WO2016192667A1 - 一种噻唑并嘧啶酮化合物及其制备方法和应用 - Google Patents

一种噻唑并嘧啶酮化合物及其制备方法和应用 Download PDF

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WO2016192667A1
WO2016192667A1 PCT/CN2016/084691 CN2016084691W WO2016192667A1 WO 2016192667 A1 WO2016192667 A1 WO 2016192667A1 CN 2016084691 W CN2016084691 W CN 2016084691W WO 2016192667 A1 WO2016192667 A1 WO 2016192667A1
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substituted
halogen
alkyl
alkoxy
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王克威
孙崎
焦文宣
唐婧姝
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北京大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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  • the present invention relates to a thiazolopyrimidinone compound, a process for its preparation, and its use in the preparation of a medicament for the treatment of diseases of the central nervous system.
  • Alzheimer's disease also known as Alzheimer's disease
  • nAChRs nicotinic acetylcholine receptor
  • ⁇ 7 nicotinic acetylcholine receptor positive allosteric modulator has increased learning and memory.
  • mice lacking the nAChR ⁇ 7 subunit are compared with the control group containing ⁇ 7nAChR subunit mice. Learning memory ability is reduced in the water maze experiment.
  • the ⁇ 7 nicotine acetylcholine receptor positive allosteric modulators act differently than agonists, are less prone to desensitization, and the potential toxic side effects are greatly reduced.
  • nAChRPAMs ⁇ 7 nicotine acetylcholine receptor positive allosteric modulators
  • the present invention provides a thiazolopyrimidinone compound having a structure represented by the formula (I):
  • R 3 is selected from H, C1-C12 hydrocarbyl, phenyl, substituted by one or more of halogen, hydroxy, carboxy, ester, C1-C4 alkyl and C1-C4 alkoxy. Phenyl, and 5- or 6-membered heterocyclic rings;
  • R 2 is selected from the group consisting of H, C1-C12 hydrocarbyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, phenyl, halogen, hydroxy, carboxy, ester, C1-C4 alkyl and One or more substituted phenyl, benzyl, in the C1-C4 alkoxy group, substituted by one or more of halogen, hydroxy, carboxy, ester, C1-C4 alkyl and C1-C4 alkoxy a benzyl, five- or six-membered heterocyclic ring, and a five- or six-membered heterocyclic ring substituted with one or more of a halogen, a hydroxyl group, a carboxyl group, an ester group, a C1-C4 alkyl group, and a C1-C4 alkoxy group;
  • R 1 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, phenyl, halogen, ester, carboxyl, C1-C4 alkyl and C1 One or more substituted phenyl groups in the -C4 alkoxy group, a phenylthio group, a benzene sulfide substituted with one or more of a halogen, an ester group, a carboxyl group, a C1-C4 alkyl group, and a C1-C4 alkoxy group.
  • a benzylthio group an arylamino group substituted by one or more of a halogen, an ester group, a carboxyl group, a C1-C4 alkyl group and a C1-C4 alkoxy group, a halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a five- or six-membered heterocyclic ring, and an arylamino group, an arylformylamino group, and a substituted one or more of a five- or six-membered heterocyclic ring substituted with a C1-C4 alkyl group or a hydroxy group a halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a five- or six-membered heterocyclic ring, and one or more substituted by one or more of a five- or six-membered heterocyclic ring substituted with a C1
  • R 1 is selected from a C1-C6 alkylthio group, a C1-C6 alkylamino group, a phenyl group, a halogen, One or more substituted phenyl groups of ester group, carboxyl group, C1-C4 alkyl group and C1-C4 alkoxy group, phenylthio group, halogen, ester group, carboxyl group, C1-C4 alkyl group and C1-C4 alkane One or more substituted phenylthio groups in the oxy group, benzylthio group, benzylthio group substituted by one or more of halogen, ester group, carboxyl group, C1-C4 alkyl group and C1-C4 alkoxy group, An arylamino group, one or more of a halogen
  • R 2 is selected from benzene substituted by one or more of halogen, hydroxy, carboxy, ester, C1-C4 alkyl and C1-C4 alkoxy Base;
  • R 3 is H.
  • the invention also provides a preparation method of the thiazolopyrimidinone compound represented by the formula (I), which comprises:
  • the above-mentioned ring-closing product IV is Is a compound of formula (I); or
  • R1 is prepared as a C1-C6 alkylamino group, a phenyl group, a phenyl group substituted with one or more of a halogen, an ester group, a carboxyl group, a C1-C4 alkyl group and a C1-C4 alkoxy group, a phenylthio group, which is halogenated One or more substituted phenylthio groups, arylamino groups, ester groups, carboxyl groups, C1-C4 alkyl groups and C1-C4 alkoxy groups, halogen, C1-C4 alkyl group, C1-C4 alkoxy group, five a ternary or six-membered heterocyclic ring and an arylamino group substituted with one or more of a five- or six-membered heterocyclic ring substituted by a C1-C4 alkyl group or a hydroxy group, an arylcarbonylamino group, or a
  • the amide reacts to form a compound of formula (I);
  • R 1 ' in the compounds III, IV, V is selected from a C1-C6 alkyl group, a phenyl group, one or more selected from the group consisting of halogen, ester group, carboxyl group, C1-C4 alkyl group and C1-C4 alkoxy group.
