WO2019100743A1 - 含有苯并呋喃的parp-1和pi3k双靶点抑制剂 - Google Patents

含有苯并呋喃的parp-1和pi3k双靶点抑制剂 Download PDF

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WO2019100743A1
WO2019100743A1 PCT/CN2018/097979 CN2018097979W WO2019100743A1 WO 2019100743 A1 WO2019100743 A1 WO 2019100743A1 CN 2018097979 W CN2018097979 W CN 2018097979W WO 2019100743 A1 WO2019100743 A1 WO 2019100743A1
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徐云根
朱启华
王均伟
储昭兴
李慧
葛亦然
何广卫
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中国药科大学
合肥医工医药有限公司
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of PARP-1 and PI3K dual target inhibitors containing a benzofuran structure, a process for their preparation, and pharmaceutical compositions containing the same and their use in antitumor.
  • PARP Poly ADP-ribose polymerase
  • Phosphatidylinositol-3-kinase is an upstream molecule in the PI3K/Akt/mTOR signal transduction pathway. As a key nodal protein in this pathway, PI3K can phosphorylate phosphatidylinositol4. The 3-hydroxyl group of 5-diphosphate (PIP2) forms phosphatidylinositol 3,4,5-triphosphate (PIP3). As a second messenger, PIP3 plays an important role in the basic reactions of cell survival, growth, proliferation and metabolism. The tumor suppressor gene PTEN can dephosphorylate PIP3 to form PIP2, which is an antagonist of PI3K catalysis.
  • PI3K Abnormal activation of PI3K can lead to disorders in this pathway, causing a range of diseases including cancer, neurological disorders, autoimmune diseases, and hematopoietic diseases.
  • PI3K has become one of the important targets for cancer treatment research.
  • PI3K inhibitors there are still several PI3K inhibitors in clinical research, but there are no reports of PARP-1/PI3K dual target inhibitors.
  • the invention discloses a compound of the general formula (I), and the pharmacodynamic test results show that the compound of the present invention or a pharmaceutically acceptable salt thereof can simultaneously act on two targets of PARP-1 and PI3K, and can be used as a tumor. a single therapeutic agent; or in combination with other anti-tumor drugs to achieve the effect of improving the efficacy of existing anti-tumor drugs and reducing the dose and toxicity.
  • X represents CH or N
  • R 1 represents R 1 preferably represents
  • Preferred partial compounds of the invention are as follows:
  • the above reaction is preferably carried out by adding a catalyst, a base and a reaction solvent, wherein the catalyst is preferably palladium chloride, palladium acetate, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1).
  • the catalyst is preferably palladium chloride, palladium acetate, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1).
  • base is preferably selected from sodium ethoxide, sodium acetate , potassium acetate, potassium phosphate, sodium carbonate or potassium carbonate
  • reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane , toluene, ethanol, water or a mixed solvent of any two or three kinds of solvents
  • the reaction temperature is preferably from 70 ° C to 115 ° C.
  • the catalyst is more preferably tetrakis(triphenylphosphine)palladium; the base is more preferably potassium carbonate; the solvent is more preferably a mixed solvent of dioxane/water; and the reaction temperature is more preferably from 95 °C to 110 °C.
  • the cyanide used is preferably from zinc cyanide, copper cyanide or cuprous cyanide. More preferred is cuprous cyanide.
  • the catalyst is preferably selected from the group consisting of palladium chloride, palladium acetate, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene] Palladium chloride or [1,1'-bis(diphenylphosphino)ferrocene] nickel dichloride. More preferred is tetrakis(triphenylphosphine)palladium.
  • the reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide. More preferred is N,N-dimethylformamide.
  • the reaction temperature is preferably from 30 ° C to 90 ° C. More preferably, it is 70-80 degreeC.
  • the base used is preferably selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate. More preferred is sodium hydroxide.
  • the reaction solvent is preferably a mixed solvent of methanol/water, ethanol/water or tetrahydrofuran/water, more preferably a methanol/water mixed solvent.
  • the reaction temperature is preferably from 20 ° C to 70 ° C, more preferably from 30 ° C to 40 ° C.
  • the condensing agent is preferably selected from the group consisting of benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt)/1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N,N'-carbonyldiimidazole (CDI), more preferably PyBOP.
  • PyBOP benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate
  • HOBt 1-hydroxybenzotriazole
  • EDCI dicyclohexylcarbodiimide
  • CDI N,N'-carbonyldiimidazole
  • the acid binding agent is preferably selected from the group consisting of triethylamine, N,N-diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), pyridine, sodium acetate, sodium carbonate or potassium carbonate, more preferably DIEA.
  • DIEA N,N-diisopropylethylamine
  • DMAP 4-dimethylaminopyridine
  • pyridine sodium acetate
  • sodium carbonate or potassium carbonate more preferably DIEA.
  • the reaction solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, more preferably N,N-dimethylformamide.
  • the reaction temperature is preferably from 10 ° C to 80 ° C, more preferably from 20 ° C to 40 ° C.
  • the catalyst used is preferably palladium chloride, palladium acetate, bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene. Palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene]nickel dichloride. More preferred is tetrakis(triphenylphosphine)palladium.
  • the base is preferably selected from the group consisting of sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, sodium carbonate or potassium carbonate, more preferably potassium carbonate.
  • the reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, toluene, ethanol, water or any two or three of them.
  • a mixed solvent of a solvent more preferably a mixed solvent of dioxane/water.
  • the reaction temperature is preferably from 70 ° C to 115 ° C, more preferably from 95 ° C to 110 ° C.
  • the above reaction is preferably carried out by adding a condensing agent, an acid binding agent, a base and a reaction solvent, wherein the condensing agent is preferably selected from PyBOP, HOBt/EDCI, DCC or CDI; the acid binding agent is preferably selected from triethylamine, DIEA, DMAP, pyridine, acetic acid. Sodium, sodium carbonate or potassium carbonate; the reaction solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; and the reaction temperature is preferably from 10 ° C to 80 ° C.
  • the condensing agent is further preferably PyBOP; the acid binding agent is further preferably DIEA; the reaction solvent is further preferably N,N-dimethylformamide; and the reaction temperature is more preferably 20 to 40 °C.
  • reactant A is hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, horse Acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid; solvent is methanol, ethanol, dichloromethane, acetone, ethyl acetate, toluene, tetrahydrofuran or a mixture of any two or three of them Solvent.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically effective amount of the compound (I) of the present invention or a salt thereof and a pharmaceutically acceptable carrier.
  • the compound of the present invention can be added into a pharmaceutically acceptable carrier to prepare common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, freeze-dried powders, injections, and can be added to spices and sweets.
  • common pharmaceutical excipients such as flavoring agents, liquid or solid fillers or diluents.
  • the compound of the present invention can be administered in a clinical manner by oral administration or injection.
  • a human dosage will range from 1 mg to 1000 mg per day. Dosages outside the range may also vary depending on the dosage form and the severity of the disease.
  • the kinase activity test methods used in this experiment are basically the same, except that different concentrations of different kinases and corresponding substrates are used to achieve the optimal detection range.
