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WO2019109647A1 - 含有吡啶并嘧啶结构的parp和pi3k双靶点抑制剂 - Google Patents

含有吡啶并嘧啶结构的parp和pi3k双靶点抑制剂 Download PDF

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WO2019109647A1
WO2019109647A1 PCT/CN2018/097980 CN2018097980W WO2019109647A1 WO 2019109647 A1 WO2019109647 A1 WO 2019109647A1 CN 2018097980 W CN2018097980 W CN 2018097980W WO 2019109647 A1 WO2019109647 A1 WO 2019109647A1
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acid
compound
arh
pharmaceutically acceptable
parp
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PCT/CN2018/097980
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English (en)
French (fr)
Inventor
徐云根
朱启华
王均伟
李慧
储昭兴
何广卫
Original Assignee
中国药科大学
合肥医工医药有限公司
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Application filed by 中国药科大学, 合肥医工医药有限公司 filed Critical 中国药科大学
Priority to US16/769,893 priority Critical patent/US11572359B2/en
Publication of WO2019109647A1 publication Critical patent/WO2019109647A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
    • B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
    • B01J2231/4211—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/824—Palladium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of PARP and PI3K dual targets containing 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine and pyridazine-1(2H)-one structures.
  • 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.
  • R 1 represents Preferably R 1 is
  • R 2 represents R 3 represents H, F, Br, Cl, CF 3 , CH 3 or OCH 3 ;
  • X represents CH or N;
  • Y represents O, NH, NCH 3 , CH 2 ;
  • m 1 or 2; preferably R 2 is
  • 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, dioxane, tetrahydrofuran , toluene, ethanol, water or a mixed solvent of any two or three kinds of solvents
  • the reaction temperature is preferably from 80 ° C to 120 ° 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 100 to 110 °C.
  • the condensing agent used 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 priority PyBOP.
  • PyBOP benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate
  • HOBt 1-hydroxybenzotriazole
  • EDCI dicyclohexylcarbodiimide
  • CDI N,N'-carbonyldiimidazole More priority PyBOP.
  • the acid binding agent is preferably selected from the group consisting of triethylamine, N,N-diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), pyridine, sodium acetate, potassium acetate, sodium carbonate or potassium carbonate. More preferred is DIEA.
  • 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 10 ° C to 80 ° C. More preferably, it is 20 ° C - 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 preferred is potassium carbonate.
  • the reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, toluene, ethanol, water or any two or three of them.
  • a mixed solvent of solvents A mixed solvent of dioxane/water is more preferable.
  • the reaction temperature is preferably from 80 ° C to 120 ° C. More preferably, it is 100 ° C - 110 °C.
  • the process for preparing compound I ⁇ A from compound I by salt formation 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, maleic acid.
  • the solvent is methanol, ethanol, dichloromethane, acetone, ethyl acetate, toluene, tetrahydrofuran or a mixed solvent of any two or three solvents.
  • 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.
  • test methods for kinase inhibitory activity 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 reaction at room temperature for 1 hour, 50 uL 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 50 ⁇ L reaction system, 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%
  • the results in Table 1 show that the compound of the present invention has a high inhibitory activity against PARP-1, and the test compound inhibits PARP-1 by more than 70% at a concentration of 10 nM; the compound also has a high inhibitory activity against PI3K ⁇ , and some compounds The inhibition rate of PI3K ⁇ was greater than 50% at a concentration of 100 nM.
  • the above results show that the compound of the present invention has dual inhibitory activity against PARP-1 and PI3K.
  • HCT116 human colon cancer cells
  • HCC1937 human breast cancer cells
  • MDA-MB-231 human breast cancer cells
  • MDA-MB-468 human breast cancer cells
  • 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.
  • Compound I-1 wherein the inhibition of tumor cell HCC1937 the most active, IC 50 reaches 0.081 ⁇ M;
  • test grouping situation is shown in Table 4.
  • 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 2 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 compounds I-1 (50 mg/kg), I-3 (50 mg/kg) and olaparib (50 mg/kg)/BKM120 (27.5 mg/kg) of the present invention can be significantly combined.
  • the inhibition rate of MDA-MB-468 nude mice xenografts was higher than that of the positive drugs olaparib and BKM120; the anti-tumor effects of compound I-1 (50mg/kg) and I-3 (50mg/kg) were obvious.
  • the antitumor effect of compound I-3 was optimal.
  • Compound I-1 can inhibit tumor growth in a dose-dependent manner.
  • the white solid was dissolved in 400 mL of water, adjusted to neutral with 1 mol/L hydrochloric acid, and a large amount of solid was precipitated, filtered, and dried to give a white solid (27.68 g, yield: 80.1%). Without further purification, the next step was taken directly.