  • halogen one or more substituted five- or six-membered heterocyclic rings of a hydroxyl group, a carboxyl group, an ester group, a C1-C4 alkyl group, and a C1-C4 alkoxy group.
  • the preparation method can be any one of the following four synthetic routes.
  • the substituent represents a C1-C6 alkylamino group, an arylamino group, a halogen or a C1-C4 alkyl group, a C1-C4 alkoxy group, a five- or six-membered heterocyclic ring, and a five- or six-membered heterocyclic group substituted by a C1-C4 alkyl group or a hydroxyl group.
  • the present invention also provides the use of the thiazolopyrimidinone compound represented by the formula (I) for the preparation of a medicament for treating diseases of the central nervous system.
  • the present invention also provides a method of treating a central nervous system disease comprising administering a thiazolopyrimidinone compound of the formula (I) of the present invention to a subject in need thereof.
  • the present invention also provides a thiazolopyrimidinone compound of the formula (I) for use in the treatment of diseases of the central nervous system.
  • the present invention also provides the use of the thiazolopyrimidinone compound of the formula (I) of the present invention for the preparation of a positive allosteric modulator of the ⁇ 7 nicotine acetylcholine receptor.
  • the present invention also provides a thiazolopyrimidinone compound of the formula (I) of the present invention as a positive allosteric modulator of the ⁇ 7 nicotine acetylcholine receptor.
  • the thiazolopyrimidinone compound of the present invention has the following beneficial effects: the ⁇ 7 nicotine acetylcholine receptor positive allosteric modulator has a strong activity, the EC 50 value is 0.1-100 ⁇ M, and the activity-concentration dose-effect relationship is obvious; High, no effect on other subtypes; no effect on hERG ion channels expressed by CHO cells, and low risk of cardiotoxicity.
  • Figure 1 is a graph showing the rate of substitution of [ 3 H]-Methyllycaconitine radioligand bound to the rat brain cell membrane with increasing concentrations of endogenous ligand antagonist PNU-282987 or LD486;
  • Figure 2 is the patch clamp response intensity of frog egg cells in 100 ⁇ M ACh without adding LD486 and adding different concentrations of LD486;
  • Figure 3 is a concentration response curve of LD486
  • the left panel of Figure 4 is the response intensity of frog egg cells to ⁇ 4 ⁇ 2 and ⁇ 3 ⁇ 4 stimulated by 30 ⁇ M ACh.
  • the right panel shows the response intensity of frog egg cells to ⁇ 4 ⁇ 2 and ⁇ 3 ⁇ 4 stimulated by 30 ⁇ M ACh and 10 ⁇ M LD486.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824. Reddish brown solid, yield 85.5%, m.p. 194-197 ° C, mp. JWX-A1106.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824. Yellow-green solid, yield 34.7%, m.p. 169-177 ° C, denoted JWX-A1114.
  • JWX-A1211 The synthesis method is the same as the compound JWX-A0824. Brown solid, yield 78.3%, m.p. 203-209 ° C, hereinafter referred to as JWX-A1211.
  • the synthesis method is the same as the compound JWX-A0824.
  • JWX-A1218 The synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound LD486.
  • the yield was 65.0%, m.p. was 335-337 ° C, and was designated as JWX-A0912.
  • the synthesis method is the same as the compound LD486. Gray solid, yield 99.9%, m.p. 272-274 ° C, designated JWX-A0918.
  • the synthesis method is the same as the compound JWX-A0728.
  • JWX-A1022 The synthesis method is the same as the compound JWX-A0728. White solid, yield 95.4%, m.p. 325-327 ° C, hereinafter referred to as JWX-A1022.
  • the synthesis method is the same as the compound JWX-A0824.
  • a white solid was obtained in a yield of 73.0%, m.p. from 151 to 153.
  • the synthesis method was the same as the compound JWX-A0828, and it was designated as LD-286.
  • the synthesis method was the same as the compound JWX-A0828, and it was designated as LD-293.
  • the synthesis was the same as the compound A2 to give a white flaky solid, yield 98.0%, which was designated as C2.
  • the crude product was directly purified without further purification.
  • the synthesis method is the same as the compound JWX-A1228. Light yellow solid, yield 60.7%, m.p. 193-196 ° C, mp. JWX-A1229.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0828. Light yellow solid, yield 45.5%, m.p. 253-256 ° C, mp. JWX-A0121.
  • the synthesis method is the same as the compound JWX-A0828. White solid, yield 47.0%, m.p. 272-274 ° C, mp. JWX-A0310.
  • the synthesis method is the same as the compound JWX-A0824.
  • a white solid was obtained in a yield of 34.7%, which was designated as JWX-A0414.
  • the synthesis method is the same as the compound JWX-A0824.
  • a yellow solid was obtained in a yield of 49.8%, which was designated as JWX-A0415.
  • the synthesis method was the same as that of A3-1 to obtain a yellow solid, yield 65.8%, which was designated as A3-2.
  • the synthesis method was the same as that of JWX-A1223 to obtain a yellow solid.
  • the yield was 44.1%, which was designated as LYH150309-2F.
