WO2022206531A1 - 含1,3-苯并二氧戊环结构的化合物及其制备方法与用途 - Google Patents

含1,3-苯并二氧戊环结构的化合物及其制备方法与用途 Download PDF

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WO2022206531A1
WO2022206531A1 PCT/CN2022/082684 CN2022082684W WO2022206531A1 WO 2022206531 A1 WO2022206531 A1 WO 2022206531A1 CN 2022082684 W CN2022082684 W CN 2022082684W WO 2022206531 A1 WO2022206531 A1 WO 2022206531A1
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compound
nch
mmol
benzo
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French (fr)
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徐云根
梁停停
朱启华
王俊杰
岑丽芳
王文杰
金佳明
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XI'AN XINTONG PHARMACEUTICAL RESEARCH Co Ltd
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Priority to JP2023534994A priority patent/JP7555642B2/ja
Priority to EP22778714.0A priority patent/EP4317162B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a class of BTK and JAK3 kinase inhibitors containing 1,3-benzodioxolane structures, their preparation methods, and pharmaceutical compositions containing these compounds and their use in the preparation of therapeutic classes Use in medicine for autoimmune diseases such as rheumatoid arthritis or B-cell lymphoma, or B-cell malignancies.
  • RA Rheumatoid arthritis
  • JAK (Janus Kinase) is a non-receptor tyrosine kinase, including four subtypes JAK1, JAK2, JAK3, TYK2.
  • JAK inhibitors are currently on the market, such as Tofacitinib, Ruxolitinib, and Baricitinib.
  • Tofacitinib was marketed in 2012 for the treatment of moderate-to-severe rheumatoid arthritis and was approved in 2017 for the treatment of psoriatic arthritis.
  • tofacitinib has serious side effects such as infection and anemia. The main reason is that tofacitinib is a pan-JAK inhibitor.
  • JAK1 and JAK3 While inhibiting JAK1 and JAK3 to produce therapeutic effects, it inhibits the activity of JAK2. side effects of anemia. Therefore, in the treatment of rheumatoid arthritis, selective JAK1 or JAK3 inhibitors should be developed. Since JAK1 can form dimers with JAK3, it can also form dimers or multimers with JAK2 or TYK2, which can cause side effects. Therefore, the side effects caused by selective inhibition of JAK3 may be less than those caused by inhibition of JAK1.
  • BTK (Bruton's tyrosine kinase), a member of the TEC family, is a non-receptor tyrosine kinase, mainly expressed in B cells, myeloid cells, mast cells, and platelets, but not in T cells and NK cells. BTK plays a crucial role in the BCR signaling pathway. In addition, BTK is also involved in the conduction of many other signaling pathways. Abnormal activation of B cells leads to B cell lymphomas and autoimmune diseases. There are currently three BTK inhibitors on the market, including ibrutinib, acalabrutinib and zanubrutinib.
  • the invention provides a class of compounds containing 1,3-benzodioxolane structure, which can inhibit BTK and JAK3 at the same time.
  • the present invention also provides a specific preparation method of the compound and its pharmaceutical application as a BTK and JAK3 kinase inhibitor.
  • the present invention provides a class of 1,3-benzodioxolane derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof:
  • X represents N or CH
  • A represents O, S, -NHCO-, -NHCOCH 2 - or -NHSO 2 -
  • m represents 0 or 1
  • n represents 0 or 1;
  • R 1 stands for: wherein p represents 0 or 1; R 4 represents H, F, Cl, Br, I, C1-C6 alkyl, CF 3 , OH, C1-C6 alkoxy, OCF 3 , CN, NO 2 , NH 2 , C1 -C6 alkylamino, N(CH 3 ) 2 , N(C 2 H 5 ) 2 , NHCOCH 3 , CONH 2 , CONHCH 3 , CONHCH 2 CF 3 , OCH 2 CH 2 OCH 3 , C 6 H 5 , R 4 can be mono-, di- or tri-substituted; Y 1 , Y 2 , Y 3 or Y 4 represents N or CR 5 , R 5 represents H, F, Cl, Br, I, CH 3 , CF 3 , OH , OCH 3 , OCF 3 or CN; Z represents O, S or NR 6 , R 6 represents H, CH 3 or C 2 H 5 or cyclo
  • R 2 represents H, Cl, Br or CN
  • R 3 represents H, substituted C1-C6 alkyl, substituted C2-C6 heterocycloalkyl, wherein the substituent is OH, NH 2 , OCH 3 , NHCH 3 or NHCOCH 3 , the heterocycloalkane
  • the radical is a four-membered, five-membered or six-membered saturated heterocycloalkyl group containing 1 to 3 O, N or S atoms.
  • A is -NHCO- or -NHSO 2 -, more preferably A is -NHCO-; when m represents 1, n preferably represents 0; when m represents 0, n preferably represents 1; R 2 , R 3 preferably represent H.
  • the compounds of the present invention preferably have the following general formula (II):
  • X and R 1 are as defined above.
  • R 1 represents wherein R 7 represents H, F, Cl, Br, CH 3 , t-Bu, CF 3 , CN, OH, OCH 3 , OCF 3 , NH 2 , N(CH 3 ) 2 , N(C 2 H 5 ) 2 , NHCOCH 3 , CONH 2 , CONHCH 3 , CONHCH 2 CF 3 , C 6 H 5 , R 7 may be mono-, di- or tri-substituted, and R 8 represents H, Cl or CH 3 .
  • R 7 preferably represents H, Cl, CH 3 , t-Bu, CF 3 , OCH 3 , N(CH 3 ) 2 , N(C 2 H 5 ) 2 or CONHCH 2 CF 3 , and R 7 may be a single Substituted, disubstituted or trisubstituted, R8 preferably represents Cl.
  • the 1,3-benzodioxolane derivatives of the present invention are I-1, I-2, I-3, I-4, I-5, I-6, I-7, I- 8. I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I- 33 or I-34.
  • 1,3-benzodioxolane derivatives of the present invention are I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I- 21, 1-22, 1-31 or 1-32.
  • 1,3-benzodioxolane derivatives of the present invention are selected from the following compounds:
  • the pharmaceutically acceptable salts of the compounds of the present invention are the acid addition salts of the compounds of the general formula (I), wherein the acids used for salt formation are: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid , tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the acids used for salt formation are: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid , tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
  • the compounds of general formula (I) of the present invention can be prepared by the following methods:
  • R 1 , R 2 , R 3 , X, A, m and n have the same definitions as before;
  • Compound (V) is prepared from compound (III) and compound (IV) by Suzuki coupling reaction, and the solvent used is selected from toluene, N,N-dimethylformamide (DMF), ethylene glycol dimethyl ether, 1,4 -Dioxane, tetrahydrofuran, methanol, ethanol, acetonitrile, acetone, water or a mixed solvent of any two solvents, preferably ethylene glycol dimethyl ether; the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate , sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or triethylamine, preferably sodium carbonate or potassium carbonate; the catalyst used is selected from tetrakis (triphenylphosphine) palladium (Pd(PPh 3 ) 4 ), [1, 1'-bis(diphenylphosphino)ferrocene] palladium dichloride (Pd(dppf
  • the reagent used is selected from trifluoroacetic acid, concentrated hydrochloric acid, hydrogen chloride/ethyl acetate solution or hydrogen chloride/methanol solution, preferably trifluoroacetic acid or hydrogen chloride/ethyl acetate solution;
  • the reaction solvent is selected from acetone, dichloromethane, ethyl acetate, 1,4-dioxane or acetonitrile, preferably ethyl acetate or dichloromethane.
  • Compound (I) is prepared by reacting compound (VI) with corresponding acid chloride, and the acid binding agent used is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate or carbonic acid Sodium, preferably triethylamine; the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, toluene or DMF, preferably dichloromethane.
  • the acid binding agent used is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate or carbonic acid Sodium, preferably triethylamine
  • the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate,
  • Compound (I) can also be prepared by reacting compound (VI) with a corresponding acid in the presence of a condensing agent selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl) yl)-3-ethylcarbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBt) or dicyclohexylcarbodiimide (DCC)/4-dimethylaminopyridine (DMAP), EDCI/HOBt is preferred.
  • a condensing agent selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl) yl)-3-ethylcarbodiimide hydrochloride (EDCI)/1-hydroxybenzotriazole (HOBt) or dicyclohexylcarbodiimide (DCC)/4-dimethylaminopyridine (DMAP),
  • the compound of the general formula (II) of the present invention can be prepared by the following method:
  • R 1 and X have the same definitions as before;
  • the solvent used is selected from toluene, DMF, ethylene glycol dimethyl ether, 1,4-dioxane, tetrahydrofuran , methanol, ethanol, acetonitrile, acetone, water or a mixed solvent composed of any two solvents, preferably ethylene glycol dimethyl ether;
  • the base used is selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, sodium hydroxide, hydrogen Potassium oxide, potassium bicarbonate, potassium carbonate, sodium carbonate or triethylamine, preferably sodium carbonate or potassium carbonate;
  • the catalyst used is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(PPh 3 ) 2 Cl 2.
  • reaction temperature is selected from 25-120°C, preferably 70-100°C; the reaction time is selected from 2-24 hours, preferably 12-18 Hour.
  • Compound (VI-A) is prepared by removing Boc protecting group from compound (V-A), and the reagent used is selected from trifluoroacetic acid, concentrated hydrochloric acid, hydrogen chloride/ethyl acetate solution or hydrogen chloride/methanol solution, preferably hydrogen chloride/ethyl acetate solution;
  • the reaction solvent is selected from acetone, dichloromethane, ethyl acetate, 1,4-dioxane or acetonitrile, preferably ethyl acetate or dichloromethane.
  • Compound (II) is prepared by reacting compound (VI-A) with acryloyl chloride, and the acid binding agent used is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate or Sodium carbonate, preferably triethylamine; the solvent used is selected from dichloromethane, tetrahydrofuran, acetone, toluene or DMF, preferably dichloromethane.
  • Compound (II) can also be prepared by reacting compound (VI-A) with acrylic acid in the presence of a condensing agent selected from CDI, EDCI/HOBt or DCC/DMAP, preferably EDCI/HOBt.
  • a condensing agent selected from CDI, EDCI/HOBt or DCC/DMAP, preferably EDCI/HOBt.
  • Compound (III) is prepared by Mitsunobu reaction of compound (VII) and compound (VIII), the phosphine ligand used is selected from triphenylphosphine (PPh 3 ) or tri-n-butylphosphine (n-Bu 3 P), preferably triphenylphosphine phosphine; the azo reagent used is selected from diethyl azodicarbonate (DEAD), diisopropyl azodicarbonate (DIAD) or N,N,N',N'-tetramethylazodicarbonamide (TMAD), preferably DIAD; the solvent used is selected from tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, toluene, acetonitrile or DMF, preferably tetrahydrofuran.
  • DEAD diethyl azodicarbonate
  • DIAD N,N,N',N'-tetramethyl
  • A is selected from -NHCO-, -NHCOCH 2 - or -NHSO 2 -, and R 1 is as defined above;
  • Benzo[d][1,3]dioxol-4-amine (IX) is dissolved in DMF, and N-bromosuccinimide (NBS) is added for bromination to obtain 7-bromobenzo [d][1,3]dioxol-4-amine (X).
  • the intermediate (IV) is prepared by reacting compound (XI) with the corresponding acid chloride, and the acid binding agent used is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate or Sodium carbonate, preferably N,N-diisopropylethylamine or triethylamine; the solvent used is selected from dichloromethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, toluene or DMF, preferably dichloromethane Chloromethane.
  • the acid binding agent used is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate or Sodium carbonate, preferably N,N-diisopropylethylamine or triethylamine
  • the solvent used
  • the present invention also discloses a pharmaceutical composition, which contains the compound of the general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compound can be added with a pharmaceutically acceptable carrier to make common pharmaceutical preparations, such as tablets, capsules, syrups, suspensions, injections, and commonly used flavors, sweeteners, liquid or solid fillers or diluents can be added. medical supplements.
  • compositions of the present invention can be administered by means of administration well known to those skilled in the art, such as oral, rectal, sublingual, pulmonary, transdermal, iontophoretic, vaginal and intranasal.
  • the pharmaceutical compositions of the present invention are preferably administered parenterally, such as by subcutaneous, intramuscular or intravenous injection.
  • the dosage varies according to the preparation form and expected action time and the condition of the object to be treated.
  • the therapeutically effective amount required for the actual treatment can be determined by the physician according to the actual situation (eg, the patient's condition, weight, etc.).
  • the dosage of the pharmaceutical composition of the present invention, calculated as the compound of formula (I) may be 1 ng-10 g per kg of adult body weight, preferably 10 ⁇ g-100 mg per kg of body weight.
  • the present invention also provides a method of treatment comprising administering to a subject in need of inhibition of BTK and/or JAK3 activity a therapeutically effective amount of a compound of general formula (I) of the present invention or a stereoisomer, hydrated compound, solvate, crystalline or pharmaceutically acceptable salt.
  • the present invention provides the compound of general formula (I) of the present invention or a stereoisomer, hydrate, solvate, crystal or pharmaceutically acceptable salt thereof in the preparation of a BTK and JAK3 dual target inhibitor drug the use of.
  • the present invention also provides a method for treating an autoimmune disease or B cell malignancy comprising administering to a subject suffering from the autoimmune disease or B cell malignancy a therapeutically effective amount of the present invention
  • the compound of general formula (I) or its stereoisomer, hydrate, solvate, crystal or pharmaceutically acceptable salt is administered to a subject suffering from the autoimmune disease or B cell malignancy a therapeutically effective amount of the present invention.
  • the beneficial effect of the present invention is to provide a 1,3-benzodioxolane derivative represented by the general formula (I).
  • the results of pharmacological experiments show that the compound (I) of the present invention can produce good effects on both BTK and JAK3 kinases. It can be used to prepare medicines for the treatment of rheumatoid arthritis caused by excessive activation of BTK and JAK3 pathways; the 1,3-benzodioxolane derivatives of the present invention have high selectivity for inhibiting the activity of JAK3, basically It does not produce inhibitory activity to JAK1 and JAK2; the present invention also provides an efficient preparation method of the 1,3-benzodioxolane derivatives.
  • Benzo[d][1,3]dioxol-4-amine (IX) (1.24 g, 9.04 mmol) and DMF (30 mL) were mixed, stirred to dissolve, cooled to -30 °C, and added in batches NBS (1.69 g, 9.50 mmol) was added, and the reaction was incubated for 1 hour.
  • Water (60 mL) was added, extracted with ethyl acetate (15 mL ⁇ 3), the organic phase was washed successively with water (10 mL ⁇ 3) and saturated sodium chloride solution (10 mL ⁇ 3), and dried over anhydrous sodium sulfate.
  • V-8-1 (900mg, 1.50mmol), HOBt (243mg, 1.80mmol), EDCI (344mg, 1.80mmol) were dissolved in 5 mL DMF, triethylamine (227mg, 2.24mmol) and trifluoroethylamine were added (156 mg, 1.57 mmol) and stirred at room temperature overnight. 25 mL of water was added, extracted with ethyl acetate, the organic layer was washed with water (10 mL ⁇ 3), washed with saturated sodium chloride (10 mL ⁇ 3), and dried over anhydrous sodium sulfate.
  • the 384-well reaction plate is divided into compound wells (10 ⁇ M initial, 3-fold dilution for a total of 10 concentrations), positive control wells and negative control wells.
  • Kinase solution is added to compound wells and positive control wells, and 1 ⁇ kinase is added to negative control wells.
  • buffer centrifuge for 30 seconds and incubate at room temperature for 10 minutes.
  • Add 15 ⁇ L of a mixed solution of ATP and substrate centrifuge, shake and incubate at room temperature (30 minutes for JAK3 and 20 minutes for BTK). The reaction was stopped by adding stop detection solution, and the conversion rate was read with Caliper EZ reader.
  • Conversion%_sample is the conversion rate reading of the sample
  • Conversion%_min is the average value of the negative control well, representing the conversion rate reading of the well without enzyme
  • Conversion%_max is the average value of the positive control ratio well, representing the conversion rate reading of the well without compound .
  • Fitting the dose-response curve take the log value of the concentration as the X-axis and the percentage inhibition rate on the Y-axis, and use the log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 to fit the dose-response curve to obtain each compound IC50 value for enzymatic activity.
  • Table 1 show that the compounds of the present invention have good inhibitory activity on BTK and JAK3 kinases, among which compounds I-6, I-7, I-10, I-11, I-13 ⁇ I-22, I-32 It exhibits good inhibitory activity against BTK and JAK3.
  • Max signal DMSO signal
  • Min signal medium signal.
  • IC50 was calculated using GraphPad Prism 5.
  • the experimental results showed that the cell proliferation inhibitory activity of the test compounds on BaF3-JAK3 was significantly better than that of ibrutinib; the test compounds showed a good proliferation inhibitory ability on Daudi cells with high BTK expression, and some of the test compounds had inhibitory effects on Daudi cells.
  • the proliferation inhibitory activity is better than ibrutinib.

