-appb-000148
Figure PCTCN2022121260-appb-000148
Figure PCTCN2022121260-appb-000149
Figure PCTCN2022121260-appb-000149
注：+示IC50值在50nM下；++示IC50值在5nM下Note: + means IC50 value under 50nM; ++ means IC50 value under 5nM
提示实施例70化合物等较AZD-9574对PARP1有较高的抑制作用或捕获能力。It is suggested that the compound of Example 70 has a higher inhibitory effect or capture ability on PARP1 than AZD-9574.
实施例117、化合物对人肿瘤细胞的增殖抑制作用Example 117, 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-9574。Results: The compounds of the examples have significant inhibitory effects on the above tumor cells, significantly better than AZD-2281 and AZD-9574.
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. IC 50 values of the test compounds on human tumor cell proliferation inhibition
Figure PCTCN2022121260-appb-000150
Figure PCTCN2022121260-appb-000150
Figure PCTCN2022121260-appb-000151
Figure PCTCN2022121260-appb-000151
Figure PCTCN2022121260-appb-000152
Figure PCTCN2022121260-appb-000152
注：+示IC50值在500nM下；++示IC50值在30nM下；+++示IC50值在5nM下。Note: + indicates IC50 value at 500nM; ++ indicates IC50 value at 30nM; +++ indicates IC50 value at 5nM.
实施例118、本发明实施例化合物大鼠药代动力学试验Embodiment 118, rat pharmacokinetic test of the 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 Dosing preparations
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、NMP  0.538mL、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, NMP 0.538mL, 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 PCTCN2022121260-appb-000153
Figure PCTCN2022121260-appb-000153
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 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 10 minutes 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 PCTCN2022121260-appb-000154
Figure PCTCN2022121260-appb-000154
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 PCTCN2022121260-appb-000155
Figure PCTCN2022121260-appb-000155
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70化合物大鼠口服给药暴露量大于AZD-9574。Results: The oral exposure of the compound of Example 70 to rats was greater than that of AZD-9574.
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 limit the protection scope 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 (11)

  1. 式(Ⅰ)结构化合物：Formula (I) structural compound:
    Figure PCTCN2022121260-appb-100001
    Figure PCTCN2022121260-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 1为氢、C 1-10烷基、C 3-10环烷基，并可被氘任意取代； R is hydrogen, 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、C 1-10烷氧基，并可被卤素、C1-C3烷基、C 1-10烷氧基、氘任意取代； R 2 is independently selected from hydrogen, halogen, C 1-10 alkyl, C 1-10 alkoxy, and can be optionally substituted by halogen, C 1-C3 alkyl, C 1-10 alkoxy, deuterium;
    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;
    R 4为氢、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 is hydrogen, halogen, cyano, C 1-10 alkyl, C 1-10 alkyl, which can be optionally substituted by deuterium, halogen, C 1-10 alkoxy, C 3-10 cycloalkyl;
    R 5为氢、C 1-10烷基、与R 5相连的碳原子连有2个取代基时，可与其相连的碳原子形成3-6元环； When R 5 is hydrogen, C 1-10 alkyl, and the carbon atom connected to R 5 has 2 substituents, it can form a 3-6 membered ring with the carbon atom connected to it;
    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、其特征在于所述的式(Ⅰ)化合物包括但不限于下列结构：The compound according to claim 1, characterized in that the compound of formula (I) includes but is not limited to the following structures:
    5-(4-((2-乙基-3-氧代-4H-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-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridine-2 - Formamide;
    6-乙基-5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-ethyl-5-(4-((2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-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-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )-6- (Trifluoromethyl)pyridine-2-carboxamide;
    5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-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-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )-6- (Difluoromethyl)pyridine-2-carboxamide;
    5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氯-N-(甲基-d 3)吡啶-2- 甲酰胺； 5-(4-((2-Ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-chloro-N-(methyl-d 3 ) pyridine-2-carboxamide;
    N-(甲基-d 3)5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) Pyridine-2-carboxamide;
    6-氯-N-(甲基-d 3)5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-chloro-N-(methyl-d 3 )5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl) pyridine-2-carboxamide;
    6-氯-N-(甲基-d 3)-5-(4-((2-(三氟甲基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Chloro-N-(methyl-d 3 )-5-(4-((2-(trifluoromethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine -1-yl) pyridine-2-carboxamide;
    N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2 - Formamide;
    6-氯-N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Chloro-N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide;
    6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-丙基-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-propyl-3,4-dihydroquinoxalin-6-yl)methyl)piperazine -1-yl) pyridine-2-carboxamide;
    6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-乙基-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-ethyl-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide;
    5-(4-((2-(1,1-二氟乙基)-3-氧代-4H-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-(1,1-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl base-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-(2,2-二氟乙基)-3-氧代-4H-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-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-(2,2-二氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-(2,2-difluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro- N-(methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((2-(2-氟乙基)-3-氧代-4H-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-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    6-氟-5-(4-((2-(2-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-(2-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    N-(甲基-d 3)-5-(4-((3-氧代-2-(2,2,2-三氟乙基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl)methyl) Piperazin-1-yl)pyridine-2-carboxamide;
    6-氟-N-(甲基-d 3)-5-(4-((3-氧代-2-(2,2,2-三氟乙基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-2-(2,2,2-trifluoroethyl)-4H-quinoxalin-6-yl ) methyl) piperazin-1-yl) pyridine-2-carboxamide;