  • the synthesis method was the same as that of A3-1, and a yellow solid was obtained with a yield of 84.5%, which was designated as A3-3.
  • the synthesis method was the same as that of JWX-A1223 to obtain a yellow solid.
  • the yield was 32.2%, and was designated as LYH150310-3F.
  • the synthesis method was the same as that of A3-1 to obtain a yellow solid, yield 73.5%, and was designated as A3-4.
  • the synthesis method was the same as that of JWX-A1223 to obtain a yellow solid.
  • the yield was 25.6%, which was designated as LYH150312-4F.
  • the synthesis method was the same as that of A3-1, and a yellow solid was obtained with a yield of 77.8%, which was designated as A3-5.
  • the synthesis method was the same as that of JWX-A1223 to obtain a yellow solid, yield 63.8%, and was designated as LYH150318-4Me.
  • the synthesis method was the same as that of A3-1 to obtain a yellow solid.
  • the yield was 85.3%, and was designated as A3-6.
  • the synthesis method was the same as that of JWX-A1223 to obtain a yellow solid.
  • the yield was 30.2%, which was designated as LYH150324-3Me.
  • the synthesis method was the same as that of A3-1, and a yellow solid was obtained with a yield of 78.9%, which was designated as A3-7.
  • the synthesis method was the same as that of JWX-A1223. A yellow solid was obtained with a yield of 63.9%, which was designated as LYH150325-2Me.
  • the synthesis method was the same as that of A3-1 to obtain a yellow solid, yield 52.8%, which was designated as A3-8.
  • the synthesis method was the same as that of JWX-A1223 to obtain a yellow solid.
  • the yield was 47.0%, and was designated as LYH150326-4OCH3.
  • the synthesis method was the same as that of A3-1, and a yellow solid was obtained.
  • the yield was 58.9%, which was designated as A3-9.
  • the synthesis method was the same as that of JWX-A1223 to obtain a yellow solid, yield 52.4%, and was designated as LYH150409-4CF3.
  • the synthesis method is the same as the compound JWX-A0824.
  • JWX-A0611 White solid, yield 74.7%, m.p., 181-183 ° C, hereinafter referred to as JWX-A0611.
  • JWX-A-C0907 The synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound JWX-A0824.
  • JWX-A0312 Yellow solid, yield 74.4%, m.p., 261-264 ° C, hereinafter referred to as JWX-A0312.
  • the synthesis method is the same as the compound JWX-A0828.
  • JWX-A-C1020 The synthesis method is the same as the compound JWX-A0828. White solid, yield 33.6%, m.p.: 312-314 ° C, hereinafter referred to as JWX-A-C1020.
  • the synthesis method is the same as the compound JWX-A0828.
  • the synthesis method is the same as the compound JWX-A0828.
  • the synthesis method is the same as the compound JWX-A0824. Yellow solid, yield 47.8%, m.p. 252-254 ° C, mp. JWX-A-C1026.
  • the synthesis method is the same as the compound JWX-A0824.
  • JWX-A-C0111 The synthesis method is the same as the compound JWX-A0824. White solid, yield 92.9%, m.p. 260-263 ° C, hereinafter referred to as JWX-A-C0111.
  • the synthesis method is the same as the compound JWX-A0824.
  • the synthesis method is the same as the compound LYH151120.
  • the synthesis method is the same as the compound LYH151120.
  • the synthesis method is the same as the compound LYH151120.
  • the compounds of the present application all have a certain ⁇ 7 nAChR positive allosteric regulatory activity.
  • LD486 does not affect the binding of endogenous ligands to the radioligand [ 3 H]-Methyllycaconitine (Radiolabeled Chemicals, USA) ([ 3 H]-MLA)
  • Radioisotope ligand binding experiments (Wallace, TL, Callahan, PM, Tehim, A., Bertrand, D., Tombaugh, G., Wang, S., Xie, W., Rowe, WB, Ong, V., Graham, E., Terry, AV, Jr., Rodefer, JS, Herbert, B., Murray, M., Porter, R., Santarelli, L., Lowe, DA, The Journal of pharmacology and experimental therapeutics.
  • Figure 2 shows the patch clamp response strength of frog egg cells in 100 ⁇ M Ach (acetylcholine, sigma, USA) without adding LD486 and adding different concentrations of LD486.
  • Ach acetylcholine, sigma, USA
  • Figure 3 shows the concentration response curve of LD486.
  • the peak current amplitude was normalized by only the amplitude produced by 100 ⁇ M ACh and different concentrations of LD486.
  • EC 50 3.2 ⁇ M
  • E max 320%
  • nHill 1.4 (all data measurements were 6 times).
  • the Millimeter equation is used to fit the dose-effect curve and the kinetic parameters are calculated.
  • the results show that the maximum tunable endogenous agonist ACh current amplitude of LD486 is about 3.2 times, and the EC 50 value is 3.2 ⁇ 0.3 ⁇ M.
  • Figures 4A and B show the response intensity curves of frog egg cells to ⁇ 4 ⁇ 2 and ⁇ 3 ⁇ 4, respectively, stimulated by 10 ⁇ M ACh.
  • Figures 4A and B show, respectively, the response intensity curves of frog egg cells to ⁇ 4 ⁇ 2, ⁇ 3 ⁇ 4 stimulated by 10 ⁇ M ACh and 10 ⁇ M LD486.
