WO2020134921A1 - 氨基喹唑啉酮和氨基异喹啉酮衍生物及其应用 - Google Patents

氨基喹唑啉酮和氨基异喹啉酮衍生物及其应用 Download PDF

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WO2020134921A1
WO2020134921A1 PCT/CN2019/122973 CN2019122973W WO2020134921A1 WO 2020134921 A1 WO2020134921 A1 WO 2020134921A1 CN 2019122973 W CN2019122973 W CN 2019122973W WO 2020134921 A1 WO2020134921 A1 WO 2020134921A1
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ring
compound
amino
cancer
methoxy
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French (fr)
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盛荣
李佳
顾东炎
周宇波
危俊
张梦梦
胡永洲
张凯祥
刘婕妤
阚伟娟
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浙江大学
中国科学院上海药物研究所
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Priority to EP19904796.0A priority Critical patent/EP3904343A4/en
Publication of WO2020134921A1 publication Critical patent/WO2020134921A1/zh
Priority to US17/358,002 priority patent/US20220017505A1/en

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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to the field of medicine, in particular to an aminoquinazolinone and aminoisoquinolinone derivative, a pharmaceutical composition containing the same and its application in the fields of anti-tumor and anti-inflammatory diseases.
  • PI3K/Akt/mTOR signaling pathway regulates various cell processes such as cell division and growth. Studies have found that this signaling pathway is often overactivated in tumor cells, and the key kinase PI3K, phosphatidylinositol 3-kinase, is often found in tumor cells. Presenting an overexpressed state, PI3K has multiple subtypes, including the inhibition of PI3K, which has gradually become an effective means of tumor therapy. On the other hand, PI3K kinase subtypes PI3K ⁇ , PI3K ⁇ are closely related to inflammation, and PI3K ⁇ and PI3K ⁇ inhibitors can be used for the treatment of inflammatory diseases such as arthritis.
  • PI3K inhibitors As a popular target for anti-tumor drugs, there are currently a number of PI3K inhibitors in clinical research, two of which have been approved by the FDA for marketing: the PI3K ⁇ inhibitor Idelalisib developed by Gilead in 2015 was approved for the treatment of recurrent chronic lymph Leukemia, follicular lymphoma, and small lymphocytic lymphoma; Copanlisib, developed by Bayer in September 2017, has also received accelerated FDA approval for the treatment of recurrent follicular lymphoma, and has received at least two Adult patient with secondary system therapy.
  • the PI3K ⁇ inhibitor Idelalisib developed by Gilead in 2015 was approved for the treatment of recurrent chronic lymph Leukemia, follicular lymphoma, and small lymphocytic lymphoma
  • Copanlisib developed by Bayer in September 2017, has also received accelerated FDA approval for the treatment of recurrent follicular lymphoma, and
  • Idelalisib causes elevated transaminases in CLL patients and has certain toxic and side effects on the liver; while Copanlisib has multiple subtypes of PI3K
  • the activities are very high, but the selectivity is poor, and the physical and chemical properties of Copanlisib are not good, so its pharmacokinetic characteristics are not good, and the distribution volume is large, reaching 32.6L/kg, which is easy to store in the patient's body, thereby causing the corresponding poisonous side Response, so clinical medication is given by injection on days 1, 8, and 15 during the 28-day treatment cycle.
  • Copanlisib modifying and optimizing the structure of Copanlisib, adjusting its physical and chemical properties, is expected to improve its pharmacokinetic properties, adjust its selectivity for various subtypes of PI3K, and obtain new anti-tumor and anti-inflammatory diseases that are more suitable for clinical use.
  • the technical problem to be solved by the present invention is to provide aminoquinazolinone and aminoisoquinolinone derivatives, which have the structures of general formula a and b:
  • X N or CH
  • R 1 is selected from hydrogen, C 1-6 alkyl, cycloalkyl, fluoroalkyl
  • R 2 is selected from hydrogen, alkyl with 1-12 carbon atoms, cycloalkyl, fluorine-containing alkyl, -(CH 2 ) n NR 5 R 6 , -(CH 2 ) n -CONR 5 R 6 ,-( CH 2 ) n -SO 2 NR 5 R 6 ,-(CH 2 ) n OR 5 , where n is an integer of 1-8, R 5 and R 6 are independent of each other, and may be the same or different, selected from hydrogen , C 1-4 alkyl, C 1-4 cycloalkyl, or NR 5 R 6 is a 4-8 membered cyclic amine, including but not limited to morpholine, piperazine, pyrrolidine, piperidine, or R 7 substituted cyclic amine, R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6- unsaturated aliphatic hydrocarbon group, C 3-8 cycloalkyl, C 3- 8 uns
  • R 3 is selected from C 1-6 alkyl, cycloalkyl, fluoroalkyl
  • Ar is an aromatic heterocycle, including but not limited to benzene ring, furan ring, thiophene ring, pyrrole ring, thiazole ring, pyrazole ring, oxazole ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, purine ring, Azapurine ring, azaindole ring, indole ring, quinoline ring, quinazoline ring, quinoxaline ring, indazole ring;
  • R 8 is selected from hydrogen, halogen, cyano, hydroxy, C 1-6 alkoxy, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkyl, C 2 -6- unsaturated aliphatic chain hydrocarbon group, C 3-8 cycloalkyl group, C 3-8 unsaturated alicyclic group, C 3-8 saturated aliphatic heterocyclic group, C 1-6 haloalkyl group;
  • R 1 in the general formula a is methyl
  • R 2 is selected from but not limited to the following groups:
  • the two oxygen atoms of the benzene ring described in structural formula b are connected by a chain to form a 5-21 membered ring, selected from but not limited to The following groups:
  • R 3 is preferably selected from —CH 3 , —CH 2 CH 3 , cyclopropyl, -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CF 3 , -CH 2 CF 2 H;
  • Ar is preferably selected from 4-methoxyphenyl, p-aminophenyl, 5- Amino-pyrazol-3-yl, 2-amino-imidazol-4yl, 2-amino-thiazol-4yl, 2-amino-oxazol-4yl, pyridin-3-yl, pyridin-2-yl, 2 -Amino-pyridin-5-yl, 2-amino-pyrimidin-5-yl, 2-amino-pyrazin-5-yl, 3-amino-pyridazin-6-yl;
  • R 8 is selected from amino, methylamino, hydroxyl , Methoxy, dimethylamino, cyano, 3,4-dimethoxy.
  • aminoquinazolinone and aminoisoquinolinone derivatives of the general formula a and b of the present invention are as follows:
  • Copanlisib is a 2,3-dihydroimidazo[1,2-c]-quinazoline derivative, and its tricyclic structure is crucial for activity (ChemMedChem2016,11,1517-1530), but the structure has a large The rigidity will affect the physical and chemical properties of the entire molecule, especially the pharmacological properties. The possible reason for the large volume of Copanlisib in the body is the tricyclic structure.
  • the present invention adopts a ring opening strategy in medicinal chemistry to open the 2,3-dihydroimidazole ring of Copanlisib and introduce C1-C3 alkyl groups in the N atom of quinazoline to improve the binding of molecules to PI3K protein Obtained a new class of quinazolinone derivatives; and further adopted a bioelectronic isosteric strategy to replace the 1-position nitrogen atom of quinazolinone with a carbon atom to design and synthesize isoquinolinone derivatives
  • the above structure optimization can effectively improve the physical and chemical properties of target molecules (such as increasing water solubility).
  • the pharmacokinetic properties of representative molecules are significantly improved compared to copanlisib and have good clinical application prospects.
  • copanlisb uses the core structure to tightly bind to PI3K ⁇ and PI3K ⁇ , while the side chain propylmorpholine is in the peripheral solvent region; while for PI3K ⁇ selective inhibitors Alpelisib (BYL719), GDC-0032 molecules Docking studies have shown that the alkylamide fragment of its side chain can form a strong hydrogen bond with the peripheral amino acid residue Gln859 of PI3K ⁇ .
  • the second object of the present invention is to provide a method for preparing the compound.
  • the specific reaction process can be:
  • Substituted benzaldehyde (Compound 1) is dissolved in a solvent and reacted with benzyl bromide or benzyl chloride under basic conditions to produce benzyl protected intermediate 2.
  • the base used includes potassium carbonate, sodium carbonate, and cesium carbonate, and the solvent used includes acetonitrile, DMF, DMSO, and the like.
  • the benzaldehyde intermediate 2 is treated with an oxidizing agent to obtain a benzoic acid intermediate 3.
  • the oxidizing agent includes sodium hypochlorite, sodium chlorite, potassium permanganate, etc.
  • the solvents used are acetic acid, water, THF, dioxane, acetone and the like.
  • the benzoic acid intermediate 3 is treated with a reducing agent to obtain anthranilic acid intermediate 4.
  • the reducing agent includes iron powder, zinc powder, Pd/CH 2 , Raney Ni-H 2 and the like.
  • the anthranilic acid intermediate 4 and the corresponding alkylamine are reacted under the action of a condensing agent to produce a benzamide intermediate 5, the condensing agent includes EDC, DCC, DIC and so on.
  • the anthranilamide intermediate 5 and the corresponding substituted aryl acyl isothiocyanate are cyclized under the action of a condensing agent to obtain a benzyl-protected aminoquinazolinone intermediate 6.
  • Condensing agents include EDC, DCC, DIC, etc. .
  • intermediate 7 undergoes a nucleophilic reaction with the corresponding halogenated hydrocarbon (chloride, bromide) to prepare target molecular product 8.
  • target molecule 8 can also be synthesized in the following ways:
  • Substituted benzaldehyde 1 first reacts with halogenated hydrocarbons under alkaline conditions, introducing R 2 group to obtain intermediate 2; alkaline reagents include potassium hydroxide, sodium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, etc.;
  • the intermediate 2 is treated with an oxidant to obtain a benzoic acid intermediate 3;
  • the oxidant includes sulfamic acid + sodium chlorite, sodium hypochlorite, potassium permanganate, etc.
  • the solvent includes acetic acid, formic acid, water, acetone, dioxane, THF, etc.;
  • Benzoic acid intermediate 3 is condensed with amine to obtain benzamide intermediate 4, and the condensing agents used include EDC, DCC, DIC, etc.;
  • the benzamide intermediate 4 is treated with a reducing agent to obtain the corresponding aminobenzamide intermediate 5, and the reducing agent includes Fe/HAc, Pd/CH 2 and the like;
  • intermediate 5 is cyclized with different substituted aryl acyl isothiocyanates under the action of a condensing agent to produce target molecule 8
  • condensing agents include EDC, DCC, DIC and so on.
  • the specific reaction process can be:
  • Hydroxime intermediate 3' was added to 15% NaOH aqueous solution, stirred at room temperature, adjusted pH and suction filtered, and the resulting solid was o-carboxyphenylacetonitrile 4';
  • the base used may be an organic base or an inorganic base.
  • the organic base may be selected from pyridine, triethylamine, N,N-diisopropyl Ethylamine and inorganic base can be selected from potassium carbonate, sodium carbonate and cesium carbonate.
  • the solvent used is generally acetonitrile or N,N-dimethylformamide (DMF).
  • the reaction temperature is between 40-70°C. example.
  • the specific reaction process can be:
  • Compound 9 reacts with alkyl dibromide, or with diethylene glycol bis(p-toluenesulfonate) and other reagents under the action of an alkaline reagent, using DMF as the solvent, to obtain the middle of the two oxygen atoms.
  • Body 10 ;
  • the intermediate 10 replaces benzaldehyde and is oxidized with an oxidizing agent to obtain the corresponding benzoic acid 11;
  • the oxidizing agent includes sodium hypochlorite, sodium chlorite, KMnO 4 and the like.
  • amide intermediate 12 Dissolve substituted benzoic acid 11 with different alkylamines and condensing agent in dichloromethane, and stir overnight at room temperature to obtain amide intermediate 12; condensing agents include EDC, DCC, DIC, etc.
  • Intermediate 12 is reduced to intermediate 13 using an iron powder/acetic acid system.
  • intermediate 13 and aryl acyl isothiocyanate are cyclically fused under the action of a condensing agent to obtain target compound 14.
  • Condensing agents include EDC, DCC, DIC, etc.
  • the specific reaction process can be:
  • Another object of the present invention is to provide the application of the aminoquinazolinone and aminoisoquinolinone derivatives in the preparation of anti-tumor and anti-inflammatory drugs, the drugs including derivatives and pharmaceutically acceptable salts thereof , Any one or more of the solvates are made with a pharmaceutically acceptable carrier.
  • the "pharmaceutically acceptable carrier” refers to a conventional pharmaceutical carrier in the pharmaceutical field, including conventional diluents in the pharmaceutical field, excipients such as water, fillers such as starch, and binders such as cellulose derivatives and gelatin. , Wetting agents such as glycerin, disintegrants such as agar, calcium carbonate, etc., absorption enhancers such as quaternary ammonium compounds, surfactants such as cetyl alcohol, adsorption carriers such as kaolin and soap clay, lubricants such as talc, etc., if necessary Flavors, sweeteners, etc. can also be added.
  • excipients such as water, fillers such as starch, and binders such as cellulose derivatives and gelatin.
  • Wetting agents such as glycerin, disintegrants such as agar, calcium carbonate, etc.
  • absorption enhancers such as quaternary ammonium compounds
  • surfactants such as cetyl alcohol
  • the pharmaceutical preparations are suitable for administration by any suitable route, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal) ), vaginal administration or parenteral administration (including subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection) route.
  • oral including buccal or sublingual
  • rectal nasal
  • topical including buccal, sublingual or transdermal
  • vaginal administration including subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection
  • parenteral administration including subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection
  • preparations can be prepared by any method known in the field of pharmacy. For example, by mixing the active ingredient with a carrier or excipient.
  • the present invention provides the compounds of the general formula a and b structures and their preferred compounds, pharmaceutically acceptable salts of the compounds, solvates of the compounds, and combinations with other drugs in the preparation of anticancer drugs use.
  • the cancer is selected from breast cancer, sarcoma, lung cancer, prostate cancer, colon cancer, rectal cancer, renal cancer, pancreatic cancer, blood cancer, neuroblastoma, glioma, head cancer, neck cancer, thyroid Cancer, liver cancer, ovarian cancer, vulvar cancer, cervical cancer, endometrial cancer, testicular cancer, bladder cancer, esophageal cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor, skin cancer, Multiple myeloma.
  • Antitumor drugs that can be used in combination with the compounds provided by the present invention or pharmaceutically acceptable salts thereof include, but are not limited to, at least one of the following types: mitotic inhibitors (such as vinblastine, vindesine, and vinorelbine); tubulin Decomposition inhibitors (such as taxol); alkylating agents (such as cisplatin, carboplatin, and cyclophosphamide); antimetabolites (such as 5-fluorouracil, tegafur, methotrexate, cytarabine, and hydroxyl groups) Urea); insertable antibiotics (such as Aresin, Mitomycin, and bleomycin); enzymes (such as aspartase); topoisomerase inhibitors (such as etoposide and camptothecin); biological response regulation Agents (such as interferon); proteasome inhibitors (such as bortezomib).