  • PARP-1 inhibitory activity assay The 96-well plates pre-coated with histones were removed, and the following enzyme reaction system and different concentrations of inhibitors were added to each well, including: 50 ⁇ L of reaction buffer (Tris*HCl, pH 8.0). , NAD + , biotinylated activated DNA, PARP-1 enzyme, and inhibitor; after reacting for 1 hour at room temperature, 50 ⁇ L of avidin-labeled HRP was added to each well for 30 minutes; then 100 ⁇ L of HRP was added. The chemiluminescence values were detected on a SpectraMax M instrument. Calculate the percentage of enzyme activity by the following formula:
  • Enzyme activity percentage (%) (OD value administration hole-OD value background) / (OD value control hole-OD value background) ⁇ 100%
  • PI3K ⁇ inhibitory activity test method 40 mM Tris, pH 7.4, 10 mM MgCl 2 , 0.1 mg/ml BSA, 1 mM DTT, 10 ⁇ M ATP, PI3K ⁇ kinase, kinase substrate; simultaneously adding different concentrations of the compound to be sieved to form a reaction system of 50 ⁇ L, After reacting at 30 ° C for 40 minutes, the ADP content in the system was detected by luciferase method, and after reacting for 5 minutes, the chemiluminescence signal was detected on the MD-SpectraMax M5 multi-function microplate reader, and the intensity of the chemiluminescence signal was Enzyme activity inhibition is directly proportional. The detected chemiluminescence signal value is substituted into the following formula:
  • Enzyme activity percentage (%) (OD value administration hole-OD value background) / (OD value control hole-OD value background) ⁇ 100%
  • Drug concentrations were diluted according to a three-fold concentration gradient and two replicate wells were detected at each concentration.
  • the drug concentration was taken as the abscissa, and the percentage of enzyme activity corresponding to each concentration was plotted on the ordinate.
  • the nonlinear regression was performed using Graphpad Prism 5, and the IC 50 value of each test compound was calculated.
  • the experimental results are shown in Table 2.
  • Table 1 show that the compound of the present invention has a high inhibitory activity against PARP-1, and most of the compounds have a inhibition rate of PARP-1 of more than 50% at a concentration of 10 nM; the compound also has a high inhibitory activity against PI3K ⁇ , and some compounds The inhibition rate of PI3K ⁇ at a concentration of 100 nM was more than 70%.
  • the above results show that the compound of the present invention has dual inhibitory activity against PARP-1 and PI3K.
  • IC 50 values of PARP-1 and PI3K ⁇ were determined by selecting some compounds, and the results are shown in Table 2.
  • Table 2 show that the compounds of the present invention have higher inhibitory activities against PARP-1 and PI3K, and most of the compounds have better inhibitory activity against PARP-1 than PI3K ⁇ , wherein compound I-1 is resistant to PARP-1.
  • the IC 50 was 6.3 nM, and the IC 50 for PI3K ⁇ was 5.8 nM, showing almost the same inhibitory activity against both targets.
  • the cells in the logarithmic growth phase (HCT116, HCC1937, MDA-MB-231, and MDA-MB-468) were seeded in a 96-well plate (200 ⁇ L/well) in an amount, and cultured for 24 hours to adhere them to the wall. There are 3 duplicate wells for each drug concentration, and corresponding zero-cut holes and blank controls are set. After 72 hours of drug action, the adherent cells were added to 50% TCA (50 ⁇ L/well), fixed at 4 ° C for 1 hour, the fixing solution was discarded, washed 5 times with distilled water, and naturally dried.
  • Table 3 show that the compounds of the present invention all have strong antitumor activity in vitro and can significantly inhibit the proliferation of tumor cells. It not only has significant inhibitory activity against BRCA-deficient HCC1937 and HCT116 cells, but also has strong inhibitory activity against BRCA wild-type MDA-MB-231 and MDA-MB-468 cells. Among them, compound I-1 had the strongest inhibitory activity against tumor cells HCT116 and HCC1937, IC 50 was 0.094 ⁇ M and 0.061 ⁇ M, respectively; compound I-10 had the strongest inhibitory activity against tumor cells MDA-MB-231 and MDA-MB-468. The IC 50 reached 0.244 ⁇ M and 1.402 ⁇ M, respectively.
  • the MDA-MB-468 cell line in logarithmic growth phase was prepared as a 2 ⁇ 10 7 /mL cell suspension under sterile conditions, and inoculated into the right axilla of nude mice in 0.1 mL.
  • the nude mice xenografts were measured with a vernier caliper to measure the diameter of the transplanted tumors, and the animals were randomly grouped after the tumors were grown to about 100 mm 3 .
  • the effect of the anti-tumor effect of the test substance was dynamically observed using a method of measuring the tumor diameter.
  • the number of measurements of tumor diameter is once every 6 days.
  • the administration volume was 0.4 mL / 20 g. After 34 days, the mice were sacrificed and the tumor pieces were surgically removed and weighed.
  • the formula for calculating tumor volume (TV) is:
  • TV 1/2 ⁇ a ⁇ b 2 , where a and b represent the length and width, respectively.
  • the aqueous layer was extracted with 50 mL of dichloromethane.
  • the compound VI-2 (1.20 g, 2.33 mmol) was used as a starting material, and the procedure of the compound VII-1 was carried out to obtain a white solid (0.89 g, yield: 84.5%). Mp 196-198 ° C.