  • Frog eggs were pre-stimulated with 10 ⁇ M LD486 for 60 seconds.
  • 44 ⁇ 2 is now also considered to be a potential therapeutic target for AD, but the purpose of the present invention is to screen ⁇ 7nAChR targeting compounds to facilitate the study of ⁇ 7nAChR in neuropsychiatric diseases; drugs targeted for nAChR development are currently found in the clinic. Intestinal adverse reactions, therefore we hope that LD486 has better target specificity in the nAChR family to reduce adverse reactions caused by other unrelated targets.
  • Frog eggs were used as exogenous expression systems to inject different alpha subunits and beta subunits in a 1:1 ratio. After 48h, the detection channel was expressed. It was found that 10 ⁇ M ACh could activate ⁇ 4 ⁇ 2 and ⁇ 3 ⁇ 4 receptors respectively, but the addition of LD486 had no significant effect on the amplitude of 10 ⁇ M ACh induced current.
  • LD486 was found to have no inhibitory effect on hERG (human ether-a-go-go related gene) channels expressed on CHO (Chinese hamster ovary cells) cell lines.
  • hERG channel does not add or add different concentrations of LD486 or cisapride (cisapride, Sigma, USA) drug-related hERG potassium channel inhibition can lead to ventricular delayed repolarization (long QT interval syndrome), may trigger tip torsade ventricular tachycardia The response current intensity under conditions such as fatal arrhythmia and even sudden death.
  • LD486 had a slight inhibitory effect on the hERG channel, but because of its weak inhibitory effect, it could still be used as a lead compound to optimize its structure in order to obtain a compound with stronger ability to regulate ⁇ 7 nAChR.

Abstract

本发明提供一种如化学式(I)所示的噻唑并嘧啶酮化合物及其制备方法，以及其在制备用于治疗中枢神经***疾病的药物中的应用，其中，X＝O或S，Y＝C或N，当Y＝C时，R3选自H，C1-C12烃基，苯基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，和五元或六元杂环；R2选自H，C1-C12烃基，C1-C6烷氧基，C1-C6烷硫基，C1-C6烷氨基，苯基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苄基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄基，五元或六元杂环，和被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的五元或六元杂环；R1选自H，C1-C6烷基，C1-C6烷氧基，C1-C6烷硫基，C1-C6烷氨基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苯硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基，苄硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄硫基，芳氨基，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，和被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基。

Description

一种噻唑并嘧啶酮化合物及其制备方法和应用 技术领域
本发明涉及一种噻唑并嘧啶酮化合物及其制备方法，以及其在制备用于治疗中枢神经***疾病的药物中的应用。
背景技术
老年痴呆症，又名阿尔茨海默症，是一种进行性发展的致死性神经退行性疾病，临床表现为认知和记忆功能不断恶化，日常生活能力进行性减退，并有各种神经精神症状和行为障碍。很多研究明确表明AD患者脑中乙酰胆碱缺乏、烟碱型乙酰胆碱受体(nAChRs)表达减少是常见的现象。
根据文献报道，α7烟碱型乙酰胆碱受体正向变构调节剂(PAM)都有增加学习记忆的作用，实验表明缺乏nAChRα7亚基的小鼠与含有α7nAChR亚基小鼠的对照组相比，在水迷宫实验中学习记忆能力降低。α7尼古丁乙酰胆碱受体正向变构调节剂(nAChRPAMs)作用方式不同于激动剂，不易产生脱敏现象，潜在的毒副作用也会大大下降。通过调控α7尼古丁乙酰胆碱受体这一通路，希望发现一种新型疗法，用于治疗一系列中枢神经***疾病如阿尔兹海默症和帕金森症等。
发明内容
因此，本发明的目的是提供一种治疗一系列中枢神经***疾病如阿尔兹海默症和帕金森症的药物活性成分。
本发明人的前期工作开发了多种一锅法串联反应和金属催化的脱硫偶联反应，利用这些反应合成了近百个结构多样的化合物。体外活性筛选发现多个化合物对α7烟碱型乙酰胆碱受体具有一定的激动或拮抗活性，其中，编号为LD486的化合物是一种结构全新的噻唑并嘧啶酮类化合物；研究结果表明：其α7尼古丁乙酰胆碱受体正向变构调节剂的活性较强，Ki值为～3μM，且活性-浓度量效关系明显；其选择性高，对其它亚型没有作用；对CHO细胞表达的hERG离子通道没有作用，心脏毒性风险小。
因此，本发明提供了一种噻唑并嘧啶酮化合物，该化合物具有如化学式(I)所示的结构：
Figure PCTCN2016084691-appb-000001
其中，X＝O或S，Y＝C或N，
当Y＝C时，R3选自H，C1-C12烃基，苯基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，和五元或六元杂环；