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Abstract

本发明提供了含1,3-苯并二氧戊环结构的化合物及其制备方法与用途。本发明公开了一种通式(I)所示的1,3-苯并二氧戊环衍生物，药理实验结果显示，本发明的化合物(I)可以对BTK和JAK3激酶均产生良好的抑制作用，可用于制备治疗BTK和/或JAK3通路过度活化所致的类风湿性关节炎的药物；本发明还公开了所述1,3-苯并二氧戊环衍生物的制备方法。

Description

含1,3-苯并二氧戊环结构的化合物及其制备方法与用途 技术领域
本发明属于药物化学领域，具体涉及一类含有1,3-苯并二氧戊环结构的BTK和JAK3激酶抑制剂，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制备治疗类风湿性关节炎或B细胞淋巴瘤等自身免疫性疾病或B细胞恶性肿瘤等药物方面的用途。
技术背景
类风湿性关节炎(RA)是一种病因未明的慢性、以炎性滑膜炎为主的自身免疫性疾病，其主要病理表现为滑膜组织炎性细胞浸润、血管翳形成以及进行性关节软骨和骨破坏，最终导致关节畸形甚至功能丧失。
JAK(Janus Kinase)属于非受体酪氨酸激酶，包含四个亚型JAK1、JAK2、JAK3、TYK2。目前已有多种JAK抑制剂上市，如托法替尼(Tofacitinib)、鲁索替尼(Ruxolitinib)和巴瑞克替尼(Baricitinib)。托法替尼于2012年上市用于治疗中度至重度类风湿性关节炎，2017年又被批准用于治疗银屑病性关节炎。但托法替尼具有较严重的感染和贫血等副作用，究其原因，主要是由于托法替尼属于泛JAK抑制剂，在抑制JAK1和JAK3产生治疗效果的同时，由于抑制了JAK2活性而产生贫血的副作用。所以在治疗类风湿性关节炎时，应开发选择性JAK1或JAK3抑制剂。由于JAK1除了可与JAK3形成二聚体外，还可与JAK2或TYK2形成二聚体或多聚体，从而引起副作用。因此选择性抑制JAK3引起的副作用可能要小于抑制JAK1产生的副作用。
BTK(Bruton’s tyrosine kinase)是TEC家族的一员，属于非受体酪氨酸激酶，主要在B细胞、髓细胞、肥大细胞、血小板中表达，在T细胞和NK细胞中不表达。BTK在BCR信号通路中起到了至关重要的作用，除此之外，BTK还参与很多其他信号通路的传导。B细胞的异常活化会导致B细胞淋巴瘤和自身免疫性疾病。目前已有三个BTK抑制剂上市，包括依鲁替尼(Ibrutinib)、阿卡替尼(Acalabrutinib)和泽布替尼(Zanubrutinib)。
有文献报道联合使用BTK抑制剂LFM-A13和JAK3抑制剂JANEX-1治疗移植物抗宿主反应(GVHD)的效果要远优于单独使用LFM-A13、JANEX-1或甲氨蝶呤的治疗效果。另外JAK3选择性抑制剂PF-06651600在临床上显示出较好的抗RA效果，究其原因，不仅与抑制JAK3有关，也与抑制BTK等TEC家族激酶密切相关。因此，本发明人认为同时抑制BTK和JAK3对治疗RA等自身免疫性疾病具有协同增效作用。然而，对此本领域技术人员会将现有的BTK抑制剂和JAK3抑制剂来组合使用，而同时具有优良的BTK和JAK3抑制活性的化合物却难以根据现有技术显而易见地获得。而本发明人令人意外地研发出了一系列化合物，其除了对BTK有抑制活性，还对JAK3有高选择性的抑制活性。
发明内容
本发明提供了一类含有1,3-苯并二氧戊环结构的化合物，能同时抑制BTK和JAK3。另外，本发明还提供了该类化合物的具体制备方法以及作为BTK和JAK3激酶抑制剂的制药应用等。
具体而言，本发明提供了一类如通式(I)所示的1,3-苯并二氧戊环衍生物或其药学上可接受的盐：
Figure PCTCN2022082684-appb-000001
其中：X代表N或CH；A代表O、S、-NHCO-、-NHCOCH 2-或-NHSO 2-；m代表0或1，n代表0或1；
R 1代表：
Figure PCTCN2022082684-appb-000002
Figure PCTCN2022082684-appb-000003
其中p代表0或1；R 4代表H、F、Cl、Br、I、C1-C6烷基、CF 3、OH、C1-C6烷氧基、OCF 3、CN、NO 2、NH 2、C1-C6的烷胺基、N(CH 3) 2、N(C 2H 5) 2、NHCOCH 3、CONH 2、CONHCH 3、CONHCH 2CF 3、OCH 2CH 2OCH 3、C 6H 5、
Figure PCTCN2022082684-appb-000004
R 4可以是单取代、双取代或三取代；Y 1、Y 2、Y 3或Y 4代表N或C-R 5，R 5代表H、F、Cl、Br、I、CH 3、CF 3、OH、OCH 3、OCF 3或CN；Z代表O、S或N-R 6，R 6代表H、CH 3或C 2H 5或环丙基；
R 2代表H、Cl、Br或CN；
R 3代表H、取代的C1-C6的烷基、取代的C2-C6的杂环烷基，其中所述取代基为OH、NH 2、OCH 3、NHCH 3或NHCOCH 3，所述杂环烷基为含有1～3个O、N或S原子的四元、五元或六元饱和杂环烷基。
优选在通式(I)中，A为-NHCO-或-NHSO 2-，更优选A为-NHCO-；当m代表1时，n优选代表0；当m代表0时，n优选代表1；R 2、R 3优选代表H。
本发明的化合物优选具有如下通式(II)：
Figure PCTCN2022082684-appb-000005
其中：X和R 1的定义同前。
优选在通式(II)中，R 1代表
Figure PCTCN2022082684-appb-000006
Figure PCTCN2022082684-appb-000007
其中R 7代表H、F、Cl、Br、CH 3、t-Bu、CF 3、CN、OH、OCH 3、OCF 3、NH 2、N(CH 3) 2、N(C 2H 5) 2、NHCOCH 3、CONH 2、CONHCH 3、CONHCH 2CF 3、C 6H 5、
Figure PCTCN2022082684-appb-000008
R 7可以是单取代、双取代或三取代，R 8代表H、Cl或CH 3。
进一步地，R 7优选代表H、Cl、CH 3、t-Bu、CF 3、OCH 3、N(CH 3) 2、N(C 2H 5) 2或CONHCH 2CF 3，R 7可以是单取代、双取代或三取代，R 8优选代表Cl。
更优选地，本发明的1,3-苯并二氧戊环衍生物为I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I-15、I-16、I-17、I-18、I-19、I-20、I-21、I-22、I-23、I-24、I-25、I-26、I-27、I-28、I-29、I-30、I-31、I-32、I-33或I-34。例如，本发明的1,3-苯并二氧戊环衍生物为I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I-15、I-16、I-17、I-18、I-19、I-20、I-21、I-22、I-31或I-32。
进一步优选地，本发明的1,3-苯并二氧戊环衍生物选自以下化合物：
Figure PCTCN2022082684-appb-000009
Figure PCTCN2022082684-appb-000010
本发明的化合物的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。
本发明通式(I)的化合物可用下列方法制备：
Figure PCTCN2022082684-appb-000011
其中，R 1、R 2、R 3、X、A、m和n的定义同前；
由化合物(III)与化合物(IV)通过Suzuki偶联反应制备化合物(V)，所用溶剂选自甲苯、N,N-二甲基甲酰胺(DMF)、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选乙二醇二甲醚；所用碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠或三乙胺，优选碳酸钠或碳酸钾；所用催化剂选自四(三苯基膦)钯(Pd(PPh 3) 4)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2)、双(三苯基磷)二氯化钯(Pd(PPh 3) 2Cl 2)、醋酸钯(Pd(OAc) 2)或(1,1'-双(二苯基膦)二茂铁)二氯化镍(NiCl 2(dppf))，优选Pd(dppf)Cl 2；反应温度选自室温至120℃，优选70～100℃。
由化合物(V)通过脱除叔丁氧羰基(Boc)保护基制备化合物(VI)，所用试剂选自三氟乙酸、浓盐酸、氯化氢/乙酸乙酯溶液或氯化氢/甲醇溶液,优选三氟乙酸或氯化氢/乙酸乙酯溶液；反应溶剂选自丙酮、二氯甲烷、乙酸乙酯、1,4-二氧六环或乙腈,优选乙酸乙酯或二氯甲烷。
由化合物(VI)与相应的酰氯反应制备化合物(I)，所用缚酸剂选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、碳酸钾或碳酸钠，优选三乙胺；所用溶剂选自二氯甲烷、四氢呋喃、1,4-二氧六环、乙酸乙酯、丙酮、甲苯或DMF，优选二氯甲烷。
化合物(I)也可由化合物(VI)与相应的酸在缩合剂存在下反应制备得到，所述缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)/1-羟基苯并三唑(HOBt)或二环己基碳二亚胺(DCC)/4-二甲氨基吡啶(DMAP)，优选EDCI/HOBt。
当A代表-NHCO-、m代表0、n代表1、R 2、R 3代表H，且哌啶3位C原子为R构型时，本发明通式(II)的化合物可用下列方法制备：
Figure PCTCN2022082684-appb-000012
Figure PCTCN2022082684-appb-000013
其中，R 1和X的定义同前；
由化合物(III-A)与化合物(IV-A)通过Suzuki偶联反应制备化合物(V-A)，所用溶剂选自甲苯、DMF、乙二醇二甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂，优选乙二醇二甲醚；所用的碱选自乙醇钠、乙酸钠、乙酸钾、磷酸钾、氢氧化钠、氢氧化钾、碳酸氢钾、碳酸钾、碳酸钠或三乙胺，优选碳酸钠或碳酸钾；所用的催化剂选自Pd(PPh 3) 4、Pd(dppf)Cl 2、Pd(PPh 3) 2Cl 2、Pd(OAc) 2或NiCl 2(dppf)，优选Pd(dppf)Cl 2；反应温度选自25～120℃，优选70～100℃；反应时间选自2～24小时，优选12～18小时。
由化合物(V-A)通过脱除Boc保护基制备化合物(VI-A)，所用试剂选自三氟乙酸、浓盐酸、氯化氢/乙酸乙酯溶液或氯化氢/甲醇溶液,优选氯化氢/乙酸乙酯溶液；反应溶剂选自丙酮、二氯甲烷、乙酸乙酯、1,4-二氧六环或乙腈,优选乙酸乙酯或二氯甲烷。
由化合物(VI-A)与丙烯酰氯反应制备化合物(II)，所用缚酸剂选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、碳酸钾或碳酸钠，优选三乙胺；所用溶剂选自二氯甲烷、四氢呋喃、丙酮、甲苯或DMF，优选二氯甲烷。
化合物(II)也可由化合物(VI-A)与丙烯酸在缩合剂存在下反应制得，所述缩合剂选自CDI、EDCI/HOBt或DCC/DMAP，优选EDCI/HOBt。
中间体(III)可用下列方法制备：
Figure PCTCN2022082684-appb-000014
其中，X、m和n的定义同前；
由化合物(VII)与化合物(VIII)通过Mitsunobu反应制备化合物(III)，所用膦配体选自三苯基膦(PPh 3)或三正丁基膦(n-Bu 3P)，优选三苯基膦；所用偶氮试剂选自偶氮二碳酸二乙酯(DEAD)、偶氮二碳酸二异丙酯(DIAD)或N,N,N',N'-四甲基偶氮二甲酰胺(TMAD)，优选DIAD；所用溶剂选自四氢呋喃、1,4-二氧六环、乙醚、二氯甲烷、甲苯、乙腈或DMF，优选四氢呋喃。
中间体(IV)可用下列方法制备：
Figure PCTCN2022082684-appb-000015
其中，A选自-NHCO-、-NHCOCH 2-或-NHSO 2-，R 1的定义同前；
苯并[d][1,3]二氧杂环戊烯-4-胺(IX)溶于DMF，加入N-溴代丁二酰亚胺(NBS)进行溴代即得7-溴苯并[d][1,3]二氧杂环戊烯-4-胺(X)。
化合物(X)和联硼酸频那醇酯溶于1,4-二氧六环中，在催化剂Pd(dppf)Cl 2和乙酸钾存在下反应即得7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-胺(XI)。
由化合物(XI)与相应的酰氯反应制备中间体(IV)，所用缚酸剂选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶、碳酸钾或碳酸钠，优选N,N-二异丙基乙胺或三乙胺；所用溶剂选自二氯甲烷、四氢呋喃、1,4-二氧六环、乙酸乙酯、丙酮、甲苯或DMF，优选二氯甲烷。
本发明还公开了一种药物组合物，其含有上述通式(I)化合物或其药学上可接受的盐及药学上可接受的载体。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、糖浆、悬浮剂、注射剂，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。
本发明的药物组合物可通过所属领域技术人员所熟知的给药方式来进行给药，例如口服、直肠、舌下、肺部、透皮、离子透入、阴道及鼻内给药。本发明的药物组合物优选胃肠道外给药，如皮下、肌内或静脉内注射。给药剂量根据制剂形式和期望的作用时间以及治疗对象的情况而有所变化，实际治疗所需的治疗有效量可以由医师根据实际情况(如，病人的病情、体重等)而确定。对于一般的成人，本发明的药物组合物的剂量，以式通式(I)化合物计，可以是每kg成人体重1ng–10g，优选为每kg体重10μg-100mg。
本发明的通式(I)化合物或其立体异构体、水合物、溶剂合物、结晶或药学上可接受的盐在制备BTK和/或JAK3抑制剂药物中的用途也在本发明的保护范围内。相应地，本发明还提供了一种治疗方法，其包括向需要抑制BTK和/或JAK3活性的受治疗者给予治疗有效量的本发明的通式(I)化合物或其立体异构体、水合物、溶剂合物、结晶或药学上可接受的盐。
优选地，本发明提供了本发明的通式(I)化合物或其立体异构体、水合物、溶剂合物、结晶或药学上可接受的盐在制备BTK和JAK3双靶点抑制剂药物中的用途。
进一步地，其中的BTK和JAK3抑制剂用于治疗自身免疫性疾病和B细胞恶性肿瘤，优选地，所述的自身免疫性疾病包括类风湿性关节炎、银屑病和斑秃等，所述的B细胞恶性肿瘤包括B细胞淋巴瘤等。相应地，本发明还提供了一种用于治疗自身免疫性疾病或B细胞恶性肿瘤的方法，其包括向患有自身免疫性疾病或B细胞恶性肿瘤的受治疗者给予治疗有效量的本发明的通式(I)化合物或其立体异构体、水合物、溶剂合物、结晶或药学上可接受的盐。
本发明的有益效果在于提供了通式(I)所示的1,3-苯并二氧戊环衍生物，药理实验结果显示，本发明的化合物(I)可以对BTK和JAK3激酶均产生良好的抑制作用，可用于制备治疗BTK、JAK3通路过度活化所致的类风湿性关节炎的药物；本发明的1,3-苯并二氧戊环衍生物抑制JAK3的活性的选择性高，基本不对JAK1和JAK2产生抑制活性；本发明还提供了所述1,3-苯并二氧戊环衍生物的高效制备方法。
具体实施方式
下面结合具体实施例对本申请作出详细说明。
实施例1
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅰ-1)的合成
(R)-3-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅲ-1)的合成
将4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶(Ⅶ-1)(1.80g,6.90mmol)、(S)-1-叔丁氧羰基-3-羟基哌啶(Ⅷ-1)(2.78g,13.79mmol)、PPh 3(3.61g,13.79mmol)、无水THF(100mL)加入250mL三颈瓶中，氮气保护，冰浴下搅拌30分钟，加入DIAD(2.40g,13.79mmol)，室温反应18小时。减压蒸除THF，加乙酸乙酯(100mL)溶解，依次用饱和碳酸钠(30mL×3)、水(30mL×3)、饱和氯化钠(30mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压蒸除溶剂得黄色油状物，柱层析分离(洗脱剂:二氯甲烷:甲醇＝150～90:1)，得白色固体2.06g，产率67.2％，m.p.178-180℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.34(s,1H,ArH),6.27(s,2H,NH 2),4.85-4.66(m,1H,CHC H 2N),4.36-4.00(m,2H,C HC H 2N),3.47-3.21(m,1H,CHCH 2CH 2C H 2N),2.92-2.72(m,1H,CHCH 2CH 2C H 2N),2.28-2.01(m,2H,CHC H 2CH 2CH 2N),1.97-1.79(m,1H,CHCH 2C H 2CH 2N),1.76-1.57(m,1H,CHCH 2C H 2CH 2N),1.45(s,9H,NBoc)。
7-溴苯并[d][1,3]二氧杂环戊烯-4-胺(X)的合成
将苯并[d][1,3]二氧杂环戊烯-4-胺(Ⅸ)(1.24g,9.04mmol)和DMF(30mL)混合，搅拌溶解，降温至-30℃，分批加入NBS(1.69g,9.50mmol)，加毕，保温反应1小时。加入水(60mL)，用乙酸乙酯(15mL×3)萃取，有机相依次用水(10mL×3)和饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压蒸干，残留物柱层析(洗脱剂:石油醚:乙酸乙酯＝30～10:1)分离，得白色固体1.01g，收率为51.7％，m.p.99-100℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):6.80(d,J＝8.67Hz,1H,ArH),6.23(d,J＝8.67Hz,1H,ArH),6.02(s,2H,OCH 2O),3.58(s,2H,NH 2)。
7-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-胺(XI)的合成
将化合物Ⅹ(3.14g,14.54mmol)、联硼酸频那醇酯(7.39g,29.07mmol)、Pd(dppf)Cl 2(0.53g,0.73mmol)、乙酸钾(4.28g,43.62mmol)和1,4-二氧六环(25mL)混合，N 2保护，升温至95℃反应12小时。经硅藻土抽滤，滤液减压蒸除溶剂，加入乙酸乙酯(20mL)溶解，依次用水(10mL×3)和饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，抽滤，滤液减压蒸干，残留物柱层析(洗脱剂:石油醚:二氯甲烷＝1:5～10)得白色固体2.70g，收率70.6％，mp.84-86℃。 1H-NMR(300MHz, CDCl 3)δ(ppm):7.09(d,J＝8.16Hz,1H,ArH),6.31(d,J＝8.19Hz,1H,ArH),5.99(s,2H,OCH 2O),3.71(br,2H,NH 2),1.34(s,12H,4CH 3)。
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-1)的合成
将化合物Ⅺ(0.56g,2.14mmol)溶于二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(0.83g,6.42mmol)，冰浴下滴加苯甲酰氯(0.45g,3.21mmol)的二氯甲烷溶液，滴毕，室温反应0.5小时。反应液依次用1mol/L盐酸(10mL×3)、饱和碳酸氢钠溶液(10mL×3)、水(10mL×3)和饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压蒸干，残留物柱层析(洗脱剂:石油醚:二氯甲烷＝1:1～8)得白色固体409mg，收率为52.1％，m.p.202-204℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):7.89-7.88(m,4H,ArH),7.57-7.47(m,3H,ArH,NH),7.29(d,J＝8.73Hz,1H,ArH),6.07(s,2H,OCH 2O),1.36(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-苯甲酰胺基苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(V-1)的合成
将化合物Ⅲ-1(1.50g,3.38mmol)和Ⅳ-1(1.49g,4.05mmol)加入100mL单颈瓶中，加入2mol/L碳酸钠溶液(3.38mL)、Pd(dppf)Cl 2(0.12g,0.17mmol)和乙二醇二甲醚(40mL)，氮气保护，85℃反应17小时。冷至室温，经硅藻土抽滤，滤液减压浓缩，乙酸乙酯(40mL)溶解，水(10mL×3)洗涤，饱和氯化钠(10mL×3)洗涤，减压浓缩得2.56g粗品。柱层析(洗脱剂:二氯甲烷:甲醇＝100～70:1)分离得926mg淡黄色固体，产率49.2％，m.p.112-114℃。 1H-NMR(300MHz,CDCl 3+D 2O)δ(ppm):8.36(s,1H,ArH),8.05-7.98(m,1H,ArH),7.92(d,J＝7.23Hz,2H,ArH),7.64-7.49(m,3H,ArH),7.15(d,J＝8.19Hz,1H,ArH),6.13(s,2H,OCH 2O),4.92-4.79(m,1H,CHC H 2NBoc),4.42-4.23(m,1H,C HCH 2NBoc),3.57-3.28(m,2H,C H 2NC H 2),2.92-2.76(m,1H,NC H 2CH 2),2.32-2.16(m,2H,NCH 2CHC H 2),1.93-1.81(m,2H,NCH 2C H 2),1.45(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅵ-1)的合成
将化合物Ⅴ-1(0.93g,1.66mmol)溶于乙酸乙酯(6mL)中，加入乙酸乙酯的氯化氢饱和溶液(10mL)，室温搅拌4小时，有大量固体析出。加入20mL水，分液，水层用乙酸乙酯洗涤两次，用1mol/L的NaOH调pH至8-9，析出固体，抽滤，烘干得721mg淡黄色固体，产率94.8％。不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅰ-1)的合成
将化合物Ⅵ-1(93mg,0.20mmol)溶于5mL无水二氯甲烷中，加入三乙胺(31mg,0.30mmol)，冰浴下滴加丙烯酰氯(22mg,0.24mmol)的无水二氯甲烷溶液，滴加完毕，室温搅拌3.5小时。水(10mL×3)洗涤，饱和氯化钠溶液(10mL×3)洗涤，减压浓缩得粗品。残留物柱层析(洗脱剂:二氯甲烷:甲醇＝100～35:1)分离得77mg白色固体，产率74.0％，m.p.141-142.5℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.39(s,1H,ArH),8.35-8.25(m,1H,NH),7.93(d,J＝7.26Hz,2H, ArH),7.86-7.76(m,1H,ArH),7.60-7.44(m,3H,ArH),7.13-7.03(m,1H,ArH),6.67-6.52(m,1H,CH＝CH 2),6.34-6.18(m,2H,CH＝CH 2,NH 2),6.09(s,2H,OCH 2O),5.75-5.60(m,1H,CH＝CH 2),4.93-4.74(m,1.5H,NC H 2CH),4.65-4.51(m,0.5H,NCH 2C H),4.27-4.14(m,0.5H,NC H 2CH),4.08-3.94(m,0.5H,NC H 2CH),3.85-3.68(m,0.5H,NC H 2CH 2),3.40-3.26(m,0.5H,NC H 2CH 2),3.24-3.08(m,0.5H,NC H 2CH 2),2.92-2.85(m,0.5H,NC H 2CH 2),2.81(s,1H,NH 2),2.46-2.30(m,1H,NCH 2CHC H 2),2.29-2.18(m,1H,NCH 2CHC H 2),2.06-1.91(m,1H,NCH 2C H 2),1.79-1.61(m,1H,NCH 2C H 2)。HRMS(ESI):m/z[M+H] +.Calcd for C 27H 26N 7O 4:512.2046；Found:512.2045.