  • mitotic inhibitors such as vinblastine, vindesine, and vinorelbine
  • the compounds synthesized by the present invention have excellent PI3K ⁇ and PI3K ⁇ inhibitory effects, most of which have significant inhibitory effects on PI3K ⁇ , and PIK3CA mutant human breast cancer cell lines (MCF7) and other tumors
  • MCF7 human breast cancer cell lines
  • the compound of the present invention can be used as a PI3K ⁇ inhibitor in the treatment of tumors related to cell proliferation in humans or animals.
  • Figure 1 is the results of in vivo drug efficacy experiments.
  • the target molecule 8a-1 by reacting the target molecule 8a-1 with equimolar hydrobromic acid, fumaric acid, maleic acid, tartaric acid, etc. in a suitable solvent, the corresponding 8a-1 hydrobromide, rich Maleate, maleate and tartrate.
  • the target molecules of this series are shown in Table 1 below.
  • compound 5a-1 is combined with pyrimidine-5-formyl isothiocyanate, pyridazine-4-formyl isothiocyanate, 2-amino-pyridine-5-formyl isothiocyanate , 6-amino-pyridazine-3-formyl isothiocyanate, 2-amino-pyrazine-5-formyl isothiocyanate, 5-aminopyridine-2-formyl isothiocyanate, 3-cyano-benzoyl isothiocyanate, pyrazine-2-formyl isothiocyanate, pyrazole-4-formyl isothiocyanate, thiazole-4-formyl isothiocyanate Ester, purine-6-formyl isothiocyanate, benzimidazole-5-formyl isothiocyanate, benzothiophene-5-formyl isothiocyanate, etc.
  • the preparation of compounds 8a-32 refers to the synthesis of 8a-1, replacing N-chloropropylmorpholine with 2-chloro-N-(2-(piperidin-1-yl)ethyl)acetamide to give a white solid.
  • the preparation of compounds 8a-33 refers to the synthesis of 8a-1, replacing N-chloropropylmorpholine with 2-chloro-N-(2-(morpholin-1-yl)ethyl)acetamide to give a white solid.
  • the preparation of compounds 8a-36 refers to the synthesis of 8a-1, replacing 2-aminopyrimidine-5-acyl isothiocyanate with 1H-pyrrolo[2,3-b]pyridine-5-acyl isothiocyanate To get a white solid.
  • the operation process is the same as the synthesis of compound 8a-1, using ethylamine hydrochloride instead of methylamine hydrochloride, and reacting with 2-amino-3-methoxy-4-benzyloxybenzoic acid (compound 4) to prepare 2 -Amino-3-methoxy-4-benzyloxy-N-ethylbenzamide (compound 5b-1), followed by condensation of 5b-1 with 2-aminopyrimidine-5-acyl isothiocyanate to give 2 -Amino-N-(3-ethyl-7-benzyloxyhydroxy-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyrimidine--5-methyl Amide (6b-1), then debenzylation via Pd/CH 2 to give 2-amino-N-(3-ethyl-7-hydroxy-8-methoxy-4-oxo-3,4- Dihydroquinazolin-2-yl)pyrimidine-5-car
  • Compound 2-amino-N-(3-ethyl-7-hydroxy-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyrimidine-5-carboxamide 7b-1 is the raw material, are chloroacetamide, chloropropionamide, N-methylchloroacetamide, N,N-dimethylchloroacetamide, 2-(2-chloroethyl)-4-methyl Porphyrin, 1-(3-chloro-propionyl)-4-methylpiperazine, chloroacetylmorpholine, 4-chlorobutanamide, difluorochloromethane, chloroethylsulfonamide, TMSCF 3 , chloropropylsulfonate Amides and the like replace N-(3-chloropropyl)morpholine to prepare compounds 8b-2 to 8b-13.
  • Table 3 The structural formulas of this series of target molecules are shown in Table 3 below.
  • the synthetic route is as follows:
  • 5b-1 Using 5b-1 as raw material, it is combined with pyrimidine-5-formyl isothiocyanate, pyridazine-4-formyl isothiocyanate, 2-amino-pyridine-5-formyl isothiocyanate, 6-amino-pyridazine-3-formyl isothiocyanate, 2-amino-pyrazine-5-formyl isothiocyanate, 5-aminopyridine-2-formyl isothiocyanate, 3 -Cyano-benzoyl isothiocyanate, pyrazine-2-formyl isothiocyanate, pyrazole-4-formyl isothiocyanate, thiazole-4-formyl isothiocyanate , Purine-6-formyl isothiocyanate, benzimidazole-5-formyl isothiocyanate, benzothiophene-5-formyl isothiocyanate, etc.
  • the operation process is the same as the synthesis of compound 8a-1, using cyclopropylamine instead of methylamine hydrochloride, and reacting with 2-amino-3-methoxy-4-benzyloxybenzoic acid (compound 4) to prepare 2-amino- 3-Methoxy-4-benzyloxy-N-cyclopropylbenzamide (compound 5d-1), followed by condensation of 5d-1 with 2-aminopyrimidine-5-acyl isothiocyanate to give 2-amine -N-(3-Cyclopropyl-7-benzyloxyhydroxy-8-methoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyrimidine--5-carboxamide (6d-1), then remove the benzyl group via Pd/CH 2 to give 2-amino-N-(3-cyclopropyl-7-hydroxy-8-methoxy-4-oxo-3,4- Dihydroquinazolin-2-yl)pyrimidine-5-carbox
  • Example 12 2-amino-N-(8-methoxy-7-(3-morpholinopropyl)-4-oxo-3-(2,2,2-trifluoroethyl)-3, Preparation of 4-dihydroquinazolinone-2-yl)pyrimidine-5-carboxamide (Compound 8e-1)
  • the amide intermediate 5-2-1 (0.05 mol) was added to 200 mL of diethyl ether, 2-amino-pyrimidine-5-formyl isothiocyanate (0.05 mol) in acetone was added dropwise thereto, stirred at room temperature overnight, and precipitated Precipitation, suction filtration to obtain a powdery white precipitate, dissolved in anhydrous DCM, added EDC (0.05mmol), stirred at room temperature overnight, suction filtration to obtain a precipitate, methanol washed multiple times to obtain the target compound, Yield: 80%, ESI-MS: 341.1 [ M+H] + .
  • the synthetic route is as follows:
  • the operation process is the same as the synthesis of compound 14a-2, using 9a as raw material, and 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, 1 ,6-Dibromohexane, 1,7-dibromoheptane and 1,8-dibromooctane are reacted to obtain etherified benzaldehyde intermediate 10-2 ⁇ 10-7, and then the aldehyde group is oxidized to obtain etherification
  • Table 9 The structural formulas of this series of compounds are shown in Table 9 below.
  • the synthetic route is as follows:
  • the operation process is the same as the synthesis of compound 14a-9, with compound 9 as the raw material, and the corresponding triethylene glycol bis-(p-toluenesulfonate compound) and triethylene glycol bis-(p-toluenesulfonic acid) Ester compound) and tetra-pentaethylene glycol bis-(p-toluenesulfonate compound) are reacted to prepare etherified intermediates 10-9 ⁇ 10-11, and then aldehyde group oxidation to obtain benzoic acid derivatives 11-9 ⁇ 11-11, then formic acid and methylamine are condensed to obtain N-methylbenzamide derivatives 12a-9 ⁇ 12a-11; then reduced by nitro to obtain 13a-9 ⁇ 13a-11, and finally with 2-amino -Condensation of pyrimidine-5-formyl isocyanate gives compounds 14a-10 to 14a-12; the structural formulas of the series of compounds are shown in Table 10 below.
  • the operation process is the same as the synthesis of compound 14a-2, using benzaldehyde intermediate 11-1 ⁇ 11-7 to condense with ethylamine to obtain intermediate 12-1 ⁇ 12-7, and then reducing nitro to obtain compound 13-1 ⁇ 13 -7, and finally condensed with 2-amino-pyrimidine-5-formyl isothiocyanate to obtain white solids 14b-2 ⁇ 14b-8, see Table 11.
  • the operation process is the same as the synthesis of compound 14a-9.
  • the benzoic acid derivatives 11-9 ⁇ 11-11 are condensed with ethylamine to obtain N-methylbenzamide derivatives 12b-9 ⁇ 12b-11; 13b-9 to 13b-11 are obtained, and finally condensed with 2-amino-pyrimidine-5-formyl isocyanate to obtain compounds 14b-10 to 14b-12, the structural formulas are shown in Table 12 below.
  • the synthetic route is as follows:
  • Carboxylic acid intermediate 3'(5 mmol) was dissolved in anhydrous methanol (10 mmol), and dichlorosulfoxide (15 mmol) was added dropwise under ice bath. The reaction was stirred at room temperature for 8 h, distilled under reduced pressure, extracted with water and ethyl acetate, ethyl acetate The ester layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the product, Yield: 99%, ESI-MS: 312.1 [M+H] + ;
  • Compound 2-amino-N-(2-ethyl-6-hydroxy-5-methoxy-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrimidine-5-carboxamide 7b '-1 is the raw material, using chlorochloroacetamide, chloropropionamide, N-methylchloroacetamide, N,N-dimethylchloroacetamide, 2-(2-chloroethyl)-4-methyl Morpholine, 1-(3-chloro-propionyl)-4-methylpiperazine, chloroacetyl morpholine, 4-chlorobutanamide, etc. replace N-(3-chloropropyl) morpholine to prepare compound 8b '-2 ⁇ 8b'-9.
  • target molecules 14a'-1 and 14a'-3 to 14a'-8 can be synthesized.
  • Example 32 Inhibitory effect of aminoquinazolinones and aminoisoquinolinone derivatives on PI3K activity in vitro
  • PI3K ⁇ and PI3K ⁇ proteins were purchased from Carna Bioscience; ADP-GLO kit was purchased from Promega.
  • Sample treatment The sample is dissolved in DMSO, stored at low temperature, and diluted in a gradient, and the concentration of DMSO in the final system is controlled within a range that does not affect activity detection.
  • the positive compounds used in the experiment were Copanlisib and Alpelisib.
  • PI3K- ⁇ recombinant protein and substrate ATP were diluted with kinase reaction buffer (50 mM Tris-HCl, pH 7.4, 2.1 mM DTT, 0.05% Tween-20, 10 mM MgCl 2 ).
  • kinase reaction buffer 50 mM Tris-HCl, pH 7.4, 2.1 mM DTT, 0.05% Tween-20, 10 mM MgCl 2 .
  • the software used for calculation is Graphpad Prism 5, the model used for fitting is sigmoidal dose-response (varible slope), and the bottom and top of the fitting curve are set to 0 and 100, respectively.
  • the selectivity of PI3K ⁇ is calculated from PI3K ⁇ IC 50 /PI3K ⁇ IC 50 , where “I” represents ⁇ 5 times, “II” represents 5 to 10 times, and “III” represents >10 times.
  • Example 33 Tumor cell proliferation inhibitory activity of aminoquinazolinones and aminoisoquinolinone derivatives
  • the CCK8 method was used, with copanlisib and alpelisib as positive controls, to test the inhibitory effect of different compounds on the proliferation of four tumor strains.
  • the IC 50 value was calculated using Graphpad Prism V5.0 software. The results are shown in Table 18 below.
  • Table 19 represents the pharmacokinetic results of the compounds
  • mice Female nude mice weighing 20 ⁇ 3g, inoculated with Kasumi-1 cell strain inoculated subcutaneously in the right armpit of nude mice, the cell inoculation amount was 1 ⁇ 10 7 per mouse, after tumor formation, the diameter of the transplanted tumor was measured with a vernier caliper Up to 100-300 mm 3 , the animals were divided into a model control group and a drug administration group according to body weight and tumor volume, 6 animals in each group, and the model control group was given an equal amount of blank solvent. After grouping, daily administration (qd), 10 mg/Kg, for 21 consecutive days, during the experiment, the diameter of the transplanted tumor and the weight of the mouse were measured twice a week.
  • qd daily administration
  • V 0 is the tumor volume measured during cage administration (ie d 0 )
  • V t is the tumor volume at each measurement.
  • the evaluation index of antitumor activity is the relative tumor proliferation rate T/C (%)
  • T/C (%) (TRTV/CRTV) ⁇ 100%
  • TRTV RTV in the treatment group
  • CRTV RTV in the negative control group .
  • the results are shown in Figure 1. From the in vivo pharmacodynamic data in the figure, it can be seen that 8a-27 and 8a-28 compounds exhibit strong tumor growth inhibitory activity, which is comparable to positive copanlisib, and therefore has good application prospects.