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Abstract

涉及药物化学领域，具体涉及一类含有5,6,7,8-四氢吡啶并[3,4-d]嘧啶和酞嗪-1(2H)-酮结构的PARP和PI3K双靶点抑制剂(I)及它们的制备方法，药效学试验证明，该化合物具有PARP和PI3K双靶点抑制活性，可用于抗肿瘤。

Description

含有吡啶并嘧啶结构的PARP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5,6,7,8-四氢吡啶并[3,4-d]嘧啶和酞嗪-1(2H)-酮结构的PARP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，从而达到提高对肿瘤的疗效并降低剂量和毒性的目的。
Figure PCTCN2018097980-appb-000001
其中R 1代表
Figure PCTCN2018097980-appb-000002
Figure PCTCN2018097980-appb-000003
优选R 1为
Figure PCTCN2018097980-appb-000004
R 2代表
Figure PCTCN2018097980-appb-000005
Figure PCTCN2018097980-appb-000006
Figure PCTCN2018097980-appb-000007
R 3代表H、F、Br、Cl、CF 3、CH 3或OCH 3；X代表CH或N；Y代表O、NH、NCH 3、CH 2；m＝1或2；优选R 2为
Figure PCTCN2018097980-appb-000008
Figure PCTCN2018097980-appb-000009
本发明更优选的部分化合物如下：
Figure PCTCN2018097980-appb-000010
Figure PCTCN2018097980-appb-000011
Figure PCTCN2018097980-appb-000012
本发明通式(I)的部分化合物可用下列方法制备：
Figure PCTCN2018097980-appb-000013
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、二氧六环、四氢呋喃、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80℃～120℃。
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100℃～110℃。
更详细地，从起始原料(4)和(III)制备的话，则包括：
Figure PCTCN2018097980-appb-000014
由化合物4与化合物III经酰化反应制备化合物IV的过程：
所用的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、乙酸钾、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IV与硼酸酯V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、二氧六环、四氢呋喃、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80℃～120℃。更优选100℃～110℃。
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抑制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50uL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.
PARP-1和PI3Kα的IC 50的测定方法：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抑制IC 50值。
选择酶抑制活性较好的部分化合物分别测定它们对PARP-1和PI3Kα的IC 50值，实验结果见表2。
表1.受试化合物在测定浓度下对PARP-1和PI3Kα的抑制活性
Figure PCTCN2018097980-appb-000015
表1结果显示，本发明化合物对PARP-1具有较高的抑制活性，受试化合物在10nM浓度下对PARP-1的抑制率大于70％；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50％。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。
表2.部分受试化合物对PARP-1和PI3Kα的IC 50值
Figure PCTCN2018097980-appb-000016
表2结果显示，本发明化合物对PARP-1和PI3K均有较好的抑制活性，大部分化合物对PARP-1的抑制活性优于对PI3Kα的抑制活性，其中以化合物I-11的活性最好，其对PARP-1的IC 50为0.376nM，对PI3Kα的IC 50为29.8nM。
(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HCT116(人结肠癌细胞)、HCC1937(人乳癌细胞)、MDA-MB-231(人乳癌细胞)和MDA-MB-468(人乳癌细胞)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(VERSAmaxTM，Molecular Device)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 PCTCN2018097980-appb-000017
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HCC1937的抑制活性最强，IC 50达到0.081μM；化合物I-1、I-3和I-11对所测的四 株肿瘤细胞的IC 50均小于1.0μM。
(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 PCTCN2018097980-appb-000018
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2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(tumor volume,TV)的计算公式为：
TV＝1/2×a×b 2，其中a、b分别表示长宽。
结果见表5和表6。
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 PCTCN2018097980-appb-000019
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 PCTCN2018097980-appb-000020
Figure PCTCN2018097980-appb-000021
由表5和6可知，本发明化合物I-1(50mg/kg)、I-3(50mg/kg)以及奥拉帕尼(50mg/kg)/BKM120(27.5mg/kg)联用均能够显著抑制MDA-MB-468裸小鼠移植瘤的生长，抑制率高于阳性药奥拉帕尼和BKM120；化合物I-1(50mg/kg)和I-3(50mg/kg)的抗肿瘤效果明显优于奥拉帕尼(50mg/kg)/BKM120(27.5mg/kg)联用组(p<0.05)，化合物I-3的抗肿瘤效果最优。同时化合物I-1能够剂量依赖性地抑制肿瘤的生长。
具体实施方式
实施例1
4-(3-(2-(2-氨基嘧啶-5-基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-1)的合成
7-苄基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-2,4(1H,3H)-二酮(2)
将1-苄基-3-氧代哌啶-4-甲酸乙酯盐酸盐(1)(40.0g,134.33mmol)，尿素(17.09g,282.01mmol)加入500mL三颈瓶中，加入250mL无水甲醇，搅拌溶解，降温至0℃，滴加甲醇钠的甲醇溶液(228.0mL,1.0mol/L)，滴加完毕，氮气保护下加热回流反应20小时左右，TLC(石油醚:乙酸乙酯＝5:1)检测原料1反应完全，停止加热，冷却至室温，析出大量白色固体，降温至0℃，继续搅拌1小时，抽滤，滤饼用50mL甲醇洗涤，得白色固体。将该白色固体溶于400mL水中，用1mol/L盐酸调至中性，析出大量固体，抽滤，干燥，得白色固体27.68g，收率80.1％。不经纯化，直接投下一步。
7-苄基-2,4-二氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(3)
将200mL三氯氧磷加入500mL三颈瓶中，降温至0℃，缓慢加入化合物2(27.68g,107.58mmol)，加毕，反应液呈粉色浑浊。氮气保护下，加热回流反应6～8小时，TLC(石油醚:乙酸乙酯＝3:1)检测原料2反应完全，停止加热，稍冷，减压蒸除三氯氧磷，残留物缓慢倒入400g碎冰中，用5mol/L NaOH溶液调pH 8～9，析出固体，抽滤，滤饼用水洗涤，干燥得类白色固体29.0g，收率91.6％。 1HNMR(300MHz,CDCl 3)δ(ppm):7.34-7.29(5H,m,ArH),3.75(2H,s,CH 2),3.67(2H,s,CH 2),2.85(4H,m,2×CH 2).