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Abstract

本发明涉及药物化学领域，具体涉及一类含有苯并呋喃结构的PARP-1和PI3K双靶点抑制剂(I)，它们的制备方法，以及含有这些化合物的药物组合物。药效学试验证明，本发明的化合物具有抗肿瘤的功效。(I)

Description

含有苯并呋喃的PARP-1和PI3K双靶点抑制剂 技术领域
本发明涉及药物化学领域，具体涉及一类含有苯并呋喃结构的PARP-1和PI3K双靶点抑制剂，它们的制备方法，以及含有这些化合物的药物组合物及其在抗肿瘤方面的用途。
背景技术
聚腺苷二磷酸核糖聚合酶(PARP)是存在于多数真核细胞中的一个多功能蛋白质翻译后修饰酶，目前该家族已被发现的亚型共18个，其中PARP-1所占比例最大，涉及到对中风、神经退行性疾病、心肌缺血、癌症、炎症和糖尿病等疾病的治疗，在DNA损伤修复中起主导作用。PARP-1抑制剂是一类通过调节DNA损伤修复而发挥细胞毒性的抗肿瘤药物，是21世纪初肿瘤治疗研究领域中最激动人心的成果之一。目前已经有三个PARP抑制剂应用于临床，它们分别是2014年上市的奥拉帕尼(Olaparib)、2016年上市的卢卡帕尼(Rucaparib)和2017年上市的尼拉帕尼(Niraparib)，主要用于乳腺癌、卵巢癌和腹膜癌等肿瘤的治疗。但随着研究的深入以及临床试验结果的陆续发布，PARP-1抑制剂的局限性也进一步呈现。一方面，目前的PARP-1抑制剂单独使用时，只针对存在BRCA1/2缺失的三阴性乳腺癌或卵巢癌有疗效，这就导致了PARP-1抑制剂的适应症较窄；另一方面，PARP-1抑制剂长期使用同样面临耐药性的问题，这些问题都将对PARP-1抑制剂的临床应用产生不利影响。
磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase,PI3K)是PI3K/Akt/mTOR信号转导通路中的上游分子，作为该通路中的关键节点蛋白，PI3K可以磷酸化磷脂酰肌醇4,5-二磷酸(PIP2)的3位羟基生成磷脂酰肌醇3,4,5-三磷酸(PIP3)。PIP3作为第二信使，在细胞的存活、生长、增殖以及代谢等基本反应中扮演重要角色。肿瘤抑制基因PTEN可以使PIP3去磷酸化生成PIP2，是PI3K催化作用的拮抗剂。PI3K的异常激活会导致该通路的紊乱，引起一系列疾病，包括癌症、神经系统病变、自身免疫性疾病以及造血性疾病。PI3K已成为肿瘤治疗研究的重要靶点之一，目前临床应用的PI3K抑制剂主要有两个，分别是2014年上市的PI3Kδ抑制剂艾代拉里斯(Idelalisib)和2017年上市的PI3Kα/PI3Kδ抑制剂Copanlisib，主要用于各种淋巴瘤的治疗；另外，尚有多个PI3K抑制剂处于临床研究阶段，但目前尚无PARP-1/PI3K双靶点抑制剂的报道。
发明内容
本发明公开了一类通式(I)的化合物，药效学试验结果显示，本发明的化合物或其药学上可接受的盐能够同时作用于PARP-1和PI3K两个靶点，可作为肿瘤的单一治疗剂；或者与其它抗肿瘤药物联用，从而达到提高现有抗肿瘤药物疗效并降低剂量和毒性的作用。
Figure PCTCN2018097979-appb-000001
其中X代表CH或N；
R 1代表
Figure PCTCN2018097979-appb-000002
Figure PCTCN2018097979-appb-000003
R 1优选代表
Figure PCTCN2018097979-appb-000004
R 2代表
Figure PCTCN2018097979-appb-000005
Figure PCTCN2018097979-appb-000006
Figure PCTCN2018097979-appb-000007
R 3代表H、F、Br、Cl、CF 3、CN、CH 3或OCH 3，Y代表CH或N，Z代表O、NH、NCH 3或CH 2，m＝1或2；R 2优选代表
Figure PCTCN2018097979-appb-000008
Figure PCTCN2018097979-appb-000009
本发明优选的部分化合物如下：
Figure PCTCN2018097979-appb-000010
Figure PCTCN2018097979-appb-000011
Figure PCTCN2018097979-appb-000012
当R 2不代表
Figure PCTCN2018097979-appb-000013
时，本发明通式(I)的化合物可用下列方法制备：
Figure PCTCN2018097979-appb-000014
上述反应优选加入催化剂、碱和反应溶剂条件下进行，其中催化剂优选自氯化钯、乙酸钯、双(三苯基膦)二氯化钯、四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯或[1,1'-双(二苯基膦基)二茂铁]二氯化镍；碱优选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、碳酸钠或碳酸钾；反应溶剂优选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙二醇二甲醚、四氢呋喃、 二氧六环、甲苯、乙醇、水或其中任意两种或三种溶剂的混合溶剂；反应温度优选为70℃～115℃。
催化剂进一步优选为四(三苯基膦)钯；碱进一步优选为碳酸钾；溶剂进一步优选为二氧六环/水的混合溶剂；反应温度进一步优选为95℃～110℃。
更详细地，从起始原料(1)制备的话，则包括：
Figure PCTCN2018097979-appb-000015
由化合物1经氰代反应制备化合物2的过程：
所用的氰化物优选自氰化锌、氰化铜或氰化亚铜。更优选氰化亚铜。
催化剂优选自氯化钯、乙酸钯、双(三苯基膦)二氯化钯、四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯或[1,1'-双(二苯基膦基)二茂铁]二氯化镍。更优选四(三苯基膦)钯。
反应溶剂优选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜。更优选N,N-二甲基甲酰胺。
反应温度优选自30℃～90℃。更优选70℃～80℃。
由化合物2经水解反应制备化合物3的过程：
所用的碱优选自氢氧化钠、氢氧化钾、氢氧化锂、碳酸钠或碳酸钾。更优选氢氧化钠。
反应溶剂优选自甲醇/水、乙醇/水或四氢呋喃/水的混合溶剂，更优选甲醇/水混合溶剂。
反应温度优选自20℃～70℃，更优选30℃～40℃。
由化合物3与化合物II经酰化反应制备化合物III的过程：
缩合剂优选自六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)、1-羟基苯并三唑(HOBt)/1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、二环己基碳二亚胺(DCC)或N,N'-羰基二咪唑(CDI)，更优先PyBOP。
缚酸剂优选自三乙胺、N,N-二异丙基乙胺(DIEA)、4-二甲氨基吡啶(DMAP)、吡啶、乙酸钠、碳酸钠或碳酸钾，更优选DIEA。
反应溶剂优选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜，更优选N,N-二甲基甲酰胺。
反应温度优选自10℃～80℃，更优选20℃～40℃。
由化合物III与硼酸酯IV经Suzuki反应制备化合物I的过程：
所用的催化剂优选自氯化钯、乙酸钯、双(三苯基膦)二氯化钯、四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯或[1,1'-双(二苯基膦基)二茂铁]二氯化镍。更优选四(三苯基膦)钯。
碱优选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、碳酸钠或碳酸钾，更优选碳酸钾。
反应溶剂优选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙二醇二甲醚、四氢呋喃、二氧六环、甲苯、乙醇、水或其中任意两种或三种溶剂的混合溶剂，更优选二氧六环/水的混合溶剂。
反应温度优选自70℃～115℃，更优选95℃～110℃。
当R 2代表
Figure PCTCN2018097979-appb-000016
时，本发明通式(I)的化合物可用下列方法制备：
Figure PCTCN2018097979-appb-000017
上述反应优选加入缩合剂、缚酸剂、碱和反应溶剂条件下进行，其中缩合剂优选自PyBOP、HOBt/EDCI、DCC或CDI；缚酸剂优选自三乙胺、DIEA、DMAP、吡啶、乙酸钠、碳酸钠或碳酸钾；反应溶剂优选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲亚砜；反应温度优选自10℃～80℃。
缩合剂进一步优选为PyBOP；缚酸剂进一步优选为DIEA；反应溶剂进一步优选为N,N-二甲基甲酰胺；反应温度进一步优选为20℃～40℃。
由化合物(I)经成盐制备化合物I·A的过程，反应物A为氯化氢、溴化氢、硫酸、磷酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸；溶剂为甲醇、乙醇、二氯甲烷、丙酮、乙酸乙酯、甲苯、四氢呋喃或其中任意两种或三种溶剂的混合溶剂。
本发明还公开了一种药物组合物，其包括药物有效剂量的本发明的化合物(I)或其盐和药学上可接受的载体。
本发明所述的化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、冻干粉针、针剂，可以加入香料、甜味剂、液体或固体填料或稀释剂等常用药用辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
一般地，本发明的化合物用于治疗时，人用剂量范围为1mg～1000mg/天。也可根据剂型的不同和疾病严重程度，使用剂量超出该范围。
本发明部分化合物的药理学实验及结果如下：
(1)检测化合物在酶水平对PARP-1和PI3K的抑制活性
实验方法
本实验中所采用的激酶活性测试方法基本相同，只是根据不同的激酶及对应的不同底物，采取不同的浓度以达到最佳的检测范围。
PARP-1抑制活性实验方法：取出已经预包被组蛋白的96孔板中，每孔加入以下酶反应 体系及不同浓度的抑制剂，包括：50μL的反应缓冲液(Tris*HCl,pH 8.0)，NAD +，生物素标记的活化DNA，PARP-1酶，及抑制剂；在室温下反应1小时以后，每孔中加入50μL亲和素标记的HRP，反应30分钟；再加入100μL的HRP底物，在SpectraMax M仪器上检测化学发光值。下列公式计算酶活性百分率：
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％
PI3Kα抑制活性实验方法：40mM Tris,pH 7.4,10mM MgCl 2,0.1mg/ml BSA,1mM DTT,10μM ATP,PI3Kα激酶，激酶底物；同时加入不同浓度的待筛化合物，组成50μL的反应体系，在30℃下反应40分钟，后用荧光素酶的方法检测体系内的ADP含量，再反应5分钟后，在MD-SpectraMax M5多功能酶标仪上检测化学发光信号，化学发光信号值强度与酶活性抑制成正比。检测到的化学发光信号值，代入如下公式：
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％
实验结果见表1。
药物浓度按照三倍浓度梯度稀释，每个浓度均检测两个复孔。将药物浓度作为横坐标，各浓度对应的酶活性百分率为纵坐标，使用Graphpad Prism5做非线性回归，计算得到各测试化合物的IC 50值。实验结果见表2。
表1.受试化合物对PARP-1和PI3Kα的抑制活性
Figure PCTCN2018097979-appb-000018
表1结果显示，本发明化合物对PARP-1具有较高的抑制活性，大部分化合物在10nM浓度下对PARP-1的抑制率大于50％；化合物对PI3Kα也具有较高的抑制活性，部分化合物在100nM浓度下对PI3Kα的抑制率大于70％以上。以上结果显示，本发明化合物对PARP-1和PI3K具有双重抑制活性。
选择部分化合物分别测定其对PARP-1和PI3Kα的IC 50值，结果见表2.