Abstract

本发明提供一种氨基喹唑啉酮和氨基异喹啉酮类衍生物，本发明经通过多次实验证实，所合成的化合物均具有优良的PI3Kα，PI3Kγ的抑制作用，其中大部分化合物对PI3Kα有显著的抑制作用，对PIK3CA突变的人乳腺癌细胞细胞株（MCF7）等肿瘤细胞株显示出强效的抑制生长作用。因此，本发明所述氨基喹唑啉酮和氨基异喹啉酮类衍生物可在制备抗肿瘤和抗炎药物中的应用，可作为PI3Kα抑制剂应用于治疗人或动物细胞增殖性相关的肿瘤的药物，所述药物包括衍生物及其药学上可接受的盐、溶剂合物中的任意一种或任意多种与药学上可接受的载体。本发明化合物通式a和b结构

Description

氨基喹唑啉酮和氨基异喹啉酮衍生物及其应用 技术领域
本发明涉及药物领域，具体涉及一种氨基喹唑啉酮和氨基异喹啉酮类衍生物、含其的药物组合物及其在抗肿瘤、抗炎性疾病等领域中的应用。
背景技术
虽然近年来肿瘤的早期诊断和治疗领域取得长足进步，抗肿瘤药物已经能够控制或延缓部分肿瘤的发展，如白血病，但是对于占恶性肿瘤90％以上的实体瘤的治疗远未达到满意的疗效。PI3K/Akt/mTOR信号通路调节细胞***生长等多种细胞过程，研究发现，该信号通路常常在肿瘤细胞中过度活化，其中的关键激酶PI3K，即磷脂酰肌醇3-激酶在肿瘤细胞中常常呈现出过表达的状态，PI3K有多种亚型，包括因此对PI3K的抑制逐渐成为肿瘤治疗的有效手段。另一方面，PI3K激酶的亚型PI3Kγ、PI3Kδ与炎症密切相关，PI3Kγ和PI3Kδ抑制剂可以用于关节炎等炎症疾病的治疗。
作为抗肿瘤药物的热门靶标，目前已有多款PI3K抑制剂进入临床研究，其中有两款已经由FDA批准上市：2015年由Gilead公司开发的PI3Kδ抑制剂Idelalisib被批准用于治疗复发性慢性淋巴白血病、滤泡性淋巴瘤和小淋巴细胞淋巴瘤；2017年9月由拜耳公司开发的Copanlisib也获得了FDA的加速批准，用于治疗罹患复发性滤泡性淋巴瘤，且已经接受了至少两次***疗法的成人患者。
尽管由许多PI3K抑制剂被人们所开发，但已上市两款药物仍然存在一定的缺陷，如Idelalisib在CLL患者中引起转氨酶升高，对肝脏有一定的毒副作用；而Copanlisib对PI3K多个亚型的活性均很高，但选择性较差，且Copanlisib理化性质不佳，因此其药代动力学特性不佳，分布容积大，达到32.6L/kg，容易在患者体内贮存，从而引发相应毒副反应，因此临床用药是在28天治疗周期内，分别在第1、8和15天注射给药。因此对Copanlisib的结构进行修饰和优化，调整其理化性质，有望改善其药代动力学特性，调整其对于PI3K各个亚型的选择性，获得更加适用于临床的抗肿瘤、抗炎性疾病新药。
发明内容
针对现有技术的不足，本发明所要解决的技术问题是提供一种氨基喹唑啉酮和氨基异喹啉酮类衍生物，具有通式a和b结构：
Figure PCTCN2019122973-appb-000001
或其药学上可接受的盐，立体异构体或溶剂合物。
其中：(1)对于结构通式a：
X＝N或CH；
R 1选自氢，C 1-6烷基，环烷基，含氟烷基；
R 2选自氢，1-12个碳原子的烷基，环烷基，含氟烷基，-(CH 2) nNR 5R 6，-(CH 2) n-CONR 5R 6，-(CH 2) n-SO 2NR 5R 6,-(CH 2) nOR 5，其中n为1～8的整数，R 5和R 6是相互独立的，可以相同也可以不相同，选自氢、C 1-4烷基、C 1-4环烷基，或者NR 5R 6是4-8元的环状胺，包括但不限于吗啉、哌嗪、吡咯烷、哌啶，或者是R 7取代的环状胺，R 7选自氢,C 1-6烷基、C 1-6烷氧基，C 2-6-不饱和脂链烃基、C 3-8环烷基、C 3-8不饱和脂环基、C 3-8饱和脂杂环基、卤素、氨基、氰基；
R 3选自C 1-6烷基，环烷基，含氟烷基；
Ar为芳杂环，包括但不限于苯环、呋喃环、噻吩环、吡咯环、噻唑环、吡唑环、噁唑环、吡啶环、嘧啶环、哒嗪环、吡嗪环、嘌呤环、氮杂嘌呤环、氮杂吲哚环、吲哚环、喹啉环、喹唑啉环、喹喔啉环、吲唑环；
R 8选自氢,卤素，氰基，羟基，C 1-6烷氧基，氨基，C 1-6烷胺基，C 1-6二烷基胺基，C 1-6烷基，C 2-6-不饱和脂链烃基，C 3-8环烷基，C 3-8不饱和脂环基，C 3-8饱和脂杂环基，C 1-6卤代烷基；
(2)对于结构通式b：
喹唑啉或喹啉苯环的两个相邻氧原子采用不同的链连接构成5-21元环，链中可以包含2-7个氧原子；结构中其余部分的定义同结构通式a：
进一步地，本发明优选的氨基喹唑啉酮和氨基异喹啉酮类化合物，结构通式a中所述的R 1为甲基时，R 2分别选自但不局限于以下基团：
Figure PCTCN2019122973-appb-000002
进一步地，本发明优选的氨基喹唑啉酮和氨基异喹啉酮类化合物，结构通式b所述的苯环两个氧原子通过链连接构成5-21元环，选自但不局限于以下基团：
Figure PCTCN2019122973-appb-000003
进一步地，本发明优选的氨基喹唑啉酮和氨基异喹啉酮类化合物，结构通式a和结构通式b中，R 3优选自-CH 3、-CH 2CH 3、环丙基、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CF 3、-CH 2CF 2H；
进一步地，本发明优选的氨基喹唑啉酮和氨基异喹啉酮类化合物，结构通式a和结构通式b中，Ar优选自4-甲氧基苯基、对氨基苯基、5-氨基-吡唑-3-基、2-氨基-咪唑-4基、2-氨基-噻唑-4基、2-氨基-恶唑-4基、吡啶-3-基、吡啶-2-基、2-氨基-吡啶-5基、2-氨基-嘧啶-5-基、2-氨基-吡嗪-5基、3-氨基-哒嗪-6-基；R 8选自氨基、甲胺基、羟基、甲氧基、二甲胺基、氰基、3，4-二甲氧基。
应了解，本发明包括本发明定义的特定基团的所有组合和亚组，包括上文的简述中定义的、在整个说明书中的各个实施例中所示例的以及所附权利要求中所述的取代基。
更具体地，本发明通式a，b结构的氨基喹唑啉酮和氨基异喹啉酮类衍生物的优选化合物如下：
Figure PCTCN2019122973-appb-000004
Figure PCTCN2019122973-appb-000005
Figure PCTCN2019122973-appb-000006
Figure PCTCN2019122973-appb-000007
Figure PCTCN2019122973-appb-000008
Figure PCTCN2019122973-appb-000009
Figure PCTCN2019122973-appb-000010
Figure PCTCN2019122973-appb-000011
Figure PCTCN2019122973-appb-000012
Figure PCTCN2019122973-appb-000013
Figure PCTCN2019122973-appb-000014
或其上述化合物药学上可接受的盐。
Copanlisib是2,3-二氢咪唑并[1,2-c]-喹唑啉衍生物，其三环结构对于活性至关重要(ChemMedChem 2016,11,1517-1530)，但是该结构具有较大的刚性，会影响整个分子的理化性质，尤其是药代性质，Copanlisib在体内分布容积大的可能原因就是三环结构所致。
本发明采用药物化学中的开环策略，将Copanlisib的2,3-二氢咪唑环进行开环，并在喹唑啉的N原子引入C1-C3的烷基，以提高分子与PI3K蛋白的结合力，获得了一类全新骨架的喹唑啉酮衍生物；并进一步采用生物电子等排策略，将喹唑啉酮的1-位氮原子替换为碳原子，设计和合成异喹啉酮类衍生物，上述结构优化，有效的改善目标分子的理化性质(如增加水溶性)，代表性分子的药代特性比copanlisib有明显提升，具有良好的临床应用前景。
另一方面，目前选择性PI3Kα抑制剂的研发取得了良好的进展，Alpelisib，Taselisib(GDC-0032)均已进入III期临床试验，用于PIK3C基因突变的血液肿瘤和多种实体瘤，包括乳腺癌、结直肠癌、胃癌等。我们通过分子对接研究发现，copanlisb利用母核结构与PI3Kα及PI3Kδ进行紧密的结合，而侧链丙基吗啉处于外周溶剂区；而对于PI3Kα选择性抑制剂Alpelisib(BYL719)、GDC-0032的分子对接研究表明，其侧链的烷基酰胺片段可以与PI3Kα的外周氨基酸残基Gln859形成强氢键，因此我们对上述两类氨基喹唑啉酮和氨基异喹啉酮类衍生物的侧链进行修饰和调整，引入多种取代烷基酰胺官能团，以提升分子对PI3Kα的结合能力，减弱对PI3Kδ的活性，降低由抑制PI3Kδ而引起的毒副作用，从而获得具有一定PI3Kα选择性的抑制剂(抑制PI3Kα活性高于抑制PI3Kδ五倍以上)。
本发明的第二个目的是提供所述化合物的制备方法。
一.通式a化合物(含类似物)的合成方法：
1.当R 1为甲基时：
Figure PCTCN2019122973-appb-000015
具体的反应过程可以是：
取代苯甲醛(化合物1)溶于溶剂，在碱性条件下与溴化苄或者氯化苄反应制得苄基保护中间体2。所用碱包括碳酸钾、碳酸钠、碳酸铯，所用溶剂包括乙腈、DMF、DMSO等。
苯甲醛中间体2用氧化剂处理得到苯甲酸中间体3，氧化剂包括次氯酸钠、亚氯酸钠、高锰酸钾等，所用的溶剂为乙酸、水、THF、二氧六环、丙酮等。
苯甲酸中间体3经还原剂处理得到邻氨基苯甲酸中间体4，还原剂包括铁粉、锌粉、Pd/C-H 2、Raney Ni-H 2等。
邻氨基苯甲酸中间体4与相应的烷基胺在缩合剂的作用下反应制得苯甲酰胺中间体5，缩合剂包括EDC、DCC、DIC等。
邻氨基苯甲酰胺中间体5和相应的取代芳基酰基异硫氰酸酯在缩合剂作用下环合得到苄基保护的氨基喹唑啉酮中间体6，缩合剂包括EDC、DCC、DIC等。
氨基喹唑啉酮中间体6利用Pd/C-H 2体系脱去苄基保护生成中间体7。
最后，中间体7与相应的卤代烃(氯代物、溴代物)发生亲核反应，制备获得目标分子产物8。
2.此外，还可以采用以下方式进行合成目标分子8：
Figure PCTCN2019122973-appb-000016
取代苯甲醛1在碱性条件下与卤代烃先反应，引入R 2基团得到中间2；碱性试剂包括氢氧化钾、氢氧化钠、碳酸铯、碳酸钾、碳酸钠等；
中间体2用氧化剂处理得到苯甲酸中间体3；氧化剂包括氨基磺酸+亚氯酸钠、次氯酸钠、高锰酸钾等，溶剂包括乙酸、甲酸、水、丙酮、二氧六环、THF等；
苯甲酸中间体3与胺进行缩合得到苯甲酰胺中间体4，采用的缩合剂包括EDC，DCC、 DIC等；
苯甲酰胺中间体4经还原剂处理后得到相应的氨基苯甲酰胺中间体5，还原剂包括Fe/HAc，Pd/C-H 2等；
最后，中间体5与不同的取代芳基酰基异硫氰酸酯在缩合剂作用下环合制得目标分子8，缩合剂包括EDC、DCC、DIC等。
3.对于X＝CH的目标分子，其反应式如下所示：
Figure PCTCN2019122973-appb-000017
具体的反应过程可以是：
5-羟基-4-甲氧基-1-茚酮(化合物1’)溶于,在碱性条件下滴加溴化苄，室温搅拌过夜，旋去溶剂，所得固体依次用水、石油醚洗涤，抽滤得到苄基保护的中间体2’。所用的碱可以是碳酸钾、碳酸钠、碳酸铯，所用的溶剂一般为乙腈或者N,N-二甲基甲酰胺(DMF)；
4-甲氧基-5-苄氧基-1-茚酮2’溶于甲叔醚，冰浴搅拌下依次滴加亚硝酸异戊酯和三甲基氯硅烷，反应完全后，抽滤得到羟肟中间体3’；
羟肟中间体3’加入到15％NaOH水溶液中，室温搅拌，调节pH后抽滤，所得固体为邻羧基苯乙腈4’；
中间体4’溶于甲醇，冰浴滴加SOCl 2反应，萃取浓缩得到甲酯5’；
将甲酯中间体5’、相应的烷基胺R 3NH 2和三乙胺溶于水，120℃闷罐反应过夜，萃取浓缩后得到氨基异喹啉酮中间体6’；
中间体6’和相应的芳香羧酸溶于DMF，依次加入N,N-二异丙基乙胺(DPIEA)、六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBop),室温反应，抽滤所得固体用乙酸乙酯洗涤，干燥后得到苄基保护的酰胺产物7’；
中间体7’在氢气、Pd/C的体系中室温搅拌脱去苄基得到6-羟基-5-甲氧基异喹啉酮中间体8’，选用溶剂为乙醇。
中间体8’在碱性条件下与R 2的氯代物反应生成产物9’，所用的碱可以是有机碱或无机碱，有机碱可以选用吡啶、三乙胺、N,N-二异丙基乙胺，无机碱可以选用碳酸钾、碳酸钠、碳酸铯，所用的溶剂一般为乙腈或者N,N-二甲基甲酰胺(DMF)，反应温度在40-70℃之间，具体情况见实施例。
二.通式b化合物(含类似物)的合成方法:
1.当X＝N时，其反应式如下所示：
Figure PCTCN2019122973-appb-000018
具体的反应过程可以是：
化合物9在碱性试剂的作用下，以DMF为溶剂，分别与烷基二溴代物，或者与缩乙二醇双(对甲苯磺酸酯)等试剂反应，得到两个氧原子合环的中间体10；
中间体10取代苯甲醛用氧化剂进行氧化，得到相应的苯甲酸11；氧化剂包括次氯酸钠，亚氯酸钠，KMnO 4等。
将取代苯甲酸11与不同的烷基胺以及缩合剂溶于二氯甲烷中，室温搅拌过夜得到酰胺中间体12；缩合剂包括EDC，DCC、DIC等。
中间体12采用铁粉/乙酸体系还原为中间体13，最后，中间体13与芳基酰基异硫氰酸酯在缩合剂作用下环合得到缩合得到目标化合物14，缩合剂包括EDC、DCC、DIC等。
2.当X＝CH时，其反应式如下所示：
Figure PCTCN2019122973-appb-000019
具体的反应过程可以是：
化合物1’在BBr 3的作用下，脱去甲基，得到邻二酚化合物10’，再分别与烷基二溴代物，或者缩乙二醇双(对甲苯磺酸酯)反应，得到两个氧原子合环的中间体11’；
中间体11’与亚硝酸异戊酯和三甲基氯硅烷反应，再用NaOH水水解，得到邻羧基苯乙腈衍生物12’；
中间体12’溶于甲醇，冰浴滴加SOCl 2反应，萃取浓缩得到甲酯，再与相应的烷基胺R 3NH 2反应，得到氨基异喹啉酮中间体13’；
中间体13’和相应的芳香羧酸溶于DMF，依次加入N,N-二异丙基乙胺(DPIEA)、六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBop),室温反应，抽滤所得固体用乙酸乙酯洗涤，干燥 后得到目标分子14’。
本发明的再一个目的是提供所述氨基喹唑啉酮和氨基异喹啉酮类衍生物在制备抗肿瘤和抗炎药物中的应用，所述药物包括衍生物及其药学上可接受的盐、溶剂合物中的任意一种或任意多种与药学上可接受的载体制成。
所述“药学上可接受的载体”是指药学领域常规的药物载体，包括药学领域的常规稀释剂、赋形剂如水等，填充剂如淀粉等，粘合剂如纤维素衍生物、明胶等，湿润剂如甘油，崩解剂如琼脂、碳酸钙等，吸收促进剂如季铵化合物，表面活性剂如十六烷醇，吸附载体如高岭土和皂黏土，润滑剂如滑石粉等，必要时还可以加入香味剂，甜味剂等。
药物制剂适用于通过任何适当途径给药，如口服(包括含服或舌下给药)、直肠给药、经鼻给药、局部给药(包括含服、舌下给药或经皮给药)、***给药或胃肠外给药(包括皮下注射、肌内注射、静脉注射或皮内注射)途径。这些制剂可由药剂学领域中已知的任何方法制备。例如通过将活性成分与载体或赋形剂混在一起的方法。
本发明提供所述的通式a和b结构的化合物及其优选化合物、所述化合物在药学上可接受的盐、所述化合物的溶剂合物、与其他药物联合使用在制备抗癌药物中的用途。进一步地，所述的癌症选自乳腺癌、肉瘤、肺癌、***癌、结肠癌、直肠癌、肾癌、胰腺癌、血癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、肝癌、卵巢癌、外阴癌、子***、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤、皮肤癌、多发性骨髓瘤。
能和本发明所提供的化合物或其可药用盐联合使用的抗肿瘤药包括但并非限定至少一种以下种类：有丝***抑制剂(如长春碱、长春地辛和长春瑞宾)；微管蛋白分解抑制剂(如泰素)；烷基化试剂(如顺铂、卡铂和环磷酰胺)；抗代谢物(如5-氟尿嘧啶、替加氟、甲氨蝶呤、阿糖胞苷和羟基脲)；可***抗生素(如阿雷素、丝裂霉素和争光霉素)；酶(如天门冬氨酶)；拓朴异构酶抑制剂(如依托伯苷和喜树碱)；生物反应调节剂(如干扰素)；蛋白酶体抑制剂(如硼替佐米)。
通过多次实验证实，本发明所合成的化合物均具有优良的PI3Kα，PI3Kγ的抑制作用，其中大部分化合物对PI3Kα有显著的抑制作用，对PIK3CA突变的人乳腺癌细胞细胞株(MCF7)等肿瘤细胞株显示出强效的抑制生长作用。因此，本发明化合物可作为PI3Kα抑制剂应用于治疗人或动物细胞增殖性相关的肿瘤的药物中。
附图说明
图1是体内药效实验结果。
具体实施方式
本发明结合实施例作进一步的说明。下面包含的特定实施例是为了举例说明，不应被理解为对本发明范围的限制。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1：2-氨基-N-(8-甲氧基-3-甲基-7-(3-吗啉代丙基)-4-氧-3，4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物8a-1)的制备
Figure PCTCN2019122973-appb-000020
步骤1 2-氨基-3-甲氧基-4-苄氧基-N-甲基苯甲酰胺(化合物5a-1)的制备
将2-氨基-3-甲氧基-4-苄氧基苯甲酸(4,546mg,2mmol)溶于20mL DCM中，依次加入甲胺盐酸盐(102mg,2.4mmol)、HOBT(405mg,3mmol)、DIC(378mg,3mmol)、三乙胺(0.83mL,6mmol)，室温搅拌2h，加入水，用二氯甲烷提取，合并有机层，饱和NaCl洗涤，无水Na 2SO 4干燥，回收溶剂得白色粉末0.48g,Yield：80％；ESI-MS:287.1[M+H] +.