4-(7-苄基-2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)吗啉(II-1)
将化合物3(29.0g,98.58mmol)溶于异丙醇(200mL)和二氯甲烷(20mL)的混合溶剂中，缓慢加入吗啉(10.31g,118.30mmol)，DIEA(32.59mL,197.16mmol)，加毕，升温至50℃反应3～5小时，TLC(石油醚:乙酸乙酯＝9:1)检测原料3反应完全，停止加热，冷却至室温，析出固体，降温至0℃，继续搅拌30分钟，抽滤，滤饼用50mL异丙醇洗涤，干燥得类白色固体23.0g。滤液减压浓缩，残留物用200mL乙酸乙酯溶解，依次用水(100mL)和饱和氯化钠溶液(100mL)洗涤，减压浓缩得黄色油状物，柱层析纯化(石油醚:乙酸乙酯＝50:1～5:1)得白色固体7.42g，总计得到产物30.42g，收率89.5％。m.p.154-156℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):7.34-7.23(5H,m,ArH),3.66-3.62(6H,m,2×CH 2),3.47-3.44(6H,m,3×CH 2),2.65-2.54(4H,m,2×CH 2).
4-(2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)吗啉(III-1)
将化合物4(21.10g,61.19mmol)溶于200mL二氯甲烷，冰浴降温至0℃，滴加氯甲酸1-氯乙酯(26.41mL,244.76mmol)，加毕，保温搅拌30分钟，升温至25℃搅拌反应8～10小时，TLC(石油醚:乙酸乙酯＝1:1)检测原料4反应完，减压蒸除溶剂，加入200mL甲醇回流反应1小时，减压蒸除溶剂，加入200mL水溶解残留物，用1mol/L NaOH溶液调节pH 8～9，二氯甲烷萃取(150mL×3)，合并有机层，饱和氯化钠溶液洗涤(200mL×2)，无水Na 2SO 4干燥。抽滤，滤液浓缩，残留物柱层析纯化(二氯甲烷:甲醇＝80:1～20:1梯度洗脱)，得黄色固体10.5g，收率67.4％。 1HNMR(300MHz,DMSO-d 6)δ(ppm):3.75-3.64(6H,m,3×CH 2), 3.44-3.41(4H,m,2×CH 2),2.79(2H,m,CH 2),2.66(1H,s,NH),2.50-2.48(2H,m,CH 2).
4-(3-(2-氯-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(IV-1)
将2-氟-5-((4-氧代-3,4-二氢酞嗪基)甲基)苯甲酸(4)(11.24g,37.68mmol)，4-(2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)吗啉(III-1)(9.60g,37.69mmol)和PyBOP(23.54g,45.23mmol)加入200mL三颈瓶中，加入100mL DMF搅拌溶解，再加入DIEA(24.92mL,150.79mmol)，于25℃搅拌反应6～8小时，TLC(二氯甲烷:甲醇＝20:1)检测原料4反应完全，将反应液倒入300mL水中，析出大量固体，抽滤，滤饼用100mL水洗涤，干燥得粗品，柱层析纯化(二氯甲烷:甲醇＝100:1～20:1梯度洗脱)，得类白色固体12.06g，收率59.8％。m.p.174-177℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.61(1H,s,CONH),8.29-8.25(1H,m,ArH),7.98(1H,d,J＝7.7Hz,ArH),7.92-7.80(2H,m,ArH),7.52-7.40(2H,m,ArH),7.32-7.24(1H,m,ArH),4.63(1H,s,0.5×CH 2),4.36(2H,s,CH 2),4.29(1H,s,0.5×CH 2),3.85-3.61(5H,m,2.5×CH 2),3.54-3.42(4H,m,2×CH 2),3.29-3.13(1H,m,0.5×CH 2),2.74-2.57(2H,m,CH 2).