表2.部分受试化合物对PARP-1和PI3Kα的IC 50值
Figure PCTCN2018097979-appb-000019
表2结果显示，本发明化合物对PARP-1和PI3K均有较高的抑制活性，大部分化合物对PARP-1的抑制活性优于对PI3Kα的抑制活性，其中化合物I-1对PARP-1的IC 50为6.3nM，对PI3Kα的IC 50为5.8nM，对两个靶点显示出几乎相同的抑制活性。
(2)检测化合物对肿瘤细胞增殖的抑制活性
实验方法
将处于对数生长期的细胞(HCT116、HCC1937、MDA-MB-231和MDA-MB-468)以一定数量接种于96孔板(200μL/孔)，培养24小时使之贴壁后加药。每个药物浓度设3个复孔，并设相应的调零孔及空白对照。药物作用72小时后，贴壁细胞加入50％TCA(50μL/孔)，4℃固定1小时，倒掉固定液，用蒸馏水洗5次，自然干燥。每孔加入100μL 4mg/mL SRB，室温染色15分钟，弃之，用1％冰醋酸洗5次，自然干燥。最后每孔加入150μL 10mM Tris溶液，摇匀，用可调波长式微孔板酶标仪在565nm波长下测定OD值。用以上公式计算细胞生长抑制率，结果见表3。
表3.化合物的体外抗肿瘤活性测试结果
Figure PCTCN2018097979-appb-000020
表3结果显示，本发明化合物均具有较强的体外抗肿瘤活性，能够显著抑制肿瘤细胞的增殖。不仅对BRCA缺陷型的HCC1937和HCT116细胞具有显著的抑制活性，而且对BRCA野生型的MDA-MB-231和MDA-MB-468细胞也具有较强的抑制活性。其中化合物I-1对肿瘤细胞HCT116和HCC1937的抑制活性最强，IC 50分别为0.094μM和0.061μM；化合物I-10对肿瘤细胞MDA-MB-231和MDA-MB-468的抑制活性最强，IC 50分别达到了0.244μM和 1.402μM。
(3)检测化合物对人乳腺癌MDA-MB-468细胞裸小鼠移植瘤生长的抑制活性试验分组情况见表4.
表4.试验分组情况及药物浓度选择
Figure PCTCN2018097979-appb-000021
实验方法
取对数生长期的MDA-MB-468细胞株，在无菌条件下后制备成2×10 7/mL细胞悬液，以0.1mL接种于裸小鼠右侧腋窝皮下。裸小鼠移植瘤用游标卡尺测量移植瘤直径，待肿瘤生长至100mm 3左右后将动物随机分组。使用测量瘤径的方法，动态观察被试物抗肿瘤的效应。肿瘤直径的测量次数为每6天一次。给药体积为0.4mL/20g。34天后，小鼠处死，手术剥取瘤块称重。肿瘤体积(TV)的计算公式为：
TV＝1/2×a×b 2，其中a、b分别表示长宽。
结果如表5和6所示，在所给剂量下，化合物I-1、I-10及奥拉帕尼/BKM120联用均能够显著抑制MDA-MB-468裸小鼠移植瘤的生长，抑瘤作用强于阳性药奥拉帕尼和BKM120，其中化合物I-I和I-10作用效果优于奥拉帕尼(50mg/kg)/BKM120(27.5mg/kg)联用组。
表5.化合物对人乳腺癌MDA-MB-468细胞裸小鼠移植瘤体积的影响
Figure PCTCN2018097979-appb-000022
表6.化合物对人乳腺癌MDA-MB-468细胞裸小鼠移植瘤瘤重的影响
Figure PCTCN2018097979-appb-000023
具体实施方式
实施例1
2-(4-(4-(2-氨基密啶-5-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-1)的合成
7-氰基苯并呋喃-2-甲酸甲酯(2)
将7-溴苯并呋喃-2-甲酸甲酯(1)(9.3g,36.46mmol)，Zn(CN) 2(8.56g,72.92mmol)，四(三苯基膦)钯(2.10g,1.82mmol)加入250mL三颈瓶中，加入100mL DMF搅拌溶解，呈白色乳浊状，氮气保护，加热至80℃反应6～8小时。TLC(石油醚:乙酸乙酯＝10:1)检测原料1反应完，冷却至室温，抽滤，滤饼用20mL DMF洗涤，将滤液倒入300mL水中，析出大量白色固体，搅拌15分钟，抽滤，滤饼用100mL水洗涤，干燥，得粗品。柱层析纯化(石油醚:乙酸乙酯＝50:1～20:1梯度洗脱，产物为极性较大的点)，得白色固体4.7g，收率64.0％，m.p.130-132℃. 1H-NMR(300MHz,CDCl 3)δ(ppm):7.97(1H,dd,J＝8.0,1.0Hz,ArH),7.79(1H,dd,J＝7.6,1.0Hz,ArH),7.62(1H,s,ArH),7.43(1H,t,J＝7.8Hz,ArH),4.02(3H,s,CH 3).
7-氨基甲酰基苯并呋喃-2-甲酸(3)
将化合物2(4.7g,23.36mmol)溶于50mL甲醇，加入30％H 2O 2(16mL)，1mol/L NaOH(47mL)，加热至40℃反应1小时，TLC(二氯甲烷:甲醇＝20:1)检测原料2反应完，停止加热，冷却至室温，加入2mol/L稀盐酸调节pH＝1～2，析出大量白色固体，室温搅拌15分钟，抽滤，干燥，得白色固体4.5g，收率93.8％，m.p.178-180℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):13.77(1H,s,COOH),7.92(1H,d,J＝7.5Hz,ArH),7.85(1H,s,1/2CONH 2),7.83(1H,d,J＝7.6Hz,ArH),7.74(1H,s,ArH),7.66(1H,s,1/2CONH 2),7.42(1H,t,J＝7.4Hz,ArH).
(2,6-二氯-4-吗啉基)-1,3,5-三嗪(5)
取三聚氯嗪(4)(10.00g,54.23mmol)溶于100mL二氯甲烷中，加入DIEA(9.92mL,56.94mmol)，降温至-78℃，将吗啉(4.73mL,54.23mmol)溶于10mL二氯甲烷中的溶液滴加入反应液中，加毕，析出大量白色固体，TLC(石油醚:乙酸乙酯＝6:1)检测原料4反应完，停止反应，抽滤，滤饼用水洗涤，干燥，得白色固体7.18g，收率56.4％. 1H NMR(300MHz,DMSO-d 6)δ(ppm):3.80-3.76(4H,CH 2O),3.69(4H,CH 2).
4-(4-氯-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酸叔丁酯(6)
将化合物5(7.00g,29.78mmol)、N-叔丁氧羰基哌嗪(5.55g,29.80mmol)和K 2CO 3(4.12g,29.81mmol)加入250mL三颈瓶中，加入100mL DMF搅拌溶解，于25℃反应5小时，TLC(石油醚:乙酸乙酯＝6:1)检测原料5反应完，停止反应，倒入300mL水中，析出大量固体，搅拌30分钟，抽滤，滤饼用水洗涤，干燥，得白色固体10.5g，收率91.6％。m.p.169-172℃. 1H-NMR(300MHz,CDCl 3)δ(ppm):3.83-3.75(12H,m,6CH 2),3.52-3.49(4H,m,2CH 2),1.53(9H,s,3CH 3).