步骤2. 2-氨基-N-(8-甲氧基-3-甲基-7-苄氧基-4-氧-3,4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物6a-1)的制备
将2-氨基-3-甲氧基-4-苄氧基-N-甲基苯甲酰胺(5a-1,0.2mmol)、2-氨基嘧啶-5-酰基异硫氰酸酯(0.2mmol)溶于100mL无水DMF中，加入EDC(0.3mmol)，室温搅拌过夜，抽滤得到沉淀，乙酸乙酯洗涤后得到目标化合物，Yield：96％，ESI-MS:433.2[M+H] +； 1H-NMR(δ,CDCl 3/MeOH＝8:1)：13.96(s,1H),9.10(s,2H),7.89(d,1H,J＝9.0Hz),7.46(m,5H),7.00(d,1H,J＝9.0Hz),5,84(s,2H),5.26(s,2H),4,43(s,3H),4.8(s,3H).
步骤3. 2-氨基-N-(8-甲氧基-3-甲基-7-羟基-4-氧-3,4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物7a-1)的制备
化合物6a-1(500mg)溶于50mL EtOH中，加入50mg 10％Pd/C，H 2氛围下室温搅拌过夜，硅藻土抽滤，滤液旋干，所得固体用乙醇洗涤，Yield：90％，ESI-MS:343.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.95(s,1H),8.98(s,1H),8.94(s,2H),7.67(d,1H,J＝8.5Hz),7.47(s,2H),6.93(d,1H,J＝8.5Hz),4.27(s,3H),3.92(s,3H).
步骤4. 2-氨基-N-(8-甲氧基-3-甲基-7-(3-吗啉代丙基)-4-氧-3,4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物8a-1)的制备
将化合物7a-1(0.1mmol)溶于10mL乙腈，加入碳酸铯(0.15mmol)，搅拌0.5h，升温至60℃，滴加N-(3-氯丙基)吗啉(0.15mmol)的20mL乙腈溶液，50℃反应10h，减压蒸馏除去溶剂，加水析出沉淀，用甲醇洗涤得到淡黄色固体8a-1，Yield：78％，ESI-MS:470.2[M+H] +； 1H-NMR(δ,CDCl 3/MeOH＝10:1)：9.03(s,2H),8.82(s,1H),7.86(d,2H,J＝8.5Hz),6.93(d,2H,J＝8.5Hz),4.23(t,2H,J＝6.0Hz),4.14(t,2H,J＝6.0Hz),4.00(s,3H),3.94(m,4H),3.80(s,1H),3.63(s,3H),3.34(m,2H),2.85(s,2H),2.30(m,4H),0.84(t,3H,J＝6.5Hz).
8a-1盐的制备：
将100mg 8a-1溶于20mL氯化氢饱和的乙酸乙酯中，固体先溶解，然后慢慢析出白色固体，得到8a-1盐酸盐；
按照类似的方法，将目标分子8a-1与等摩尔的氢溴酸、富马酸、马来酸、酒石酸等在合适的溶剂中反应，可以分别制备相应的8a-1氢溴酸盐、富马酸盐、马来酸盐和酒石酸盐等。
实施例2：化合物8a-2～8a-13的合成
以化合物7a-1为原料，分别采用氯乙酰胺、氯丙酰胺、N-甲基氯乙酰胺、N,N-二甲基氯乙酰胺、2-(2-氯乙基)-4-甲基吗啉、1-(3-氯-丙酰基)-4-甲基哌嗪、氯乙酰基吗啉、4-氯丁酰胺、二氟氯甲烷、氯乙基磺酰胺、Togni试剂、氯丙基磺酰胺替代N-(3-氯丙基)吗啉，制备得到化合物8a-2～8a-13。
该系列目标分子如下表1所示。
表1
Figure PCTCN2019122973-appb-000021
实施例3：化合物8a-14～8a-26的合成
合成路线如下图所示
Figure PCTCN2019122973-appb-000022
以化合物5a-1为原料，分别与嘧啶-5-甲酰基异硫氰酸酯、哒嗪-4-甲酰基异硫氰酸酯、2-氨基-吡啶-5-甲酰基异硫氰酸酯、6-氨基-哒嗪-3-甲酰基异硫氰酸酯、2-氨基-吡嗪-5-甲酰基异硫氰酸酯、5-氨基吡啶-2-甲酰基异硫氰酸酯、3-氰基-苯甲酰基异硫氰酸酯、吡嗪-2-甲酰基异硫氰酸酯、吡唑-4-甲酰基异硫氰酸酯、噻唑-4-甲酰基异硫氰酸酯、嘌呤-6-甲酰基异硫氰酸酯、苯并咪唑-5-甲酰基异硫氰酸酯、苯并噻吩-5-甲酰基异硫氰酸酯等先反应，然后在EDC作用下合环得到中间体6a-2～6a-14，再与Pd/C催化氢化脱苄基得到7a-2～7a-14，，最后他们与N-(3-氯丙基)吗啉反应最后得到目标分子8a-14～8a-26。其结构式如下表2所示。
表2
Figure PCTCN2019122973-appb-000023
Figure PCTCN2019122973-appb-000024
实施例4：化合物8a-27～8a-69的合成
(S)-2-氨基-N-(7-(2-羟基-3-吗啉代丙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-27)
化合物8a-27的制备参考8a-1的合成，将N-氯丙基吗啉替换为(S)-1-氯-3-吗啉代丙烷-2-醇，得白色固体。收率56.3％；ESI-MS:486.2[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.93(s,1H),8.95(s,2H),7.78(d,1H,J＝9.0Hz),7.42(s,2H),7.19(d,1H,J＝9.0Hz),5.04(d,1H,J＝5.0Hz),4,21(dd,1H,J 1＝9.5Hz,J 2＝3.5Hz),4.11(m,2H),3.98(s,3H),3.58(t,4H,J＝5.0Hz),3.54(s,3H),2.47(m,6H).
(R)-2-氨基-N-(7-(2-羟基-3-吗啉代丙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-28)
化合物8a-28的制备参考8a-1的合成，将N-氯丙基吗啉替换为(R)-1-氯-3-吗啉代丙烷-2-醇，得白色固体。收率48％；ES8a-MS:486.2[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.93(s,1H),8.95(s,2H),7.78(d,1H,J＝9.0Hz),7.42(s,2H),7.19(d,1H,J＝9.0Hz),5.04(d,1H,J＝5.0Hz),4,21(dd,1H,J 1＝9.5Hz,J 2＝3.5Hz),4.11(m,2H),3.98(s,3H),3.58(t,4H,J＝5.0Hz),3.54(s,3H),2.47(m,6H).
2-((2-(2-氨基嘧啶-5-甲酰胺基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-7-基)氧基)乙酸乙酯(化合物8a-29)
化合物8a-29的制备参考8a-1的合成，将N-氯丙基吗啉替换为氯乙酸乙酯，得白色固体。收率42％；ESI-MS:453.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.96(s,1H),8.96(s,2H),7.76(d,1H,J＝9.0Hz),7.37(d,2H),7.10(d,1H,J＝9.0Hz),5.04(s,2H),4.22(m,2H),4.00(s,3H),3.54(s,3H),1.24(m,3H).
2-氨基-N-(8-甲氧基-3-甲基-7-(2-(甲基磺酰胺基)乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-30)
化合物8a-30的制备参考8a-1的合成，N-氯丙基吗啉替换为N-(2-溴乙基)甲磺酰胺，得白色固体。收率38％；ESI-MS:464.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.95(s,1H),8.96(s,2H),7.79(d,1H,J＝9.0Hz),7.42(s,2H),7.40(t,1H,J＝6.0Hz),7.18(d,J＝8.5Hz),4.24(t,1H,J＝5.5Hz),3.99(s,3H),3.54(s,3H),3.45(q,2H,J＝5.5Hz),2.99(s,3H).
2-氨基-N-(8-甲氧基-3-甲基-7-(2-(甲基氨基)-2-氧乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-31)
化合物8a-31的制备参考8a-1的合成，将N-氯丙基吗啉替换为2-氯-N-甲基乙酰胺，得白色固体。收率41％；ESI-MS:414.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.96(s,1H),8.96(s,2H),7.79(d,1H,J＝9.0Hz),7.42(m,1H),7.40(t,1H,J＝6.0Hz),7.18(d,J＝8.5Hz),4.24(t,1H,J＝5.5Hz),3.99(s,3H),3.54(s,3H),3.45(q,2H,J＝5.5Hz),2.99(s,3H),2.65(d,3H,J＝4.5Hz).2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(2-氧代-2-((2-(哌啶-1-基)乙基)氨基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-32)
化合物8a-32的制备参考8a-1的合成，将N-氯丙基吗啉替换为2-氯-N-(2-(哌啶-1-基) 乙基)乙酰胺，得白色固体。收率40％；ESI-MS:511.1[M+H] +；14.01(s,1H),8.96(s,2H),7.77(d,1H,J＝8.5Hz),7.05(d,1H,J＝8.5Hz),6.73(s,2H),4.74(s,2H),4.00(s,3H),3.55(s,3H),3.27-3.23(m,2H),2.36-2.32(m,6H),1.49-1.45(m,4H),1.39-1.35(m,2H).
2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(2-氧代-2-((2-(吗啉-1-基)乙基)氨基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-33)
化合物8a-33的制备参考8a-1的合成，将N-氯丙基吗啉替换为2-氯-N-(2-(吗啉-1-基)乙基)乙酰胺，得白色固体。收率39％；ESI-MS:513.1[M+H] +； 1H-NMR(δ,DMSO-d 6,one drop TFA-d)：13.96(s,1H),9.87(s,1H),9.00(s,2H),8.45(t,1H,J＝6.0Hz),7.79(d,1H,J＝8.5Hz),7.65(s,1H),7.08(d,J＝9.0Hz),4.81(s,2H),4.00(s,3H),3.98(s,2H),3.67(t,2H,J＝12.5Hz),3.55(s,3H),3.54(m,4H),3.26(t,2H,J＝6.5Hz),3.15(m,2H).
2-氨基-N-(3-乙基-8-甲氧基-4-氧代-7-(2-(2-氧代-7-氮杂螺[3.5]壬烷-7-基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-34)
化合物8a-34的制备参考8a-1的合成，将N-氯丙基吗啉替换为7-(2-氯乙基)-7-氮杂螺[3.5]壬烷-2-酮，得白色固体。收率37％；ESI-MS:508.2[M+H] +； 1H-NMR(δ,DMSO-d 6)：14.05(s,1H),8.61(s,2H),7.67(d,1H,J＝9.0Hz),7.36(s,2H),7.22(d,1H,J＝9.0Hz),4.07(t,2H,J＝6.5Hz),3.83(s,3H),3.54(s,3H),2.91(s,4H),2.64(t,2H,J＝6.5Hz),2.45(t,4H,J＝5.0Hz),1.38(t,4H,J＝5.0Hz).
5-氨基-N-(8-甲氧基-3-甲基-7-(3-吗啉代丙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)吡嗪-2-羧酰胺(化合物8a-35)
化合物8a-35的制备参考8a-1的合成，将2-氨基嘧啶-5-酰基异硫氰酸酯替换为5-氨基吡嗪-2-酰基异硫氰酸酯，得白色固体。收率44％；ESI-MS:470.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：14.03(s,1H),8.92(s,1H),7.95(s,1H),7.79(d,1H,J＝9.0Hz),7.17(d,1H,J＝9.0Hz),4.23(t,2H,J＝6.5Hz),3.95(s,3H),3.59(t,4H,J＝4.5Hz),3.54(s,3H),2.47(t,2H,J＝7.0Hz),2.39(t,4H,J＝4.0Hz),1.99(m,2H).
N-(8-甲氧基-3-甲基-7-(3-吗啉代丙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺(化合物8a-36)
化合物8a-36的制备参考8a-1的合成，将2-氨基嘧啶-5-酰基异硫氰酸酯替换为1H-吡咯并[2,3-b]吡啶-5-酰基异硫氰酸酯，得白色固体。收率44％；ESI-MS:493.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：14.09(s,1H),12.00(s,1H),9.12(s,1H),8.78(s,1H),7.78(d,1H,J＝8.5Hz),7.57-7.56(m,1H),7.16(d,1H,J＝9.0Hz),6.61(s,1H),4.21(t,2H,J＝6.5Hz),3.98(s,3H),3.61(m,6H),3.36(s,3H),2.40(m,4H),1.98(t,3H,J＝7.5Hz).
6-氨基-N-(8-甲氧基-3-甲基-7-(3-吗啉代丙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)烟酰胺(化合物8a-37)
化合物8a-37的制备参考8a-1的合成，将2-氨基嘧啶-5-酰基异硫氰酸酯替换为6-氨基吡啶-3-酰基异硫氰酸酯，得白色固体。收率44％；ESI-MS:469.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：14.05(s,1H),8.83(d,1H,J＝2.0Hz),8.11(dd,1H,J 1＝9.0Hz,J 2＝2.5Hz),7.78(d,1H,J＝9.0Hz),7.16(d,1H,J＝9.0Hz),6.67(s,2H),6.47(d,1H,J＝9.0Hz),4.23(d,2H,J＝6.5Hz),3.95(s,3H),3.59(t,4H,J＝5.0Hz),3.54(s,3H),2.39(s,4H),1.99(m,2H).