4-(3-(2-(2-氨基嘧啶-5-基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-1)
将化合物IV-1(9.06g,16.94mmol)和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(V-1)(5.61g,25.40mmol)加入250mL反应瓶中，加入100mL二氧六环搅拌溶解。将K 2CO 3(9.37g,67.76mmol)溶于10mL水中，缓慢入反应液,再加入四三苯基膦钯(0.98g,0.85mmol)。氮气保护下，加热回流反4～6小时，析出黄色固体，TLC(二氯甲烷:甲醇＝20:1)检测原料IV-1反应完，冷却至室温，抽滤，滤饼依次用水(40mL)和乙酸乙酯(20mL)洗涤，干燥得粗品，加入120mL乙酸乙酯打浆2小时，抽滤，干燥得浅黄色固体5.80g，收率57.7％。m.p.159-160℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.73(1H,s,CONH),,9.16(1H,s,ArH),9.07(1H,s,ArH),8.37(1H,t,J＝6.8Hz,ArH),8.11-7.88(3H,m,ArH),7.63-7.54(2H,m,ArH),7.40(1H,t,J＝8.7Hz,ArH),7.30(2H,s,NH 2),4.81(1H,s,0.5×CH 2),4.47(2H,s,CH 2),4.45(1H,s,0.5×CH 2),3.95-3.55(10H,m,5×CH 2),2.85-2.71(2H,m,CH 2). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.12,163.67,162.66,160.27,159.89,159.34,157.75,154.92,144.85,134.85,133.44,132.01,131.54,129.05,127.85,126.03,125.43,123.67,119.47,117.77,115.88,112.42,65.97,50.45,47.69,46.43,36.44,26.14.HRMS(ESI):m/z[M+H] +.Calcd for C 31H 28FN 9O 3:594.2372；Found:594.2371.
实施例2
4-(3-(2-(6-氨基吡啶-3-基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-2)的合成
将化合物IV-1(300mg,0.56mmol)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(V-2)(136mg,0.62mmol)加入100mL三颈瓶中，加入20mL二氧六环搅拌溶解。将K 2CO 3(310mg,2.24mmol)溶于2mL水中，加入反应液,再加入四三苯基膦钯(65mg,0.06mmol)。氮气保护下，加热回流反应4～5小时，TLC(二氯甲烷:甲醇＝20:1)检测原料IV-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，残留物柱层析纯化(二氯甲烷:甲醇＝100:1～30:1)，得浅黄色固体220mg，收率66.3％。m.p.206-207℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.61(1H,s,CONH),8.89-8.80(1H,m,ArH),8.28-8.12(2H,m,ArH),8.00-7.78(3H,m,ArH),7.51-7.45(2H,m,ArH),7.29(1H,t,J＝9.1Hz,ArH),6.51-6.47(1H,m,ArH),6.44(2H,s,NH 2),4.69(1H,s,0.5×CH 2),4.36(2H,s,CH 2),4.33(1H,s,0.5×CH 2),3.88-3.47(10H,m,5×CH 2),2.73-2.58(2H,m,CH 2). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.39,163.78,161.00,160.22,159.84,159.37,154.97,148.57,144.84,136.17,134.88,133.43,132.04,131.52,129.07,127.88,126.04,125.42,123.77,121.29,116.10,115.83,111.90,107.18,65.98,47.77,46.51,43.74,36.47,26.03.HRMS(ESI):m/z[M+H] +.Calcd  for C 32H 29FN 8O 3:593.2419；Found:593.2418.
实施例3
4-(3-(2-(6-氨基-4-(三氟甲基)吡啶-3-基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-3)的合成
以化合物IV-1(1.0g,1.87mmol)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(V-3)(646mg,2.24mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～20:1梯度洗脱)，得浅黄色固体680mg，收率55.1％。m.p.158-160℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.56(1H,s,CONH),8.51-8.42(1H,m,ArH),8.25(1H,t,J＝7.3Hz,ArH),7.98-7.75(3H,m,ArH),7.50-7.43(2H,m,ArH),7.30-7.22(1H,m,ArH),6.82(1H,s,ArH),6.80(2H,s,NH 2),4.68(1H,s,1/2ArCH 2N),4.35(2H,s,ArCH 2),4.32(1H,s,1/2ArCH 2N),3.84-3.39(10H,m,5CH 2),2.76-2.60(2H,m,NCH 2 CH 2 ). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.43,164.03,163.55,160.50,159.82,159.37,158.22,154.98,152.35,144.79,135.56,134.89,133.38,131.96,131.47,129.08,127.90,126.03,125.38,123.47,121.34,119.67,116.10,112.56,104.37,66.00,47.70,46.29,43.64,36.50,25.99.HRMS(ESI):m/z[M+H] +.Calcd for C 33H 28F 4N 8O 3:661.2293；Found:661.2298.