实施例2
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)噻吩-2-甲酰胺(Ⅰ-2)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)噻吩-2-甲酰胺(Ⅳ-2)的合成
将噻吩-2-甲酸(0.73g,5.70mmol)溶于无水二氯甲烷(12mL)中，加入3滴DMF，冰浴下滴加草酰氯(1.09g,8.55mmol)的无水二氯甲烷溶液。滴毕，室温搅拌。TLC(石油醚:乙酸乙酯＝3:1)监测，原料反应完全后，减压除去溶剂，无水二氯甲烷(15mL)溶解，待用。
向50mL茄形瓶中加入化合物Ⅺ(1.00g,3.80mmol)和二氯甲烷(20mL)，搅拌溶解，加入N,N-二异丙基乙胺(1.47g,11.40mmol)，冰浴下滴加上述酰氯，室温反应6小时。有机相依次用1mol/L盐酸(10mL×3)、水(10mL)、饱和碳酸氢钠溶液(10mL)、饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压浓缩得淡黄色固体。石油醚:乙酸乙酯8:1打浆(1g/6mL)，得白色固体1.25g，产率88.1％，不经进一步纯化，直接投下一步。
(R)-3-(4-氨基-3-(7-(噻吩-2-甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-2)的合成
以化合物Ⅲ-1(0.90g,2.03mmol)和Ⅳ-2(0.91g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体583mg，产率51.1％，m.p.142-144℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.35(s,1H,ArH),7.94-7.87(m,2H,ArH,NH),7.69(d,J＝3.66Hz,1H,ArH),7.60(d,J＝5.01Hz,1H,ArH),7.20-7.08(m,2H,ArH),6.12(s,2H,OCH 2O),5.93(br,2H,NH 2),4.93-4.78(m,1H,CHC H 2NBoc),4.46-4.07(m,2H,C HC H 2NBoc),3.56-3.29(m,1H,NC H 2CH 2),2.94-2.75(m,1H,NC H 2CH 2),2.35-2.13(m,2H,NCH 2CHC H 2),1.98-1.82(m,1H,NCH 2C H 2),1.77-1.59(m,1H,NCH 2C H 2),1.45(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-噻吩-2-甲酰胺(Ⅵ-2)的合成
以化合物Ⅴ-2(400mg,0.71mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体329mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)噻吩-2-甲酰胺(Ⅰ-2)的合成
以化合物Ⅵ-2(300mg,0.65mmol)和丙烯酰氯(64mg,0.71mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体131mg，产率39.1％，m.p.140-142℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.37(s,1H,ArH),8.02(s,1H,NH),7.89(d,J＝7.98Hz,1H,ArH),7.73(d,J＝3.27Hz,1H,ArH),7.62(d,J＝4.74Hz,1H,ArH),7.18(d,J＝3.60Hz,1H,ArH),7.12(d,J＝8.70Hz,1H,ArH),6.72-6.54(m,1H,CH＝CH 2),6.39-6.25(m,1H,CH＝CH 2),6.14(s,2H,OCH 2O),5.96(s,1H,NH 2),5.79-5.63(m,1H,CH＝CH 2),4.99-4.82(m,1.5H,NC H 2C H),4.71-4.58(m,0.5H,NCH 2C H),4.32-4.18(m,0.5H,NC H 2CH),4.12-3.99(m,0.5H,NC H 2CH),3.89-3.73(m,0.5H,NC H 2CH 2),3.47-3.32(m,0.5H,NC H 2CH 2),3.30-3.14(m,0.5H,NC H 2CH 2),2.97-2.79(m,0.5H,NC H 2CH 2),2.49-2.34(m,1H,NCH 2CHC H 2),2.33-2.23(m,1H,NCH 2CHC H 2),2.20(s,1H,NH 2),2.07-1.96(m,1H,NCH 2C H 2),1.83-1.67(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 25H 24N 7O 4S:518.1610；Found:518.1611.
实施例3
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡咯-2-甲酰胺(Ⅰ-3)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡咯-甲酰胺(Ⅳ-3)的合成
以化合物Ⅺ(1.00g,3.80mmol)和吡咯-2-羧酸(0.63g,5.70mmol)为原料，操作过程同化合物Ⅳ-2，得白色固体1.17g，产率86.4％，不经进一步纯化，直接投下一步。
(R)-3-(3-(7-(1H-吡咯-2-甲酰胺)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-3)的合成
以化合物Ⅲ-1(0.90g,2.03mmol)和Ⅳ-3(1.36g,3.85mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体550mg，产率49.5％，m.p.138-140℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):11.67(s,1H,NH),8.42(s,1H,ArH),7.77(d,J＝8.52Hz,1H,ArH),7.70(s,1H,NH),7.15-7.10(m,1H,ArH),7.08(d,J＝8.60Hz,1H,ArH),6.87-6.82(m,1H,ArH),6.38-6.31(m,1H,ArH),6.11(s,2H,OCH 2O),5.30(s,1H,NH 2),4.92-4.78(m,1H,CHC H 2NBoc),4.50-4.24(m,1H,C HCH 2NBoc),4.24-4.03(m,1H,CHC H 2NBoc),3.58-3.29(m,1H,NC H 2CH 2),2.91-2.75(m,1H,NC H 2CH 2),2.36-2.16(m,3H,NCH 2CHC H 2,NH 2),1.96-1.82(m,1H,NCH 2C H 2),1.78-1.63(m,1H,NCH 2C H 2),1.45(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡咯-2-甲酰胺(Ⅵ-3)的合成
以化合物Ⅴ-3(450mg,0.82mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体383mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡咯-2-甲酰胺(Ⅰ-3)的合成
以化合物Ⅵ-3(360mg,0.81mmol)和丙烯酰氯(77mg,0.85mmol)为原料，操作过程同化合 物Ⅰ-1，得白色固体212mg，产率52.5％，m.p.156-158℃。 1H-NMR(300MHz,CDCl 3+D 2O)δ(ppm):8.40(s,1H,ArH),7.80-7.60(m,1H,ArH),7.18-6.99(m,2H,ArH),6.94-6.81(m,1H,ArH),6.70-6.52(m,1H,CH＝CH 2),6.43-6.22(m,2H,ArH,CH＝CH 2),6.09(s,2H,OCH 2O),5.80-5.60(m,1H,CH＝CH 2),5.07-4.54(m,4H,NC H 2C H,N H 2),4.31-4.15(m,0.5H,NC H 2CH),4.10-3.93(m,0.5H,NC H 2CH),3.87-3.65(m,0.5H,NC H 2CH 2),3.46-3.30(m,0.5H,NC H 2CH 2),3.26-3.11(m,0.5H,NC H 2CH 2),2.95-2.76(m,0.5H,NC H 2CH 2),2.48-2.14(m,2H,NCH 2CHC H 2),2.05-1.89(m,1H,NCH 2C H 2),1.83-1.60(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 25H 25N 8O 4:501.1999；Found:501.2003。
实施例4
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)吡啶-2-甲酰胺(Ⅰ-4)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)吡啶-2-甲酰胺(Ⅳ-4)的合成
以化合物Ⅺ(0.70g,2.66mmol)和吡啶-2-甲酰氯盐酸盐(0.57g,3.19mmol)为原料，操作过程同化合物Ⅳ-1，得灰白色固体612mg，产率62.5％，m.p.190-192℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.11(s,1H,NH),8.70-8.66(m,1H,ArH),8.29(d,J＝7.65Hz,1H,ArH),8.00(d,J＝8.43Hz,1H,ArH),7.93(t,J＝7.56Hz,1H,ArH),7.54-7.44(m,1H,ArH),7.30(d,J＝8.55Hz,1H,ArH),6.11(s,2H,OCH 2O),1.37(s,12H,4CH 3).
(R)-3-(4-氨基-3-(7-(吡啶-2-甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-4)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和化合物Ⅳ-4(0.80g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体476mg，产率47.4％，m.p.118-120℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.17(s,1H,NH),8.70-8.66(m,1H,ArH),8.39(s,1H,ArH),8.33(d,J＝7.77Hz,1H,ArH),8.17(d,J＝8.70Hz,1H,ArH),7.96(td,J 1＝7.74Hz,J 2＝1.65Hz,1H,ArH),7.58-7.51(m,1H,ArH),7.18(d,J＝8.70Hz,1H,ArH),6.18(s,2H,OCH 2O),5.79(s,2H,NH 2),4.94-4.81(m,1H,CHC H 2NBoc),4.43-4.27(m,1H,C HCH 2NBoc),4.23-4.10(m,1H,CHC H 2NBoc),3.52-3.39(m,1H,NC H 2CH 2),2.94-2.79(m,1H,NC H 2CH 2),2.34-2.27(m,1H,NCH 2CHC H 2),2.26-2.20(m,1H,NCH 2CHC H 2),1.98-1.90(m,2H,NCH 2C H 2),1.47(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)吡啶-2-甲酰胺(Ⅵ-4)的合成
将化合物Ⅴ-4(0.40g,0.72mmol)溶于无水二氯甲烷(5mL)中，加入三氟醋酸(5mL)，室温搅拌10小时。减压蒸去溶剂，乙酸乙酯溶解，1mol/L NaOH调pH至8-9，分液，水层用乙酸乙酯萃取1次，有机层用饱和氯化钠(10mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压浓缩得280mg淡黄色产品，产率85.37％。不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊 烯-4-基)吡啶-2-甲酰胺(Ⅰ-4)的合成
将化合物Ⅵ-4(230mg,0.50mmol)、丙烯酸(43mg,0.60mmol)、HOBt(102mg,0.75mmol)、EDCI(145mg,0.75mmol)和TEA(102mg,1.00mmol)溶于6mL DMF中，室温搅拌12h。加入30mL水，乙酸乙酯(10mL×3)萃取，有机层依次用1mol/L盐酸(10mL×3)、饱和碳酸钠(10mL×3)和饱和氯化钠(10mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压浓缩得粗品。柱层析(洗脱剂:二氯甲烷:甲醇＝100～50:1)得白色固体201mg，产率78.2％，m.p.154-156℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.11(s,1H,NHCO),8.61(s,1H,ArH),8.36-8.21(m,2H,ArH),8.16-8.03(m,1H,ArH),7.97-7.84(m,1H,ArH),7.55-7.40(m,1H,ArH),7.16-7.02(m,1H,ArH),6.64-6.46(m,1H,CH＝CH 2),6.34-6.19(m,1H,CH＝CH 2),6.12(s,2H,OCH 2O),5.78(s,1H,NH 2),5.68-5.57(m,1H,CH＝CH 2),4.96-4.74(m,1.5H,NC H 2CH),4.65-4.52(m,0.5H,NCH 2C H),4.24-4.12(m,0.5H,NC H 2CH),4.05-3.92(m,0.5H,NC H 2CH),3.80-3.67(m,0.5H,NC H 2CH 2),3.42-3.26(m,0.5H,NC H 2CH 2),3.20-3.07(m,0.5H,NC H 2CH 2),2.90-2.73(m,0.5H,NC H 2CH 2),2.44-2.15(m,2H,NCH 2CHC H 2),2.04-1.84(m,3H,NCH 2C H 2,NH 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 26H 25N 8O 4:513.1999；Found:513.1999。
实施例5
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-氯苯甲酰胺(Ⅰ-5)的合成
2-氯-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-5)的合成
以化合物Ⅺ(0.80g,3.04mmol)和邻氯苯甲酰氯(0.80g,4.56mmol)为原料，操作过程同化合物Ⅳ-1，得白色固体800mg，产率65.5％，m.p.96-98℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.16(s,1H,NHCO),7.91(d,J＝8.37Hz,1H,ArH),7.81(d,J＝6.57Hz,1H,ArH),7.48-7.37(m,3H,ArH),7.31(d,J＝8.22Hz,1H,ArH),6.08(s,2H,OCH 2O),1.39(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(2-氯苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-5)的合成
以化合物Ⅲ-1(0.65g,1.46mmol)和Ⅳ-5(0.71g,1.76mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体651mg，产率75.2％，m.p.124-126℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.36(s,1H,ArH),8.16(s,1H,NH),8.06(d,J＝8.58Hz,1H,ArH),7.86(d,J＝6.24Hz,1H,ArH),7.52-7.40(m,3H,ArH),7.15(d,J＝8.70Hz,1H,ArH),6.12(s,2H,OCH 2O),5.75(s,2H,NH 2),4.93-4.77(m,1H,CHC H 2NBoc),4.44-4.23(m,1H,C HCH 2NBoc),4.22-4.04(m,1H,CHC H 2NBoc),3.54-3.35(m,1H,NC H 2CH 2),2.91-2.76(m,1H,NC H 2CH 2),2.32-2.18(m,2H,NCH 2CHC H 2),1.78-1.61(m,2H,NCH 2C H 2),1.45(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-氯苯甲酰胺(Ⅵ-5)的合成
以化合物Ⅴ-5(600mg,1.01mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体524mg， 不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-氯苯甲酰胺(Ⅰ-5)的合成
以化合物Ⅵ-5(450mg,0.91mmol)和丙烯酰氯(87mg,0.96mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体270mg，产率54.0％，m.p.156.5-158℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.39-8.27(m,2H,ArH,CONH),8.03(d,J＝8.61Hz,1H,ArH),7.83(d,J＝7.47Hz,1H,ArH),7.52-7.36(m,3H,ArH),7.13(d,J＝8.55Hz,1H,ArH),6.68-6.52(m,1H,CH＝CH 2),6.34-6.22(m,1H,CH＝CH 2),6.12(s,2H,OCH 2O),6.04(s,1H,NH 2),5.76-5.61(m,1H,CH＝CH 2),4.95-4.79(m,1.5H,NC H 2C H),4.70-4.56(m,0.5H,NCH 2C H),4.28-4.16(m,0.5H,NC H 2CH),4.09-3.96(m,0.5H,NC H 2CH),3.84-3.70(m,0.5H,NC H 2CH 2),3.44-3.29(m,0.5H,NC H 2CH 2),3.25-3.11(m,0.5H,NC H 2CH 2),2.92-2.77(m,0.5H,NC H 2CH 2),2.52-2.19(m,3H,NCH 2CHC H 2,NH 2),2.04-1.91(m,1H,NCH 2C H 2),1.82-1.63(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 27H 25ClN 7O 4:546.1657；Found:546.1656.
实施例6
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-氯苯甲酰胺(Ⅰ-6)的合成
3-氯-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-6)的合成
以化合物Ⅺ(0.80g,3.04mmol)和间氯苯甲酰氯(0.80g,4.56mmol)为原料，操作过程同化合物Ⅳ-1。得白色固体987mg，产率80.8％，m.p.150-152℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):7.88-7.86(m,1H,ArH),7.84-7.80(m,2H,ArH,NH),7.74(d,J＝7.68Hz,1H,ArH),7.53(d,J＝8.04Hz,1H,ArH),7.43(t,J＝7.80Hz,1H,ArH),7.28(d,J＝8.31Hz,1H,ArH),6.07(s,2H,OCH 2O),1.36(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(3-氯苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-6)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和Ⅳ-6(0.87g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体1.02g(粗品)，产率95.6％，m.p.128-130℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.35(s,1H,ArH),8.03(s,1H,NH),7.95-7.85(m,2H,ArH),7.79(d,J＝7.29Hz,1H,ArH),7.55(d,J＝7.98Hz,1H,ArH),7.44(t,J＝7.71Hz,1H,ArH),7.13(d,J＝8.58Hz,1H,ArH),6.12(s,2H,OCH 2O),5.89(s,2H,NH 2),4.93-4.75(m,1H,CHC H 2NBoc),4.47-4.22(m,1H,C HCH 2NBoc),4.21-4.02(m,1H,CHC H 2NBoc),3.56-3.29(m,1H,NC H 2CH 2),2.93-2.75(m,1H,NC H 2CH 2),2.36-2.19(m,2H,NCH 2CHC H 2),1.97-1.79(m,1H,NCH 2C H 2),1.77-1.60(m,1H,NCH 2C H 2),1.45(s,9H,Boc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-氯苯甲酰胺(Ⅵ-6)的合成
以化合物Ⅴ-6(1.00g,1.69mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体882mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-氯苯甲酰胺(Ⅰ-6)的合成
以化合物Ⅵ-6(500mg,1.02mmol)和丙烯酰氯(97mg,1.07mmol)为原料，操作过程同化合物Ⅰ-1，得372mg白色固体，产率67.0％，m.p.143-144.5℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.34(d,J＝11.04Hz,1H,ArH),8.21(d,J＝9.12Hz,1H,ArH),7.92(s,1H,NH),7.90-7.77(m,2H,ArH),7.55(d,J＝7.77Hz,1H,ArH),7.45(t,J＝7.65Hz,1H,ArH),7.16-7.05(m,1H,ArH),6.68-6.52(m,1H,CH＝CH 2),6.34-6.22(m,1H,CH＝CH 2),6.12(s,2H,OCH 2O),6.02(s,1H,NH 2),5.76-5.61(m,1H,CH＝CH 2),4.95-4.78(m,1.5H,NC H 2C H),4.68-4.55(m,0.5H,NCH 2C H),4.28-4.16(m,0.5H,NC H 2CH),4.10-3.97(m,0.5H,NC H 2CH),3.85-3.69(m,0.5H,NC H 2CH 2),3.45-3.29(m,0.5H,NC H 2CH 2),3.26-3.11(m,0.5H,NC H 2CH 2),2.93-2.79(m,0.5H,NC H 2CH 2),2.49-2.18(m,3H,NCH 2CHC H 2,NH 2),2.07-1.91(m,1H,NCH 2C H 2),1.81-1.64(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 27H 25ClN 7O 4:546.1657；Found:546.1662.
实施例7
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氯苯甲酰胺(Ⅰ-7)的合成
4-氯-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-7)的合成
以化合物Ⅺ(0.80g,3.04mmol)和对氯苯甲酰氯(0.80g,4.56mmol)为原料，操作过程同化合物Ⅳ-1，得白色固体1.02g，产率83.6％，m.p.210-212℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):7.99-7.76(m,4H,ArH),7.60-7.45(m,2H,ArH,NH),7.32-7.26(m,1H,ArH),6.07(s,2H,OCH 2O),1.36(s,12H,4CH 3).
(R)-3-(4-氨基-3-(7-(4-氯苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-7)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和Ⅳ-7(0.87g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体1.14g，m.p.120-122℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.35(s,1H,ArH),7.99(s,1H,NH),7.96-7.81(m,3H,ArH),7.48(d,J＝7.83Hz,2H,ArH),7.13(d,J＝8.43Hz,1H,ArH),6.12(s,2H,OCH 2O),5.87(s,2H,NH 2),4.92-4.77(m,1H,CHC H 2NBoc),4.46-4.23(m,1H,C HCH 2NBoc),4.20-4.02(m,1H,CHC H 2NBoc),3.52-3.28(m,1H,NC H 2CH 2),2.93-2.74(m,1H,NC H 2CH 2),2.37-2.18(m,2H,NCH 2CHC H 2),1.98-1.80(m,1H,NCH 2C H 2),1.79-1.59(m,1H,NCH 2C H 2),1.45(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氯苯甲酰胺(Ⅵ-7)的合成
以化合物Ⅴ-7(1.00g,1.69mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体777mg， 不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氯苯甲酰胺(Ⅰ-7)的合成
以化合物Ⅵ-7(500mg,1.02mmol)和丙烯酰氯(97mg,1.07mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体240mg，产率43.2％，m.p.159.5-161℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.32(d,J＝11.08Hz,1H,ArH),8.13(s,1H,CONH),7.98-7.90(m,1H,ArH),7.87(d,J＝6.92Hz,2H,ArH),7.52(d,J＝7.12Hz,2H,ArH),7.10(d,J＝6.04Hz,1H,ArH),6.67-6.53(m,1H,CH＝CH 2),6.35-6.23(m,1H,CH＝CH 2),6.11(br,3H,OCH 2O,NH),5.76-5.61(m,1H,CH＝CH 2),4.95-4.82(m,1.5H,NC H 2C H),4.67-4.56(m,0.5H,NCH 2C H),4.28-4.15(m,0.5H,NC H 2CH),4.08-3.97(m,0.5H,NC H 2CH),3.85-3.72(m,0.5H,NC H 2CH 2),3.42-3.29(m,0.5H,NC H 2CH 2),3.25-3.13(m,0.5H,NC H 2CH 2),2.93-2.79(m,0.5H,NC H 2CH 2),2.65(s,1H,NH 2),2.47-2.32(m,1H,NCH 2CHC H 2),2.31-2.18(m,1H,NCH 2CHC H 2),2.04-1.92(m,1H,NCH 2C H 2),1.80-1.64(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 27H 25ClN 7O 4:546.1657；Found:546.1655.