(S)-6-氨基-N-(7-(2-羟基-3-吗啉代丙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)烟酰胺(化合物8a-38)
化合物8a-38的制备参考8a-27的合成，将2-氨基嘧啶-5-酰基异硫氰酸酯替换为6-氨基吡啶-3-酰基异硫氰酸酯，得白色固体，收率36％；ESI-MS:485.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：14.06(s,1H),8.83(d,1H,J＝2.5Hz),8.11(dd,1H,J 1＝8.6Hz,J 2＝2.0Hz),7.78(d,1H,J＝9.0Hz),7.17(d,1H,J＝9.0Hz),6.72(s,2H),6.47(d,1H,J＝9.0Hz),5.03(d,2H,J＝5.0Hz),4.21(m,2H),4.11(m,2H),3.97(s,3H),3.58(t,4H,J＝5.0Hz),3.54(s,3H),2.43(m,4H)。
(R)-6-氨基-N-(7-(2-羟基-3-吗啉代丙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)烟酰胺(化合物8a-39)
化合物8a-39的制备参考8a-28的合成，将2-氨基嘧啶-5-酰基异硫氰酸酯替换为6-氨基吡啶-3-酰基异硫氰酸酯，得白色固体，收率38％；ESI-MS:485.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：14.06(s,1H),8.83(d,1H,J＝2.5Hz),8.11(dd,1H,J 1＝8.6Hz,J 2＝2.0Hz),7.78(d,1H,J＝9.0Hz),7.17(d,1H,J＝9.0Hz),6.72(s,2H),6.47(d,1H,J＝9.0Hz),5.03(d,2H,J＝5.0Hz),4.21(m,2H),4.11(m,2H),3.97(s,3H),3.58(t,4H,J＝5.0Hz),3.54(s,3H),2.43(m,4H).
6-氨基-N-(8-甲氧基-3-甲基-7-(2-(甲基磺酰胺基)乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)烟酰胺(化合物8a-40)
化合物8a-40的制备参考8a-41的合成，将2-氨基嘧啶-5-酰基异硫氰酸酯替换为6-氨基吡啶-3-酰基异硫氰酸酯，收率35％；ESI-MS:463.1[M+H] +； 1H-NMR(δ,DMSO-d 6)：14.08(s,1H),8.83(s,2H),8.11(dd,1H,J 1＝8.5Hz,J 2＝2.5Hz),7.78(d,1H,J＝9.0Hz),7.40(t,1H,J＝6.0Hz),7.17(d,1H,J＝9.0Hz),6.72(s,2H),6.47(d,1H,J＝8.5Hz),4.24(t,1H,J＝5.5Hz),3.99(s,3H),3.54(s,3H),3.45(q,2H,J＝5.5Hz),2.99(s,3H).
2-氨基-N-(8-甲氧基-3-甲基-7-(3-吗啉代丙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-41)
化合物8a-41的制备参考8a-1的合成，将N-氯丙基吗啉替换为N-氯乙基吗啉，得白色固体，收率36％；ESI-MS:463.1[M+H] +；
(R)-2-氨基-N-(8-甲氧基-3-甲基-7-(2-(4-甲基吗啉-2-基)乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-42)
化合物8a-42的制备参考8a-1的合成，将N-氯丙基吗啉替换为(R)-2-(2-氯乙基)-4-甲基吗啉，得白色固体，收率35％；ESI-MS:470.2[M+H] +；
(S)-2-氨基-N-(8-甲氧基-3-甲基-7-(2-(4-甲基吗啉-2-基)乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-43)
化合物8a-43的制备参考8a-1的合成，将N-氯丙基吗啉替换为(S)-2-(2-氯乙基)-4-甲基吗啉，得白色固体，收率33％；ESI-MS:470.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-7-(2-(4-(甲基磺酰基)哌嗪-1-基)乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-44)
化合物8a-44的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)-4-(甲基磺酰基)哌嗪，得白色固体，收率42％；ESI-MS:533.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-7-(3-(4-(甲基磺酰基)哌嗪-1-基)丙氧基)-4-氧代-3,4-二氢 喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-45)
化合物8a-45的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(3-氯丙基)-4-(甲基磺酰基)哌嗪，得白色固体，收率24％；ESI-MS:547.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-7-(2-(4-甲基哌嗪-1-基)乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-46)
化合物8a-46的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)-4-甲基哌嗪，得白色固体，收率21％；ESI-MS:469.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-7-(3-(4-甲基哌嗪-1-基)丙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-47)
化合物8a-47的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(3-氯丙基)-4-甲基哌嗪，得白色固体，收率33％；ESI-MS:483.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(2-(哌啶-1-基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-48)
化合物8a-48的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)哌啶，得白色固体，收率27％；ESI-MS:454.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(3-(哌啶-1-基)丙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-49)
化合物8a-49的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(3-氯丙基)哌啶，得白色固体，收率35％；ESI-MS:468.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(2-(吡咯烷-1-基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-50)
化合物8a-50的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)吡咯烷，得白色固体，收22％；ESI-MS:440.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(3-(吡咯烷-1-基)丙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-51)
化合物8a-51的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(3-氯丙基)吡咯烷，得白色固体，收率29％；ESI-MS:454.2[M+H] +；
2-氨基-N-(7-(2-(3-，3-二氟吡咯烷-1-基)乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-52)
化合物8a-52的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)-3,3-二氟吡咯烷，得白色固体，收率28％；ESI-MS:476.2[M+H] +；
2-氨基-N-(7-(2-(2-(4,4-二甲基哌啶-1-基)乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-53)
化合物8a-53的制备参考8a-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)-4,4-二甲基哌啶，得白色固体，收率26％；ESI-MS:482.2[M+H] +；
N-(7-(2-(6-(6-氮杂螺[2.5]辛烷-6-基)乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)-2-氨基嘧啶-5-羧酰胺(化合物8a-54)
化合物8a-54的制备参考8a-1的合成，将N-氯丙基吗啉替换为6-(2-氯乙基)-6-氮杂螺 [2.5]辛烷，得白色固体，收率32％；ESI-MS:480.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(2-(2-氧代-7-氮杂螺[3.5]壬烷-7-基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-55)
化合物8a-55的制备参考8a-1的合成，将N-氯丙基吗啉替换为7-(2-氯乙基)-7-氮杂螺[3.5]壬烷-2-酮，得白色固体，收率39％；ESI-MS:508.2[M+H] +；
2-氨基-N-(7-(2-(2-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-56)
化合物8a-56的制备参考8a-1的合成，将N-氯丙基吗啉替换为7-(2-氯乙基)-7氮杂螺[3.5]壬烷-2-醇，得白色固体，收率41％；ESI-MS:510.2[M+H] +；
N-(7-(2-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基-2-氨基嘧啶-5-羧酰胺(化合物8a-57)
化合物8a-57的制备参考8a-1的合成，将N-氯丙基吗啉替换为7-(2-氯乙基)-2-氧杂-7-氮杂螺[3.5]壬烷，得白色固体，收率35％；ESI-MS:496.2[M+H] +；
N-(7-(2-(2-(2-氧杂-8-氮杂螺[4.5]辛烷-8-yl)乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)-2-氨基嘧啶-5-羧酰胺(化合物8a-58)
化合物8a-58的制备参考8a-1的合成，将N-氯丙基吗啉替换为8-(2-氯乙基)-2-氧杂-8-氮杂螺[4.5]癸烷，得白色固体，收率38％；ESI-MS:510.2[M+H] +；
3-((2-(2-氨基嘧啶-5-甲酰胺基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-7-基)氧基)丙酸乙酯(化合物8a-59)
化合物8a-59的制备参考8a-1的合成，将N-氯丙基吗啉替换为3-氯丙酸乙酯，得白色固体，得白色固体，收率28％；ESI-MS:443.1[M+H] +；
4-((2-(2-氨基嘧啶-5-羧酰胺基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-7-基)氧基)丁酸乙酯(化合物8a-60)
化合物8a-60的制备参考8a-1的合成，将N-氯丙基吗啉替换为4-氯丁酸乙酯，得白色固体，得白色固体，收率33％；ESI-MS:457.2[M+H] +；
2-氨基-N-(7-(2-氰基乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-61)
化合物8a-61的制备参考8a-1的合成，将N-氯丙基吗啉替换为3-氯丙腈，得白色固体，收率37％；ESI-MS:396.1[M+H] +；
2-氨基-N-(7-(2-(二甲基氨基)-2-氧代乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-62)
化合物8a-62的制备参考8a-1的合成，将N-氯丙基吗啉替换为2-氯-N，N-二甲基乙酰胺，得白色固体，收率22％；ESI-MS:428.1[M+H] +；
2-氨基-N-(7-(3-(二甲基氨基)-3-氧代丙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-63)
化合物8a-63的制备参考8a-1合成，将N-氯丙基吗啉替换为3-氯-N，N-二甲基丙酰胺，得白色固体，收率28％；ESI-MS:442.2[M+H] +；
2-氨基-N-(7-(2-(异丙基氨基)-2-氧乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2- 基)嘧啶-5-羧酰胺(化合物8a-64)
化合物8a-64的制备参考8a-1的合成，将N-氯丙基吗啉替换为2-氯-N-异丙基乙酰胺，得白色固体，收率19％；ESI-MS:442.2[M+H] +；
2-氨基-N-(7-(2-(环丙基氨基)-2-氧乙氧基)-8-甲氧基-3-甲基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-65)
化合物8a-65的制备参考8a-1的合成，将N-氯丙基吗啉替换为2-氯-N-环丙基乙酰胺，得白色固体，收率26％；ESI-MS:440.2[M+H] +；
2-氨基-N-(8-甲氧基-3-甲基-7-(2-吗啉代-2-氧代乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a-66)
化合物8a-66的制备参考8a-1的合成，将N-氯丙基吗啉替换为2-氯-1-吗啉代-1-酮，得白色固体，收率31％；ESI-MS:470.2[M+H] +。
实施例5 2-氨基-N-(8-甲氧基-3-乙基-7-(3-吗啉代丙基)-4-氧-3，4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物8b-1)的制备
操作过程同化合物8a-1的合成，用乙胺盐酸盐代替甲胺盐酸盐，与2-氨基-3-甲氧基-4-苄氧基苯甲酸(化合物4)反应，制得2-氨基-3-甲氧基-4-苄氧基-N-乙基苯甲酰胺(化合物5b-1)，随后5b-1与2-氨基嘧啶-5-酰基异硫氰酸酯缩合得到2-胺基-N-(3-乙基-7-苄氧基羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶--5-甲酰胺(6b-1),然后经Pd/C-H 2脱去苄基得到2-胺基-N-(3-乙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺(7b-1)，最后与N-(3-氯丙基)吗啉反应得到化合物8b-1.ESI-MS:484.2[M+H] +； 1H-NMR(δ,CDCl 3/MeOH＝5:1)：8.96(s,2H),7.78(d,1H,J＝9.0Hz),6.88(d,1H,J＝9.0Hz),4.31(q,2H,J＝7.0Hz),4.13(t,2H,J＝6.0Hz),3.95(s,3H),3.64(s,4H),3.25(m,2H),2.49(m,5H),1.99(s,2H),1.27(t,3H,J＝6.0Hz),1.14(s,2H).