实施例4
4-(3-(2-(6-氨基-5-(三氟甲基)吡啶-3-基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-5)的合成
以化合物IV-1(300mg,0.56mmol)和5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3-(三氟甲基)吡啶-2-胺(V-4)(178mg,0.62mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～40:1)，得浅黄色固体250mg，收率67.6％。m.p.256-258℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.61(1H,s,CONH),9.11-9.03(1H,m,ArH),8.51-8.41(1H,m,ArH),8.26(1H,t,J＝7.2Hz,ArH),8.00-7.76(3H,m,ArH),7.56-7.44(2H,m,ArH),7.29(1H,t,J＝8.7Hz,ArH),7.01(2H,s,NH 2),4.71(2H,s,CH 2),4.36(2H,s,CH 2),3.93-3.39(10H,m,5×CH 2),2.75-2.61(2H,m,CH 2). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.40,163.93,160.42,160.06,159.35,157.93,156.51,152.23,144.81,137.91,134.97,133.87,133.41,131.94,131.50,129.61,129.09,128.84,127.90,126.04,125.43,123.71,120.89,116.11,112.64,65.96,47.72,46.48,43.71,36.47,26.12.HRMS(ESI):m/z[M+H] +.Calcd for C 33H 28F 4N 8O 3:661.2293；Found:661.2290.
实施例5
4-(3-(2-(4-氨基-2-氟苯基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-6)的合成
以化合物IV-1(300mg,0.56mmol)和3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(V-5)(147mg,0.62mmol)为原料，操作同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145mg，收率42.5％。m.p.204-206℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.58(1H,s,CONH),8.28-8.22(1H,s,ArH),8.00-7.68(4H,m,ArH),7.51-7.43(2H,m,ArH),7.30-7.25(1H,m,ArH),6.44-6.27(2H,m,ArH),5.81(2H,s,NH 2),4.65(1H,s,0.5×CH 2),4.35(2H,s,CH 2),4.30(1H,s,0.5×CH 2),3.82-3.38(10H,m,5×CH 2),2.72-2.57(2H,m,CH 2). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.37,163.99,163.53,160.07,159.36,152.55,144.84,134.88,133.43,132.10,131.53,129.06,128.79,127.87,126.04,125.43,123.77,123.50,121.31,115.85,112.61,111.47,109.46,100.48,100.09,65.96,47.76,46.44,43.70,36.46,25.96.HRMS(ESI):m/z[M+H] +.Calcd for C 33H 29F 2N 7O 3:610.2373；Found:610.2368.
实施例6
4-(3-(2-(3-氨基-4-氟苯基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-7)的合成
以化合物IV-1(300mg,0.56mmol)和2-氟-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(V-6)(147mg,0.62mmol)为原料，操作同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160mg，收率46.9％。m.p.236-239℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.59(1H,s,CONH),8.25(1H,t,J＝6.6Hz,ArH),7.97(1H,d,J＝7.8Hz,ArH),7.91-7.71(3H,m,ArH),7.58-7.42(3H,m,ArH),7.29(1H,t,J＝9.0Hz,ArH),7.15-7.04(1H,m,ArH),4.74(1H,s,0.5×CH 2),4.38(1H,s,0.5×CH 2),4.35(2H,m,CH 2),3.84-3.39(10H,m,5×CH 2),2.77-2.62(2H,m,CH 2). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.43,164.02,163.28,159.36,158.34,154.99,144.80,138.50,134.89,133.42,132.18,131.52,129.09,128.81,127.90,126.04,125.42,123.55,117.40,116.62,116.15,115.87,115.18,114.93,112.34,66.01,47.81,45.59,43.55,36.48,26.21.HRMS(ESI):m/z[M+H] +.Calcd for C 33H 29F 2N 7O 3:610.2373；Found:610.2374.
实施例7
4-(3-(2-(1H-吲唑-4-基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-8)的合成
以化合物IV-1(300mg,0.56mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑(V-7)(151mg,0.62mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～40:1)，得浅黄色固体130mg，收率37.6％。m.p.198-200℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):13.24(1H,s,NH),12.60(1H,s,CONH),8.82-8.70(1H,m,ArH),8.28-8.07(2H,m,ArH),7.97(t,J＝7.2Hz,1H),7.91-7.72(2H,m,ArH),7.67(1H,t,J＝7.0Hz,ArH),7.50-7.40(3H,m,ArH),7.32-7.25(1H,m,ArH),4.83(1H,s,0.5×CH 2),4.46(1H,s,0.5×CH 2),4.36(2H,s,CH 2),3.88-3.49(10H,m,5×CH 2),2.80-2.66(2H,m,CH 2). 13CNMR(75MHz,DMSO-d 6)δ(ppm):169.67,164.47,164.19,160.48,159.36,158.23,154.85,144.82,140.74,134.99,133.42,131.93,131.52,130.29,129.10,127.91,126.05,125.42,123.76,123.51,121.14,120.79,116.12,115.83,113.43,112.42,66.03,48.04,46.56,43.68,36.49,26.18.HRMS(ESI):m/z[M+H] +.Calcd for C 34H 29FN 8O 3:617.2419；Found:617.2425.