4-(4-氯-6-吗啉基-1,3,5-三嗪-2-基)哌嗪盐酸盐(II-1)
将化合物6(10.0g,25.98mmol)溶于50mL乙酸乙酯中，加入饱和HCl的乙酸乙酯溶液(20mL)，于25℃搅拌反应2小时，TLC(石油醚:乙酸乙酯＝6:1)检测原料6反应完，停止反应，抽滤，滤饼用乙酸乙酯洗涤，干燥，得白色固体7.65g，收率91.6％。 1H-NMR(300MHz,MeOD)δ(ppm):4.06(4H,t,J＝5.2Hz,2CH 2O),3.81-3.77(4H,m,2CH 2),3.70-3.67(4H,m,2CH 2),3.27(4H,t,J＝5.4Hz,2CH 2).
2-(4-(4-氯-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(III-1)
将化合物3(1.35g,6.60mmol)、II-1(2.12g,6.60mmol)和PyBOP(4.12g,7.92mmol)加入100mL三颈瓶中，加入50mL DMF搅拌溶解，再加入DIEA(3.82mL,23.10mmol)，于25℃搅拌反应4～6小时，TLC(二氯甲烷:甲醇＝20:1)检测原料3反应完，停止反应，将反应液倒入150mL水中，析出大量固体，搅拌10分钟，抽滤，滤饼用50mL水洗涤，干燥，得粗品，柱层析纯化(二氯甲烷:甲醇＝120:1～80:1梯度洗脱)，得白色固体2.5g，收率80.3％，m.p.142-144℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):7.94(1H,d,J＝7.8Hz,ArH),7.86(1H,d,J＝7.1Hz,ArH),7.84(1H,s,1/2CONH 2),7.77(1H,s,1/2CONH 2),7.58(1H,s,ArH),7.46(1H,t,J＝7.7Hz,ArH),3.90-3.66(16H,m,6CH 2N,2CH 2O).
2-(4-(4-(2-氨基密啶-5-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-1)
将化合物III-1(2.5g,5.30mmol)、5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)嘧啶-2-胺(IV-1)(1.76g,7.95mmol)加入250mL三颈瓶中，加入80mL二氧六环搅拌溶解。将K 2CO 3(2.92g,21.20mmol)溶于8mL水中，加入反应液,再加入四(三苯基膦)钯(0.62g,0.53mmol)。氮气保护下，加热回流反应6～8h，TLC(二氯甲烷:甲醇＝20:1)检测原料III-1反应完，析出大量浅黄色固体，停止加热，冷却至室温。抽滤，滤饼依次用20mL水、20mL乙酸乙酯洗涤，干燥，得粗品，加入30mL乙酸乙酯打浆2h，抽滤，干燥，得白色固体1.67g，收率59.4％。m.p.>250℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):9.06(2H,s,ArH),7.90(1H,d,J＝7.3Hz,ArH),7.82(1H,s,1/2CONH 2),7.81(1H,d,J＝5.4Hz,ArH),7.74(1H,s,1/2CONH 2),7.55(1H,s,ArH),7.42(1H,t,J＝7.1Hz,ArH),7.30(2H,s,NH 2),4.00-3.64(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):170.89,169.81,168.69,165.88,163.43,162.49,155.64,153.48,147.68,132.41,131.42,130.17,128.39,124.68,123.38,115.86,70.73,51.14,48.02,47.48.HRMS(ESI):m/z[M+H] +.Calcd for C 25H 26N 10O 4:531.2211；Found:531.2209.
实施例2
2-(4-(4-(6-氨基吡啶-3-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-2)的合成
将化合物III-1(300mg,0.64mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-胺(IV-2)(154mg,0.70mmol)加入50mL三颈瓶中，加入20mL二氧六环，搅拌溶解。将K 2CO 3(354mg,2.56mmol)溶于2mL水中，加入反应液中，再加入四(三苯基膦)钯(74mg,0.06mmol)。氮气保护下，加热回流反应4～6小时，TLC(二氯甲烷:甲醇＝20:1)检测原料III-1反应完，停止加热，冷却至室温，抽滤，滤液浓缩，残留物加入40mL乙酸乙酯，混合液依次用水(20mL×1)和饱和氯化钠溶液(20mL×2)洗涤，无水Na 2SO 4干燥，抽滤，滤液浓缩，残留物用柱层析纯化(二氯甲烷:甲醇＝80:1～20:1梯度洗脱)，得浅黄色固体156mg，收率46.0％。m.p.>250℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):8.88(1H,s,ArH),8.34(1H,d,J＝7.7Hz,ArH),7.90(1H,d,J＝7.8Hz,ArH),7.82(1H,s,ArH),7.80(1H,s,1/2CONH 2),7.75(1H,s,1/2CONH 2),7.55(1H,s,ArH),7.42(1H,t,J＝7.6Hz,ArH),7.06(2H,s,NH 2),6.62(1H,d,J＝8.6Hz,ArH),4.00-3.57(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):168.63,165.07,164.28,161.90,158.67,150.87,149.66,148.74,136.66,131.46,127.66,126.66,125.43,123.64,120.11,119.92,111.08,106.90,66.01,43.22,28.94,26.51.HRMS(ESI):m/z[M+H] +.Calcd for C 26H 27N 9O 4:530.2259；Found:530.2252.
实施例3
2-(4-(4-(6-氨基-4-(三氟甲基)吡啶-3-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-3)的合成
以化合物III-1(300mg,0.64mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-4-(三氟甲基)吡啶-2-胺(IV-3)(202mg,0.70mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝80:1～20:1，梯度洗脱)，得类白色固体185mg，收率48.4％。m.p.>250℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):8.62(1H,s,ArH),7.92(1H,d,J＝7.8Hz,ArH),7.83(1H,d,J＝7.4Hz,ArH),7.77(1H,s,1/2CONH 2),7.71(1H,s,1/2CONH 2),7.55(1H,s,ArH),7.43(1H,t,J＝7.7Hz,ArH),6.94(2H,s,NH 2),6.83(1H,s,ArH),3.92-3.65(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):174.24,169.82,168.83,165.92,163.46,157.27,155.63,153.42,140.63,132.41,131.40,130.18,129.61,128.37,125.99,124.66,123.40,115.80,109.39,70.67,59.63,47.94,47.24.HRMS(ESI):m/z[M+H] +.Calcd for C 27H 26F 3N 9O 4:598.2133；Found:598.2136.
实施例4
2-(4-(4-(4-氨基-3-氟苯基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-4)的合成
以化合物III-1(300mg,0.64mmol)和2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(IV-4)(166mg,0.70mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝80:1～20:1，梯度洗脱)，得浅黄色固体170mg，收率48.6％。m.p.>250℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):7.96-7.91(3H,m,ArH),7.84(1H,d,J＝7.2Hz,ArH),7.80(1H,s,1/2CONH 2),7.73(1H,s,1/2CONH 2),7.56(1H,s,ArH),7.44(1H,t,J＝7.7Hz,ArH),6.80(1H,t,J＝8.9Hz,ArH),5.78(2H,s,NH 2),4.02-3.62(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):168.77,165.39,164.38,159.01,150.82,148.16,139.69,127.64,126.89,125.97,125.19,124.32,123.80,121.69,119.10,114.96,114.55,114.30,111.19,72.86,65.98,43.19,42.42.HRMS(ESI):m/z[M+H] +.Calcd for C 27H 27FN 8O 4:547.2212；Found:547.2211.
实施例5
2-(4-(4-(1H-吲哚-5-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-5)的合成
以化合物III-1(300mg,0.64mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚(IV-5)(170mg,0.70mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～30:1，梯度洗脱)，得浅黄色固体160mg，收率45.2％。m.p.164-166℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):11.28(1H,s,NH),8.65(1H,s,ArH),8.17(1H,d,J＝8.6Hz,ArH),7.91(1H,d,J＝7.8Hz,ArH),7.82(1H,d,J＝7.5Hz,ArH),7.79(1H,s,1/2CONH 2),7.72(1H,s,1/2CONH 2),7.55(1H,s,ArH),7.45-7.38(3H,m,ArH),6.55(1H,s,ArH),4.08-3.67(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):177.92,170.63,165.46,164.51,159.05,150.83,148.06,137.85,127.62,127.44,127.28,126.95,126.19,126.03,123.81,121.48,121.13,118.95,111.21,110.82,102.37,66.00,45.70,43.19,42.50.HRMS(ESI):m/z[M+H] +.Calcd for C 29H 28N 8O 4:553.2306；Found:553.2306.