实施例8
(R)-N 1-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-N 3-(2,2,2-三氟乙基)间苯二甲酰胺(Ⅰ-8)的合成
3-((7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-氨甲酰基)苯甲酸甲酯(Ⅳ-8)的合成
以化合物Ⅺ(1.00g,3.80mmol)和间苯二甲酸单甲酯(1.03g,5.72mmol)为原料，操作过程同化合物Ⅳ-2，得白色固体1.45g，产率89.7％，不经进一步纯化，直接投下一步。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.51(s,1H,NH),8.22(d,J＝7.77Hz,1H,ArH),8.12(d,J＝7.89Hz,1H,ArH),7.91(s,1H,ArH),7.84(d,J＝8.43Hz,1H,ArH),7.59(t,J＝7.71Hz,1H,ArH),7.29(d,J＝8.49Hz,1H,ArH),6.08(s,2H,OCH 2O),3.96(s,3H,CH 3),1.37(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(3-甲氧羰基苯甲酰胺)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-8)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和Ⅳ-8(1.15g,2.70mmol)为原料，操作过程同化合物Ⅴ-1，得灰色固体1.52g，产物不经纯化，直接投下一步。
(R)-3-((7-(4-氨基-1-(1-叔丁氧羰基)哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)氨基甲酰基)苯甲酸(Ⅴ-8-1)的合成
将化合物Ⅴ-8(1.40g,2.27mmol)、一水合氢氧化锂(0.14g,3.41mmol)和甲醇/水(12mL/4mL)混合，室温搅拌过夜。减压蒸去甲醇，加入水和乙酸乙酯，除去有机层，水层用2mol/L盐酸调pH至3-4，抽滤，烘干得1.13g白色固体，产率82.6％，m.p.168-170℃。
(R)-3-(4-氨基-3-(7-(3-((2,2,2-三氟乙基)氨甲酰基)苯甲酰胺)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-8-2)的合成
将Ⅴ-8-1(900mg,1.50mmol)、HOBt(243mg,1.80mmol)、EDCI(344mg,1.80mmol)溶于5 mL DMF中，加入三乙胺(227mg,2.24mmol)和三氟乙胺(156mg,1.57mmol)，室温搅拌过夜。加入25mL水，乙酸乙酯萃取，有机层水洗(10mL×3),饱和氯化钠洗(10mL×3)，无水硫酸钠干燥。抽滤，滤液减压蒸干，残留物柱层析纯化(洗脱剂:二氯甲烷:甲醇＝100～40:1)得白色固体667mg，产率65.3％，m.p.143-145℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.40(s,1H,ArH),8.32(s,1H,NH),8.27(s,1H,ArH),8.04(q,J＝7.92Hz,2H,ArH),7.76(d,J＝7.92Hz,1H,ArH),7.56(t,J＝7.71Hz,1H,ArH),7.22(s,1H,NH),7.09(d,J＝8.79Hz,1H,ArH),6.06(s,2H,OCH 2O),5.87(s,2H,NH 2),4.88-4.74(m,1H,CHC H 2NBoc),4.37-4.25(m,1H,C HCH 2NBoc),4.21-4.05(m,3H,CHC H 2NBoc,C H 2CF 3),3.49-3.30(m,1H,NC H 2CH 2),2.90-2.74(m,1H,NC H 2CH 2),2.29-2.14(m,2H,NCH 2CHC H 2),1.94-1.81(m,1H,NCH 2C H 2),1.76-1.60(m,1H,NCH 2C H 2),1.43(s,9H,3CH3)。
(R)-N 1-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-N 3-(2,2,2-三氟乙基)间苯二甲酰胺(Ⅵ-8)的合成
以化合物Ⅴ-8-2(550mg,0.81mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体430mg,产率91.62％，不经进一步纯化，直接投下一步。
(R)-N 1-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-N 3-(2,2,2-三氟乙基)间苯二甲酰胺(Ⅰ-8)的合成
以化合物Ⅵ-8(400mg,0.69mmol)和丙烯酰氯(65mg,0.72mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体231mg，产率52.8％，m.p.174-176℃。 1H-NMR(300MHz,DMSO-d 6)δ(ppm):10.43(s,1H,NH),9.30(s,1H,NH),8.50(s,1H,ArH),8.33-8.00(m,2H,ArH),7.66(s,1H,ArH),7.35-6.97(m,2H,ArH),6.95-6.55(m,2H,ArH,CH＝CH 2),6.37-5.92(m,3H,CH＝CH 2,OCH 2O),5.83-5.49(m,1H,CH＝CH 2),4.86-4.46(m,1.5H,NC H 2C H),4.37-3.91(m,3H,NC H 2C H,NHC H 2CF 3),3.79-3.58(m,0.5H,NC H 2CH),3.07-2.84(m,1H,NC H 2CH 2),2.36-2.03(m,2H,NC H 2CH 2,NCH 2CHC H 2),2.02-1.80(m,1H,NCH 2CHC H 2),1.72-1.46(m,1H,NCH 2C H 2),1.36-1.10(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 30H 28F 3N 8O 5:637.2135；Found:637.2134。
实施例9
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-三氟甲基苯甲酰胺(Ⅰ-9)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-三氟甲基苯甲酰胺(Ⅳ-9)的合成
以化合物Ⅺ(0.50g,1.90mmol)和4-三氟甲基苯甲酰氯(0.60g,2.85mmol)为原料，操作过程同化合物Ⅳ-1，得白色固体654mg，产率79.1％，m.p.240-242℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):7.99(d,J＝8.16Hz,2H,ArH),7.88-7.81(m,2H,ArH,NH),7.76(d,J＝8.19Hz,2H,ArH),7.29(d,J＝8.52Hz,1H,ArH),6.08(s,2H,OCH 2O),1.37(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(4-三氟甲基苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d] 嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-9)的合成
以化合物Ⅲ-1(0.50g,1.13mmol)和Ⅳ-9(0.59g,1.35mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体0.62g，产率88.1％，m.p.140-142℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.38(s,1H,ArH),8.05(d,J＝8.13Hz,2H,ArH),8.01-7.95(m,2H,ArH,NH),7.81(d,J＝8.28Hz,2H,ArH),7.18(d,J＝8.73Hz,1H,ArH),6.16(s,2H,OCH 2O),5.74(s,2H,NH 2),4.93-4.81(m,1H,CHC H 2NBoc),4.42-4.27(m,1H,C HCH 2NBoc),4.21-4.10(m,1H,CHC H 2NBoc),3.54-3.39(m,1H,NC H 2CH 2),2.95-2.79(m,1H,NC H 2CH 2),2.35-2.19(m,2H,NCH 2CHC H 2),1.96-1.87(m,1H,NCH 2C H 2),1.78-1.68(m,1H,NCH 2C H 2),1.47(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-三氟甲基苯甲酰胺(Ⅵ-9)的合成
以化合物Ⅴ-9(550mg,0.88mmol)为原料，操作过程同化合物Ⅵ-1的合成过程，得淡黄色固体420mg，产率90.91％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-三氟甲基苯甲酰胺(Ⅰ-9)的合成
以化合物Ⅵ-9(500mg,0.95mmol)和丙烯酰氯(103mg,1.14mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体289mg，产率52.4％，m.p.148.5-150℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.43-8.23(m,2H,ArH,NH),8.05(d,J＝7.62Hz,2H,ArH),7.92-7.81(m,1H,ArH),7.76(d,J＝7.44Hz,2H,ArH),7.20-7.04(m,1H,ArH),6.70-6.48(m,1H,CH＝CH 2),6.35-6.19(m,1H,CH＝CH 2),6.11(s,2H,OCH 2O),5.96(s,1H,NH 2),5.75-5.59(m,1H,CH＝CH 2),4.98-4.75(m,1.5H,NC H 2C H),4.67-4.48(m,0.5H,NCH 2C H),4.30-4.13(m,0.5H,NC H 2CH),4.09-3.92(m,0.5H,NC H 2CH),3.88-3.67(m,0.5H,NC H 2CH 2),3.45-3.28(m,0.5H,NC H 2CH 2),3.26-3.09(m,0.5H,NC H 2CH 2),2.96-2.80(m,0.5H,NC H 2CH 2),2.50-2.31(m,1H,NCH 2CHC H 2),2.29-2.18(m,2H,NCH 2CHC H 2,NH 2),2.07-1.89(m,1H,NCH 2C H 2),1.81-1.60(m,1H,NCH 2C H 2)； 13C-NMR(75MHz,DMSO-d 6)δ(ppm):164.55,163.98,158.03,155.89,155.66,153.71,145.90,140.95,138.29,137.78,128.73,128.32,127.29,125.69,125.40,122.11,120.95,118.82,111.82,101.72,98.64,52.91(0.5C),52.19(0.5C),49.19(0.5C),48.70(0.5C),45.65(0.5C),45.10(0.5C),30.38(0.5C),29.57(0.5C),26.78(0.5C),24.81(0.5C)；HRMS(ESI):m/z[M+H] +.Calcd for C 28H 25F 3N 7O 4:580.1920；Found:580.1918。
实施例10
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲氧基苯甲酰胺(Ⅰ-10)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲氧基苯甲酰胺(Ⅳ-10)的合成
以化合物Ⅺ(1.50g,5.70mmol)和4-甲氧基苯甲酰氯(1.46g,8.55mmol)为原料，操作过程同化合物Ⅳ-1，得白色固体1.92g，产率84.1％，m.p.176-178℃。 1H-NMR(300MHz,CDCl 3)δ(ppm): 7.93-7.81(m,3H,ArH),7.78(br,1H,NH),7.28(d,J＝8.31Hz,1H,ArH),6.97(d,J＝8.58Hz,2H,ArH),6.06(s,2H,OCH 2O),3.87(s,3H,OCH 3),1.36(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(4-甲氧基苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-10)的合成
以化合物Ⅲ-1(1.20g,2.70mmol)和Ⅳ-10(1.29g,3.24mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体1.49g，产率93.7％，m.p.104-106℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.38(s,1H,ArH),8.01(d,J＝8.70Hz,1H,ArH),7.90(d,J＝8.85Hz,2H,ArH),7.87(br,1H,NH),7.15(d,J＝8.70Hz,1H,ArH),7.02(d,J＝8.82Hz,2H,ArH),6.14(s,2H,OCH 2O),5.75(s,2H,NH 2),4.94-4.80(m,1H,CHC H 2NBoc),4.44-4.25(m,1H,C HCH 2NBoc),4.23-4.06(m,1H,CHC H 2NBoc),3.91(s,3H,OCH 3),3.56-3.36(m,1H,NC H 2CH 2),2.93-2.78(m,1H,NC H 2CH 2),2.34-2.17(m,2H,NCH 2CHC H 2),1.98-1.83(m,2H,NCH 2C H 2),1.47(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲氧基苯甲酰胺(Ⅵ-10)的合成
以化合物Ⅴ-10(1.27g,2.17mmol)为原料,操作过程同化合物Ⅵ-1,得淡黄色固体1.04g,产率98.01％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲氧基苯甲酰胺(Ⅰ-10)的合成
以化合物Ⅵ-10(100mg,0.21mmol)和丙烯酰氯(19mg,0.22mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体89mg，产率80.1％，m.p.216-218℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.35(s,1H,ArH),8.02-7.93(m,2H,ArH,NH),7.90(d,J＝7.68Hz,2H,ArH),7.12(d,J＝8.16Hz,1H,ArH),7.00(d,J＝7.74Hz,2H,ArH),6.71-6.51(m,1H,CH＝CH 2),6.38-6.22(m,1H,CH＝CH 2),6.12(s,2H,OCH 2O),5.90(s,1H,NH 2),5.77-5.61(m,1H,CH＝CH 2),4.96-4.80(m,1.5H,NC H 2C H),4.71-4.53(m,0.5H,NCH 2C H),4.29-4.16(m,0.5H,NC H 2CH),4.08-3.98(m,0.5H,NC H 2CH),3.90(s,3H,OCH 3),3.82-3.69(m,0.5H,NC H 2CH 2),3.51-3.32(m,0.5H,NCH 2CH 2),3.29-3.10(m,0.5H,NC H 2CH 2),2.97-2.75(m,0.5H,NC H 2CH 2),2.51-2.35(m,1H,NCH 2CHC H 2),2.35-2.14(m,2H,NCH 2CHC H 2,NH 2),2.09-1.89(m,1H,NCH 2C H 2),1.83-1.64(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 28H 28N 7O 5:542.2152；Found:542.2156。
实施例11
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-叔丁基苯甲酰胺(Ⅰ-11)的合成
4-叔丁基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-11)的合成
以化合物Ⅺ(1.00g,3.80mmol)和4-叔丁基苯甲酸(1.02g,5.70mmol)为原料，操作过程同化合物Ⅳ-2，得白色固体982mg，产率61.0％，m.p.170-172℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):7.91(d,J＝8.52Hz,1H,ArH),7.86(s,1H,NHCO),7.82(d,J＝8.46Hz,2H,ArH),7.51(d,J＝ 8.46Hz,2H,ArH),7.28(d,J＝8.52Hz,1H,ArH),6.07(s,2H,OCH 2O),1.36(s,12H,4CH 3),1.35(s,9H,C(CH 3) 3)。
(R)-3-(4-氨基-3-(7-(4-叔丁基苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-11)的合成
以化合物Ⅲ-1(0.75g,1.69mmol)和Ⅳ-11(0.86g,2.03mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体969mg，产率93.5％，m.p.140-142℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.39(s,1H,ArH),8.07-7.99(m,2H,ArH,NH),7.89(d,J＝8.34Hz,2H,ArH),7.56(d,J＝8.31Hz,2H,ArH),7.16(d,J＝8.67Hz,1H,ArH),6.16(s,2H,OCH 2O),5.93(s,1H,NH 2),4.96-4.82(m,1H,CHC H 2NBoc),4.49-4.10(m,2H,C HC H 2NBoc),3.62-3.32(m,1H,NC H 2CH 2),2.97-2.79(m,1H,NC H 2CH 2),2.27-2.14(m,3H,NCH 2CHC H 2,NH 2),1.99-1.87(m,1H,NCH 2C H 2),1.80-1.68(m,1H,NCH 2C H 2),1.48(s,9H,3CH 3),1.40(s,9H,3CH 3)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-叔丁基苯甲酰胺(Ⅵ-11)的合成
以化合物Ⅴ-11(900mg,1.47mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体697mg，产率92.5％，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-叔丁基苯甲酰胺(Ⅰ-11)的合成
以化合物Ⅵ-11(600mg,1.17mmol)和丙烯酰氯(111mg,1.23mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体242mg，产率36.5％，m.p.136-138℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.32(d,J＝11.08Hz,1H,ArH),8.12(s,1H,NH),7.98-7.89(m,1H,ArH),7.86(d,J＝6.92Hz,2H,ArH),7.52(d,J＝7.12Hz,2H,ArH),7.10(d,J＝6.04Hz,1H,ArH),6.68-6.51(m,1H,CH＝CH 2),6.36-6.21(m,1H,CH＝CH 2),6.17-6.01(m,3H,NH 2,OCH 2O),5.76-5.60(m,1H,CH＝CH 2),4.95-4.78(m,1.5H,NC H 2C H),4.67-4.50(m,0.5H,NCH 2C H),4.29-4.14(m,0.5H,NC H 2CH),4.09-3.95(m,0.5H,NC H 2CH),3.84-3.69(m,0.5H,NC H 2CH 2),3.41-3.27(m,0.5H,NC H 2CH 2),3.24-3.10(m,0.5H,NC H 2CH 2),2.92-2.78(m,0.5H,NC H 2CH 2),2.65(s,1H,NH 2),2.48-2.31(m,1H,NCH 2CHC H 2),2.30-2.16(m,1H,NCH 2CHC H 2),2.04-1.89(m,1H,NCH 2C H 2),1.79-1.61(m,1H,NCH 2C H 2),1.35(s,9H,3CH 3)；HRMS(ESI):m/z[M+H] +.Calcd for C 31H 34N 7O 4:568.2672；Found:568.2674。
实施例12
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3,4-二甲氧基苯甲酰胺(Ⅰ-12)的合成
3,4-二甲氧基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-12)的合成
以化合物Ⅺ(1.00g,3.80mmol)和3,4-二甲氧基苯甲酰氯(1.14g,5.70mmol)为原料，操作过程同化合物Ⅳ-1，得白色固体926mg，产率57.2％，m.p.166-168℃。 1H-NMR(300MHz,CDCl 3) δ(ppm):7.90-7.82(m,2H,ArH,NHCO),7.51(s,1H,ArH),7.41(d,J＝8.31Hz,1H,ArH),7.28(d,J＝8.04Hz,1H,ArH),6.91(d,J＝8.34Hz,1H,ArH),6.07(s,2H,OCH 2O),3.95(s,3H,OCH 3),3.95(s,3H,OCH 3),1.36(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(3,4-二甲氧基苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-12)的合成
以化合物Ⅲ-1(0.70g,1.58mmol)和Ⅳ-12(0.81g,1.89mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体731mg，产率75.1％，m.p.120-122℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.37(s,1H,ArH),8.00(d,J＝8.94Hz,1H,ArH),7.88(s,1H,ArH),7.54(s,1H,NH),7.44(d,J＝8.37Hz,1H,ArH),7.15(d,J＝8.91Hz,1H,ArH),6.94(d,J＝8.01Hz,1H,ArH),6.13(s,2H,OCH 2O),5.78(s,2H,NH 2),4.92-4.78(m,1H,CHC H 2NBoc),4.38-4.24(m,1H,C HCH 2NBoc),4.20-4.08(m,1H,CHC H 2NBoc),3.98(s,3H,OC H 3),3.97(s,3H,OC H 3),3.52-3.37(m,1H,NC H 2CH 2),2.91-2.77(m,1H,NC H 2CH 2),2.33-2.24(m,1H,NCH 2CHC H 2),2.23-2.14(m,1H,NCH 2CHC H 2),1.96-1.84(m,1H,NCH 2C H 2),1.77-1.65(m,1H,NCH 2C H 2),1.45(s,9H,NBoc).