实施例6：化合物8b-2～8b-13的合成
以化合物2-胺基-N-(3-乙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺7b-1为原料，分别采用氯乙酰胺、氯丙酰胺、N-甲基氯乙酰胺、N,N-二甲基氯乙酰胺、2-(2-氯乙基)-4-甲基吗啉、1-(3-氯-丙酰基)-4-甲基哌嗪、氯乙酰基吗啉、4-氯丁酰胺、二氟氯甲烷、氯乙基磺酰胺、TMSCF 3、氯丙基磺酰胺等替代N-(3-氯丙基)吗啉，制备得到化合物8b-2～8b-13。该系列目标分子的结构式如下表3所示。
表3
Figure PCTCN2019122973-appb-000025
Figure PCTCN2019122973-appb-000026
实施例7：化合物8b-14～8b-26的合成
合成路线如下所示：
Figure PCTCN2019122973-appb-000027
以5b-1为原料，分别与嘧啶-5-甲酰基异硫氰酸酯、哒嗪-4-甲酰基异硫氰酸酯、2-氨基-吡啶-5-甲酰基异硫氰酸酯、6-氨基-哒嗪-3-甲酰基异硫氰酸酯、2-氨基-吡嗪-5-甲酰基异硫氰酸酯、5-氨基吡啶-2-甲酰基异硫氰酸酯、3-氰基-苯甲酰基异硫氰酸酯、吡嗪-2-甲酰基异硫氰酸酯、吡唑-4-甲酰基异硫氰酸酯、噻唑-4-甲酰基异硫氰酸酯、嘌呤-6-甲酰基异硫氰酸酯、苯并咪唑-5-甲酰基异硫氰酸酯、苯并噻吩-5-甲酰基异硫氰酸酯等先反应，然后在EDC作用下合环得到中间体6b-2～6b-14，再与Pd/C催化氢化脱苄基得到7b-2～7b-14，最后他们与N-(3-氯丙基)吗啉反应最后得到目标分子8b-14～8b-26，见表4。
表4
Figure PCTCN2019122973-appb-000028
Figure PCTCN2019122973-appb-000029
实施例8：化合物8b-27～8b-49的合成
(S)-2-氨基-N-(3-乙基-7-(2-羟基-3-吗啉代丙氧基)-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-27)
化合物8b-27的制备参考8b-1合成，将N-氯丙基吗啉替换为(S)-1-氯-3-吗啉代丙烷-2-醇，得白色固体；ESI-MS:500.2[M+H] +。
(R)-2-氨基-N-(3-乙基-7-(2-羟基-3-吗啉代丙氧基)-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-28)
化合物8b-28的制备参考8b-1的合成，将N-氯丙基吗啉替换为(R)-1-氯-3-吗啉代丙烷-2-醇，得白色固体；ESI-MS:500.2[M+H] +。
2-氨基-N-(3-乙基-8-甲氧基-7-(2-(甲基磺酰胺基)乙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-29)
化合物8b-29的制备参考8b-1的合成，将N-氯丙基吗啉替换为N-(2-溴乙基)甲磺酰胺，得白色固体；ESI-MS:478.2[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.95(s,1H),8.94(s,2H),7.80(d,1H,J＝9.0Hz),7.36(s,2H),7.35(d,1H,J＝6.0Hz),7.19(d,1H,J＝9.0Hz),4.30(q,2H,J＝7.0Hz),4.25(t,2H,J＝5.0Hz),3.99(s,3H),3.45(q,2H,J＝5.5Hz),2.98(s,3H),1.29(t,3H,J ＝7.0Hz)。
2-氨基-N-(3-乙基-8-甲氧基-7-(2-(甲基磺酰胺基)丙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-30)
化合物8b-30的制备参考8b-1的合成，将N-氯丙基吗啉替换为N-(2-溴丙基)甲磺酰胺，得白色固体；ESI-MS:492.2[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.95(s,1H),8.94(s,2H),7.81(d,1H,J＝9.0Hz),7.36(s,2H),7.19(d,1H,J＝9.0Hz),7.10(s,1H),4.29(m,2H),3.96(s,3H),3.18(m,2H),2.91(s,3H),2.02(t,2H,J＝6.5Hz),1.29(t,3H,J＝7.0Hz)。
2-氨基-N-(3-乙基-8-甲氧基-7-(3-(4-甲基哌嗪-1-基)丙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-31)
化合物8b-31的制备参考8b-1的合成，将N-氯丙基吗啉替换为1-(3-氯丙基)-4-甲基哌嗪，得白色固体；ESI-MS:497.3[M+H] +。
2-氨基-N-(3-乙基-8-甲氧基-4-氧代-7-(2-(哌啶-1-基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-32)
化合物8b-32的制备参考8b-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)哌啶，得白色固体；ESI-MS:468.2[M+H] +。
2-氨基-N-(3-乙基-8-甲氧基-4-氧代-7-(3-(哌啶-1-基)丙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-33)
化合物8b-33的制备参考8b-1的合成，将N-氯丙基吗啉替换为1-(3-氯丙基)哌啶，得白色固体；ESI-MS:482.2[M+H] +。
2-氨基-N-(3-乙基-8-甲氧基-4-氧代-7-(2-(吡咯烷-1-基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-34)
化合物8b-34的制备参考8b-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)吡咯烷，得白色固体；ESI-MS:454.2[M+H] +。
2-氨基-N-(3-乙基-8-甲氧基-4-氧代-7-(3-(吡咯烷-1-基)丙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-35)
化合物8b-35的制备参考8b-1的合成，将N-氯丙基吗啉替换为1-(3-氯丙基)吡咯烷，得白色固体；ESI-MS:469.2[M+H] +。
2-氨基-N-(7-(2-(3-，3-二氟吡咯烷-1-基)乙氧基)-3-乙基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-36)
化合物8b-36的制备参考8b-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)-3,3-二氟吡咯烷，得白色固体；ESI-MS:490.2[M+H] +；
2-氨基-N-(7-(2-(2-(4,4-二甲基哌啶-1-基)乙氧基)-3-乙基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-37)
化合物8b-37的制备参考8b-1的合成，将N-氯丙基吗啉替换为1-(2-氯乙基)-4,4-二甲基哌啶，得白色固体；ESI-MS:496.3[M+H] +；
N-(7-(2-(6-(6-氮杂螺[2.5]辛烷-6-基)乙氧基)-3-乙基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)-2-氨基嘧啶-5-羧酰胺(化合物8b-38)
化合物8b-38的制备参考8b-1的合成，将N-氯丙基吗啉替换为6-(2-氯乙基)-6-氮杂 螺[2.5]辛烷，得白色固体；ESI-MS:494.2[M+H] +；
2-氨基-N-(3-乙基-7-(2-(2-羟基-7-氮杂螺[3.5]壬烷-7-基)乙氧基)-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-39)
化合物8b-39的制备参考8b-1的合成，将N-氯丙基吗啉替换为7-(2-氯乙基)-7-氮杂螺[3.5]壬烷-2-醇，得白色固体；ESI-MS:524.3[M+H] +。
N-(7-(2-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)乙氧基)-3-乙基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基-2-氨基嘧啶-5-羧酰胺(化合物8b-40)
化合物8b-40的制备参考8b-1的合成，将N-氯丙基吗啉替换为7-(2-氯乙基)-2-氧杂-7-氮杂螺[3.5]壬烷，得白色固体；ESI-MS:510.2[M+H] +；
N-(7-(2-(2-氧杂-8-氮杂螺[4.5]癸烷-8-基)乙氧基)-3-乙基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基-2-氨基嘧啶-5-羧酰胺(化合物8b-41)
化合物8b-41的制备参考8b-1的合成，将N-氯丙基吗啉替换为8-(2-氯乙基)-2-氧杂-8-氮杂螺[4.5]癸烷，得白色固体；ESI-MS:524.3[M+H] +；
2-氨基-N-(7-(2-氰基乙氧基)-3-乙基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-42)
化合物8b-42的制备参考8b-1的合成，将N-氯丙基吗啉替换为3-氯丙腈，得白色固体；ESI-MS:410.2[M+H] +。
2-氨基-N-(3-乙基-7-(2-(异丙基氨基)-2-氧乙氧基)-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-43)
化合物8b-43的制备参考8b-1的合成，将N-氯丙基吗啉替换为2-氯-N-异丙基乙酰胺，得白色固体；ESI-MS:456.2[M+H] +。
2-氨基-N-(7-(2-(环丙基氨基)-2-氧乙氧基)-3-乙基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-44)
化合物8b-44的制备参考8b-1的合成，将N-氯丙基吗啉替换为2-氯-N-环丙基乙酰胺，得白色固体；ESI-MS:454.2[M+H] +。
2-氨基-N-(3-乙基-8-甲氧基-7-(3-吗啉代-3-氧代丙氧基)-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b-45)
化合物8b-45的制备参考8b-1的合成，将N-氯丙基吗啉替换为3-氯-1-吗啉代丙烷-1-酮，得白色固体；ESI-MS:498.2[M+H] +。
(S)-6-氨基-N-(3-乙基-7-(2-羟基-3-吗啉代丙氧基)-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)烟酰胺(化合物8b-46)
化合物8b-46的制备参考8b-16的合成，将N-氯丙基吗啉替换为(S)-1-氯-3-吗啉代丙烷-2-醇，得白色固体；ESI-MS:499.2[M+H] +。
(R)-6-氨基-N-(3-乙基-7-(2-羟基-3-吗啉代丙氧基)-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)烟酰胺(化合物8b-47)
化合物8b-47的制备参考8b-45的合成，将N-氯丙基吗啉替换为(R)-1-氯-3-吗啉代丙烷-2-醇，得白色固体；ESI-MS:499.2[M+H] +。
6-氨基-N-(3-乙基-8-甲氧基-7-(2-((2-吗啉代乙基)氨基)-2-氧乙氧基)-4-氧代-3,4-二氢 喹唑啉-2-基)烟酰胺(化合物8b-48)
化合物8b-48的制备参考8b-16的合成，将N-氯丙基吗啉替换为2-氯-N-(2-吗啉代乙基)乙酰胺，得白色固体；ESI-MS:526.2[M+H] +。
实施例9：2-氨基-N-(8-甲氧基-3-异丙基-7-(3-吗啉代丙基)-4-氧-3,4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物8c-1)的制备
操作过程同化合物8a-1的合成，用异丙胺代替甲胺盐酸盐，与2-氨基-3-甲氧基-4-苄氧基苯甲酸(化合物4)反应，制得2-氨基-3-甲氧基-4-苄氧基-N-异丙基苯甲酰胺(化合物5c-1)，随后5c-1与2-氨基嘧啶-5-酰基异硫氰酸酯缩合得到2-胺基-N-(3-异丙基-7-苄氧基羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶--5-甲酰胺(6c-1),然后经Pd/C-H 2脱去苄基得到2-胺基-N-(3-异丙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺(7c-1)，最后与N-(3-氯丙基)吗啉反应得到化合物8c-1.ESI-MS:498.3[M+H] +； 1H-NMR(δ,CDCl 3/MeOH＝5:1)：9.07(s,2H),7.81(d,1H,J＝9.0Hz),6.88(d,1H,J＝9.0Hz),5.71(m,1H),4.17(t,2H,J＝6.0Hz),3.98(s,3H),3.73(m,5H),2.53(m,6H),2.08(s,2H),1.59(m,8H)。
实施例10：目标化合物8c-2～8c-9的合成
以2-胺基-N-(3-异丙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺(7c-1)为原料，分别采用氯乙酰胺、氯丙酰胺、N-甲基氯乙酰胺、N,N-二甲基氯乙酰胺、2-(2-氯乙基)-4-甲基吗啉、1-(3-氯-丙酰基)-4-甲基哌嗪、氯乙酰基吗啉、4-氯丁酰胺等替代N-(3-氯丙基)吗啉，制备得到化合物8c-2～8c-9。该系列化合物结构式如下表5所示。
表5
Figure PCTCN2019122973-appb-000030
Figure PCTCN2019122973-appb-000031
实施例11：2-氨基-N-(8-甲氧基--3-环丙基-7-(3-吗啉代丙基)-4-氧-3,4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物8d-1)的制备
操作过程同化合物8a-1的合成，用环丙胺代替甲胺盐酸盐，与2-氨基-3-甲氧基-4-苄氧基苯甲酸(化合物4)反应，制得2-氨基-3-甲氧基-4-苄氧基-N-环丙基苯甲酰胺(化合物5d-1)，随后5d-1与2-氨基嘧啶-5-酰基异硫氰酸酯缩合得到2-胺基-N-(3-环丙基-7-苄氧基羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶--5-甲酰胺(6d-1),然后经Pd/C-H 2脱去苄基得到2-胺基-N-(3-环丙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺(7d-1)，最后与N-(3-氯丙基)吗啉反应得到化合物8d-1.ESI-MS:496.2[M+H] +。
实施例10：化合物8d-2～8d-5的合成
以2-胺基-N-(3-环丙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺(7d-1)为原料，分别采用氯乙酰胺、氯丙酰胺、N-甲基氯乙酰胺、N,N-二甲基氯乙酰胺等替代N-(3-氯丙基)吗啉，制备得到化合物8d-2～8d-5，其结构式如下表6所示。
表6
Figure PCTCN2019122973-appb-000032
实施例12：2-氨基-N-(8-甲氧基-7-(3-吗啉代丙基)-4-氧-3-(2,2,2-三氟乙基)-3,4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物8e-1)的制备
操作过程同化合物8a-1的合成，用2,2,2-三氟乙胺代替甲胺盐酸盐，与2-氨基-3-甲氧基-4-苄氧基苯甲酸(化合物4)反应，制得2-氨基-3-甲氧基-4-苄氧基-N-三氟乙胺基苯甲酰胺(化合物5e-1)，随后5e-1与2-氨基嘧啶-5-酰基异硫氰酸酯缩合得到2-胺基-N-(3-三氟乙基-7-苄氧基羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶--5-甲酰胺(6e-1),然后经Pd/C-H 2脱去苄基得到2-胺基-N-(3-三氟乙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺(7e-1)，最后与N-(3-氯丙基)吗啉反应得到化合物8e-1.白色固体，ESI-MS:538.2[M+H] +； 1H NMR(δ,CDCl 3/MeOH＝5:1)：8.96(s,2H),7.78(d,1H,J＝9.0Hz),6.88(d,1H,J＝9.0Hz),5.31 (s,2H),4.13(t,2H,J＝6.0Hz),3.95(s,3H),3.64(s,4H),3.25(m,2H),2.49(m,5H),1.99(s,2H),1.14(s,2H)。
实施例13：化合物8e-2～8e-5的合成