实施例6
2-(4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-6)的合成
4-(4-氯-6-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-1,3,5-三嗪-2-基)吗啉(V-1)
将2-(二氟甲基)-1H-苯并[d]咪唑(7)(1.43g,8.51mmol)、化合物5(2.00g,8.51mmol)和K 2CO 3(1.18g,8.51mmol)加入50mL三颈瓶中，加入25mL DMF搅拌溶解，于25℃反应4小时，TLC(石油醚:乙酸乙酯＝5:1)检测原料5反应完，停止反应，将反应液倒入80mL水中，析出大量白色固体，搅拌10分钟，抽滤，滤饼用水洗涤，干燥，得白色固体2.7g，收率86.5％。m.p.244-247℃. 1H-NMR(300MHz,CDCl 3)δ(ppm):8.44(1H,d,J＝7.7Hz,ArH),7.91(1H,d,J＝7.5Hz,ArH),7.59(1H,CHF 2),7.53-7.43(2H,m,ArH),4.02-3.95(4H,m,CH 2),3.87-3.81(4H,m,CH 2).
4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酸叔丁酯(VI-1)
将化合物V-1(2.70g,7.36mmol)、N-叔丁氧羰基哌嗪(1.44g,7.73mmol)和K 2CO 3(1.53g,11.0 4mmol)加入100mL三颈瓶中，加入50mL丙酮搅拌呈浑浊状，于30℃反应8小时，TLC(石油醚:乙酸乙酯＝5:1)检测原料V-1反应完，停止反应，减压蒸干溶剂，加入50mL二氯甲烷溶解残留物，加入50mL水萃取洗涤，水层再用30mL二氯甲烷萃取，合并二氯甲烷层，饱和氯化钠溶液洗涤(50mL×2)，无水Na 2SO 4干燥，抽滤，浓缩滤液，得泡沫状固体3.50g，收率92.1％。m.p.184-187℃. 1H-NMR(300MHz,CDCl 3)δ(ppm):8.34(1H,d,J＝7.6Hz,ArH),7.90(1H,d,J＝6.9Hz,ArH),7.57(1H,t,J＝53.6Hz,CHF 2),7.48-7.39(2H,m,ArH),3.92-3.85(8H,m,CH 2),3.80(4H,s,CH 2),3.55(4H,s,CH 2),1.50(9H,s,CH 3).
4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-(哌嗪-1-基)-1,3,5-三嗪-2-基)吗啉盐酸盐(VII-1)
将化合物VI-1(3.50g,6.78mmol)加入50mL三颈瓶中，加入20mL乙酸乙酯搅拌溶解，滴加饱和HCl的乙酸乙酯溶液(5mL)，析出大量白色固体，25℃搅拌4小时，TLC(石油醚:乙酸乙酯＝5:1)检测原料VI-1反应完，抽滤，滤饼用乙酸乙酯洗涤，干燥，得白色固体2.72g，收率88.6％。m.p.230-232℃. 1H NMR(300MHz,CDCl 3)δ(ppm):8.36(1H,d,J＝7.3Hz,ArH),7.91(1H,d,J＝7.1Hz,ArH),7.59(1H,CHF 2),7.49-7.39(2H,m,ArH),3.98-3.87(8H,m,CH 2),3.81(4H,s,CH 2),3.02(4H,s,CH 2).
2-(4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-吗啉基-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-6)
将化合物3(180mg,0.88mmol)、化合物VII-1(400mg,0.88mmol)和PyBOP(550mg,1.06mmol)加入50mL三颈瓶中，加入20mL DMF搅拌溶解，再加入DIEA(0.44mL,2.64mmol)，加毕，于25℃反应8～10小时，TLC(二氯甲烷:甲醇＝20:1)检测原料3反应完，停止反应，将反应液倒入60mL水中，析出大量白色固体，搅拌10分钟，抽滤，滤饼用20mL水洗涤，干燥，得粗品。柱层析纯化(二氯甲烷:甲醇＝100:1～60:1，梯度洗脱)，得白色固体220mg，收率41.4％。m.p.189-191℃. 1H-NMR(300MHz,CDCl 3)δ(ppm):8.33(1H,d,J＝7.7Hz,ArH),8.22(1H,d,J＝7.3Hz,ArH),7.92(1H,d,J＝7.1Hz,ArH),7.86(1H,d,J＝8.0Hz,ArH),7.56(1H,t,J＝53.6Hz,CHF 2),7.45(3H,m,ArH),7.35(1H,s,ArH),7.22(1H,s,1/2CONH 2),6.02(1H,s,1/2CONH 2),4.03-3.81(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):165.07,164.33,161.28,158.81,150.92,148.61,145.83,141.30,132.88,127.68,126.68,125.90,125.44,124.31,123.62,120.65,119.91,115.83,111.03,108.56,87.07,65.84,45.99,43.65,43.08.HRMS(ESI):m/z[M+H] +.Calcd for C 29H 27F 2N 9O 4:604.2227；Found:604.2233.
实施例7
2-(4-2'-氨基-2-吗啉基-[4,5'-二嘧啶]-6-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-7)的合成
4-(4,6-二氯嘧啶-2-基)吗啉(9)
将2,4,6-三氯嘧啶(8)(10.00g,54.52mmol)加入250mL三颈瓶中，加入100mL二氯甲烷，搅拌溶解，加入DIEA(8.50mL,48.70mmol)，降温至-78℃，缓慢滴加吗啉(4.30mL,49.40mmol)，加毕，保温搅拌反应1～2小时，TLC(石油醚:乙酸乙酯＝6:1)检测原料8反应完，停止反应，将反应液倒入150mL水中，萃取，分出二氯甲烷层，水层再用50mL二氯甲烷萃取，合并二氯甲烷层，饱和氯化钠溶液洗涤两次(80mL×2)，无水Na 2SO 4干燥，抽滤，浓缩滤液得粗品，加入混合溶剂(石油醚:乙酸乙酯＝50:1,100mL)打浆2小时，抽滤，干燥，得白色固体9.4g，收率73.7％。m.p.122-124℃. 1H NMR(300MHz,CDCl 3)δ(ppm):6.56(1H,s,ArH),3.83-3.80(4H,m,2CH 2O),3.76-3.72(4H,m,2CH 2).
4-(6-氯-2-吗啉基嘧啶-4-基)哌嗪-1-甲酸叔丁酯(10)
将化合物9(2.00g,8.54mmol)和N-叔丁氧羰基哌嗪(3.98g,21.35mmol)加入100mL三颈瓶中，加入50mL丙酮，搅拌溶解，再加入三乙胺(4.00mL,28.86mmol)，加热回流反应10小时左右，TLC(二氯甲烷:甲醇＝20:1)检测原料9反应完，停止反应，冷却至室温，析出 大量白色固体，抽滤，滤饼用丙酮洗涤，干燥，得白色固体2.84g，收率86.6％。m.p.215-217℃. 1H-NMR(300MHz,CDCl 3)δ(ppm):5.87(1H,s,ArH),3.78-3.73(8H,m,2CH 2O,2CH 2NCO),3.57-3.54(4H,m,2CH 2),3.48-3.44(4H,m,2CH 2).