R2选自H，C1-C12烃基，C1-C6烷氧基，C1-C6烷硫基，C1-C6烷氨基，苯基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苄基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄基，五元或六元杂环，和被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的五元或六元杂环；
R1选自H，C1-C6烷基，C1-C6烷氧基，C1-C6烷硫基，C1-C6烷氨基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苯硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基，苄硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄硫基，芳氨基，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，和被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基。
优选地，本发明提供的噻唑并嘧啶酮化合物的化学式(I)中，X＝O，Y＝C，R1选自C1-C6烷硫基，C1-C6烷氨基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苯硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基，苄硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄硫基，芳氨基，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，和被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4 烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基；R2选自被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基；R3为H。
本发明还提供了化学式(I)所示的噻唑并嘧啶酮化合物的制备方法，该方法包括：
(1)将氯乙酰氯与R2-NH2反应生成化合物II；
(2)将化合物II与氰胺二硫代甲酸二钾，以及碘甲烷，或碘乙烷，或卤代的C1-C6烷基，或卤代的C1-C6烷基胺，或被卤素、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，或芳胺，或被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳胺，或被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄基卤反应生成化合物III(2-烷硫基-4-氨基-噻唑-5-甲酰胺)；
(3)将化合物III与甲酸或NaNO2反应，生成合环产物IV(2-烷硫基噻唑并[4,5-d]嘧啶-7(6H)-酮或6-烷硫基噻唑并[4,5-d][1,2,3]三嗪-4(3H)-酮)；
当制备R1为C1-C6烷硫基或被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄硫基时，上述合环产物IV即为式(I)所示的化合物；或
当制备R1为C1-C6烷氨基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苯硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基，芳氨基，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，或被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基时，将化合物IV进行步骤(4)，或者将化合物IV在氧化剂作用下生成化合物V(2-烷磺酰基噻唑并[4,5-d]嘧啶-7(6H)-酮或6-烷磺酰基噻唑并[4,5-d][1,2,3]三嗪-4(3H)-酮)再进行步骤(4)；
(4)化合物IV或V与C1-C6烷基胺，苯硼酸，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硼酸，苯硫酚，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫酚，芳胺，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳胺，芳甲酰胺，或被 卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰胺反应生成式(I)所示的化合物；
其中，化合物III、IV、V中的R1’选自C1-C6烷基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苄基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄基，五元或六元杂环，或被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的五元或六元杂环。
Figure PCTCN2016084691-appb-000002
具体地，对于不同的式(I)化合物，其制备方法可以为以下四种合成路线中的任一种。
合成路线一：
Figure PCTCN2016084691-appb-000003
其中，取代基
Figure PCTCN2016084691-appb-000004
表示C1-C6烷氨基，芳氨基，被卤素、C1-C4烷基、 C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，或被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基，或-NH-R2。
合成路线二：
Figure PCTCN2016084691-appb-000005
合成路线三：
Figure PCTCN2016084691-appb-000006
合成路线四：
Figure PCTCN2016084691-appb-000007
本发明还提供了化学式(I)所示的噻唑并嘧啶酮化合物在制备用于治疗中枢神经***疾病的药物中的应用。
本发明还提供了一种治疗中枢神经***疾病的方法，其包括给予需要的受试者本发明的化学式(I)所示的噻唑并嘧啶酮化合物。
本发明还提供了化学式(I)所示的噻唑并嘧啶酮化合物，其用于治疗中枢神经***疾病。
本发明还提供了本发明的化学式(I)所示的噻唑并嘧啶酮化合物在制备α7尼古丁乙酰胆碱受体正向变构调节剂中的应用。
本发明还提供了本发明的化学式(I)所示的噻唑并嘧啶酮化合物，其作为α7尼古丁乙酰胆碱受体正向变构调节剂。
本发明的噻唑并嘧啶酮化合物具有以下有益效果：其α7尼古丁乙酰胆碱受体正向变构调节剂的活性较强，EC50值为0.1～100μM，且活性-浓度量效关系明显；其选择性高，对其它亚型没有作用；对CHO细胞表达的hERG离子通道没有作用，心脏毒性风险小。
附图的简要说明
以下，结合附图来详细说明本发明的实施方案，其中：
图1是在逐渐提高内源性配体拮抗剂PNU-282987或LD486的浓度情况下取代结合于大鼠脑细胞膜的[3H]-Methyllycaconitine放射性配体的速率曲线；
图2是100μM ACh在不添加LD486以及添加不同浓度的LD486下蛙***膜片钳响应强度；
图3是LD486的浓度响应曲线；
图4左图是在30μM ACh刺激下的蛙***对α4β2及α3β4的响应强度曲线，右图是在30μM ACh以及10μM LD486刺激下的蛙***对α4β2及α3β4的响应强度曲线。