以化合物7e-1为原料，分别采用氯乙酰胺、氯丙酰胺、N-甲基氯丙酰胺、氯丙酰吗啉等替代N-(3-氯丙基)吗啉，制备得到化合物8e-2～8e-5，其结构式如下表7所示。
表7
Figure PCTCN2019122973-appb-000033
实施例14：2-氨基-N-(8-甲氧基-7-(3-吗啉代丙基)-4-氧-3-(2,2-二氟乙基)-3,4-二氢喹唑啉酮-2-基)嘧啶-5-甲酰胺(化合物8f-1)的制备
用2,2-二氟乙胺代替甲胺盐酸盐，与2-氨基-3-甲氧基-4-苄氧基苯甲酸(化合物4)反应，制得2-氨基-3-甲氧基-4-苄氧基-N-二氟乙胺基苯甲酰胺(化合物5f-1)，随后5f-1与2-氨基嘧啶-5-酰基异硫氰酸酯缩合得到2-胺基-N-(3-二氟乙基-7-苄氧基羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶--5-甲酰胺(6f-1),然后经Pd/C-H 2脱去苄基得到2-胺基-N-(3-二氟乙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺(7f-1)，最后与N-(3-氯丙基)吗啉反应得到化合物白色固体，ESI-MS:520.2[M+H] +； 1H-NMR(δ,DMSO-d 6)：13.87(s,1H),8.92(s,2H),7.82(d,1H,J＝9.0Hz),7.26(s,2H),7,21(d,1H,J＝9.0Hz),6.52(tt,1H,J 1＝56.0Hz,J 2＝4.0Hz),4.71(td,2H,J 1＝14.0Hz,J 2＝4.0Hz),4.25(t,2H,J＝6.5Hz),3.96(s,3H),3.59(t,4H,J＝5.0Hz),2.48(t,2H,J＝7.0Hz)2.38(s,4H),2.00(m,2H)。
实施例15：化合物8f-2～8f-3的合成
以2-胺基-N-(3-二氟乙基-7-羟基-8-甲氧基-4-氧代-3,4-二氢喹唑啉-2-基)嘧啶-5-甲酰胺(7f-1)为原料，分别采用氯乙酰胺、氯丙酰胺等替代N-(3-氯丙基)吗啉，制备得到化合物8f-2～8f-3。该系列化合物结构式如下表8所示。
表8
Figure PCTCN2019122973-appb-000034
Figure PCTCN2019122973-appb-000035
实施例16：2-氨基-N-(7-乙基-6-氧代-6,7-二氢-[1,3]二氧杂环戊烯并[4,5-H]喹唑啉-8-基)嘧啶-5-甲酰胺(化合物14a-1)的制备
Figure PCTCN2019122973-appb-000036
步骤1.化合物5-2-1的制备
化合物4-2-1(0.1mol)溶于100mL，依次加入甲胺盐酸盐8.1g,EDC 28.8g，室温搅拌过夜，萃取浓缩后得到5-2-1，Yield：89％，ESI-MS:195.1[M+H] +；
步骤2.化合物14a-1的制备
酰胺中间体5-2-1(0.05mol)加入到200mL***中，向其中滴加2-氨基-嘧啶-5-甲酰基异硫氰酸酯(0.05mol)的丙酮溶液，室温搅拌过夜，析出沉淀，抽滤得到粉白色沉淀，溶于无水DCM后加入EDC(0.05mmol)，室温搅拌过夜，抽滤得到沉淀，甲醇多次洗涤得到目标化合物，Yield：80％，ESI-MS:341.1[M+H] +。
实施例17：2-氨基-N-(3-甲基-4-氧代-3,4,8,9-四氢-[1,4]二氧杂环己二烯并[2,3-H]喹唑啉-2-基)嘧啶-5-甲酰胺(化合物14a-2)的制备
合成路线如下：
Figure PCTCN2019122973-appb-000037
步骤1.化合物10-2的制备
3,4-二羟基-2-硝基苯甲醛(化合物9，0.1mol)溶于100mL DMF，加入碳酸钾55.2g，再加入1，2-二溴乙烷(0.11mol)，滴加升温至60℃反应，待反应结束后加入水和乙酸乙酯萃取，乙酸乙酯层用饱和食盐水洗，无水硫酸钠干燥后浓缩得到化合物10-2，Yield：62％，ESI-MS:210.1[M+H] +；
步骤2.化合物11-2的制备
化合物10-2(0.06mol)溶于100mL冰乙酸中，加入氨基磺酸(0.08mol)和NaClO 2溶液(0.12mol)，低温反应4h后，加入大量水析出沉淀，抽滤得到化合物11-2，Yield：88％，ESI-MS:226.2[M+H] +；
步骤3.化合物12a-2的制备
化合物11-2(0.04mol)溶于100mL二氯甲烷，依次加入甲胺盐酸盐(0.05mol),EDC(0.06mol)，室温搅拌过夜，加入NaHCO 3溶液，分出有机层，用饱和NaCl溶液洗涤，无水硫酸钠干燥，减压回收溶剂后得到化合物12a-2，Yield：80％，ESI-MS:239.2[M+H] +；
步骤4.化合物13a-2的制备
化合物12a-2(0.03mol)溶于100mL乙醇中，加入(0.05mol)还原铁粉和(0.06mol)冰醋酸，升温至60度，反应8h，抽滤除去铁粉，加入水后减压蒸馏除去乙醇，调节pH＝10，抽滤得到产物13a-2，Yield：78％，ESI-MS:209.1[M+H] +；
步骤5.化合物14a-2的制备
化合物13a-1(0.005mol)加入到100mL***中，向其中滴加2-氨基-嘧啶-5-甲酰基异硫氰酸酯(0.005mol)的丙酮溶液，室温搅拌过夜，析出沉淀，抽滤得到的固体溶于100mL DCM，然后加入EDC(0.008mmol)，室温搅拌过夜，抽滤得到沉淀，甲醇多次洗涤得到目标化合物14a-2，Yield：48％，ESI-MS:355.1[M+H] +。
实施例18：化合物14a-3～14a-8的合成
操作过程同化合物14a-2的合成，以9a为原料，在碱性试剂作用下分别与1,3-二溴丙烷、1,4-二溴丁烷、1,5-二溴戊烷、1,6-二溴己烷、1,7-二溴庚烷、1,8-二溴辛烷进行反应，得到醚化苯甲醛中间体10-2～10-7，然后醛基氧化得到醚化苯甲醛中间体11-2～11-7，再经甲胺化得苯甲酰胺衍生物12a-2～12a-7，再经硝基还原得到13a-2～13a-7，最后与2-氨基-嘧啶-5-甲酰基异硫氰酸酯缩合得到化合物14a-3～14a-8。该系列化合物结构式如下表9所示。
表9
Figure PCTCN2019122973-appb-000038
实施例19：2-氨基-N-(3-甲基-4-氧代-3,4,8,9,11,12-六氢-[1,4,7]三氧代[2,3-H]喹唑啉-2-基)嘧 啶-5-甲酰胺(化合物14a-9)的制备
合成路线如下：
Figure PCTCN2019122973-appb-000039
步骤1.化合物10-9的制备
3,4-二羟基-2-硝基苯甲醛(化合物9，0.01mol)溶于100mL DMF，加入碳酸钾(0.012mol)，再加入一缩二乙二醇双(对甲苯磺酸酯)(0.011mol)，滴加升温至60℃反应，反应结束后加入水和乙酸乙酯，乙酸乙酯层用饱和食盐水洗，无水硫酸钠干燥，浓缩得到化合物10-9，Yield：62％，ESI-MS:254.1[M+H] +；
步骤2.化合物11-8的制备
化合物10-9(0.006mol)溶于80mL二氯甲烷中加入50mL 15％NaOH溶液，升温至55℃，滴加NaClO水溶液(0.012mol)，反应4h后减压蒸馏除去甲醇，体系用6N HCl调节pH至2-3，析出沉淀，抽滤得到化合物11-9，Yield：88％，ESI-MS:270.1[M+H] +；
步骤3.化合物12a-9的制备
化合物11-9(0.004mol)溶于100mL二氯甲烷中，依次加入甲胺盐酸盐(0.006mol),EDC(0.006mol)，三乙胺(0.006mol),室温搅拌过夜，加入NaHCO3溶液洗涤，浓缩有机层后得到化合物12a-9，Yield：80％，ESI-MS:283.1[M+H] +；
步骤4.化合物13a-9的制备
化合物12a-9(0.003mol)溶于100mL乙醇中，加入还原铁粉(0.008mol)和20mL冰醋酸，机械搅拌下反应8h，抽滤除去铁粉，加入水后减压蒸馏除去乙醇，调节pH至10，抽滤得到产物13a-9，Yield：78％，ESI-MS:253.1[M+H] +；
步骤5.化合物14a-9的制备
将化合物13a-9与2-氨基-嘧啶-5-甲酰基异硫氰酸酯反应后，再经EDC缩合得到14a-9，Yield：48％，ESI-MS:399.1[M+H] +。
实施例20：化合物14a-10～14a-12的合成
操作过程同化合物14a-9的合成，以化合物9为原料，分别与相应的二缩三乙二醇双-(对甲苯磺酸酯化合物)、三缩四乙二醇双-(对甲苯磺酸酯化合物)、四缩五乙二醇双-(对甲苯磺酸酯化合物)进行反应，制备得到醚化中间体10-9～10-11，再经醛基氧化得到苯甲酸衍生物11-9～11-11，然后甲酸与甲胺进行缩合，得到N-甲基苯甲酰胺衍生物12a-9～12a-11；再经硝基还原得到13a-9～13a-11，最后与2-氨基-嘧啶-5-甲酰基异氰酸酯缩合得到化合物14a-10～14a-12；该系列化合物结构式如下表10所示。
表10
Figure PCTCN2019122973-appb-000040
实施例21：2-氨基-N-(7-乙基-6-氧代-6,7-二氢-[1,3]二氧杂环戊烯并[4,5-H]喹唑啉-8-基)嘧啶-5-甲酰胺(化合物14b-1)的制备
Figure PCTCN2019122973-appb-000041
反应步骤如上所示，与化合物14a-1的合成相同方法，以4-2-1为原料，先与乙胺进行反应得到苯甲酰乙胺中间体5-2-2，然后与2-氨基-嘧啶-5-甲酰基异硫氰酸酯缩合得到产物14b-1，ESI-MS:355.1[M+H] +。
实施例22：化合物14b-2～14b-8的制备
操作过程同化合物14a-2的合成，用苯甲醛中间体11-1～11-7与乙胺缩合，获得中间体12-1～12-7，然后经还原硝基得到化合物13-1～13-7，最后与2-氨基-嘧啶-5-甲酰基异硫氰酸酯缩合得到白色固体14b-2～14b-8，见表11。
表11
Figure PCTCN2019122973-appb-000042
Figure PCTCN2019122973-appb-000043
实施例23：化合物14b-9～14b-12的合成
操作过程同化合物14a-9的合成，苯甲酸衍生物11-9～11-11与乙胺进行缩合，得到N-甲基苯甲酰胺衍生物12b-9～12b-11；再经硝基还原得到13b-9～13b-11，最后与2-氨基-嘧啶-5-甲酰基异氰酸酯缩合得到化合物14b-10～14b-12,其结构式如下表12所示。
表12
Figure PCTCN2019122973-appb-000044
实施例24：2-氨基-N-(2-甲基-5-甲氧基-6-(3-吗啉代)-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-甲酰胺(化合物8a’-1)的制备
合成路线如下所示：
Figure PCTCN2019122973-appb-000045
步骤1. 5-(苄氧基)-4-甲氧基-2,3-二氢-1-茚酮(化合物2’)的合成
将5-(苄氧基)-4-羟基-2,3-二氢-1-茚酮(10mmol)和碳酸钾(3.45g)溶于DMF(30mL)中，滴加溴化苄(11mmol)，室温搅拌过夜，反应完全后，萃取浓缩得到化合物2’,Yield：92％，ESI-MS:269.1[M+H] +；
步骤2. 4-(苄氧基)-2-(氰基甲基)-3-甲氧基苯甲酸(化合物3’)的合成
5-(苄氧基)-4-甲氧基-2,3-二氢-1-茚酮(9mmol)溶于甲叔醚(30mL)，冰浴下依次滴加亚硝酸异戊酯(13.5mmol)和三甲基氯硅烷(13.5mmol)，反应完全后，冷却至室温，抽滤得到固体，固体加入到15％NaOH溶液(20mL)中，室温搅拌过夜，调节pH至2-3，抽滤，所得固体即为羧酸产物,Yield：56％，ESI-MS:298.1[M+H] +；
步骤3 4-(苄氧基)-2-(氰基甲基)-3-甲氧基苯甲酸甲酯(化合物4’)的合成
羧酸中间体3’(5mmol)溶于无水甲醇(10mmol)中，冰浴下滴加二氯亚砜(15mmol)，室温搅拌反应8h，减压蒸馏，用水和乙酸乙酯萃取，乙酸乙酯层用饱和食盐水洗涤，经无水硫酸钠干燥后浓缩得到产物，Yield：99％，ESI-MS:312.1[M+H] +；
步骤4. 4-(苄氧基)-2-(氰基甲基)-3-甲氧基苯甲酸甲酯(化合物5a’-1)的合成
化合物4a’(5mmol)溶于甲胺水溶液(10mmol)中，与闷罐中升温至120℃反应12h，水和乙酸乙酯萃取，有机层用饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩得到化合物5a’，Yield：88％，ESI-MS:311.1[M+H] +；
步骤5. 2-氨基-N-(6-(苄氧基)-2-甲基-5-甲氧基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-甲酰胺(化合物6a’-1)的制备
3-氨基-6-(苄氧基)-5-甲氧基-2-甲基异喹啉-1-(2H)-酮(化合物5a’-1)和2-氨基-嘧啶-5-甲酸溶于DMF，依次加入N,N-二异丙基乙胺(DPIEA)、六氟磷酸苯并***-1-基-氧基三吡咯烷基磷(PyBop)，室温反应2天，抽滤，所得固体用乙酸乙酯洗涤，干燥后得到苄基保护的酰胺中间体6a’-1，Yield：40％，ESI-MS:432.2[M+H] +；
步骤6. 2-氨基-N-(2-甲基-6-羟基-5-甲氧基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-甲酰胺(化合物7a’-1)的制备
在连接氢气还原装置的反应瓶中投入中间体6a’-1(3.0mmol),10％Pd/C(50mg)和30mL乙醇，抽真空通氢三次，室温反应6小时，铺上硅藻土抽滤除去Pd/C，滤液减压浓缩得到白色固体，Yield：88％，ESI-MS:342.1[M+H] +；
步骤7. 2-氨基-N-(2-甲基-5-甲氧基-6-(3-吗啉代)-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-甲酰胺(化合物8a’-1)的制备
化合物7a’-1(1.0eq)溶于乙腈，加入碳酸铯(2.5eq)，搅拌0.5h，加入N-氯丙基吗啉，60℃反应过夜，减压蒸馏，沉淀用水洗涤，得到白色固体，Yield：83％，ESI-MS:469.2[M+H] +。
实施例25：化合物8a’-2～8a’-7的合成
以化合物7a’-1为原料，分别采用氯乙酰胺、氯丙酰胺、N-甲基氯乙酰胺、N,N-二甲基氯乙酰胺、2-(2-氯乙基)-4-甲基吗啉、1-(3-氯-丙酰基)-4-甲基哌嗪等替代N-(3-氯丙基)吗啉，制备得到化合物8a’-2～8a’-7。
另外，以5’a-1为原料，分别用嘧啶-5-甲酸、哒嗪-4-甲酸、2-氨基-吡啶-5-甲酸、6-氨基-哒嗪-3-甲酸、2-氨基-吡嗪-5-甲酸、5-氨基吡啶-2-甲酸等替换2-氨基-嘧啶-5甲酸进行缩合反 应得到6’a-2～6’a-7，进一步经过Pd/C-H 2脱保护基得到7’a-2～7’a-7，最后与N-氯丙基吗啉反应合成8a’-8～8a’12，其结构式如下表13所示。
表13
Figure PCTCN2019122973-appb-000046
实施例26：化合物8a’-13～8a’-19的合成
(S)-2-氨基-N-(6-(2-羟基-3-吗啉代丙氧基)-5-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-羧酰胺(化合物8a’-13)的制备
按照化合物8a’-1的制备方法，用(S)-1-氯-3-吗啉代丙烷-2-醇替换N-氯丙基吗啉，制备得到目标产物，ESI-MS:485.2[M+H] +。
(R)-2-氨基-N-(6-(2-羟基-3-吗啉代丙氧基)-5-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-羧酰胺(化合物8a’-14)的制备
按照化合物8a’-1的制备方法，用(R)-1-氯-3-吗啉代丙烷-2-醇替换N-氯丙基吗啉，制 备得到目标产物，ESI-MS:485.2[M+H] +。
N-(6-(2-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)乙氧基)-5-甲氧基-2-甲基-1-氧代1,2-二氢异喹啉-3-基-2-氨基嘧啶-5-羧酰胺(化合物8a’-15)的制备
按照化合物8a’-1的制备方法，将N-氯丙基吗啉替换为7-(2-氯乙基)-2-氧杂-7-氮杂螺[3.5]壬烷，制备得到目标产物，ESI-MS:495.2[M+H] +。
2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(2-氧代-2-((2-(哌啶-1-基)乙基)氨基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8a’-16)的制备
按照化合物8a’-1的制备方法，将N-氯丙基吗啉替换为2-氯-N-(2-(哌啶-1-基)乙基)乙酰胺，制备得到目标产物，ESI-MS:511.2[M+H] +。
2-氨基-N-(5-甲氧基-2-甲基-6-(2-((2-吗啉代乙基)氨基)-2-氧乙氧基)-1-氧代1,2,2-二氢异喹啉-3-基)嘧啶-5-羧酰胺(化合物8a’-17)的制备