    6-氟-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl ) pyridine-2-carboxamide;
    6-甲基-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Methyl-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine-1- Base) pyridine-2-carboxamide;
    N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2 - Formamide;
    6-氟-N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazine- 1-yl) pyridine-2-carboxamide;
    6-氟-N-甲基-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-methyl-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine -2-formamide;
    N-(甲基-d 3)-5-(4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl) Pyridine-2-carboxamide;
    6-氟-5-(4-((2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl- d3 ) pyridine-2-carboxamide;
    5-(4-((2-异丙基-3-氧代-4H-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-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridine- 2-formamide;
    5-(4-((2-环丙基-3-氧代-4H-喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-cyclopropyl-3-oxo-4H-oxolin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-环丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-cyclopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl- d3 ) pyridine-2-carboxamide;
    5-(4-((2-环丙基-3-氧代-4H-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-cyclopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridine- 2-formamide;
    6-氟-N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2- Formamide;
    6-甲基-N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； 6-Methyl-N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2 - Formamide;
    N-(甲基-d 3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(methyl-d 3 )-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)pyridine-2-carboxamide;
    6-氟-N-(甲基-d3)-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-(methyl-d3)-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine- 2-formamide;
    6-氟-N-甲基-5-(4-((3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-N-methyl-5-(4-((3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)pyridine-2-carboxamide ;
    6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶酰胺； 5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridineamide ;
    5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl- d3 ) pyridine-2-carboxamide;
    6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基-d2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl-d2)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide;
    6-氟-5-(4-((2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2- 甲酰胺； 6-fluoro-5-(4-((2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)-N-methyl Pyridine-2-carboxamide;
    5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    6-(二氟甲基)-5-(4-(2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-(Difluoromethyl)-5-(4-(2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)pyridine-2-carboxamide ;
    6-甲基-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-methyl-5-(4-((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine -2-formamide;
    5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    6-氯-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-乙基-5-氟-3-氧代-4H-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-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl -d 3 ) pyridine-2-carboxamide;
    5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
    6-氯-5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((2,5-dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl -d 3 ) pyridine-2-carboxamide;
    5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-氟吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-6-fluoropyridine-2 - Formamide;
    5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl- d 2 )piperazin-1-yl)-6-methylpyridine -2-formamide;
    5-(4-((2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺； 5-(4-((2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-6-methylpyridine- 2-formamide;
    6-氯-5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d3)吡啶-2-甲酰胺；5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl Base-d3) pyridine-2-carboxamide;
    5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氯-2-乙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-ethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    (R)-6-氟-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-6-fluoro-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
    (S)-6-氟-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-6-fluoro-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
    (R)-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； (R)-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
    (S)-5-(4-((5-氟-2-(1-氟乙基)-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((5-fluoro-2-(1-fluoroethyl)-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氯-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-chloro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-(1,1-二氟乙基)-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-(1,1-difluoroethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- 6-methyl-N-(methyl-d 3 )pyridine-2-carboxamide;
    6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-N -(methyl-d 3 )pyridine-2-carboxamide;
    6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)-N-甲基吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)-N -Methylpyridine-2-carboxamide;
    6-氯-5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-乙基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((2-乙基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-Ethyl-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-乙基-5-甲基-3-氧代-4H-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-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    6-(二氟甲基)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-(Difluoromethyl)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl) -N-(methyl-d 3 )pyridine-2-carboxamide;
    6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基-d 2)哌嗪-1-基)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl-d 2 )piperazin-1-yl)pyridine- 2-formamide;