实施例8
4-(3-(2-(1H-吲哚-5-基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-9)的合成
以化合物IV-1(300mg,0.56mmol)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(V-8)(151mg,0.62mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～60:1梯度洗脱)，得浅黄色固体153mg，收率44.4％。m.p.238-240℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.59(1H,s,CONH),11.24(1H,s,NH),8.60-8.51(1H,m,ArH),8.26(1H,t,J＝6.5Hz,ArH),8.18-8.05(1H,m,ArH),8.00-7.75(3H,m,ArH),7.50-7.36(4H,m,ArH),7.28(1H,t,J＝8.9Hz,ArH),6.53(1H,d,J＝9.6Hz,ArH),4.73(1H,s,0.5×CH 2),4.38(1H,s,0.5×CH 2),4.36(2H,s,CH 2),3.86-3.40(10H,m,5×CH 2),2.75-2.61(2H,m,CH 2). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.41,164.05,161.34,160.29,159.92,159.36,151.00,144.83,137.37,134.99,133.43,131.90,131.52,129.09,128.49,127.90,127.59,126.05,125.44,121.11,120.19,117.44,116.13,112.10,111.01,102.17,90.23,66.02,47.87,46.56,43.76,36.50,26.05.HRMS(ESI):m/z[M+H] +.Calcd for C 35H 30FN 7O 3:616.2467；Found:616.2462.
实施例9
4-(3-(2-(1H-吲哚-4-基)-4-吗啉基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪 -1(2H)-酮(I-10)
以化合物IV-1(300mg,0.56mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚(V-9)(151mg,0.62mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～60:1梯度洗脱)，得类白色固体125mg，收率36.3％。m.p.178-181℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.62(1H,s,CONH),11.29(1H,s,NH),8.26(1H,t,J＝8.9Hz,ArH),8.12(1H,d,J＝6.9Hz,ArH),8.02-7.74(4H,m,ArH),7.55-7.40(4H,m,ArH),7.34-7.14(2H,m,ArH),4.80(1H,s,0.5×CH 2),4.45(1H,s,0.5×CH 2),4.37(2H,s,CH 2),3.90-3.46(10H,m,5×CH 2),2.80-2.66(2H,m,CH 2). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.47,164.10,162.16,160.20,159.89,159.35,158.23,151.45,144.82,140.70,137.03,134.91,133.42,132.03,131.51,129.10,128.85,127.89,126.10,125.41,123.79,120.36,116.11,115.85,113.69,112.56,103.32,66.05,48.09,46.59,43.77,36.49,26.05.HRMS(ESI):m/z[M+H] +.Calcd for C 35H 30FN 7O 3:616.2467；Found:616.2464.
实施例10
(S)-4-(3-(2-(2-氨基嘧啶-5-基)-4-(3-甲基吗啉基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-11)的合成
(S)-4-(7-苄基-2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3-甲基吗啉(II-2)
将中间体3(2.0g,6.80mmol)溶于异丙醇(20mL)和二氯甲烷(4mL)的混合溶剂中，缓慢加入(S)-3-甲基吗啉(0.83g,8.20mmol)，DIEA(2.24mL,13.56mmol)，加毕，升温至50℃反应8～10小时，TLC(石油醚:乙酸乙酯＝9:1)检测原料3反应完，停止加热，稍冷，减压蒸除溶剂，残留物用50mL乙酸乙酯溶解，依次用水(50mL)和饱和氯化钠溶液(50mL×2)洗涤，无水Na 2SO 4干燥。抽滤，滤液减压浓缩得黄色油状物，柱层析纯化(石油醚:乙酸乙酯＝20:1～5:1梯度洗脱)，得黄色固体1.4g，收率57.4％。 1HNMR(300MHz,CDCl 3)δ(ppm):7.39-7.30(5H,m,ArH),4.18-4.11(1H,m,0.5×CH 2),3.97-3.92(1H,m,0.5×CH 2),3.78-3.44(9H,m,4×CH 2,CH),2.82-2.57(4H,m,2×CH 2),1.34(3H,d,J＝6.8Hz,CH 3).
(S)-4-(2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3-甲基吗啉(III-2)
将中间体II-2(1.10g,3.07mmol)溶于20mL二氯甲烷，降温至0℃，滴加1-氯乙基氯甲酸酯(1.43mL,13.28mmol)，保温搅拌15min，升温至25℃搅拌反应6～10小时，TLC(石油醚:乙酸乙酯＝1:1)检测原料II-2反应完，减压蒸除溶剂，加入20mL甲醇回流反应30分钟，减压蒸除溶剂，残留物用20mL水溶解，用1mol/L NaOH溶液调节pH 8～9，二氯甲烷萃取(30mL×3)，合并有机层，饱和氯化钠溶液洗涤(40mL×3)，无水Na 2SO 4干燥。抽滤，滤液浓缩得棕色油状物，柱层析纯化(二氯甲烷:甲醇＝40:1～5:1梯度洗脱)，得黄色固体550mg，收率66.7％。 1HNMR(300MHz,CDCl 3)δ(ppm):4.12(1H,m,0.5×CH 2),3.99(2H,s,CH 2),3.95-3.91(1H,m,0.5×CH 2),3.78-3.59(4H,m,2×CH 2),3.53-3.43(1H,m,CH),3.14-3.07(1H,m,0.5×CH 2),3.00-2.92(1H,m,0.5×CH 2),2.66-2.53(2H,m,CH 2),2.29(1H,s,NH),1.32(3H,d,J＝6.8Hz,CH 3).