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3,4-二甲氧基苯甲酰胺(Ⅵ-12)的合成
以化合物Ⅴ-12(700mg,1.13mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体587mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3,4-二甲氧基苯甲酰胺(Ⅰ-12)的合成
以化合物Ⅵ-12(537mg,1.04mmol)和丙烯酰氯(99mg,1.09mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体309mg，产率52.1％，m.p.164-165℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.41-8.25(m,1H,ArH),8.05(s,1H,NH),7.94-7.87(m,1H,ArH),7.56-7.51(m,1H,ArH),7.49-7.44(m,1H,ArH),7.11(d,J＝8.64Hz,1H,ArH),6.93(d,J＝8.40Hz,1H,ArH),6.68-6.52(m,1H,CH＝CH 2),6.36-6.23(m,1H,CH＝CH 2),6.12(s,2H,OCH 2O),5.95(br,1H,NH 2),5.78-5.60(m,1H,CH＝CH 2),4.94-4.83(m,1.5H,NC H 2C H),4.66-4.55(m,0.5H,NCH 2C H),4.26-4.17(m,0.5H,NC H 2CH),4.09-4.00(m,0.5H,NC H 2CH),3.96(s,3H,OCH 3),3.96(s,3H,OCH 3),3.83-3.73(m,0.5H,NC H 2CH 2),3.41-3.31(m,0.5H,NC H 2CH 2),3.24-3.13(m,0.5H,NC H 2CH 2),2.94-2.81(m,0.5H,NC H 2CH 2),2.45-2.34(m,1H,NCH 2CHC H 2),2.29-2.23(m,2H,NCH 2CHC H 2,NH 2),2.02-1.94(m,1H,NCH 2C H 2),1.79-1.64(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 29H 30N 7O 6:572.2258；Found:572.2252。
实施例13
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二甲基氨基)苯甲酰胺(Ⅰ-13)的合成
4-(二甲氨基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-13)的合成
以化合物Ⅺ(1.00g,3.80mmol)和4-二甲氨基苯甲酰氯(1.05g,5.70mmol)为原料，操作过程同化合物Ⅳ-1，得白色固体950mg，产率60.9％，不经进一步纯化，直接投下一步。
(R)-3-(4-氨基-3-(7-(4-(二甲氨基)苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-13)的合成
以化合物Ⅲ-1(0.60g,1.35mmol)和Ⅳ-13(0.67g,1.62mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体678mg，产率83.5％，m.p.138-140℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.36(s,1H,ArH),8.04(d,J＝9.03Hz,1H,ArH),7.89-7.76(m,3H,ArH,NH),7.12(d,J＝7.98Hz,1H,ArH),6.73(d,J＝8.61Hz,2H,ArH),6.12(s,2H,OCH 2O),5.75(s,2H,NH 2),4.90-4.79(m,1H,CHC H 2NBoc),4.40-4.26(m,1H,C HCH 2NBoc),4.22-4.06(m,1H,CHC H 2NBoc),3.54-3.35(m,1H,NC H 2CH 2),3.07(s,6H,N(C H 3) 2),2.90-2.74(m,1H,NC H 2CH 2),2.34-2.15(m,2H,NCH 2CHC H 2),1.99-1.82(m,2H,NCH 2C H 2),1.45(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二甲氨基)苯甲酰胺(Ⅵ-13)的合成
以化合物Ⅴ-13(850mg,1.42mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体588mg，产率83.0％，不经进一步纯化,直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二甲基氨基)苯甲酰胺(Ⅰ-13)的合成
以化合物Ⅵ-13(540mg,1.08mmol)和丙烯酰氯(103mg,1.13mmol)为原料，操作过程同目标化合物Ⅰ-1的合成，得白色固体342mg，产率57.2％，m.p.160-162℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.33(s,1H,ArH),8.04-7.88(m,2H,ArH,NH),7.81(d,J＝6.66Hz,2H,ArH),7.09(d,J＝8.07Hz,1H,ArH),6.71(d,J＝6.96Hz,2H,ArH),6.65-6.52(m,1H,CH＝CH 2),6.36-6.21(m,1H,CH＝CH 2),6.17-5.99(m,3H,NH 2,OCH 2O),5.76-5.59(m,1H,CH＝CH 2),4.96-4.79(m,1.5H,NC H 2C H),4.69-4.57(m,0.5H,NCH 2C H),4.28-4.15(m,0.5H,NC H 2CH),4.08-3.96(m,0.5H,NC H 2CH),3.85-3.70(m,0.5H,NC H 2CH 2),3.43-3.28(m,0.5H,NC H 2CH 2),3.24-3.14(m,0.5H,NC H 2CH 2),3.06(s,6H,2CH 3),2.89-2.72(m,1.5H,NC H 2CH 2,NH 2),2.47-2.31(m,1H,NCH 2CHC H 2),2.30-2.16(m,1H,NCH 2CHC H 2),2.04-1.89(m,1H,NCH 2C H 2),1.80-1.61(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 29H 31N 8O 4:555.2468；Found:555.2466。
实施例14
N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二甲基氨基)苯甲酰胺(Ⅰ-14)的合成
3-(4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅲ-2)的合成
以化合物Ⅶ-1(3.00g,11.49mmol)和1-叔丁氧羰基-3-羟基哌啶(Ⅷ-2)(4.63g,22.99mmol)为原料，操作过程同化合物Ⅲ-1，得3.91g白色固体，产率76.5％，m.p.176-178℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.31(s,1H,ArH),6.17(s,2H,NH 2),4.82-4.68(m,1H,CHC H 2N),4.22-4.05(m,1H,C HCH 2N),3.79-3.67(m,1H,CHC H 2N),3.22-3.02(m,1H,CHCH 2CH 2C H 2N), 2.91-2.74(m,1H,CHCH 2CH 2C H 2N),2.19-2.08(m,2H,CHC H 2CH 2CH 2N),1.95-1.81(m,2H,CHCH 2C H 2CH 2N),1.45(s,9H,NBoc)。
3-(4-氨基-3-(7-(4-(二甲氨基)苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-14)的合成
以化合物Ⅲ-2(0.95g,2.14mmol)和Ⅳ-13(1.05g,2.57mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体890mg，产率69.5％，m.p.140-142℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.38(s,1H,ArH),8.04(d,J＝8.73Hz,1H,ArH),7.89(s,1H,NHCO),7.85(d,J＝8.88Hz,2H,ArH),7.15(d,J＝8.70Hz,1H,ArH),6.75(d,J＝8.94Hz,2H,ArH),6.15(s,2H,OCH 2O),5.94(s,2H,NH 2),4.94-4.81(m,1H,NC H 2CH),4.33-4.12(m,2H,NC H 2C H),3.59-3.37(m,1H,NC H 2CH 2),3.10(s,6H,N(CH 3) 2),2.93-2.81(m,1H,NC H 2CH 2),2.27-2.19(m,2H,NCH 2CHC H 2),1.98-1.87(m,1H,NCH 2C H 2),1.78-1.66(m,1H,NCH 2C H 2),1.48(s,9H,NBoc)。
N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二甲氨基)苯甲酰胺(Ⅵ-14)的合成
以化合物Ⅴ-14(850mg,1.42mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体436mg，产率61.6％，不经进一步纯化，直接投下一步。
N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二甲基氨基)苯甲酰胺(Ⅰ-14)的合成
以化合物Ⅵ-14(420mg,0.84mmol)和丙烯酰氯(80mg,0.88mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体213mg，产率45.7％，m.p.160-162℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.33(s,1H,ArH),8.03(d,J＝8.97Hz,1H,ArH),7.86-7.76(m,3H,ArH,NH),7.11(d,J＝8.82Hz,1H,ArH),6.71(d,J＝7.32Hz,2H,ArH),6.67-6.52(m,1H,CH＝CH 2),6.36-6.22(m,1H,CH＝CH 2),6.11(s,2H,OCH 2O),5.97(br,1H,NH 2),5.77-5.63(m,1H,CH＝CH 2),4.97-4.80(m,1.5H,NC H 2C H),4.72-4.58(m,0.5H,NCH 2C H),4.30-4.17(m,0.5H,NC H 2CH),4.11-3.99(m,0.5H,NC H 2CH),3.85-3.65(m,0.5H,NC H 2CH 2),3.48-3.34(m,0.5H,NC H 2CH 2),3.26-3.13(m,0.5H,NC H 2CH 2),3.06(s,6H,N(CH 3) 2),2.93-2.70(m,1.5H,NC H 2CH 2,NH 2),2.46-2.32(m,1H,NCH 2CHC H 2),2.31-2.19(m,1H,NCH 2CHC H 2),2.06-1.92(m,1H,NCH 2C H 2),1.83-1.65(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 29H 31N 8O 4:555.2468；Found:555.2470。
实施例15
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二乙基氨基)苯甲酰胺(Ⅰ-15)的合成
4-(二乙氨基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-15)的合成
以化合物Ⅺ(1.00g,3.80mmol)和4-二乙氨基苯甲酸(1.10g,5.70mmol)为原料，操作过程同化合物Ⅳ-2，得棕色油状物2.04g，不经进一步纯化，直接投下一步。
(R)-3-(4-氨基-3-(7-(4-(二乙氨基)苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d] 嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-15)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和Ⅳ-15(0.95g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体657mg，产率58.0％，m.p.116-118℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.35(s,1H,ArH),8.06(d,J＝8.25Hz,1H,ArH),7.83-7.76(m,3H,ArH,NH),7.12(d,J＝8.52Hz,1H,ArH),6.69(d,J＝8.43Hz,2H,ArH),6.12(s,2H,OCH 2O),6.03(s,2H,NH 2),4.89-4.78(m,1H,CHC H 2NBoc),4.37-4.26(m,1H,C HCH 2NBoc),4.17-4.10(m,1H,CHC H 2NBoc),3.47-3.39(m,5H,NC H 2CH 2,N(C H 2CH 3) 2),2.87-2.80(m,1H,NC H 2CH 2),2.25-2.15(m,2H,NCH 2CHC H 2),1.91-1.84(m,1H,NCH 2C H 2),1.72-1.66(m,1H,NCH 2C H 2),1.45(s,9H,NBoc),1.24-1.19(m,6H,N(CH 2C H 3) 2)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二乙氨基)苯甲酰胺(Ⅵ-15)的合成
以化合物Ⅴ-15(657mg,1.05mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体328mg，产率59.4％，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二乙基氨基)苯甲酰胺(Ⅰ-15)的合成
以化合物Ⅵ-15(300mg,0.57mmol)和丙烯酰氯(54mg,0.60mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体209mg，产率63.2％，m.p.158-160℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.34(s,1H,ArH),8.06-7.95(m,1H,ArH),7.92-7.85(m,1H,ArH),7.85-7.73(m,2H,ArH,NH),7.18-7.03(m,1H,ArH),6.77-6.51(m,3H,ArH,CH＝CH 2),6.39-6.22(m,1H,CH＝CH 2),6.11(s,2H,OCH 2O),6.00(s,1H,NH 2),5.79-5.61(m,1H,CH＝CH 2),4.98-4.79(m,1.5H,NC H 2C H),4.72-4.55(m,0.5H,NCH 2C H),4.31-4.16(m,0.5H,NC H 2CH),4.12-3.96(m,0.5H,NC H 2CH),3.87-3.71(m,0.5H,NC H 2CH 2),3.53-3.30(m,4H,N(C H 2CH 3) 2),3.28-3.12(m,0.5H,NC H 2CH 2),2.94-2.77(m,0.5H,NC H 2CH 2),2.46-2.20(m,3.5H,NC H 2CH 2,NCH 2CHC H 2,NH 2),2.08-1.91(m,1H,NCH 2C H 2),1.84-1.63(m,1H,NCH 2C H 2),1.31-1.15(m,6H,N(CH 2C H 3) 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 31H 35N 8O 4:583.2781；Found:583.2777。
实施例16
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-氯苯并[b]噻吩-2-甲酰胺(Ⅰ-16)的合成
3-氯-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯并[b]噻吩-2-甲酰胺(Ⅳ-16)的合成
以化合物Ⅺ(800mg,3.04mmol)和3-氯苯并[b]噻吩-2-羧酸(1.00g,4.70mmol)为原料，操作过程同化合物Ⅳ-2，得黄色固体1.02g，产率73.4％，不经进一步纯化，直接投下一步。(R)-3-(4-氨基-3-(7-(3-氯苯并[b]噻吩-2-甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-16)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和Ⅳ-16(0.99g,2.16mmol)为原料，操作过程同化合物 Ⅴ-1，得淡黄色固体998mg，产率85.3％，m.p.218-220℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):9.13(s,1H,NH),8.36(s,1H,ArH),8.08(d,J＝8.85Hz,1H,ArH),7.97-7.85(m,2H,ArH),7.58-7.50(m,2H,ArH),7.16(d,J＝8.73Hz,1H,ArH),6.19(s,2H,OCH 2O),5.94(s,2H,NH 2),4.94-4.76(m,1H,CHC H 2NBoc),4.42-4.24(m,1H,C HCH 2NBoc),4.22-4.07(m,1H,CHC H 2NBoc),3.56-3.31(m,1H,NC H 2CH 2),2.93-2.74(m,1H,NC H 2CH 2),2.51-2.35(m,1H,NCH 2CHC H 2),2.24-2.12(m,1H,NCH 2CHC H 2),1.96-1.80(m,1H,NCH 2C H 2),1.78-1.64(m,1H,NCH 2C H 2),1.45(s,9H,3CH 3)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-氯苯并[b]噻吩-2-甲酰胺(Ⅵ-16)的合成
以化合物Ⅴ-16(1.77g,1.47mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体797mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-氯苯并[b]噻吩-2-甲酰胺(Ⅰ-16)的合成
以化合物Ⅵ-16(500mg,0.91mmol)和丙烯酰氯(87mg,0.96mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体312mg，产率56.8％，m.p.172-174℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):9.13(s,1H,NH),8.36(s,1H,ArH),8.08(d,J＝8.64Hz,1H,ArH),7.97-7.91(m,1H,ArH),7.91-7.85(m,1H,ArH),7.59-7.48(m,2H,ArH),7.15(d,J＝8.68Hz,1H,ArH),6.67-6.54(m,1H,CH＝CH 2),6.36-6.24(m,1H,CH＝CH 2),6.19(s,2H,OCH 2O),5.89(s,1H,NH 2),5.77-5.61(m,1H,CH＝CH 2),4.96-4.80(m,1.5H,NC H 2C H),4.69-4.59(m,0.5H,NCH 2C H),4.28-4.16(m,0.5H,NC H 2CH),4.09-3.97(m,0.5H,NC H 2CH),3.86-3.73(m,0.5H,NC H 2CH 2),3.47-3.34(m,0.5H,NC H 2CH 2),3.26-3.15(m,0.5H,NC H 2CH 2),2.93-2.80(m,0.5H,NC H 2CH 2),2.50-2.34(m,1H,NCH 2CHC H 2),2.31-2.22(m,2H,NCH 2CHC H 2,NH 2),2.06-1.93(m,1H,NCH 2C H 2),1.81-1.66(m,1H,NCH 2C H 2)； 13C-NMR(101MHz,CDCl 3)δ(ppm):165.71,158.68,157.87,155.78,155.56,154.14,145.15,138.71,138.35,137.56,136.90,132.84,127.96,127.70,125.71,123.42,123.27,122.93,122.22,119.39,115.63,111.52,102.26,99.65,53.75(0.5C),52.65(0.5C),49.97(0.5C),46.02(0.5C),45.87(0.5C),42.12(0.5C),30.31(0.5C),30.05(0.5C),25.25(0.5C),23.99(0.5C)；HRMS(ESI):m/z[M+H] +.Calcd for C 29H 25ClN 7O 4S:602.1377；Found:602.1378.
实施例17
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1-萘甲酰胺(Ⅰ-17)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1-萘甲酰胺(Ⅳ-17)的合成
以化合物Ⅺ(1.00g,3.80mmol)和1-萘甲酰氯(1.09g,5.70mmol)为原料，操作过程同化合物Ⅳ-1，得红棕色固体1.47g，产率93.0％，m.p.174-176℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.39(d,J＝7.65Hz,1H,ArH),7.95(d,J＝7.92Hz,2H,ArH),7.88(d,J＝6.99Hz,1H,ArH),7.78 (s,1H,NHCO),7.74(d,J＝6.87Hz,1H,ArH),7.60-7.52(m,2H,ArH),7.52-7.42(m,1H,ArH),7.31(d,J＝8.31Hz,1H,ArH),6.01(s,2H,OCH 2O),1.37(s,12H,4CH 3)。
(R)-3-(3-(7-(1-萘甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-17)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和Ⅳ-17(0.90g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体751mg，产率68.6％，m.p.144-146℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.45-8.40(m,1H,ArH),8.36(s,1H,ArH),8.14-8.07(m,1H,ArH),8.00(d,J＝8.22Hz,1H,ArH),7.95-7.90(m,1H,ArH),7.87(s,1H,NH),7.83-7.77(m,1H,ArH),7.62-7.56(m,2H,ArH),7.56-7.52(m,1H,ArH),7.18(d,J＝8.67Hz,1H,ArH),6.10(s,2H,OCH 2O),5.91(s,2H,NH 2),4.92-4.78(m,1H,CHC H 2NBoc),4.39-4.23(m,1H,C HCH 2NBoc),4.21-4.07(m,1H,CHC H 2NBoc),3.56-3.32(m,1H,NC H 2CH 2),2.92-2.75(m,1H,NC H 2CH 2),2.23-2.14(m,2H,NCH 2CHC H 2),1.97-1.82(m,1H,NCH 2C H 2),1.77-1.63(m,1H,NCH 2C H 2),1.45(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1-萘甲酰胺(Ⅵ-17)的合成
以化合物Ⅴ-17(700mg,1.15mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体498mg，产率85.2％，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1-萘甲酰胺(Ⅰ-17)的合成
以化合物Ⅵ-17(441mg,0.87mmol)和丙烯酰氯(83mg,0.91mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体214mg，产率43.8％，m.p.172.0-174℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.42(d,J＝7.98Hz,1H,ArH),8.35(s,1H,ArH),8.09(d,J＝7.38Hz,1H,ArH),8.00(d,J＝8.16Hz,1H,ArH),7.96-7.87(m,2H,ArH,NH),7.80(d,J＝6.72Hz,1H,ArH),7.68-7.47(m,3H,ArH),7.17(d,J＝8.55Hz,1H,ArH),6.68-6.51(m,1H,CH＝CH 2),6.34-6.21(m,1H,CH＝CH 2),6.10(s,2H,OCH 2O),5.88(s,1H,NH 2),5.75-5.61(m,1H,CH＝CH 2),4.98-4.80(m,1.5H,NC H 2C H),4.67-4.54(m,0.5H,NCH 2C H),4.28-4.14(m,0.5H,NC H 2CH),4.07-3.94(m,0.5H,NC H 2CH),3.84-3.68(m,0.5H,NC H 2CH 2),3.42-3.29(m,0.5H,NC H 2CH 2),3.24-3.09(m,0.5H,NC H 2CH 2),2.94-2.78(m,0.5H,NC H 2CH 2),2.47-2.33(m,1H,NCH 2CHC H 2),2.30-2.19(m,1H,NCH 2CHC H 2),2.06(s,1H,NH 2),2.02-1.92(m,1H,NCH 2C H 2),1.82-1.64(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 31H 28N 7O 4:562.2203；Found:562.2199。
实施例18
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘甲酰胺(Ⅰ-18)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘甲酰胺(Ⅳ-18)的合成
以化合物Ⅺ(1.00g,3.80mmol)和2-萘甲酰氯(1.09g,5.70mmol)为原料，操作过程同化合物 Ⅳ-1，得白色固体1.51g，产率95.2％，m.p.152-154℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.40(s,1H,NH),8.02-7.88(m,6H,ArH),7.64-7.55(m,2H,ArH),7.31(d,J＝8.58Hz,1H,ArH),6.11(s,2H,OCH 2O),1.37(s,12H,4CH 3)。