按照化合物8a’-1的制备方法，将N-氯丙基吗啉替换为2-氯-N-(2-吗啉代乙基)乙酰胺，制备得到目标产物，ESI-MS:512.2[M+H] +。
2-氨基-N-(5-甲氧基-2-甲基-6-(2-(甲基磺酰胺基)乙氧基)-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-羧酰胺(化合物8a’-19)的制备
按照化合物8a’-1的制备方法，将N-氯丙基吗啉替换为N-(2-氯乙基)甲磺酰胺，制备得到目标产物，ESI-MS:463.1[M+H] +。
实施例27：2-氨基-N-(2-甲基-5-甲氧基-6-(3-吗啉代)-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-甲酰胺(化合物8b’-1)的制备
操作过程同化合物8a’-1的合成，用3-氨基-6-(苄氧基)-5-甲氧基-2-乙基异喹啉-1-(2H)-酮(5b’-1)代替3-氨基-6-(苄氧基)-5-甲氧基-2-甲基异喹啉-1-(2H)-酮(5a’-1)，先与2-氨基-嘧啶-5-甲酸缩合得到2-氨基-N-(2-乙基-6-苄氧基-5-甲氧基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-甲酰胺(6b’-1)，然后用Pd/C-H 2脱保护基得到2-氨基-N-(2-乙基-6-羟基-5-甲氧基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-甲酰胺(7b’-1)，最后与(N-氯丙基)-吗啉缩合得到白色固体8b’-1,ESI-MS:483.2[M+H] +。
实施例28：化合物8b’-2～8b’-7的合成
以化合物2-氨基-N-(2-乙基-6-羟基-5-甲氧基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-甲酰胺7b’-1为原料，分别采用氯氯乙酰胺、氯丙酰胺、N-甲基氯乙酰胺、N,N-二甲基氯乙酰胺、2-(2-氯乙基)-4-甲基吗啉、1-(3-氯-丙酰基)-4-甲基哌嗪、氯乙酰基吗啉、4-氯丁酰胺等替代N-(3-氯丙基)吗啉,制备得到化合物8b’-2～8b’-9。
另外，以5’b-1为原料，分别用嘧啶-5-甲酸、哒嗪-4-甲酸、2-氨基-吡啶-5-甲酸、6-氨基-哒嗪-3-甲酸、2-氨基-吡嗪-5-甲酸、5-氨基吡啶-2-甲酸等替换2-氨基-嘧啶-5甲酸进行缩合反应得到6’b-2～6’b-7，进一步经过Pd/C-H 2脱保护基得到7’b-2～7’b-7，最后与N-氯丙基吗啉反应合成8b’-8～8b’-12，其结构式如下表14所示。
表14
Figure PCTCN2019122973-appb-000047
Figure PCTCN2019122973-appb-000048
实施例29：化合物8b’-16～8b’-21的合成
(S)-2-氨基-N-(6-(2-羟基-3-吗啉代丙氧基)-5-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-羧酰胺(化合物8b’-16)的制备
按照化合物8b’-1的制备方法，用(S)-1-氯-3-吗啉代丙烷-2-醇替换N-氯丙基吗啉，制备得到目标产物，ESI-MS:485.2[M+H] +。
(R)-2-氨基-N-(6-(2-羟基-3-吗啉代丙氧基)-5-甲氧基-2-甲基-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-羧酰胺(化合物8b’-17)的制备
按照化合物8b’-1的制备方法，用(R)-1-氯-3-吗啉代丙烷-2-醇替换N-氯丙基吗啉，制备得到目标产物，ESI-MS:485.2[M+H] +。
N-(6-(2-(2-氧杂-7-氮杂螺[3.5]壬烷-7-基)乙氧基)-5-甲氧基-2-甲基-1-氧代1,2-二氢异喹啉-3-基-2-氨基嘧啶-5-羧酰胺(化合物8b’-18)的制备
按照化合物8b’-1的制备方法，将N-氯丙基吗啉替换为7-(2-氯乙基)-2-氧杂-7-氮杂螺[3.5]壬烷，制备得到目标产物，ESI-MS:495.2[M+H] +。
2-氨基-N-(8-甲氧基-3-甲基-4-氧代-7-(2-氧代-2-((2-(哌啶-1-基)乙基)氨基)乙氧基)-3,4-二氢喹唑啉-2-基)嘧啶-5-羧酰胺(化合物8b’-19)的制备
按照化合物8b’-1的制备方法，将N-氯丙基吗啉替换为2-氯-N-(2-(哌啶-1-基)乙基)乙酰胺，制备得到目标产物，ESI-MS:511.2[M+H] +。
2-氨基-N-(5-甲氧基-2-甲基-6-(2-((2-吗啉代乙基)氨基)-2-氧乙氧基)-1-氧代1,2,2-二氢异喹啉-3-基)嘧啶-5-羧酰胺(化合物8b’-20)的制备
按照化合物8b’-1的制备方法，将N-氯丙基吗啉替换为2-氯-N-(2-吗啉代乙基)乙酰胺，制备得到目标产物，ESI-MS:512.2[M+H] +。
2-氨基-N-(5-甲氧基-2-甲基-6-(2-(甲基磺酰胺基)乙氧基)-1-氧代-1,2-二氢异喹啉-3-基)嘧啶-5-羧酰胺(化合物8b’-21)的制备
按照化合物8b’-1的制备方法，将N-氯丙基吗啉替换为N-(2-氯乙基)甲磺酰胺，制备得到目标产物，ESI-MS:463.1[M+H] +。
实施例30：化合物14’a-2的制备
Figure PCTCN2019122973-appb-000049
化合物1’经BBr 3脱甲基后制得邻二酚10’，然后与二溴乙烷进行缩合，得到化合物11’-2，然后与异丁基亚硝酸酯、氢氧化钠水解制得化合物12’-2，再经二氯亚砜酰氯化，烷胺基缩合得到13’a-2，最后与芳香羧基缩合制得目标分子14’a-2。
按照相类似的方法，改变醚键的长度，可以合成目标分子14a’-1，以及14a’-3～14a’-8。
该系列分子的结构式如下表15所示。
表15
Figure PCTCN2019122973-appb-000050
Figure PCTCN2019122973-appb-000051
实施例31：化合物14b’-3～14b’-8的合成
操作过程同化合物14a’-2的合成，制备得到化合物14b’-1～14b’-8，其结构式如下表16所示。
表16
Figure PCTCN2019122973-appb-000052
实施例32：氨基喹唑啉酮类和氨基异喹啉酮类衍生物对体外PI3K活性的抑制作用
1.实验方法：
仪器：酶标仪Envision TM(PerkinElmer,USA)
材料：人源重组PI3Kα、PI3Kδ蛋白购自Carna Bioscience公司；ADP-GLO试剂盒，购自Promega公司。
样品处理：样品用DMSO溶解，低温保存，梯度稀释，且DMSO在最终体系中的浓度控制在不影响活性检测的范围以内。实验采用的阳性化合物为Copanlisib和Alpelisib。
以PI3Kα分子活性测试为例，描述PI3K亚型的测定方法：
PI3K-α重组蛋白和底物ATP用激酶反应缓冲液(50mM Tris-HCl，pH7.4,2.1mM DTT,0.05％Tween-20,10mM MgCl 2)稀释。将1μL梯度浓度的化合物分别加入384反应板中(ProxiPlate TM-384Plus,PerkinElmer)，具体反应体系为2％的DMSO，0.8ng/μL PI3K-α,100μM  ATP，同时设置阳性化合物对照组和空白对照孔，每个样品每个浓度设3个复孔。室温孵育2个小时后，分别加入ADP-GLO Reagent和Kinase Detection Reagent后，利用Envision TM检测萤光读值。通过样品读值计算样品活性率，计算公式为：活性率＝(OD 化合物-OD 空白)/(OD DMSO-O 空 白)×100％，活性率对样品浓度进行非线性拟和得到IC 50，计算所用软件为Graphpad Prism 5，拟合所使用的模型为sigmoidal dose-response(varible slope)，拟合曲线底部和顶部分别设定为0和100。
2.实验结果：具体结果见表17。
表17部分化合物对PI3Kα/PI3Kδ活性抑制作用
Figure PCTCN2019122973-appb-000053
Figure PCTCN2019122973-appb-000054
Figure PCTCN2019122973-appb-000055
“++++”代表<20nM；“+++”代表20-200nM；“++”代表200-1000nM；“+”代表>1000nM；“-”表示未测定。
PI3Kα的选择性，由PI3KδIC 50/PI3KαIC 50计算而得，其中“I”代表<5倍，“II”代表5～10倍，“III”代表>10倍。
实施例33：氨基喹唑啉酮类和氨基异喹啉酮类衍生物肿瘤细胞增殖抑制活性
1.实验方法和结果
采用CCK8法，以copanlisib和alpelisib作为阳性对照，测试不同化合物对四种瘤株增殖抑制作用，IC 50值采用Graphpad Prism V5.0软件计算得出，结果见下表18。
表18部分化合物对不同肿瘤细胞的增殖抑制作用
Figure PCTCN2019122973-appb-000056
Figure PCTCN2019122973-appb-000057
“++++”代表<20nM；“+++”代表20-200nM；“++”代表200-1000nM；“+”代表>1000nM。
实施例34代表性分子的体内药代动力学测定：
体重200±20g的健康SD大鼠，雄性，随机分组，每组6只，尾静脉注射给药，给药剂量为1mg/kg。药动学分析的取血时间点：给药后5min、15min、30min、2、4、6、8、24、48h；经眼眶采全血约0.3mL，置肝素化试管中，6000rpm离心10min，分离血浆，-80℃保存，待测。用安捷伦液质联用仪(LC-MS/MS，Agilent Jet Stream Electrometric spray ion)检测各化合物的血药浓度，采用WinNonLin 7.0药动学软件非房室模型法计算相关药代动力学参数，结果见下表19。
表19代表化合物的药代动力学结果
Figure PCTCN2019122973-appb-000058
Figure PCTCN2019122973-appb-000059
药代动力学实验表明Copanlisib在大鼠体内的分布容积很大，达到33.5L/kg，容易发生药物聚积，从而产生毒副作用。本发明的代表性化合物的分布容积明显下降，Vss(L/kg)值在2.4-4.2L/h/kg之间，且T 1/2有所下降，大约4小时；因此上述化合物在大鼠体内不容易发生聚积，不容易引发因药物聚积而引起的副作用。因此可以推断，上述化合物与Copanlisib相比，在临床上将有可能显示出更为优良的药代动力学特征，减少药物在人体内的聚积，降低毒副作用。
实施例35代表性分子的体内药效测定：
雌性裸小鼠，体重20±3g，接种Kasumi-1细胞株接种裸小鼠右侧腋窝皮下，细胞接种量为1×10 7/只，待成瘤后，用游标卡尺测量移植瘤直径，肿瘤长至100-300mm 3，将动物按体重和肿瘤体积分为模型对照组和给药组，每组6只，模型对照组则给等量空白溶剂。分组后每天给药(qd)，10mg/Kg，连续21天，实验过程中，每周2次测量移植瘤直径及称量小鼠体重。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。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝V t/V 0。其中V 0为分笼给药时(即d 0)测量所得肿瘤体积，V t为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV。瘤重抑制率，计算公式如下：瘤重抑制率％＝(Wc-WT)/Wc×100％，Wc：对照组瘤重，WT：治疗组瘤重。结果见图1，由图中的体内药效活性数据可知，8a-27和8a-28化合物呈现出较强的肿瘤生长抑制活性，与阳性copanlisib相当，因此具有良好的应用前景。

Claims (8)

  1. 氨基喹唑啉酮和氨基异喹啉酮类衍生物，具有以下结构通式a和b：
    Figure PCTCN2019122973-appb-100001
    或其药学上可接受的盐，立体异构体或溶剂合物；
    其中：
    (1)对于结构通式a：
    X＝N或CH；
    R 1选自氢，C 1-6烷基，环烷基，含氟烷基；
    R 2选自氢，1-12个碳原子的烷基，环烷基，含氟烷基，-(CH 2) nNR 5R 6，-(CH 2) n-CONR 5R 6，-(CH 2) n-SO 2NR 5R 6，-(CH 2) nOR 5，其中n为1～8的整数，R 5和R 6是相互独立的，可以相同也可以不相同，选自氢、C 1-4烷基、C 1-4环烷基，或者NR 5R 6是4-8元的环状胺，包括但不限于吗啉、哌嗪、吡咯烷、哌啶，或者是R 7取代的环状胺，R 7选自氢，C 1-6烷基、C 1-6烷氧基，C 2-6-不饱和脂链烃基、C 3-8环烷基、C 3-8不饱和脂环基、C 3-8饱和脂杂环基、卤素、氨基、氰基；
    R 3选自C 1-6烷基，环烷基，含氟烷基；
    Ar为芳杂环，包括但不限于苯环、呋喃环、噻吩环、吡咯环、噻唑环、吡唑环、噁唑环、吡啶环、嘧啶环、哒嗪环、吡嗪环、嘌呤环、氮杂嘌呤环、氮杂吲哚环、吲哚环、喹啉环、喹唑啉环、喹喔啉环、吲唑环；
    R 8选自氢，卤素，氰基，羟基，C 1-6烷氧基，氨基，C 1-6烷胺基，C 1-6二烷基胺基，C 1-6烷基，C 2-6-不饱和脂链烃基，C 3-8环烷基，C 3-8不饱和脂环基，C 3-8饱和脂杂环基，C 1-6卤代烷基；
    (2)对于结构通式b：
    喹唑啉或喹啉苯环的两个相邻氧原子采用不同的链连接构成5-21元环，链中包含2-7个氧原子；结构中其余部分的定义同结构通式a：
  2. 根据权利要求1所述的氨基喹唑啉酮和氨基异喹啉酮类化合物，其特征在于，对于结构通式a，所述的R 1为甲基时，R 2分别选自但不局限于以下基团：
    Figure PCTCN2019122973-appb-100002
  3. 根据权利要求1所述的氨基喹唑啉酮和氨基异喹啉酮类化合物，其特征在于，结构通 式b所述的苯环两个氧原子通过链连接构成5-21元环，选自但不局限于以下基团：
    Figure PCTCN2019122973-appb-100003
  4. 根据权利要求1所述的氨基喹唑啉酮和氨基异喹啉酮类化合物，其特征在于，R 3选自但不局限于：-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、环丙基、-CH 2CF 3、-CH 2CF 2H。
  5. 根据权利要求1所述的氨基喹唑啉酮和氨基异喹啉酮类化合物，其特征在于，所述Ar选自苯环、呋喃环、噻吩环、吡咯环、噻唑环、吡唑环、噁唑环、吡啶环、嘧啶环、哒嗪环、吡嗪环、嘌呤环、氮杂嘌呤环、氮杂吲哚环、吲哚环、喹啉环、喹唑啉环、喹喔啉环、吲唑环；
    R 8取自氢，卤素，氰基，羟基，C 1-6烷氧基，氨基，C 1-6烷胺基，C 1-6二烷基胺基，C 1-6烷基，C 2-6-不饱和脂链烃基，C 3-8环烷基，C 3-8不饱和脂环基，C 3-8饱和脂杂环基，C 1-6卤代烷基。
  6. 根据权利要求1所述的化合物，其特征在于，选自下列化合物：
    Figure PCTCN2019122973-appb-100004
    Figure PCTCN2019122973-appb-100005
    Figure PCTCN2019122973-appb-100006
    Figure PCTCN2019122973-appb-100007
    Figure PCTCN2019122973-appb-100008
    Figure PCTCN2019122973-appb-100009
    Figure PCTCN2019122973-appb-100010
    Figure PCTCN2019122973-appb-100011
    Figure PCTCN2019122973-appb-100012
    Figure PCTCN2019122973-appb-100013
    Figure PCTCN2019122973-appb-100014
    或其上述化合物药学上可接受的盐或溶剂化物。
  7. 根据权利要求1-6任一所述化合物，其特征在于，所述化合物所形成的盐，包括但不限于盐酸盐、氢溴酸盐、甲磺酸盐、硫酸盐、富马酸盐、酒石酸盐、马来酸盐、苹果酸盐、枸橼酸盐。
  8. 根据权利要求1-6任一所述的化合物在制备抗肿瘤和抗炎药物中的应用，其特征在于，所述的肿瘤为白血病、淋巴瘤、骨髓增生症、非霍奇金氏淋巴瘤、多发性骨髓瘤、乳腺癌、肉瘤、肺癌、***癌、结肠癌、直肠癌、肾癌、胰腺癌、成神经细胞瘤、神经胶质瘤、头癌、颈癌、甲状腺癌、肝癌、卵巢癌、子***、子宫内膜癌、睾丸癌、膀胱癌、食管癌、胃癌、鼻咽癌、颊癌、口腔癌、胃肠道间质瘤、皮肤癌、多发性骨髓瘤；所述炎性疾病为过敏、哮喘、类风湿性关节炎、骨关节炎、过敏性结膜炎、过敏性角膜炎、慢性阻塞性肺病、红斑狼疮、牛皮癣、多发性硬化症和晚期肾病；所述化合物包括药学上可接受的盐、剂合物。
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