4-(4-氯-6-(哌嗪-1-基)嘧啶-2-基)吗啉盐酸盐(II-2)
将化合物10(2.84g,7.40mmol)加入50mL三颈瓶中，加入15mL乙酸乙酯搅拌溶解，再加入饱和HCl的乙酸乙酯溶液(5mL)，25℃搅拌反应2～3小时，析出大量白色固体，TLC(二氯甲烷:甲醇＝20:1)检测原料10反应完，停止反应，抽滤，滤饼用乙酸乙酯洗涤，干燥，得白色固体2.36g，收率99.6％。 1H NMR(300MHz,DMSO-d 6)δ(ppm):9.53(1H,s,HCl),6.92(1H,s,NH),6.30(1H,s,ArH),3.90(4H,t,J＝4.8Hz,2CH 2O),3.67-3.58(8H,m,4CH 2N),3.12(4H,s,2CH 2N).
2-(4-(6-氯-2-吗啉嘧啶-4-取代)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(III-2)
将化合物3(500mg,2.44mmol)、II-2(780mg,2.44mmol)和PyBOP(1.52g,2.92mmol)加入50mL三颈瓶中，加入25mL DMF搅拌溶解，再加入DIEA(1.21mL,7.32mmo)，于25℃搅拌反应3～5小时，TLC(二氯甲烷:甲醇＝20:1)检测原料3反应完，停止反应，将反应液倒入80mL水中，析出大量固体，搅拌10分钟，抽滤，滤饼用20mL水洗涤，干燥，得白色固体(VI-1)0.9g，收率78.3％，不经纯化，直接用于一步反应。
2-(4-2'-氨基-2-吗啉基-[4,5'-二嘧啶]-6-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-7)
将化合物III-2(300mg,0.64mmol)和IV-1(155mg,0.70mmol)加入50mL三颈瓶中，加入20mL二氧六环，搅拌溶解。将K 2CO 3(354mg,2.56mmol)溶于2mL水中，加入反应液中，再加入四(三苯基膦)钯(74mg,0.06mmol)。氮气保护下，加热回流反应4～6小时，TLC(二氯甲烷:甲醇＝20:1)检测原料III-2反应完，停止加热，冷却至室温，抽滤，滤液浓缩，残留物加入40mL乙酸乙酯，混合液依次用水(20mL×1)和饱和氯化钠溶液(20mL×2)洗涤，无水Na 2SO 4干燥，抽滤，滤液浓缩，残留物用柱层析纯化(二氯甲烷:甲醇＝80:1～60:1梯度洗脱)，得浅黄色固体160mg，收率47.4％，m.p.>250℃. 1H-NMR(300MHz,DMSO-d 6+D 2O)δ(ppm):8.92(2H,s,ArH),7.93(1H,d,J＝7.7Hz,ArH),7.83(1H,d,J＝7.2Hz,ArH),7.53(1H,s,ArH),7.43(1H,t,J＝7.7Hz,ArH),6.55(1H,s,ArH),3.86-3.61(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):164.99,163.94,163.34,160.75,159.39,158.73,156.90,154.93,150.85,148.73,127.68,126.65,125.49,123.64,119.89,119.72,110.88,86.68,65.91,44.05,43.41.HRMS(ESI):m/z[M+H] +.Calcd for C 26H 27N 9O 4:530.2259；Found:530.2250.
实施例8
2-(4-(6-(6-氨基-4-(三氟甲基)吡啶-3-基)-2-吗啉基嘧啶-4-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-8)的合成
以化合物III-2(300mg,0.64mmol)和化合物IV-3(202mg,0.70mmol)为原料，操作同I-7的方法，柱层析纯化(二氯甲烷:甲醇＝80:1～60:1，梯度洗脱)，得浅黄色固体175mg，收率45.8％，m.p.208-210℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):8.17(1H,s,ArH),7.91(1H,d,J＝8.3Hz,ArH),7.82(1H,d,J＝7.1Hz,ArH),7.79(1H,s,1/2CONH 2),7.72(1H,s,1/2CONH 2),7.53(1H,s,ArH),7.42(1H,t,J＝7.6Hz,ArH),6.82(1H,s,ArH),6.73(2H,s,NH 2),6.25(1H,s,ArH),4.03-3.59(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):165.33,162.88,162.71,160.33,159.95,159.00,150.80,150.34,148.22,136.06,127.64,126.82,125.89,124.80,123.75,121.29,119.14,110.99,104.62,92.01,65.82,49.83,43.79,43.32.HRMS(ESI):m/z[M+H] +.Calcd for C 28H 27F 3N 8O 4:597.2180；Found:597.2177.
实施例9
2-(4-(6-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-2-吗啉基嘧啶-4-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-9)的合成
4-(4-氯-6-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)嘧啶-2-基)吗啉(V-2)
以化合物7(500mg,2.97mmol)和化合物9(700mg,2.99mmol)为原料，操作同化合物V-1的方法，得白色固体1.00g，收率92.1％。m.p.197-200℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):8.31(1H,d,J＝8.1Hz,ArH),7.86(1H,d,J＝7.7Hz,ArH),7.69(1H,CHF 2),7.55-7.42(2H,m,ArH),7.09(1H,s,ArH),3.74(8H,brs,2CH 2O,2CH 2).
4-(6-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-2-吗啉基嘧啶-4-基)哌嗪-1-甲酸叔丁酯(VI-2)
以化合物V-2(1.00g,2.73mmol)、N-叔丁氧羰基哌嗪(0.54g,2.87mmol)为原料，操作同化合物VI-1的方法，得白色固体1.25g，收率88.8％。m.p.195-198℃. 1H-NMR(300MHz,CDCl 3)δ(ppm):8.22(1H,d,J＝7.1Hz,ArH),7.90(1H,d,J＝7.1Hz,ArH),7.51(1H,CHF 2),7.44-7.35(2H,m,ArH),5.52(1H,s,ArH),3.84-3.81(4H,m,2CH 2O),3.65-3.57(12H,m,6CH 2).4-(4-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-6-(哌嗪-1-基)嘧啶-2-基)吗啉盐酸盐(VII-2)
以化合物VI-2(1.20g,2.33mmol)为原料，操作同化合物VII-1的方法，得白色固体0.89g，收率84.5％。m.p.196-198℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):9.10(2H,brs,NH,HCl),8.20(1H,d,J＝8.1Hz,ArH),7.82(1H,d,J＝7.7Hz,ArH),7.68(1H,CHF 2),7.49-7.39(2H,m,ArH),6.08(1H,s,ArH),3.88-3.65(12H,m,2CH 2O,4CH 2),3.18(4H,brs,2CH 2).
2-(4-(6-(2-(二氟甲基)-1H-苯并[d]咪唑-1-基)-2-吗啉基嘧啶-4-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-9)
以化合物3(90mg,0.44mmol)和化合物VII-2(199mg,0.44mmol)为原料，操作同化合物I-6的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～50:1，梯度洗脱)，得类白色固体120mg，收率45.4％。m.p.126-128℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):8.23(1H,d,J＝8.1Hz,ArH),7.91(1H,d,J＝7.8Hz,ArH),7.84-7.80(2H,m,ArH),7.75(1H,s,1/2CONH 2)7.70(1H,t,J＝52.7Hz,CHF 2),7.56(1H,s,ArH),7.49-7.36(3H,m,ArH),6.04(1H,s,ArH),3.96-3.64(16H,m,6CH 2N,2CH 2O). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):229.53,197.77,165.05,163.81,163.32,162.48,158.79,153.78,150.93,148.66,141.22,127.69,126.65,125.45,123.81,121.86,120.50,119.92,114.94,111.04,108.61,79.51,65.78,45.80,44.52,25.82.HRMS(ESI):m/z[M+H] +.Calcd for C 30H 28F 2N 8O 4:603.2274；Found:603.2278.