(R)-3-(3-(7-(2-萘甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-18)的合成
以化合物Ⅲ-1(0.75g,1.69mmol)和Ⅳ-18(0.85g,2.03mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体757mg，产率73.8％，m.p.118-120℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.44(s,1H,ArH),8.37(s,1H,ArH),8.12-8.04(m,2H,ArH,NH),8.02-7.89(m,4H,ArH),7.67-7.55(m,2H,ArH),7.17(d,J＝8.76Hz,1H,ArH),6.16(s,2H,OCH 2O),5.76(s,2H,NH 2),4.94-4.78(m,1H,CHC H 2NBoc),4.42-4.24(m,1H,C HCH 2NBoc),4.21-4.04(m,1H,CHC H 2NBoc),3.57-3.37(m,1H,NC H 2CH 2),2.92-2.75(m,1H,NC H 2CH 2),2.34-2.14(m,2H,NCH 2CHC H 2),1.95-1.82(m,1H,NCH 2C H 2),1.77-1.62(m,1H,NCH 2C H 2),1.45(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘甲酰胺(Ⅵ-18)的合成
以化合物Ⅴ-18(700mg,1.15mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体448mg，产率76.6％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘甲酰胺(Ⅰ-18)的合成
以化合物Ⅵ-18(420mg,0.83mmol)和丙烯酰氯(79mg,0.87mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体247mg，产率53.1％，m.p.172.5-174℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.44(s,1H,ArH),8.39-8.30(m,1H,ArH),8.30-8.22(m,1H,ArH),8.05-7.86(m,4H,ArH),7.68-7.53(m,2H,ArH),7.14(d,J＝8.25Hz,1H,ArH),6.68-6.51(m,1H,CH＝CH 2),6.37-6.22(m,1H,CH＝CH 2),6.14(s,2H,OCH 2O),5.97(br,1H,NH 2),5.77-5.61(m,1H,CH＝CH 2),4.97-4.77(m,1.5H,NC H 2C H),4.68-4.55(m,0.5H,NCH 2C H),4.27-4.15(m,0.5H,NC H 2CH),4.09-3.95(m,0.5H,NC H 2CH),3.86-3.69(m,0.5H,NC H 2CH 2),3.44-3.29(m,0.5H,NC H 2CH 2),3.26-3.09(m,0.5H,NC H 2CH 2),2.93-2.76(m,0.5H,NC H 2CH 2),2.49-2.31(m,1H,NCH 2CHC H 2),2.30-2.11(m,2H,NCH 2CHC H 2,NH 2),2.03-1.91(m,1H,NCH 2C H 2),1.79-1.62(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 31H 28N 7O 4:562.2203；Found:562.2205。
实施例19
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲基-1-萘甲酰胺(Ⅰ-19)的合成
4-甲基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1-萘甲酰胺(Ⅳ-19)的合成
以化合物Ⅺ(1.00g,3.80mmol)和4-甲基-1-萘甲酸(1.06g,5.70mmol)为原料，操作过程同化合物Ⅳ-2，得淡黄色固体1.52g，产率92.7％，m.p.142-144℃。 1H-NMR(300MHz,CDCl 3)δ (ppm):8.48-8.39(m,1H,ArH),8.09-8.01(m,1H,ArH),8.00-7.92(m,1H,ArH),7.71(s,1H,NHCO),7.65(d,J＝6.87Hz,1H,ArH),7.61-7.53(m,2H,ArH),7.38-7.27(m,2H,ArH),6.02(s,2H,OCH 2O),2.74(s,3H,CH 3),1.37(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(4-甲基-1-萘甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-19)的合成
以化合物Ⅲ-1(0.73g,1.65mmol)和Ⅳ-19(1.07g,2.48mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体719mg，产率70.0％，m.p.140-142℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.48-8.38(m,1H,ArH),8.29(s,1H,ArH),8.22(s,1H,NH),8.07-7.98(m,1H,ArH),7.97-7.88(m,1H,ArH),7.64(d,J＝7.11Hz,1H,ArH),7.60-7.49(m,2H,ArH),7.28(d,J＝7.35Hz,1H,ArH),7.10(d,J＝8.49Hz,1H,ArH),6.24(br,2H,NH 2),6.03(s,2H,OCH 2O),4.86-4.73(m,1H,CHC H 2NBoc),4.41-4.22(m,1H,C HCH 2NBoc),4.17-3.99(m,1H,CHC H 2NBoc),3.52-3.24(m,1H,NC H 2CH 2),2.82-2.61(m,4H,NC H 2CH 2,CH 3),2.31-2.07(m,2H,NCH 2CHC H 2),1.92-1.76(m,1H,NCH 2C H 2),1.74-1.57(m,1H,NCH 2C H 2),1.44(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲基-1-萘甲酰胺(Ⅵ-19)的合成
以化合物Ⅴ-19(700mg,1.13mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体548mg，产率93.4％，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲基-1-萘甲酰胺(Ⅰ-19)的合成
以化合物Ⅵ-19(500mg,0.96mmol)和丙烯酰氯(91mg,1.01mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体289mg，产率53.3％，m.p.178-179℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.44(s,1H,ArH),8.31(d,J＝7.62Hz,1H,ArH),8.21-7.92(m,3H,ArH,NH),7.68(d,J＝6.48Hz,1H,ArH),7.64-7.49(m,2H,ArH),7.33(d,J＝6.09Hz,1H,ArH),7.13(d,J＝7.17Hz,1H,ArH),6.66-6.48(m,1H,CH＝CH 2),6.31-6.20(m,1H,CH＝CH 2),6.17-5.98(m,3H,OCH 2O,NH 2),5.75-5.57(m,1H,CH＝CH 2),4.95-4.76(m,1.5H,NC H 2C H),4.67-4.50(m,0.5H,NCH 2C H),4.29-4.09(m,0.5H,NC H 2CH),4.08-3.89(m,0.5H,NC H 2CH),3.83-3.64(m,0.5H,NC H 2CH 2),3.42-3.26(m,0.5H,NC H 2CH 2),3.22-3.08(m,0.5H,NC H 2CH 2),2.90-2.79(m,0.5H,NC H 2CH 2),2.73(s,3H,CH 3),2.56-2.17(m,3H,NCH 2CHC H 2,NH 2),2.03-1.87(m,1H,NCH 2C H 2),1.78-1.58(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 32H 30N 7O 4:576.2359；Found:576.2357。
实施例20
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-5,6,7,8-四氢化萘-1-甲酰胺(Ⅰ-20)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-5,6,7,8-四氢化萘-1-甲酰胺(Ⅳ-20)的合成
以化合物Ⅺ(1.00g,3.80mmol)和5,6,7,8-四氢-1-萘甲酸(1.00g,5.70mmol)为原料，操作 过程同化合物Ⅳ-2，得白色固体1.51g，产率94.4％，m.p.168-170℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):7.92(d,J＝8.37Hz,1H,ArH),7.47(s,1H,NHCO),7.33-7.27(m,2H,ArH),7.21-7.14(m,2H,ArH),6.04(s,2H,OCH 2O),3.02-2.77(m,4H,C H 2CH 2CH 2C H 2),1.88-1.73(m,4H,CH 2C H 2C H 2CH 2),1.36(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(5,6,7,8-四氢化萘-1-甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-20)的合成
以化合物Ⅲ-1(0.75g,1.69mmol)和Ⅳ-20(0.85g,2.03mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体784mg，产率75.9％，m.p.150-152℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.36(s,1H,ArH),8.05(d,J＝8.76Hz,1H,ArH),7.56(s,1H,NH),7.37-7.30(m,1H,ArH),7.25-7.10(m,3H,ArH),6.10(s,2H,OCH 2O),5.80(s,2H,NH 2),4.91-4.78(m,1H,CHC H 2NBoc),4.41-4.22(m,1H,C HCH 2NBoc),4.21-4.06(m,1H,CHC H 2NBoc),3.53-3.33(m,1H,NC H 2CH 2),3.05-2.91(m,2H,CH 2C),2.90-2.76(m,3H,CH 2C,NC H 2CH2),2.33-2.15(m,2H,NCH 2CHC H 2),1.96-1.86(m,1H,NCH 2C H 2),1.86-1.76(m,4H,CCH 2C H 2C H 2CH 2C),1.74-1.63(m,1H,NCH 2C H 2),1.45(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-5,6,7,8-四氢化萘-1-甲酰胺(Ⅵ-20)的合成
以化合物Ⅴ-20(700mg,1.14mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体472mg，产率80.62％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-5,6,7,8-四氢化萘-1-甲酰胺(Ⅰ-20)的合成
以化合物Ⅵ-20(420mg,0.82mmol)和丙烯酰氯(78mg,0.86mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体316mg，产率68.1％，m.p.158-160℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.33(s,1H,ArH),8.11-7.92(m,1H,ArH),7.63(s,1H,NH),7.38-7.29(m,1H,ArH),7.24-7.15(m,2H,ArH),7.12(d,J＝8.40Hz,1H,ArH),6.67-6.50(m,1H,CH＝CH 2),6.34-6.20(m,1H,CH＝CH 2),6.09(s,2H,OCH 2O),5.88(br,1H,NH 2),5.75-5.58(m,1H,CH＝CH 2),4.97-4.75(m,1.5H,NC H 2C H),4.69-4.52(m,0.5H,NCH 2C H),4.27-4.13(m,0.5H,NC H 2CH),4.10-3.94(m,0.5H,NC H 2CH),3.86-3.67(m,0.5H,NC H 2CH 2),3.45-3.29(m,0.5H,NC H 2CH 2),3.26-3.11(m,0.5H,NC H 2CH 2),3.03-2.90(m,2H,C H 2CH 2CH 2C H 2),2.89-2.75(m,2.5H,NC H 2CH 2,C H 2CH 2CH 2C H 2),2.46-2.31(m,1H,NCH 2CHC H 2),2.30-2.20(m,1H,NCH 2CHC H 2),2.10(br,1H,NH 2),2.03-1.91(m,1H,NCH 2C H 2),1.86-1.65(m,5H,CH 2C H 2C H 2CH 2,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 31H 32N 7O 4:566.2516；Found:566.2512。
实施例21
(R)-N-(7-(7-(1-丙烯酰基哌啶-3-基)-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1-萘甲酰胺(Ⅰ-21)的合成
(R)-3-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(Ⅲ-3)的合成
将5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(Ⅶ-2)(1.00g,3.85mmol)、(S)-1-叔丁氧羰基-3-羟基哌啶(Ⅷ-1)(1.55g,7.69mmol)、PPh 3(2.02g,7.69mmol)、无水THF(100mL)加入250mL三颈瓶中，氮气保护，冰浴下搅拌30分钟，加入DIAD(1.56g,7.69mmol)，加毕，室温反应18小时。建议蒸去THF，加乙酸乙酯(100mL)溶解，依次用饱和碳酸钠(30mL×3)、水(30mL×3)和饱和氯化钠(30mL×3)洗涤，无水硫酸钠干燥。抽滤，滤液减压蒸除溶剂，残留物柱层析分离(洗脱剂:DCM:MeOH＝150～60:1)，得1.71g白色固体，产率70.6％，m.p.126-128℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.30(s,1H,ArH),7.16(s,1H,ArH),5.92(s,2H,NH 2),4.82-4.66(m,1H,NC H 2CH),4.30-4.11(m,1H,NCH 2C H),4.07-3.94(m,1H,NC H 2CH),3.35-3.19(m,1H,NC H 2CH 2),3.10-2.93(m,1H,NC H 2CH 2),2.24-2.12(m,1H,CHC H 2CH 2),2.09-1.97(m,1H,CHC H 2CH 2),1.91-1.79(m,1H,CHCH 2C H 2),1.78-1.68(m,1H,CHCH 2C H 2),1.49(s,9H,C(CH 3) 3)。
(R)-3-(5-(7-(1-萘甲酰胺)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氨基-7H-吡咯并[2,3-d]嘧啶-7-基)哌啶-1-甲酸叔丁酯(Ⅴ-21)的合成
以化合物Ⅲ-3(0.48g,1.08mmol)和Ⅳ-17(0.54g,1.30mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体353mg，产率53.7％，m.p.124-126℃。
(R)-N-(7-(4-氨基-7-(哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1-萘甲酰胺(Ⅵ-21)的合成
以化合物Ⅴ-21(580mg,0.96mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体340mg，产率70.2％，不经进一步纯化，直接投下一步。
(R)-N-(7-(7-(1-丙烯酰基哌啶-3-基)-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯并[d][1,3]二氧杂环戊烯-4-基)-1-萘甲酰胺(Ⅰ-21)的合成
以化合物Ⅵ-21(337mg,0.67mmol)和丙烯酰氯(65mg,0.70mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体189mg，产率50.7％，m.p.166-167.5℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.43(d,J＝7.41Hz,1H,ArH),8.31(s,1H,ArH),8.06-7.96(m,2H,ArH),7.94-7.84(m,2H,ArH),7.79(d,J＝6.51Hz,1H,ArH),7.65-7.46(m,3H,ArH,NH),7.16(s,1H,ArH),7.01(d,J＝8.49Hz,1H,ArH),6.70-6.54(m,1H,CH＝CH 2),6.37-6.25(m,1H,CH＝CH 2),6.05(s,2H,OCH 2O),5.78-5.65(m,1H,CH＝CH 2),5.40(s,1H,NH 2),4.89-4.53(m,2H,NC H 2C H),4.39-4.23(m,0.5H,NC H 2CH),4.09-3.89(m,0.5H,NC H 2CH),3.44-3.14(m,1.5H,NC H 2CH 2),2.96-2.77(m,0.5H,NC H 2CH 2),2.34-2.24(m,1H,NCH 2CHC H 2),2.22-2.09(m,2H,NCH 2CHC H 2,NH 2),2.02-1.88(m,1H,NCH 2C H 2),1.82-1.65(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 32H 29N 6O 4:561.2250；Found:561.2253。
实施例22
(R)-N-(7-(7-(1-丙烯酰基哌啶-3-基)-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘甲酰胺(Ⅰ-22)的合成
(R)-3-(5-(7-(2-萘甲酰胺)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氨基-7H-吡咯并[2,3-d]嘧啶-7-基)哌 啶-1-甲酸叔丁酯(Ⅴ-22)的合成
以化合物Ⅲ-3(1.00g,2.26mmol)和Ⅳ-18(1.13g,2.71mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体988mg，产率72.2％，m.p.124-126℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.43(s,1H,ArH),8.33(s,1H,ArH),8.09(s,1H,NH),8.03-7.86(m,5H,ArH),7.66-7.55(m,2H,ArH),7.19(s,1H,ArH),7.00(d,J＝8.91Hz,1H,ArH),6.10(s,2H,OCH 2O),5.36(s,2H,NH 2),4.84-4.67(m,1H,CHC H 2N),4.33-4.19(m,1H,C HCH 2N),4.11-3.96(m,1H,CHC H 2N),3.31-3.16(m,1H,NC H 2CH 2),3.02-2.85(m,1H,NC H 2CH 2),2.33-2.15(m,2H,CHC H 2CH 2),2.08-1.99(m,1H,CHCH 2C H 2),1.87-1.78(m,1H,CHCH 2C H 2),1.46(s,9H,C(CH 3) 3)。
(R)-N-(7-(4-氨基-7-(哌啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘甲酰胺(Ⅵ-22)的合成
以化合物Ⅴ-22(988mg,1.63mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体825mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(7-(1-丙烯酰基哌啶-3-基)-4-氨基-7H-吡咯并[2,3-d]嘧啶-5-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘甲酰胺(Ⅰ-22)的合成
以化合物Ⅵ-22(825mg,1.63mmol)和丙烯酰氯(155mg,1.71mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体356mg，产率38.9％，m.p.149.5-151℃。 1H-NMR(400MHz,CDCl 3)δ(ppm):8.44(s,1H,ArH),8.32(s,1H,ArH),8.23(s,1H,NH),8.01-7.88(m,5H,ArH),7.68-7.53(m,2H,ArH),7.23-7.12(m,1H,ArH),6.99(s,1H,ArH),6.70-6.57(m,1H,CH＝CH 2),6.38-6.27(m,1H,CH＝CH 2),6.10(s,2H,OCH 2O),5.78-5.66(m,1H,CH＝CH 2),5.47(s,1H,NH 2),4.91-4.67(m,1.5H,NC H 2C H),4.67-4.55(m,0.5H,NCH 2C H),4.39-4.27(m,0.5H,NC H 2CH),4.08-3.94(m,0.5H,NC H 2CH),3.45-3.33(m,0.5H,NC H 2CH 2),3.31-3.15(m,1H,NC H 2CH 2),2.92-2.79(m,0.5H,NC H 2CH 2),2.42-2.26(m,2H,NCH 2CHC H 2,NH 2),2.23-2.09(m,1H,NCH 2CHC H 2),2.02-1.88(m,1H,NCH 2C H 2),1.83-1.66(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 32H 29N 6O 4:561.2250；Found:561.2254。
实施例23
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-苯基乙酰胺(Ⅰ-23)的合成
2-苯基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)乙酰胺(Ⅳ-23)的合成
将化合物Ⅺ(500mg,1.90mmol)、苯乙酸(388mg,2.85mmol)和1H-苯并三唑-1-基氧三吡咯烷基鏻六氟磷酸盐(PyBOP)(1.48g,2.84mmol)溶于DMF(6mL)中，加入DIEA(491mg,3.80mmol)，室温反应10小时。后处理方法同化合物IV-2，得白色固体215mg，产率29.7％，m.p.152-154℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):7.72(d,J＝8.10Hz,1H,ArH),7.45-7.29(m,5H,ArH),7.20(d,J＝8.46Hz,1H,ArH),7.14(s,1H,CONH),5.96(s,2H,OCH 2O),3.76(s,2H,COCH 2Ph),1.34(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(2-苯基乙酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-23)的合成
以化合物Ⅲ-1(0.20g,0.45mmol)和Ⅳ-23(0.21g,0.54mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体125mg，产率48.5％，m.p.130-132℃。 1H-NMR(300MHz,CDCl 3+D 2O)δ(ppm):8.33(s,1H,ArH),7.83(d,J＝8.67Hz,1H,ArH),7.46-7.30(m,5H,ArH),7.05(d,J＝8.70Hz,1H,ArH),6.00(s,2H,OCH 2O),4.90-4.75(m,1H,CHC H 2NBoc),4.38-4.21(m,1H,C HCH 2NBoc),4.18-4.03(m,1H,CHC H 2NBoc),3.78(s,2H,COC H 2Ph),3.49-3.29(m,1H,NC H 2CH 2),2.89-2.74(m,1H,NC H 2CH 2),2.31-2.10(m,2H,NCH 2CHC H 2),1.91-1.77(m,1H,NCH 2C H 2),1.74-1.57(m,1H,NCH 2C H 2),1.43(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-苯基乙酰胺(Ⅵ-23)的合成
以化合物Ⅴ-23(0.21g,0.37mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体136mg，产率78.51％。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-苯基乙酰胺(Ⅰ-23)的合成
以化合物Ⅵ-23(136mg,0.29mmol)和丙烯酰氯(31mg,0.34mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体61mg，产率40.4％，m.p.118-119.5℃。 1H-NMR(300MHz,CDCl3)δ(ppm):8.36(s,1H,ArH),7.87(d,J＝7.20Hz,1H,ArH),7.51-7.33(m,5H,ArH,NH),7.23(s,1H,NH),7.08(d,J＝8.46Hz,1H,ArH),6.70-6.52(m,1H,CH＝CH 2),6.37-6.23(m,1H,CH＝CH 2),6.03(s,2H,OCH 2O),5.78-5.60(m,3H,CH＝CH 2,NH 2),4.94-4.82(m,1H,NC H 2CH),4.70-4.56(m,0.5H,NCH 2C H),4.29-4.13(m,0.5H,NCH 2C H),4.10-3.96(m,0.5H,NC H 2CH),3.88-3.73(m,2.5H,NC H 2CH,COC H 2Ph),3.46-3.30(m,0.5H,NC H 2CH 2),2.96-2.81(m,0.5H,NC H 2CH 2),2.50-2.35(m,1H,NC H 2CH 2),2.32-2.25(m,1H,NCH 2CHC H 2),2.08-1.94(m,1H,NCH 2CHC H 2),1.93-1.87(m,1H,NCH 2C H 2),1.76-1.66(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 28H 28N 7O 4:526.2203；Found:526.2199.