    6-氯-5-(4-((2-甲基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-chloro-5-(4-((2-methyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    N-(乙基-2,2,2-d 3)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺； N-(ethyl-2,2,2-d 3 )-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl ) methyl) piperazin-1-yl) pyridine-2-carboxamide;
    N-(乙基-2,2,2-d 3)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基吡啶-2-甲酰胺； N-(ethyl-2,2,2-d 3 )-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl) Piperazin-1-yl)-6-methylpyridine-2-carboxamide;
    5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide;
    6-氟-5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
    4-氯-5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 4-Chloro-5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)- N-(methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((5-氟-3-氧代-2-(三氟甲基)-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-3-oxo-2-(trifluoromethyl)-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl Base-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 )pyridine-2- Formamide;
    6-氯-5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-Chloro-5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
    5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N-(methyl-d 3 ) pyridine-2-carboxamide;
    6-氟-5-(4-((5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) Pyridine-2-carboxamide;
    5-(4-((2-(二氟甲基)-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-(Difluoromethyl)-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl -N-(methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    6-氟-5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氟-2-甲氧基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-methoxy-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide;
    6-氟-5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3) 吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((5-氟-2-异丙基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((5-fluoro-2-isopropyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-fluoro-N-( Methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N- (Methyl-d 3 )pyridine-2-carboxamide;
    5-(4-((2-环丙基-5-氟-3-氧代-4H-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-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N-(methyl-d 3 ) pyridine-2-carboxamide;
    5-(4-((2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(甲基-d 3)吡啶-2-甲酰胺； 5-(4-((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-6-methyl-N -(methyl-d 3 )pyridine-2-carboxamide;
    6-氟-5-(4-((2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-fluoro-5-(4-((2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N- (Methyl-d 3 )pyridine-2-carboxamide;
    6-(二氟甲基)-5-(4-(2-甲氧基-5-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-(Difluoromethyl)-5-(4-(2-methoxy-5-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl )-N-(methyl-d 3 )pyridine-2-carboxamide;
    6-(二氟甲基)-5-(4-(2,5-二甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； 6-(Difluoromethyl)-5-(4-(2,5-Dimethyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazin-1-yl)-N -(methyl-d 3 )pyridine-2-carboxamide;
    (S)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(S)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-N-methylpyridine-2-carboxamide;
    (S)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide;
    (S)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(S)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl) -N-methylpyridine-2-carboxamide;
    (S)-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N，6-二甲基吡啶-2-甲酰胺；(S)-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl) -N,6-lutidine-2-carboxamide;
    (S)-6-氟-N-甲基-5-(2-甲基-4-((2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)哌嗪-1-基)吡啶-2-甲酰胺；(S)-6-fluoro-N-methyl-5-(2-methyl-4-((2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)piperazine -1-yl) pyridine-2-carboxamide;
    (S)-5-(4-((2-乙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((2-Ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl) -6-fluoro-N-(methyl-d 3 )pyridine-2-carboxamide;
    (S)-5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-(甲基-d 3)吡啶-2-甲酰胺； (S)-5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl )-6-fluoro-N-(methyl-d 3 )pyridine-2-carboxamide;
    (S)-5-(4-((2-环丙基-5-氟-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-6-氟-N-甲基吡啶-2-甲酰胺；(S)-5-(4-((2-cyclopropyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazin-1-yl )-6-fluoro-N-methylpyridine-2-carboxamide;
    (R)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-(甲基-d 3)吡啶-2-甲酰胺或 (R)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 1-yl)-N-(methyl-d 3 )pyridine-2-carboxamide or
    (R)-6-氟-5-(4-((5-氟-2-甲基-3-氧代-4H-喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶-2-甲酰胺；(R)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl)-2-methylpiperazine- 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.
  3. 一种药物组合物，其包含权利要求1-2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, which comprises the compound, isomer, deuterated derivative or pharmaceutically acceptable salt thereof described in any one of claims 1-2.
  4. 根据权利要求3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 3, further comprising a pharmaceutically acceptable carrier, excipient, diluent or a combination thereof.
  5. 根据权利要求4所述的药物组合物，在癌症治疗中的使用。The use of the pharmaceutical composition according to claim 4 in cancer treatment.
  6. 根据权利要求5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 5, wherein the cancer lacks the HR-dependent DNA DSB repair pathway.
  7. 根据权利要求5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 5, wherein the cancer cells have a BRCA1 or BRCA2 deficient phenotype.
  8. 根据权利要求5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 5, wherein the cancer is heterozygous for mutations in genes encoding components of the HR-dependent DNA DSB repair pathway.
  9. 根据权利要求5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 5, wherein the cancer is heterozygous for mutations in BRCA1 and/or BRCA2.
  10. 根据权利要求5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 5, wherein the cancer cells include but not limited to breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.
  11. 根据权利要求3-10任一项所述的药物组合物，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 any one of claims 3-10 in the preparation of drugs for preventing or treating diseases related to PARP-1.
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