实施例10
2-(4-(4-吗啉基-6-(6-(2-吗啉基乙酰氨基)-4-(三氟甲基)吡啶-3-基)-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-10)的合成
2-氯-N-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-4-(三氟甲基)吡啶-2-基)乙酰胺(11)
将化合物IV-3(600mg,2.08mmol)溶于15mL二氯甲烷中，加入DIEA(1.03mL,6.24mmol)，降温至-15℃，氮气保护下，缓慢加入氯乙酰氯(235μL,3.12mmol)，加毕，保温反应1～2小时，TLC(二氯甲烷:甲醇＝20:1)检测原料IV-3反应完，停止反应，加入15mL水淬灭反应。萃取分出有机层，水层再用15mL二氯甲烷萃取一次，合并有机层，饱和氯化钠溶液洗涤(15mL×2)，无水Na 2SO 4干燥，抽滤，浓缩滤液，柱层析纯化(石油醚:乙酸乙酯＝50:1～10:1梯度洗脱)，得黄色油状物580mg，收率76.5％。 1H-NMR(300MHz,CDCl 3)δ(ppm):9.08(1H,s,CONH),8.71(1H,s,ArH),8.53(1H,s,ArH),4.24(2H,s,COCH 2Cl),1.39(12H,s,4CH 3).MS(ESI(+)70V)m/z:387.1[M+Na] +.
2-吗啉基-N-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-4-(三氟甲基)吡啶-2-基)乙酰胺(IV-6)
将化合物11(500mg,1.37mmol)溶于15mL二氯甲烷，加入三乙胺(380μL,2.74mmol)和吗啉(170μL,2.05mmol)，加热回流反应8～10小时，TLC(二氯甲烷:甲醇＝20:1)检测原料11反应完，停止加热，冷却至室温，加入15mL水，萃取分出有机层，水层再用15mL二氯甲烷萃取一次，合并有机层，饱和氯化钠溶液洗涤(15mL×2)，无水Na 2SO 4干燥，抽滤，浓缩滤液，柱层析纯化(二氯甲烷:甲醇＝100:1～40:1梯度洗脱)，得浅黄色固体(IV-6)465mg， 收率81.7％。m.p.144-146℃. 1H-NMR(300MHz,CDCl 3)δ(ppm):9.75(1H,s,CONH),8.68(1H,s,ArH),8.57(1H,s,ArH),3.83(4H,t,J＝4.5Hz,2CH 2O),3.22(2H,s,COCH 2N),2.66(4H,t,J＝4.4Hz,2CH 2N),1.38(12H,s,4CH 3).MS(ESI(+)70V)m/z:416.2[M+H] +.
2-(4-(4-吗啉基-6-(6-(2-吗啉基乙酰氨基)-4-(三氟甲基)吡啶-3-基)-1,3,5-三嗪-2-基)哌嗪-1-甲酰基)苯并呋喃-7-甲酰胺(I-10)
以化合物III-1(300mg,0.64mmol)和IV-6(290mg,0.70mmol)为原料，操作同化合物I-2的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～50:1，梯度洗脱)，得浅黄色固体(I-10)300mg，收率65.1％。m.p.120-122℃. 1H-NMR(300MHz,DMSO-d 6)δ(ppm):10.70(1H,s,CONH),8.90(1H,s,ArH),8.56(1H,s,ArH),7.92(1H,d,J＝7.7Hz,ArH),7.83(1H,d,J＝7.2Hz,ArH),7.81(1H,s,1/2CONH 2),7.74(1H,s,1/2CONH 2),7.56(1H,s,ArH),7.43(1H,t,J＝7.6Hz,ArH),3.94-3.63(20H,m,10CH 2),3.29(2H,s,COCH 2N),2.56(4H,s,2CH 2).
将化合物I-10(250mg)溶于4mL乙酸乙酯中，滴加HCl饱和的乙酸乙酯溶液，析出白色固体，直至溶液pH＝1～2，室温搅拌15分钟，抽滤，乙酸乙酯洗涤滤饼，真空干燥得I-10的盐酸盐235mg，HPLC:99.40％. 1H-NMR(300MHz,DMSO-d 6+D 2O)δ(ppm):8.95(1H,s,ArH),8.51(1H,s,ArH),7.96(1H,d,J＝7.9Hz,ArH),7.85(1H,d,J＝7.5Hz,ArH),7.58(1H,s,ArH),7.46(1H,t,J＝7.6Hz,ArH),4.34(2H,s,COCH 2N),4.09-3.86(12H,m,6CH 2),3.75-3.31(12H,m,6CH 2). 13C-NMR(75MHz,DMSO-d 6)δ(ppm):168.73,165.08,163.98,158.77,152.72,151.29,150.91,148.65,146.44,137.01,127.67,126.68,125.45,123.63,120.77,120.14,119.87,114.50,111.10,110.03,65.89,63.27,57.32,52.05,43.28,28.32,13.80.HRMS(ESI):m/z[M+H] +.Calcd for C 33H 36F 3N 10O 6:725.2766；Found:725.2760.

Claims (10)

  1. 通式(I)的化合物或其药学上可接受的盐：
    Figure PCTCN2018097979-appb-100001
    其中X代表CH或N；
    R 1代表
    Figure PCTCN2018097979-appb-100002
    Figure PCTCN2018097979-appb-100003
    R 2代表
    Figure PCTCN2018097979-appb-100004
    Figure PCTCN2018097979-appb-100005
    Figure PCTCN2018097979-appb-100006
    R 3代表H、F、Br、Cl、CF 3、CN、CH 3或OCH 3；Y代表CH或N；Z代表O、NH、NCH 3或CH 2；m＝1或2。
  2. 权利要求1的化合物(I)或其药学上可接受的盐，其中R 1代表
    Figure PCTCN2018097979-appb-100007
    Figure PCTCN2018097979-appb-100008
    R 2代表
    Figure PCTCN2018097979-appb-100009
    Figure PCTCN2018097979-appb-100010
  3. 一种制备权利要求1的化合物的方法，当R 2不代表
    Figure PCTCN2018097979-appb-100011
    时，包括：
    Figure PCTCN2018097979-appb-100012
    其中R 1、R 2的定义同权利要求1。
  4. 权利要求3的方法，是在加入催化剂、碱和反应溶剂条件下进行，其中催化剂选自双(三苯基膦)二氯化钯、四(三苯基膦)钯或[1,1'-双(二苯基膦基)二茂铁]二氯化钯；碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、碳酸钠或碳酸钾；反应溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙二醇二甲醚、四氢呋喃、二氧六环、甲苯、乙醇、水或其中任意两种或三种溶剂的混合溶剂；反应温度为95℃～110℃。
  5. 一种制备权利要求1的化合物的方法，当R 2代表
    Figure PCTCN2018097979-appb-100013
    时，包括：
    Figure PCTCN2018097979-appb-100014
    其中R 1、R 3的定义同权利要求1。
  6. 权利要求5的方法，是在加入缩合剂、缚酸剂和反应溶剂条件下进行，其中缩合剂为六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷，缚酸剂为N,N-二异丙基乙胺；反应溶剂为N,N-二甲基甲酰胺。
  7. 权利要求1的化合物或其药学上可接受的盐，其中药学上可接受的盐为通式(I)化合物的酸加成盐，其中用于成盐的酸为：氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
  8. 一种药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
  9. 权利要求1的化合物或其药学上可接受的盐在制备PARP-1和PI3K双靶点抑制剂药物中的用途。
  10. 权利要求9的用途，其中PARP-1和PI3K双靶点抑制剂药物是抗肿瘤药物。
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CN104230896A (zh) * 2013-06-17 2014-12-24 上海汇伦生命科技有限公司 苯并咪唑-2-哌嗪杂环类化合物、其药物组合物及其制备方法和用途
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CN112174870B (zh) * 2020-10-12 2023-07-21 蔡霈 (r)-1-烷烃酰基-2-取代吡咯烷-2-甲酰胺的制备方法及其药用用途
WO2022214701A1 (en) * 2021-04-09 2022-10-13 Universität Basel Triazine derivative as covalent inhibitors of pi3k

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