实施例24
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-[1,1’-联苯]-4-甲酰胺(Ⅰ-24)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-[1,1’-联苯]-4-甲酰胺(Ⅳ-24)的合成
以化合物Ⅺ(1.00g,3.80mmol)和4-苯基苯甲酸(1.13g,5.70mmol)为原料，操作过程同化合物Ⅳ-2，得白色固体1.48g，产率88.1％，m.p.120-122℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.00-7.88(m,4H,ArH),7.72(d,J＝8.01Hz,2H,ArH),7.63(d,J＝6.96Hz,2H,ArH),7.52-7.45(m,2H,ArH,NH),7.43-7.40(m,1H,ArH),7.30(d,J＝8.64Hz,1H,ArH),6.09(s,2H,OCH 2O),1.37(s,12H,4CH 3)。
(R)-3-(3-(7-([1,1’-联苯]-4-基甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-24)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和Ⅳ-24(0.96g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体821mg，产率71.9％，m.p.151-152℃。 1H-NMR(300MHz,CDCl 3+D 2O)δ(ppm):8.36(s,1H,ArH),8.09-7.95(m,3H,ArH),7.79-7.72(m,2H,ArH),7.69-7.61(m,2H,ArH),7.54-7.38(m,3H,ArH),7.16(d,J＝8.16Hz,1H,ArH),6.15(s,2H,OCH 2O),4.96-4.76(m,1H,CHC H 2NBoc),4.40-4.23(m,1H,C HCH 2NBoc),4.19-4.08(m,1H,CHC H 2NBoc),3.59-3.25(m,1H,NC H 2CH 2),2.96-2.74(m,1H,NC H 2CH 2),2.38-2.15(m,2H,NCH 2CHC H 2),1.94-1.86(m,1H,NCH 2C H 2),1.79-1.62(m,1H,NCH 2C H 2),1.45(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-[1,1’-联苯]-4-甲酰胺(Ⅵ-24)的合成
以化合物Ⅴ-24(750mg,1.18mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体468mg，产率74.1％，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-[1,1’-联苯]-4-甲酰胺(Ⅰ-24)的合成
以化合物Ⅵ-24(416mg,0.78mmol)和丙烯酰氯(74mg,0.82mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体212mg，产率46.3％，m.p.216-218℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.37(s,1H,ArH),8.14-7.94(m,4H,ArH,NH),7.74(d,J＝7.65Hz,2H,ArH),7.65(d,J＝7.65Hz,2H,ArH),7.56-7.37(m,3H,ArH),7.15(d,J＝8.67Hz,1H,ArH),6.69-6.51(m,1H,CH＝CH 2),6.35-6.25(m,1H,CH＝CH 2),6.15(s,2H,OCH 2O),5.77(s,1H,NH 2),5.73-5.63(m,1H,CH＝CH 2),4.98-4.82(m,1.5H,NC H 2C H),4.70-4.58(m,0.5H,NCH 2C H),4.27-4.16(m,0.5H,NC H 2CH),4.11-3.99(m,0.5H,NC H 2CH),3.85-3.73(m,0.5H,NC H 2CH 2),3.47-3.35(m,0.5H,NC H 2CH 2),3.26-3.14(m,0.5H,NC H 2CH 2),2.94-2.80(m,0.5H,NC H 2CH 2),2.49-2.34(m,1H,NCH 2CHC H 2),2.31-2.21(m,1H,NCH 2CHC H 2),2.07-1.94(m,1H,NCH 2C H 2),1.88(s,1H,NH 2),1.78-1.65(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 33H 30N 7O 4:588.2359；Found:588.2359。
实施例25
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲氧基苯磺酰胺(Ⅰ-25)的合成
4-甲氧基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯磺酰胺(Ⅳ-25)的合成
将Ⅺ(1.00g,3.80mmol)、吡啶(1.50g,19.00mmol)和二氯甲烷(20mL)混合，冰浴搅拌下，滴加4-甲氧基苯磺酰氯(0.94g,4.56mmol)的二氯甲烷溶液，滴毕，室温反应8.5小时。后处理方法同化合物IV-1，得淡黄色固体985mg，产率59.7％，m.p.186-188℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):7.74(d,J＝8.67Hz,2H,ArH),7.15(d,J＝8.37Hz,1H,ArH),7.02(d,J＝8.28Hz,1H,ArH),6.88(d,J＝8.55Hz,2H,ArH),6.56(s,1H,NH),5.88(s,2H,OCH 2O),3.83(s,3H,OCH 3), 1.33(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(4-甲氧基苯磺酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-25)的合成
以化合物Ⅲ-1(0.46g,1.04mmol)和Ⅳ-25(0.54g,1.24mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体592mg，产率91.5％，m.p.182-184℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.34(s,1H,ArH),7.80(d,J＝8.85Hz,2H,ArH),7.26(s,1H,NH),7.19(d,J＝8.70Hz,1H,ArH),7.03(d,J＝8.70Hz,1H,ArH),6.94(d,J＝8.88Hz,2H,ArH),5.95(s,2H,OCH 2O),5.69(s,2H,NH 2),4.89-4.77(m,1H,CHC H 2NBoc),4.37-4.23(m,1H,C HCH 2NBoc),4.19-4.08(m,1H,CHC H 2NBoc),3.86(s,3H,OMe),3.47-3.33(m,1H,NC H 2CH 2),2.89-2.77(m,1H,NC H 2CH 2),2.27-2.11(m,2H,NCH 2CHC H 2),1.94-1.81(m,2H,NCH 2C H 2),1.44(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲氧基苯磺酰胺(Ⅵ-25)的合成
以化合物Ⅴ-25(500mg,0.80mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色油状物741mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-甲氧基苯磺酰胺(Ⅰ-25)的合成
以化合物Ⅵ-25(500mg,0.96mmol)和丙稀酸(91mg,1.00mmol)为原料，操作过程同化合物Ⅰ-4，得白色固体287mg，产率52.0％，m.p.157.5-159.0℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.32(s,1H,ArH),7.80(d,J＝8.52Hz,2H,ArH),7.18(d,J＝8.88Hz,1H,ArH),7.02(d,J＝8.61Hz,1H,ArH),6.94(d,J＝8.67Hz,2H,ArH),6.68-6.49(m,1H,CH＝CH 2),6.34-6.21(m,1H,CH＝CH 2),5.95(s,2H,OCH 2O),5.86(s,1H,NH 2),5.75-5.60(m,1H,CH＝CH 2),4.96-4.77(m,1.5H,NC H 2C H),4.66-4.53(m,0.5H,NCH 2C H),4.23-4.12(m,0.5H,NC H 2CH),4.08-3.97(m,0.5H,NC H 2CH),3.86(s,3H,OCH 3),3.53-3.43(m,0.5H,NC H 2CH 2),3.39-3.27(m,0.5H,NC H 2CH 2),3.24-3.10(m,0.5H,NC H 2CH 2),2.97-2.78(m,0.5H,NC H 2CH 2),2.46-2.19(m,2H,NCH 2CHC H 2,NH 2),2.11-1.91(m,2H,NCH 2CHC H 2C H 2),1.81-1.64(m,1H,NCH 2CHCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 27H 28N 7O 6S:578.1822；Found:578.1819。
实施例26
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘磺酰胺(Ⅰ-26)的合成
N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)萘-2-磺酰胺(Ⅳ-26)的合成
以化合物Ⅺ(1.00g,3.80mmol)和2-萘磺酰氯(1.29g,5.70mmol)为原料，操作过程同化合物Ⅳ-25，得白色固体1.02g，产率59.2％，m.p.180-182℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.41(s,1H,ArH),7.94-7.84(m,3H,ArH),7.81(d,J＝8.76Hz,1H,ArH),7.66-7.54(m,2H,ArH),7.16-7.07(m,2H,ArH),6.76(s,1H,NHCO),5.80(s,2H,OCH 2O),1.30(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(2-萘磺酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-26)的合成
以化合物Ⅲ-1(0.80g,1.80mmol)和Ⅳ-26(0.98g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体718mg，产率61.9％，m.p.172-174℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.44(s,1H,ArH),8.32(s,1H,ArH),7.99-7.80(m,4H,ArH),7.70-7.57(m,2H,ArH),7.50(s,1H,NH),7.30-7.23(m,1H,ArH),7.03(d,J＝8.46Hz,1H,ArH),5.85(s,2H,OCH 2O),5.66(s,2H,NH 2),4.88-4.73(m,1H,CHC H 2NBoc),4.36-4.19(m,1H,C HCH 2NBoc),4.17-4.03(m,1H,CHC H 2NBoc),3.43-3.28(m,1H,NC H 2CH 2),2.88-2.73(m,1H,NC H 2CH 2),2.25-2.08(m,2H,NCH 2CHC H 2),1.91-1.79(m,1H,NCH 2C H 2),1.73-1.60(m,1H,NCH 2C H 2),1.42(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘磺酰胺(Ⅵ-26)的合成
以化合物Ⅴ-26(907mg,1.41mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体588mg，产率76.7％，不经进一步纯化,直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-2-萘磺酰胺(Ⅰ-26)的合成
以化合物Ⅵ-26(500mg,0.92mmol)和丙烯酰氯(87mg,0.80mmol)为原料，操作过程同目标化合物Ⅰ-1，得白色固体134mg，产率24.3％，m.p.166.5-167℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.44(s,1H,ArH),8.30(d,J＝8.85Hz,1H,ArH),8.02-7.80(m,4H,ArH),7.71-7.54(m,2H,ArH),7.21(d,J＝8.13Hz,1H,ArH),7.00(d,J＝7.95Hz,1H,ArH),6.70-6.46(m,1H,CH＝CH 2),6.38-6.19(m,1H,CH＝CH 2),6.03-5.77(m,3H,NH 2,OCH 2O),5.75-5.59(m,1H,CH＝CH 2),4.92-4.74(m,1.5H,NC H 2C H),4.67-4.52(m,0.5H,NCH 2C H),4.23-4.09(m,0.5H,NC H 2CH),4.08-3.95(m,0.5H,NC H 2CH),3.78-3.63(m,0.5H,NC H 2CH 2),3.38-3.23(m,0.5H,NC H 2CH 2),3.21-3.09(m,0.5H,NC H 2CH 2),2.91-2.76(m,0.5H,NC H 2CH 2),2.45-2.08(m,3H,NCH 2CHC H 2,NH 2),2.03-1.88(m,1H,NCH 2C H 2),1.78-1.52(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 30H 28N 7O 5S:598.1873；Found:598.1873。
实施例27
(R)-N-(7-(4-氨基-1-(1-(2-氰基-3-环丙基丙烯酰基)哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅰ-27)的合成
(R)-N-(7-(4-氨基-1-(1-(2-氰基乙酰基)哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅻ-27)的合成
将化合物Ⅵ-1(300mg,0.66mmol)、氰乙酸(67mg,0.79mmol)、HOBt(133mg,0.98mmol)、EDCI(189mg,0.98mmol)和TEA(133mg,1.31mmol)溶于6mL DMF中，室温搅拌12小时。后处理方法同化合物I-4，得白色固体210mg，产率61.1％，m.p.167.5-169.5℃。 1H-NMR(300MHz,DMSO-d 6)δ(ppm):10.25(s,1H,NH),8.24(d,J＝6.09Hz,1H,ArH),7.99(d,J＝7.95Hz,2H,ArH),7.68-7.49(m,3H,ArH),7.20(d,J＝7.95Hz,1H,ArH),7.10-6.99(m,1H,ArH),6.15(s,2H,OCH 2O), 4.92-4.80(m,0.5H,NC H 2CH),4.77-4.64(m,0.5H,NC H 2CH),4.48-4.38(m,0.5H,NCH 2C H),4.16-4.06(m,2H,CNC H 2CO),4.05-3.99(m,0.5H,NCH 2C H),3.97-3.85(m,0.5H,NC H 2CH),3.80-3.64(m,1H,NC H 2CH,NC H 2CH 2),3.27-3.13(m,1H,NC H 2CH 2),3.06-2.95(m,0.5H,NC H 2CH 2),2.25-2.03(m,2H,NCH 2CHC H 2),1.94-1.54(m,2H,NCH 2C H 2)。
(R)-N-(7-(4-氨基-1-(1-(2-氰基-3-环丙基丙烯酰基)哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅰ-27)的合成
将Ⅻ-27(100mg,0.19mmol)、甲醇(3mL)、哌啶(24mg,0.29mmol)和环丙甲醛(20mg,0.29mmol)混合，室温反应2小时。减压浓缩，用乙酸乙酯溶解，依次用水(10mL×3)、饱和氯化钠(10mL×3)洗涤，减压浓缩得粗品，柱层析(洗脱剂:二氯甲烷:甲醇＝100～60:1)分离得68mg白色固体，产率61.8％，m.p.155.5-157℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.37(s,1H,ArH),8.07(s,1H,NH),8.03-7.92(m,3H,ArH),7.67-7.50(m,3H,ArH),7.16(d,J＝8.61Hz,1H,ArH),6.70-6.49(m,1H,CH＝CH 2),6.15(s,2H,OCH 2O),5.97(s,2H,NH 2),5.04-4.89(m,1H,NC H 2CH),4.69-4.47(m,0.5H,NCH 2C H),4.37-4.18(m,1H,NC H 2C H),3.74-3.48(m,0.5H,NC H 2CH),3.41-3.06(m,1H,NC H 2CH 2),2.52-2.38(m,1H,NC H 2CH 2),2.35-2.24(m,1H,CHC H 2CH 2),2.23-2.12(m,2H,CHC H 2C H 2),2.11-1.99(m,2H,CHCH 2C H 2,C＝CC H),1.93-1.74(m,1H,C＝CCHC H 2CH 2),1.39-1.13(m,3H,C＝CCHC H 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 31H 29N 8O 4:577.2312；Found:577.2318。
实施例28
(S)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-(二甲基氨基)苯甲酰胺(Ⅰ-28)的合成
以(R)-1-叔丁氧羰基-3-羟基哌啶(Ⅷ-3)替换化合物VIII-1，实验操作参照化合物I-1或I-13的制备，得白色固体I-28，m.p.160-162℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.32(s,1H,ArH),8.00(d,J＝8.88Hz,1H,ArH),7.86(s,1H,NH),7.81(d,J＝8.04Hz,2H,ArH),7.10(d,J＝8.73Hz,1H,ArH),6.71(d,J＝8.49Hz,2H,ArH),6.66-6.52(m,1H,CH＝CH 2),6.35-6.22(m,2H,CH＝CH 2,NH 2),6.11(s,2H,OCH 2O),5.75-5.61(m,1H,CH＝CH 2),4.97-4.80(m,1.5H,NC H 2C H),4.70-4.54(m,0.5H,NCH 2C H),4.30-4.14(m,0.5H,NC H 2CH),4.09-3.95(m,0.5H,NC H 2CH),3.86-3.69(m,0.5H,NC H 2CH 2),3.46-3.31(m,0.5H,NC H 2CH 2),3.25-3.13(m,0.5H,NC H 2CH 2),3.06(s,6H,N(CH 3) 2),2.92-2.79(m,1.5H,NC H 2CH 2,NH 2),2.47-2.35(m,1H,NCH 2CHC H 2),2.30-2.17(m,1H,NCH 2CHC H 2),2.08-1.91(m,1H,NCH 2C H 2),1.82-1.64(m,1H,NCH 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 29H 31N 8O 4:555.2468；Found:555.2471。
实施例29
(S)-N-(7-(1-((1-丙烯酰基吡咯烷-2-基)甲基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-二甲氨基苯甲酰胺(Ⅰ-29)的合成
(S)-2-((4-氨基-3-碘-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)吡咯烷-1-甲酸叔丁酯(Ⅲ-5)的合成
将化合物Ⅶ-1(1.50g,5.75mmol)、Boc-L-脯氨醇(Ⅷ-4)(2.31g,11.49mmol)、PPh 3(3.01g, 11.49mmol)和无水THF(100mL)混合，氮气保护，冰浴下搅拌30分钟，加入DIAD(2.32g,11.49mmol)，加毕，室温反应18小时。后处理方法同化合物III-1，得1.48g淡黄色固体，产率58.0％，m.p.176-178℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.36(s,1H,ArH),6.24(s,2H,NH 2),4.65-4.27(m,3H,NC H 2C HNBoc),3.51-3.26(m,2H,CH 2CH 2C H 2NBoc),2.00-1.77(m,4H,C H 2C H 2CH 2NBoc),1.48(s,9H,3CH 3).
(S)-2-((4-氨基-3-(7-(4-(二甲基氨基)苯甲酰氨基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)甲基)吡咯烷-1-甲酸叔丁酯(Ⅴ-29)的合成
以化合物Ⅲ-5(0.80g,1.80mmol)和Ⅳ-13(0.89g,2.16mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体820mg，产率75.8％，m.p.138-140℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.38(s,1H,ArH),8.06(d,J＝8.64Hz,1H,ArH),7.91-7.82(m,3H,ArH,NHCO),7.17(d,J＝8.73Hz,1H,ArH),6.76(d,J＝8.70Hz,2H,ArH),6.15(s,2H,OCH 2O),5.95(br,2H,NH 2),4.72-4.59(m,1H,NC H 2CHNBoc),4.46-4.35(m,1H,NC H 2CHNBoc),3.50-3.38(m,1H,NCH 2C HNBoc),3.35-3.24(m,1H,CH 2CH 2C H 2NBoc),3.11(s,6H,N(CH 3) 2),3.07-3.03(m,1H,CH 2CH 2C H 2NBoc),2.01-1.78(m,4H,C H 2C H 2CH 2NBoc),1.48(s,9H,3CH 3)。
(S)-N-(7-(4-氨基-1-(吡咯烷-2-基甲基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-二甲氨基苯甲酰胺(Ⅵ-29)的合成
以化合物Ⅴ-29(650mg,1.08mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体443mg，产率81.8％，不经进一步纯化,直接投下一步。
(S)-N-(7-(1-((1-丙烯酰基吡咯烷-2-基)甲基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-二甲氨基苯甲酰胺(Ⅰ-29)的合成
以化合物Ⅵ-29(360mg,0.72mmol)和丙烯酰氯(68mg,0.76mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体168mg，产率42.1％，m.p.98-100℃。 1H-NMR(300MHz,CDCl 3+D 2O)δ(ppm):8.28(d,J＝8.19Hz,1H,ArH),7.89-7.72(m,3H,ArH),7.01(d,J＝8.52Hz,1H,ArH),6.64(d,J＝8.52Hz,2H,ArH),6.42-6.31(m,1H,CH＝CH 2),6.28-6.16(m,1H,CH＝CH 2),6.09-5.97(m,2H,OCH 2O),5.71-5.45(m,1H,CH＝CH 2),4.85-4.26(m,5H,NC H 2C HN,NH 2),3.70-3.52(m,1H,NC H 2CH 2),3.48-3.37(m,1H,NC H 2CH 2),3.00(s,6H,2CH 3),2.11-1.53(m,4H,NCH 2C H 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 29H 31N 8O 4:555.2468；Found:555.2471。
实施例30
(R)-N-(7-(1-((1-丙烯酰基吡咯烷-2-基)甲基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-4-二甲氨基苯甲酰胺(Ⅰ-30)的合成
以Boc-D-脯氨醇(VIII-5)替换化合物Ⅷ-4，实验操作参照化合物I-29的制备，得白色固体157mg，产率30.7％，m.p.98-100℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.37(d,J＝7.65Hz,1H,ArH),8.05-7.94(m,2H,ArH,NHCO),7.85(d,J＝8.70Hz,2H,ArH),7.11(d,J＝8.61Hz,1H,ArH),6.74(d,J＝8.79Hz,2H,ArH),6.48-6.41(m,1H,CH＝CH 2),6.38-6.27(m,1H,CH＝CH 2),6.18-6.10(m,3H,NH 2,OCH 2O),5.76-5.58(m,1H,CH＝CH 2),4.81-4.36(m,3H,NC H 2C HN), 3.82-3.61(m,1H,NC H 2CH 2),3.56-3.45(m,1H,NC H 2CH 2),3.09(s,6H,2CH 3),2.73(s,1H,NH 2),2.19-1.79(m,4H,NCH 2C H 2C H 2)；HRMS(ESI):m/z[M+H] +.Calcd for C 29H 31N 8O 4:555.2468；Found:555.2470。
实施例31
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)--5-氟苯并呋喃-2-甲酰胺(Ⅰ-31)合成
4-甲氧基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-5-氟苯并[b]呋喃-2-甲酰胺(Ⅳ-31)的合成
以Ⅺ(321mg,0.12mol)、5-氟苯并[b]呋喃-2甲酸(200mg,0.11mol)为原料，操作过程同化合物Ⅳ-2,得黄色固体407mg，产率87.01％，m.p.92.0-94.0℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.39(s,1H,NHCO),7.94(d,J＝8.49Hz,1H,ArH),7.62(s,1H,ArH),7.56(dd,J＝9.06Hz,1H,ArH),7.41(dd,J＝8.16Hz,1H,ArH),7.34(d,J＝8.49Hz,1H,ArH),7.24(td,J＝9.00Hz,1H,ArH),6.18(s,2H,OCH 2O),1.42(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(5-氟苯并[b]呋喃-2-甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-31)的合成