(S)-4-(3-(2-氯-4-(3-甲基吗啉基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(IV-2)
将化合物4(555mg,1.86mmol)、化合物III-2(500mg,1.86mmol)和PyBOP(1.16g,2.23mmol)加入100mL三颈瓶中，加入20mL DMF搅拌溶解，再加入DIEA(1.08mL,6.51mmol)，于25℃搅拌反应6～8小时，TLC(二氯甲烷:甲醇＝20:1)检测原料III-2反应完全，将反应液倒入60mL水中，析出黄色固体，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＝100:1～20:1梯度洗脱)得黄色固体740mg，收率72.5％。m.p.144-147℃. 1HNMR(300MHz,CDCl 3)δ(ppm):10.82(1H,s,CONH),8.51-8.46(1H,m,ArH),7.83-7.70(3H,m,ArH),7.45-7.36(2H,m,ArH),7.12-7.04(1H,m,ArH),4.46(1H,s,0.5×CH 2),4.33(1H,s,0.5×CH 2),4.30(2H,s,CH 2),4.17-4.06(2H,m,CH 2),3.95(2H,m,CH 2),3.73-3.51(7H,m,3×CH 2, CH),1.38(3H,d,J＝6.7Hz,CH 3).
(S)-4-(3-(2-(2-氨基嘧啶-5-基)-4-(3-甲基吗啉基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-11)
以化合物IV-2(300mg,0.55mmol)和化合物V-1(181mg,0.82mmol)为原料，操作同I-2的方法，柱层析纯化(二氯甲烷:甲醇＝60:1～20:1梯度洗脱)，得浅黄色固体170mg，收率50.9％。m.p.214-216℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.60(1H,s,CONH),9.03(1H,s,ArH),8.94(1H,s,ArH),8.25(1H,t,J＝6.7Hz,ArH),7.99-7.76(3H,m,ArH),7.49-7.42(2H,s,ArH),7.28(1H,t,J＝9.1Hz,ArH),7.15(2H,s,NH 2),4.78-4.58(H,m,0.5×CH 2),4.35(2H,s,CH 2),4.16-4.04(H,m,0.5×CH 2),3.87-3.38(9H,m,4×CH 2,CH),2.71-2.58(2H,m,CH 2),1.23(3H,d,J＝7.2Hz,CH 3). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.36,164.13,163.63,160.35,159.97,159.35,157.67,144.83,134.88,133.43,132.01,131.53,129.04,127.87,126.82,126.03,125.44,123.71,123.45,119.53,116.10,112.56,70.27,66.25,49.54,46.52,43.71,42.06,36.45,26.15,14.09.HRMS(ESI):m/z[M+H] +.Calcd for C 32H 30FN 9O 3:608.2528；Found:608.2535.
实施例11
4-(3-(2-(2-氨基嘧啶-5-基)-4-((2S,6R)-2,6-二甲基吗啉基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-12)的合成
(2S,6R)-4-(7-苄基-2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-2,6-二甲基吗啉(II-3)
将化合物3(2.0g,6.80mmol)溶于30mL异丙醇中，加入4mL二氯甲烷助溶，缓慢加入(2R,6S)-2,6-二甲基吗啉(0.94g,8.16mmol)和DIEA(2.24mL,13.56mmol)，加毕，升温至50℃反应8～10小时，TLC(石油醚:乙酸乙酯＝9:1)检测原料3反应完，稍冷，减压蒸除溶剂，残留物用100mL乙酸乙酯溶解，依次用水(50mL)和饱和氯化钠溶液(50mL×2)洗涤，无水Na 2SO 4干燥，抽滤，滤液浓缩得黄色油状物1.86g，收率73.2％，不经纯化，直接用于下一步反应。
(2S,6R)-4-(2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-2,6-二甲基吗啉(III-3)
将化合物II-3(1.66g,4.45mmol)溶于20mL二氯甲烷，降温至0℃，滴加氯甲酸1-氯乙酯(2.08mL,19.24mmol)，保温搅拌15分钟，升温至25℃搅拌反应8～10小时，TLC(石油醚:乙酸乙酯＝1:1)检测原料II-3反应完，减压蒸除溶剂，加入20mL甲醇，加热回流反应30分钟，减压蒸除溶剂，残留物用20mL水溶解，再用1mol/L NaOH溶液调节pH 8～9，二氯甲烷萃取(20mL×3)，合并有机层，用饱和氯化钠溶液(30mL×2)洗涤，无水Na 2SO 4干燥，抽滤，滤液浓缩得棕色油状物，柱层析纯化(二氯甲烷:甲醇＝40:1～5:1梯度洗脱)得黄色固体0.90g，收率71.4％。
4-(3-(2-氯-4-((2S,6R)-2,6-二甲基吗啉基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(IV-3)