实施发明的最佳方式
下面结合具体实施方式对本发明进行进一步的详细描述，给出的实施例仅为了阐明本发明，而不是为了限制本发明的范围。
实施例1：制备6-(2-氯-6-甲基苯基)-2-苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0824)
1、合成2-氯-N-(2-氯-6-甲基苯基)乙酰胺(A2)
Figure PCTCN2016084691-appb-000008
将化合物A1(14.2g，100mmol)溶于100mL乙酸和80mL乙酸钠饱和水溶液，冰浴下加入氯乙酰氯(17.0g，150mmol)，很快出现浑浊，缓慢升至室温，搅拌过夜。加水100mL，抽滤、水洗、烘干，得白色固体12.7g，记作A2，收率58.0％。粗品未经纯化，直接投下一步。
2、合成4-氨基-N-(2-氯-6-甲基苯基)-2-乙硫基噻唑-5-甲酰胺(A3)
Figure PCTCN2016084691-appb-000009
将化合物A2(10.9g，50mmol)溶于100mL丙酮，室温下将溶有氰胺二硫代甲酸二钾盐(9.7g，50mmol)水溶液100mL加到体系中，加入2mol/LNaOH水溶液25mL，室温搅拌2h，再加热到80℃反应0.5h，冷却至室 温。滴加碘乙烷(7.8g，50mmol)，很快出现大量黄色固体，室温反应1h后倒入冰水中，抽滤、水洗、烘干，得黄色固体13.3g，记作A3，收率81.0％。
3、合成6-(2-氯-6-甲基苯基)-2-乙磺酰基噻唑并[4,5-d]嘧啶-7(6H)-酮(A5)
Figure PCTCN2016084691-appb-000010
将化合物A3(6.56g，20mmol)溶于15mL甲酸中，加热回流1h，冷却至室温。加水100mL，用乙酸乙酯萃取5次，旋干，得A4。加入100mL乙醇，加入Na2WO4·2H2O(1.00g，3.0mmol)。缓慢滴加30％双氧水20mL，室温反应1h。升温至50℃继续反应1h。加水100mL，抽滤、水洗、烘干，得白色固体3.98g，记作A5，收率54.0％。
4、合成6-(2-氯-6-甲基苯基)-2-苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0824)
Figure PCTCN2016084691-appb-000011
将化合物A5(0.370g，1mmol)溶于7mL乙酸中，加入苯胺a1(0.189g，2mmol)，40℃反应过夜。加水、抽滤、水洗、烘干，得白色固体0.155g，收率42.0％，m.p.为150-153℃，记作JWX-A0824。
1H-NMR(400MHz,CDCl3)δ10.42(s,1H),8.04–6.91(m,9H),2.13(s,3H).13C-NMR(101MHz,CDCl3)δ170.7,166.1,155.7,149.2,139.1,138.7,133.7,132.9,130.9,129.7,129.5,128.1,125.0,120.5,108.6,18.4.HRMS:m/z理论值C18H14ClN4OS[M+H]+369.0571；实测值369.0573.
实施例2：制备2-(6-氯-2-甲基嘧啶-4-氨基)-6-(2-氯-6-甲基苯基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LD486)
Figure PCTCN2016084691-appb-000012
将化合物A5(370mg，1.0mmol)和2-甲基-4-氨基-6-氯嘧啶b1(287mg，2.0mmol)溶于3mL无水THF中，加入NaH(48mg，2.0mmol)，加干燥冷凝管，上方加气球。加热回流0.5h。停止反应，冷却至室温，倒入冰水中，滴加稀盐酸调节PH至中性，析出大量固体。抽滤，洗涤，烘干，得黄色固体398mg，收率95.0％。乙醇重结晶，m.p.为315-317℃，记作LD486。
1H-NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.65–7.40(m,3H),6.99(s,1H),2.56(s,3H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.8,164.0,159.5,158.1,155.9,150.9,139.1,134.0,132.3,131.4,130.3,128.1,112.0,104.6,25.5,18.2.HRMS:m/z理论值C17H13Cl2N6OS[M+H]+419.0243；实测值419.0243.
实施例3：制备6-(2-氯-6-甲基苯基)-2-对甲基苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1029)
Figure PCTCN2016084691-appb-000013
合成方法同化合物JWX-A0824。白色固体，收率88.8％，m.p.为241-246℃，记作JWX-A1029。
1H-NMR(400MHz,CDCl3)δ10.08(s,1H),7.81(s,1H),7.45(d,J＝8.3Hz,2H),7.33(d,J＝7.8Hz,1H),7.26(t,J＝7.8Hz,1H),7.19(d,J＝9.8Hz,1H),7.12(d,J＝8.2Hz,2H),2.27(s,3H),2.13(s,3H).13C-NMR(101MHz,CDCl3)δ171.41,165.98,155.47,149.13,138.64,136.39,135.17,133.73,132.90,130.77,130.08,129.59,128.03,121.07,108.21,21.02,18.35.
实施例4：制备6-(2-氯-6-甲基苯基)-2-(4-甲氧基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1030)
Figure PCTCN2016084691-appb-000014
合成方法同化合物JWX-A0824。灰白色固体，收率75.0％，m.p.为214-218℃，记作JWX-A1030。
1H-NMR(400MHz,CDCl3)δ10.21(s,1H),7.90(s,1H),7.58(d,J＝8.9Hz,2H),7.46–7.25(m,3H),6.96(d,J＝8.9Hz,2H),3.85(s,3H),2.23(s,3H).13C-NMR(101MHz,CDCl3)δ172.46,166.09,157.67,155.39,149.16,138.64,133.75,132.90,131.86,130.73,129.57,128.01,123.67,114.82,108.10,55.55,18.33.
实施例5：制备6-(2-氯-6-甲基苯基)-2-(4-氯苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1104)
Figure PCTCN2016084691-appb-000015
合成方法同化合物JWX-A0824。白色固体，收率94.0％，m.p.为258-264℃，记作JWX-A1104。
1H-NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.40(s,1H),7.78(d,J＝8.7Hz,2H),7.62–7.33(m,5H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.46,166.29,155.15,150.81,139.08,138.92,133.98,132.28,131.40,130.21,129.55,128.05,127.41,120.56,108.67,18.16.