以化合物Ⅲ-1(345mg,0.78mmol)和Ⅳ-31(300mg,0.7mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体314mg，产率72.86％，m.p.204-206℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):8.40(s,1H,NHCO),8.39(s,1H,ArH),8.05(d,J＝8.7Hz,1H,ArH),7.63(s,1H,ArH),7.56(dd,J＝9.56Hz,1H,ArH),7.40(dd,J＝8.13Hz,1H,ArH),7.23(td,J＝9.00Hz,1H,ArH),7.17(d,J＝8.73Hz,1H,ArH),6.20(s,2H,OCH 2O),5.76(s,2H,NH 2),4.98-4.80(m,1H,CHC H 2NBoc),4.50-4.25(m,1H,C HCH 2NBoc),4.25-4.10(m,1H,CHC H 2NBoc),3.50-3.32(m,1H,NC H 2CH 2),2.95-2.80(m,1H,NC H 2CH 2),2.38-2.26(m,1H,NCH 2CHC H 2),2.25-2.17(m,1.0H,NCH 2CHC H 2,NCH 2C H 2),1.81-1.72(m,1.0H,NCH 2C H 2),1.47(s,9H,NBoc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-5-氟苯并[b]呋喃-2-甲酰胺(Ⅵ-31)的合成
以化合物Ⅴ-31(300mg,0.49mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体206mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-5-氟苯并[b]呋喃-2-甲酰胺(Ⅰ-31)的合成
以化合物Ⅵ-31(200mg,0.39mmol)和丙稀酰氯(37mg,0.4mmol)为原料，操作过程同化合物Ⅰ-1，得白色固体72mg，产率32.3％，m.p.184.0-186.0℃。 1H-NMR(300MHz,CDCl 3)δ(ppm):10.55(s,1H,NHCO),8.26(s,1H,ArH),7.84(s,1H,ArH),7.80(q,J＝9.27Hz,1H,ArH),7.69(q,J＝8.64Hz,1H,ArH),7.40(td,J＝9.21Hz,1H,ArH),7.25(d,J＝8.64Hz,1H,ArH),7.08(d,J＝8.49Hz,1H,ArH),6.95-6.70(m,1H,C H＝CH 2),6.20(s,2H,OCH 2O),6.15-6.04(m,1H,CH＝C H 2),5.86(s,2H,NH 2),5.78-5.60(m,1H,CH＝C H 2),4.79-4.65(m,1H,CHC H 2NBoc), 4.63-4.51(m,0.5H,C HCH 2NBoc),4.35-4.20(m,1H,CHC H 2NBoc),4.18-4.04(m,1H,NC H 2CH),3.81-3.65(m,0.5H,C HCH 2NBoc),3.29-3.22(m,1H,NC H 2CH 2),2.37-2.23(m,1H,NCH 2CHC H 2),2.20-2.10(m,1H,NCH 2CHC H 2),2.00-1.90(m,1H,NCH 2C H 2)，1.72-1.53(m,1H,NCH 2C H 2)。
实施例32
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-苯并[b]噻吩-2-甲酰胺(Ⅰ-32)合成
4-甲氧基-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-苯并[b]噻吩-2-甲酰胺(Ⅳ-32)的合成
以Ⅺ(2.28g,0.018mol)、苯并[b]噻吩-2甲酸(1.63g,0.0091mol)为原料，操作过程同化合物Ⅳ-2,得黄色固体2.78g，产率72.09％，m.p.124-125℃。 1H-NMR(300MHz,CDCl3):δ(ppm):10.56(s,1H,NHCO),8.39(s,1H,ArH),8.08(d,J＝7.08Hz,1H,ArH),8.03(d,1H,J＝6.66Hz),7.58-7.46(m,2H,ArH),7.09(m,2H,ArH),6.12(s,2H,OCH 2O),1.32(s,12H,CH 3)。
(R)-3-(4-氨基-3-(7-(苯并[b]噻吩-2-甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-32)的合成
以化合物Ⅲ-1(1.4g,3.1mmol)和Ⅳ-32(1.2g,2.8mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体834mg，产率48.53％，m.p.126.0-128.0℃。 1H-NMR(300MHz,CDCl3),δ(ppm):8.42(s,1H,NHCO),8.03(d,1H,J＝8.82Hz,ArH),8.00(s,1H,ArH),7.99-7.92(m,3H,ArH),7.58-7.44(m,2H,ArH),7.20(d,1H,J＝8.70Hz,ArH),6.20(s,2H,OCH 2O),5.80(s,2H,NH 2),4.90(m,1H,CHC H 2NBoc),4.52-4.28(m,1H,C HCH 2NBoc),4.27-4.13(m,1H,CHC H 2NBoc),3.62-3.33(m,1H,NC H 2CH 2),2.88(m,1H,NC H 2CH 2),2.40-2.28(m,1H,NCH 2CHC H 2),2.28-2.22(m,1H,NCH 2CHC H 2),1.83-1.74(m,1H,NCH 2C H 2),1.74-1.65(1H,NCH 2C H 2),1.51(s,9H,CH 3)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-苯并[b]噻吩-2-甲酰胺(Ⅵ-32)的合成
以化合物Ⅴ-32(0.8g,1.3mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体301mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-苯并[b]噻吩-2-甲酰胺(Ⅰ-32)的合成
以化合物Ⅵ-32(300mg,0.58mmol)和丙稀酰氯(63mg,0.696mmol)为原料，操作过程同化合物Ⅰ-4，得白色固体79mg，产率24.01％，m.p.162.0-164.0℃。
1H-NMR(300MHz,CDCl3):δ(ppm): 1H-NMR(300MHz,CDCl3),δ(ppm):8.42(s,1H,NHCO),8.03(d,1H,J＝8.91Hz,ArH),8.01(s,1H,ArH),7.98(d,2H,J＝3.57Hz,ArH),7.95(s,1H,ArH),7.52(m,2H,ArH),7.19(d,J＝8.64Hz,1H,ArH),6.75-6.60(m,1H,C H＝CH 2),6.42-6.30(m,1H,CH＝C H 2),6.21(s,2H,OCH 2O),5.85-5.7(m,3H,CH＝C H 2,NH 2),5.01-4.87(m,1.5H,CHC H 2NBoc,C HCH 2NBoc),4.76-4.63(m,0.5H,C HCH 2NBoc),4.32-4.22(m,0.5H,CHC H 2NBoc),4.15-4.04(m,0.5H,CHC H 2NBoc),3.89-3.77(m,0.5H,NC H 2CH 2),3.75-3.52(m, 0.5H,NC H 2CH 2),3.49-3.37(m,0.5H,NC H 2CH 2),3.32-3.18(m,0.5H,NC H 2CH 2),2.99-2.83(m,1H,NCH 2CHC H 2),2.51-2.38(m,1H,NCH 2CHC H 2),2.37-2.21(m,1H,NCH 2C H 2),2.11-1.99(m,1H,NCH 2C H 2)。
实施例33
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-(4-甲基哌嗪-1-基)苯甲酰胺(Ⅰ-33)合成
3-(4-甲基哌嗪-1-基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)-苯甲酰胺(Ⅳ-33)的合成
以Ⅺ(1.43g,0.0055mol)、3-(4-甲基哌嗪-1-基)苯甲酸(1.00g,0.0045mol)为原料，操作过程同化合物Ⅳ-2,得白色固体1.80g，产率85.98％，m.p.142.0-144.0℃。 1H-NMR(300MHz,DMSO):δ(ppm):10.20(s,1H,NHCO),8.41(s,1H,ArH),7.67(d,J＝7.95Hz,1H,ArH),7.52(d,J＝8.46Hz,1H,ArH),7.36-7.30(m,1H,ArH),7.24(s,1H,ArH),7.12(t,J＝7.34Hz,1H,ArH),6.12(s,2H,OCH 2O),3.99(s,3H,NCH 3),1.32(s,12H,CH 3)。
(R)-3-(4-氨基-3-(7-(3-(4-甲基哌嗪-1-基)苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-33)的合成
以化合物Ⅲ-1(0.178g,4mmol)和Ⅳ-33(0.17g,37mmol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体98mg，产率40.42％，m.p.182-184℃。 1H-NMR(300MHz,DMSO),δ(ppm):9.56(s,1H,NHCO),8.41(s,1H,ArH),8.02(d,J＝8.7Hz,1H,ArH),7.93(s,1H,ArH),7.52-7.47(m,1H,ArH),7.35(s,1H,ArH),7.18(d,J＝8.64,1H,ArH),7.13-7.17(m,1H,ArH),6.16(s,2H,OCH 2O),5.78(s,2H,NH 2),4.96-4.83(m,1H,C H 2CHNBoc),4.47-4.27(m,1H,CH 2C HNBoc),4.26-4.17(m,1H,C H 2CHNBoc),3.41-3.35(m,4H,CH 2NCH 2),3.25-3.19(m,4H,C H 2N(CH 3)C H 2),2.95-2.81(m,1H,NC H 2CH 2),2.49(s,3H,NC H 3),2.40-2.29(m,1H,NC H 2CH 2),2.28-2.19(m,1.5H,NCH 2CHC H 2,NCH 2C H 2),1.79-1.69(m,1.5H,NCH 2C H 2),1.49(s,9H,Boc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-(4-甲基哌嗪-1-基)苯甲酰胺(Ⅵ-33)的合成
以化合物Ⅴ-33(98mg,17mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体80mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-(4-甲基哌嗪-1-基)苯甲酰胺(Ⅰ-33)合成
以化合物Ⅵ-33(80mg,0.14mmol)和丙稀酰氯(15mg,0.16mmol)为原料，操作过程同化合物Ⅰ-4，得白色固体49mg，产率55.85％，m.p.152.0-154.0℃。 1H-NMR(300MHz,DMSO),δ(ppm):10.23(s,1H,NHCO),8.41(s,1H,ArH),8.04(d,J＝8.7Hz,1H,ArH),7.52-7.47(m,1H,ArH),7.33(d,J＝7.08Hz,1H,ArH),7.18(d,1H,J＝8.7Hz,ArH),7.16(s,1H,ArH),7.12-7.07(m,1H,ArH),6.71-6.58(m,1H,C H＝CH 2),6.39-6.29(m,1H,CH＝C H 2),6.16(s,2H,OCH 2O),5.80-5.66(m,3H,NH 2,CH＝C H 2),4.99-4.85(m,1.5H,C H 2CHNBoc,CH 2C HNBoc),4.72-4.62(m,0.5H, CH 2C HNBoc),4.30-4.20(m,0.5H,C H 2CHNBoc),4.15-4.02(m,0.5H,C H 2CHNBoc),3.86-3.73(m,0.5H,NC H 2CH 2),3.41-3.36(m,4H,CH 2NCH 2),3.25-3.19(m,4H,CH 2N(CH 3)CH 2),2.97-2.84(m,0.5H,NC H 2CH 2),2.49(s,3H,CH 3),2.45-2.36(m,1H,NC H 2CH 2),2.35-2.26(m,1H,C H 2CHNBoc),2.08-1.99(m,1H,NC H 2CHCH 2),1.79-1.70(m,2H,NC H 2CHCH 2)。
实施例34
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-(吗啉甲基)苯甲酰胺(Ⅰ-34)合成
3-(吗啉甲基)-N-(7-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯并[d][1,3]二氧杂环戊烯-4-基)苯甲酰胺(Ⅳ-34)的合成
以Ⅺ(0.65g,0.0025mol)、3-(吗啉甲基)苯甲酸(0.5g,0.0023mol)为原料，操作过程同化合物Ⅳ-2,得白色固体732mg，产率73.32％，m.p.192-194℃。 1H-NMR(300MHz,DMSO):δ(ppm):10.21(s,1H,NHCO),7.92(s,1H,ArH),7.89(d,J＝8.31Hz,1H,ArH),7.56(d,J＝6.69Hz,1H,ArH),7.50(t,J＝7.77Hz,1H,ArH),7.09(d,J＝7.86Hz,1H,ArH),7.04(d,J＝8.31Hz,1H,ArH),6.09(s,2H,OCH 2O),5.73(s,2H,NH 2),3.66-3.60(m,4H,C H 2NC H 2),3.56(s,2H,CH 2),2.46-2.36(m,4H,C H 2OC H 2),1.32(s,12H,4CH 3)。
(R)-3-(4-氨基-3-(7-(3-(吗啉甲基)苯甲酰胺基)苯并[d][1,3]二氧杂环戊烯-4-基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯(Ⅴ-34)的合成
以化合物Ⅲ-1(0.77g,0.0017mol)和Ⅳ-34(0.7g,0.0016mol)为原料，操作过程同化合物Ⅴ-1，得淡黄色固体546mg，产率51.99％，m.p.182-184℃。 1H-NMR(300MHz,DMSO),δ(ppm):10.28(s,1H,NHCO),8.27(s,1H,ArH),8.03-7.86(m,2H,ArH),7.69-7.46(m,2H,ArH),7.22(d,J＝7.95Hz,1H,ArH),7.07(d,J＝7.62Hz,1H,ArH),6.98-6.73(m,1H,C H＝CH 2),6.28-6.02(m,3H,OCH 2O,CH＝C H 2),5.75(s,2H,NH 2)5.85-5.58(m,1H,CH＝C H 2),4.83-4.66(m,1H,C H 2CHNBoc),4.54-4.65(m,0.5H,CH 2C HNBoc),4.38-4.20(m,1H,C H 2CHNBoc),4.20-4.02(m,0.5H,CH 2C HNBoc),3.82-3.70(m,0.5H,NC H 2CH 2),3.71-3.53(m,4H,CH 2NCH 2),3.59(s,2H,CH 2),3.31-3.16(m,1H,NC H 2CH 2),3.09-2.92(m,0.5H,NC H 2CH 2)2.50-2.42(m,4H,CH 2OCH 2),2.35-2.23(m,1H,NCH 2CHC H 2)2.22-2.19(m,1H,NCH 2CHC H 2),2.06-1.90(m,1H,NCH 2C H 2),1.75-1.54(m,1H,NCH 2C H 2),1.42(s,9H,Boc)。
(R)-N-(7-(4-氨基-1-(哌啶-3-基)-1H-吡唑[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-(吗啉甲基)苯甲酰胺(Ⅵ-34)的合成
以化合物Ⅴ-34(0.54g,082mmol)为原料，操作过程同化合物Ⅵ-1，得淡黄色固体472mg，不经进一步纯化，直接投下一步。
(R)-N-(7-(1-(1-丙烯酰基哌啶-3-基)-4-氨基-1H-吡唑并[3,4-d]嘧啶-3-基)苯并[d][1,3]二氧杂环戊烯-4-基)-3-(吗啉甲基)苯甲酰胺(Ⅰ-34)的合成
以化合物Ⅵ-34(400mg,0.72mmol)和丙稀酰氯(72mg,0.79mmol)为原料，操作过程同化合物Ⅰ-4，得白色固体225mg，产率46.67％，m.p.148.0-150.0℃。 1H-NMR(300MHz,DMSO),δ(ppm): 10.25(s,1H,NHCO),8.24(s,1H,ArH),7.93(s,1H,ArH),7.92-7.87(m,1H,ArH)7.57-7.53(m,1H,ArH),7.50(t,J＝7.44Hz,1H,ArH),7.18(d,J＝8.58Hz,1H,ArH),7.05(d,J＝8.55Hz,1H,ArH),6.93-6.71(m,1H,C H＝CH 2),6.14(s,2H,OCH 2O),6.13-6.03(m,1H,CH＝C H 2),5.78(s,2H,NH 2),5.75-5.59(m,1H,CH＝C H 2),4.78-4.65(m,1H,C H 2CHNBoc),4.62-4.53(m,0.5H,CH 2C HNBoc),4.31-4.18(m,1H,C H 2CHNBoc),4.15-4.08(m,0.5H,CH 2C HNBoc),3.74-3.64(m,1H,NC H 2CH 2),3.63-3.58(m,4H,C H 2NC H 2),3.57-3.54(s,2H,CH 2),3.27-3.20(m,1H,NC H 2CH 2),2.45-2.35(m,4H,C H 2OC H 2),2.31-2.21(m,1H,NCH 2CHC H 2),2.17-2.08(m,1H,NCH 2CHC H 2),1.98-1.88(m,1H,NCH 2C H 2),1.69-1.52(m,1H,NCH 2C H 2)
实施例35
上述制备所得部分化合物的药理学实验及结果如下：
1.BTK、JAK3激酶抑制活性实验
实验方法：384孔反应板分为化合物孔(10μM起始，3倍稀释共10个浓度)、阳性对照孔和阴性对照孔，化合物孔和阳性对照孔加入激酶溶液，阴性对照孔加入1×kinase buffer，离心30秒后室温孵育10min。加入15μL的ATP和底物的混合溶液，离心后震荡混匀室温孵育(JAK3孵育30分钟，BTK孵育20分钟)。加入终止检测液停止反应，用Caliper EZ reader读取转化率。
[根据细则26改正08.04.2022]　
数据分析：计算公式
Figure WO-DOC-FIGURE-42
其中：Conversion％_sample是样品的转化率读数；Conversion％_min是阴性对照孔均值，代表没加酶孔的转化率读数；Conversion％_max是阳性对照比值孔均值，代表没加化合物孔的转化率读数。
拟合量效曲线：以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。
实验结果：对本发明部分化合物进行体外BTK、JAK3激酶抑制活性的筛选，结果见表1。
注：A:IC 50:0.001～0.05μM；B:IC 50:0.05～0.5μM；C:IC 50:>0.5μM。
表1.部分化合物对BTK、JAK3激酶的抑制活性
Figure PCTCN2022082684-appb-000017
Figure PCTCN2022082684-appb-000018
表1结果显示，本发明化合物对BTK、JAK3激酶均有较好的抑制活性，其中化合物I-6、I-7、I-10、I-11、I-13～I-22、I-32对BTK和JAK3呈现出良好的抑制活性。
2.化合物对BaF3-TEL-JAK3和Daudi细胞的增殖抑制作用
实验过程：将处于对数生长期的细胞以一定数量接种于96孔板37℃培养后加药。药物作用72h后，将96孔细胞板平衡至室温后，每孔加40μL Cell
Figure PCTCN2022082684-appb-000019
试剂，振摇2分钟静置10分钟；用MD SpectraMax Paradigm酶标仪检测化学发光信号。
[根据细则26改正08.04.2022]　
数据分析：计算公式
Figure WO-DOC-FIGURE-43
Max signal:DMSO信号；Min signal:介质信号。
使用GraphPad Prism 5计算IC 50。
注：A:IC 50:0.01～0.5μM,B:IC 50:0.5～1μM,C:IC 50:>1μM。
表2.部分化合物对BaF3-JAK3和Daudi细胞的增殖抑制活性
Figure PCTCN2022082684-appb-000021
Figure PCTCN2022082684-appb-000022
实验结果显示，受试化合物对BaF3-JAK3的细胞增殖抑制活性明显优于依鲁替尼；受试化合物对BTK高表达的Daudi细胞表现出较好的增殖抑制能力，部分受试化合物对Daudi细胞的增殖抑制活性优于依鲁替尼。

Claims (15)

  1. 通式(I)的化合物或其药学上可接受的盐：
    Figure PCTCN2022082684-appb-100001
    其中：X代表N或CH；A代表O、S、-NHCO-、-NHCOCH 2-或-NHSO 2-；m代表0或1，n代表0或1；
    R 1代表：
    Figure PCTCN2022082684-appb-100002
    Figure PCTCN2022082684-appb-100003
    其中p代表0或1；R 4代表H、F、Cl、Br、I、C1-C6烷基、CF 3、OH、C1-C6烷氧基、OCF 3、CN、NO 2、NH 2、C1-C6的烷胺基、N(CH 3) 2、N(C 2H 5) 2、NHCOCH 3、CONH 2、CONHCH 3、CONHCH 2CF 3、OCH 2CH 2OCH 3、C 6H 5、
    Figure PCTCN2022082684-appb-100004
    R 4可以是单取代、双取代或三取代；Y 1、Y 2、Y 3、Y 4代表N或C-R 5，R 5代表H、F、Cl、Br、I、CH 3、CF 3、OH、OCH 3、OCF 3或CN；Z代表O、S或N-R 6，R 6代表H、CH 3、C 2H 5或环丙基；
    R 2代表H、Cl、Br或CN；
    R 3代表H、取代的C1-C6的烷基、取代的C2-C6的杂环烷基，其中所述取代基为OH、NH 2、OCH 3、NHCH 3或NHCOCH 3，所述杂环烷基为含有1～3个O、N或S原子的四元、五元或六元饱和杂环烷基。
  2. 权利要求1的化合物或其药学上可接受的盐，其特征在于，A代表-NHCO-或-NHSO 2-；m代表1，n代表0；R 2、R 3代表H。
  3. 权利要求1的化合物或其药学上可接受的盐，其特征在于，A代表-NHCO-或-NHSO 2-；m＝0，n＝1；R 2、R 3代表H。
  4. 权利要求1的化合物或其药学上可接受的盐，其特征在于，所述化合物具有如下结构通式(II)：
    Figure PCTCN2022082684-appb-100005
    Figure PCTCN2022082684-appb-100006
    其中：X和R 1的定义同权利要求1。
  5. 权利要求4的化合物或其药学上可接受的盐，其特征在于，R 1代表
    Figure PCTCN2022082684-appb-100007
    Figure PCTCN2022082684-appb-100008
    Figure PCTCN2022082684-appb-100009
    其中R 7代表H、F、Cl、Br、CH 3、t-Bu、CF 3、CN、OH、OCH 3、OCF 3、NH 2、N(CH 3) 2、N(C 2H 5) 2、NHCOCH 3、CONH 2、CONHCH 3、CONHCH 2CF 3、C 6H 5、
    Figure PCTCN2022082684-appb-100010
    R 7可以是单取代、双取代或三取代，R 8代表H、Cl或CH 3。
  6. 权利要求5的化合物或其药学上可接受的盐，其中R 7代表H、Cl、CH 3、t-Bu、CF 3、OCH 3、N(CH 3) 2、N(C 2H 5) 2或CONHCH 2CF 3，R 7可以是单取代、双取代或三取代，R 8代表Cl。
  7. 权利要求1的化合物或其药学上可接受的盐，其特征在于，所述化合物为I-1、I-2、I-3、I-4、I-5、I-6、I-7、I-8、I-9、I-10、I-11、I-12、I-13、I-14、I-15、I-16、I-17、I-18、I-19、I-20、I-21、I-22、I-23、I-24、I-25、I-26、I-27、I-28、I-29、I-30、I-31、I-32、I-33或I-34。
  8. 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权利要求1的通式(I)化合物与下列酸形成的酸加成盐：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。
  9. 一种药物组合物，其特征在于，其包含权利要求1～8中任一项的化合物或其药学上可接受的盐，以及药学上可接受的载体。
  10. 权利要求1的化合物的制备方法，其化学反应路线如下：
    Figure PCTCN2022082684-appb-100011
    Figure PCTCN2022082684-appb-100012
    其中，R 1、R 2、R 3、X、A、m和n的定义同权利要求1。
  11. 权利要求10的制备方法，其还包括通式(III)的化合物的制备步骤，所述步骤的化学反应路线如下：
    Figure PCTCN2022082684-appb-100013
    其中，X、m和n的定义同权利要求1。
  12. 权利要求10的制备方法，其还包括通式(IV)的化合物的制备步骤，所述步骤的化学反应路线如下：
    Figure PCTCN2022082684-appb-100014
    其中，A选自-NHCO-、-NHCOCH 2-或-NHSO 2-，R 1的定义同权利要求1。
  13. 权利要求1～8中任一项的化合物或其药学上可接受的盐在制备BTK和/或JAK3抑制剂药物中的用途。
  14. 权利要求13的用途，其是权利要求1～8中任一项的化合物或其药学上可接受的盐在制备BTK和JAK3双靶点抑制剂药物中的用途。
  15. 权利要求14的用途，其中，所述的BTK和JAK3双靶点抑制剂药物是治疗类风湿性关节炎或B细胞淋巴瘤的药物。
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