将中间体4(0.95g,3.19mmol)、化合物III-3(0.90g,3.18mmol)和PyBOP(1.99g,3.82mmol)加入50mL三颈瓶中，加入20mL DMF，搅拌溶解，再加入DIEA(1.84mL,11.14mmol)，于25℃搅拌反应6～8小时，TLC(二氯甲烷:甲醇＝20:1)检测原料III-3反应完，将反应液倒入60mL水中，析出黄色固体，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＝100:1～40:1梯度洗脱)得黄色固体1.02g，收率57.0％。m.p.149-152℃. 1HNMR(300MHz,CDCl 3)δ(ppm):11.03(1H,s,CONH),8.51-8.46(1H,m,ArH),7.83-7.70(3H,m,ArH),7.46-7.35(2H,m,ArH),7.12-7.04(1H,m,ArH),4.45(1H,s,0.5×CH 2),4.33(1H,s,0,5×CH 2),4.30(2H,s,CH 2),3.92-3.67(6H,m,2×CH 2,2×CH),2.78-2.74(4H,m,2×CH 2),1.27-1.23(6H,m,2CH 3).
4-(3-(2-(2-氨基嘧啶-5-基)-4-((2S,6R)-2,6-二甲基吗啉基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-7-甲酰基)-4-氟苄基)酞嗪-1(2H)-酮(I-12)
以化合物IV-3(300mg,0.53mmol)和化合物V-1(177mg,0.80mmol)为原料，操作同I-2 的方法，柱层析纯化(二氯甲烷:甲醇＝100:1～20:1梯度洗脱)，得浅黄色固体160mg，收率48.6％。m.p.204-206℃. 1HNMR(300MHz,DMSO-d 6)δ(ppm):12.60(1H,s,CONH),9.03(1H,s,ArH),8.94(1H,s,ArH),8.25(1H,t,J＝6.9Hz,ArH),8.00-7.76(3H,m,ArH),7.50-7.42(2H,m,ArH),7.27(1H,t,J＝9.0Hz,ArH),7.14(2H,s,NH 2),4.68(1H,s,0.5×CH 2),4.35-4.32(3H,m,1.5×CH 2),3.95-3.79(3H,m,1.5×CH 2),3.69-3.62(2H,m,2CH),3.42-3.38(1H,m,0.5×CH 2),2.74-2.58(4H,m,2×CH 2),1.14(3H,d,J＝6.2Hz,CH 3),1.09(3H,d,J＝6.1Hz,CH 3). 13CNMR(75MHz,DMSO-d 6)δ(ppm):164.42,164.13,163.38,160.31,159.88,159.34,157.74,154.81,144.81,134.74,133.41,132.07,131.50,129.10,127.89,126.07,125.43,123.53,119.45,116.21,115.82,112.38,70.95,52.63,46.49,43.75,36.47,26.15,18.59.HRMS(ESI):m/z[M+H] +.Calcd for C 33H 32FN 9O 3:622.2685；Found:622.2691.

Claims (10)

  1. 通式I的化合物或其药学上可接受的盐：
    Figure PCTCN2018097980-appb-100001
    其中R 1代表
    Figure PCTCN2018097980-appb-100002
    Figure PCTCN2018097980-appb-100003
    R 2代表
    Figure PCTCN2018097980-appb-100004
    Figure PCTCN2018097980-appb-100005
    Figure PCTCN2018097980-appb-100006
    R 3代表H、F、Br、Cl、CF 3、CN、CH 3或OCH 3；X代表CH或N；Y代表O、NH、NCH 3或CH 2；m＝1或2。
  2. 权利要求1的化合物或其药学上可接受的盐，其中R 1代表
    Figure PCTCN2018097980-appb-100007
    Figure PCTCN2018097980-appb-100008
  3. 权利要求1的化合物或其药学上可接受的盐，其中R 2代表
    Figure PCTCN2018097980-appb-100009
    Figure PCTCN2018097980-appb-100010
  4. 权利要求1的化合物的制备方法，包括：
    Figure PCTCN2018097980-appb-100011
    其中R 1、R 2的定义同权利要求1。
  5. 权利要求4的制备方法，其中Suzuki反应是在加入催化剂、碱和反应溶剂条件下进行，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、二氧六环、四氢呋喃、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80℃～120℃。
  6. 权利要求5的制备方法，其中催化剂为四(三苯基膦)钯；碱为碳酸钾；溶剂为二氧六环和水的混合溶剂；反应温度为100℃～110℃。
  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双靶点抑制剂用于抗肿瘤。
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