实施例6：制备6-(2-氯-6-甲基苯基)-2-(4-溴苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1105)
Figure PCTCN2016084691-appb-000016
合成方法同化合物JWX-A0824。白色固体，收率82.7％，m.p.为281-286℃，记作JWX-A1105。
1H-NMR(400MHz,DMSO-d6)δ11.28(s,1H),8.40(s,1H),7.73(d,J＝8.5Hz,2H),7.51(ddd,J＝19.5,15.6,8.0Hz,5H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.40,166.28,155.15,150.83,139.33,139.08,133.97,132.45,132.28,131.41,130.22,128.05,120.91,115.37,108.70,18.17.
实施例7：制备6-(2-氯-6-甲基苯基)-2-(3-甲氧苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1106)
Figure PCTCN2016084691-appb-000017
合成方法同化合物JWX-A0824。红棕色固体，收率85.5％，m.p.为194-197℃，记作JWX-A1106。
1H-NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.39(s,1H),7.68–7.13(m,6H),6.71(d,J＝6.6Hz,1H),3.78(s,3H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.74,166.39,160.39,155.15,150.75,141.06,139.09,134.02,132.31,131.37,130.52,130.19,128.04,111.50,109.19,108.36,105.25,55.60,18.17.
实施例8：制备6-(2-氯-6-甲基苯基)-2-(3-溴苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1113)
Figure PCTCN2016084691-appb-000018
合成方法同化合物JWX-A0824。白色固体，收率75.0％，m.p.为261-265℃，记作JWX-A1113。
1H-NMR(400MHz,DMSO-d6)δ11.33(s,1H),8.42(s,1H),8.16(s,1H),7.65–7.26(m,6H),2.14(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.36,166.17,155.17,150.87,141.49,139.08,133.96,132.28,131.59,131.43,130.23,128.06,126.33,122.46,121.18,117.84,108.87,18.18.
实施例9：制备6-(2-氯-6-甲基苯基)-2-(3-氯苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1116)
Figure PCTCN2016084691-appb-000019
合成方法同化合物JWX-A0824。白色固体，收率81.1％，m.p.为244-252℃，记作JWX-A1116。
1H-NMR(400MHz,DMSO-d6)δ11.33(s,1H),8.41(s,1H),8.02(s,1H),7.60–7.37(m,5H),7.16(d,J＝7.9Hz,1H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.39,166.17,155.17,150.86,141.35,139.07,134.01,133.95,132.27,131.42,131.29,130.22,128.05,123.42,118.37,117.46,108.87,18.16.
实施例10：制备6-(2-氯-6-甲基苯基)-2-(4-氟苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1119)
Figure PCTCN2016084691-appb-000020
合成方法同化合物JWX-A0824。泛红白色固体，收率73.0％，m.p.为285-291℃，记作JWX-A1119。
1H-NMR(400MHz,DMSO-d6)δ11.18(s,1H),8.38(s,1H),7.76(dd,J＝8.6,4.7Hz,2H),7.62–7.41(m,3H),7.27(t,J＝8.7Hz,2H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.94,166.43,159.87,157.47,155.11,150.77,139.09,136.41,134.01,132.30,131.38,130.20,128.04,121.15,121.07,116.45,116.22,108.33,18.16.
实施例11：制备6-(2-氯-6-甲基苯基)-2-苯基甲氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1114)
Figure PCTCN2016084691-appb-000021
合成方法同化合物JWX-A0824。黄绿色固体，收率34.7％，m.p.为169-177℃，记作JWX-A1114。
1H-NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.51(m,8H),3.60(s,3H),2.10(s,3H).13C-NMR(101MHz,DMSO-d6)δ173.08,166.80,154.92,150.84,144.60,139.09,134.03,132.32,131.36,130.80,130.18,128.94, 128.04,126.46,108.41,41.22,18.13.
实施例12：制备6-(2-氯-6-甲基苯基)-2-间甲基苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1211)
Figure PCTCN2016084691-appb-000022
合成方法同化合物JWX-A0824。棕色固体，收率78.3％，m.p.为203-209℃，记作JWX-A1211。
1H-NMR(400MHz,DMSO-d6)δ11.09(s,1H),8.37(s,1H),7.61–7.42(m,5H),7.29(t,J＝8.0Hz,1H),6.95(d,J＝7.4Hz,1H),2.34(s,3H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ168.46,166.97,155.64,151.21,140.41,139.58,134.52,132.80,131.89,130.71,130.07,128.54,125.35,120.19,116.99,108.68,22.21,18.67.
实施例13：制备6-(2-氯-6-甲基苯基)-2-(3-氟苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1214)
Figure PCTCN2016084691-appb-000023
合成方法同化合物JWX-A0824。白色固体，收率93.6％，m.p.为238-245℃，记作JWX-A1214。
1H-NMR(400MHz,DMSO-d6)δ11.38(s,1H),8.41(s,1H),7.82(d,J＝10.9Hz,1H),7.64–7.34(m,5H),6.94(s,1H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.42,166.19,164.10,161.69,155.21,150.87,141.63,141.52,139.08,133.94,132.26,131.44,131.36,131.27,130.24,128.06,114.83,110.32,110.11,108.82,106.00,105.73,18.16.
实施例14：制备6-(2-氯-6-甲基苯基)-2-对甲基苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1218)
Figure PCTCN2016084691-appb-000024
合成方法同化合物JWX-A0824。白色固体，收率63.2％，m.p.为236-244℃，记作JWX-A1218。
1H-NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.35(s,2H),7.81–7.39(m,10H),7.24(d,J＝7.9Hz,4H),2.59(dd,J＝14.5,7.1Hz,4H),2.13(s,6H),1.18(t,J＝7.4Hz,6H).13C-NMR(101MHz,DMSO-d6)δ168.08,166.65,155.07,150.60,139.58,139.11,138.06,134.11,132.34,131.31,130.17,128.89,128.02,119.54,107.87,28.09,18.17,16.12.
实施例15：制备6-(2-氯-6-甲基苯基)-2-(3,4-二甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0315)
Figure PCTCN2016084691-appb-000025
合成方法同化合物JWX-A0824。白色针状固体，收率87.7％，m.p.为226-228℃，记作JWX-A0315。
1H-NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.38(s,1H),7.57(d,J＝7.5Hz,1H),7.47(dd,J＝20.9,8.3Hz,4H),7.17(d,J＝7.8Hz,1H),2.25(s,3H),2.21(s,3H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ168.16,166.58,155.10,150.72,139.10,137.71,137.55,134.06,132.31,131.39,130.59,130.21,128.05,120.60,117.01,107.88,20.17,19.31,18.18.
实施例16：制备6-(2-氯-6-甲基苯基)-2-(3,4,5-三甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0322)
Figure PCTCN2016084691-appb-000026
合成方法同化合物JWX-A0824。淡黄色固体，收率82.0％，m.p.为260-262 ℃，记作JWX-A0322。
1H-NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.37(s,1H),7.56(d,J＝7.3Hz,1H),7.47(dd,J＝19.2,7.2Hz,2H),7.31(s,2H),2.26(s,6H),2.13(s,3H),2.10(s,3H).13C-NMR(101MHz,DMSO-d6)δ168.36,166.60,155.09,150.67,139.10,137.35,136.94,134.08,132.32,131.37,130.95,130.20,128.04,118.75,107.75,20.97,18.18,15.17.
实施例17：制备6-(2-氯-6-甲基苯基)-2-(吡啶-2-氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0828)
Figure PCTCN2016084691-appb-000027
将化合物A5(370mg，1.0mmol)和2-氨基吡啶b2(189mg，2.0mmol)溶于3mL无水THF中，加入NaH(48mg，2.0mmol)，加干燥冷凝管，上方加气球。加热回流0.5h。停止反应，冷却至室温，加少量乙醇破坏剩余NaH。浓缩拌样，经柱层析分离纯化(CH2Cl2:MeOH＝50:1)得黄色固体208mg，收率56.2％，m.p.为270-271℃，记作JWX-A0828。
1H-NMR(400MHz,DMSO-d6)δ12.33(s,1H),8.50–8.42(m,1H),8.38(s,1H),7.89–7.80(m,1H),7.59–7.45(m,3H),7.19(d,J＝8.3Hz,1H),7.13–7.10(m,1H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ164.3,164.0,155.4,150.7,150.0,146.4,138.7,133.7,131.9,130.8,129.7,127.6,117.8,111.8,109.5,17.7.HRMS:m/z理论值C17H13ClN5OS[M+H]+370.0524；实测值370.0526.
实施例18：制备6-(2-氯-6-甲基苯基)-2-(6-氯嘧啶-4-氨基)噻唑并[4,5-d]嘧啶-7(6H)酮(编号：JWX-A0912)
Figure PCTCN2016084691-appb-000028
合成方法同化合物LD486。收率65.0％，m.p.为335-337℃，记作JWX-A0912。
1H-NMR(400MHz,DMSO-d6)δ12.90(s,1H),8.88(s,1H),8.46(s, 1H),7.65–7.40(m,3H),7.20(s,1H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ163.97,159.66,158.17,155.89,150.94,139.13,133.96,132.30,131.45,130.25,128.08,112.07,107.83,18.21.
实施例19：制备6-(2-氯-6-甲基苯基)-2-(6-氯哒嗪-3-氨基)噻唑并[4,5-d]嘧啶-7(6H)酮(编号：JWX-A0918)
Figure PCTCN2016084691-appb-000029
合成方法同化合物LD486。灰色固体，收率99.9％，m.p.为272-274℃，记作JWX-A0918。
1H-NMR(400MHz,DMSO-d6)δ12.77(s,1H),8.46(s,1H),7.91(d,J＝9.3Hz,1H),7.53(ddd,J＝19.2,15.3,8.3Hz,4H),2.16(s,3H).13C-NMR(101MHz,DMSO-d6)δ163.97,155.96,153.10,151.05,150.89,139.15,134.04,132.34,131.42,131.35,130.24,128.07,121.44,18.21.
实施例20：制备6-(2-氯-6-甲基苯基)-2-(6-(4-(2-羟乙基)哌嗪-1-基)-2-甲基嘧啶-4-氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0728)
Figure PCTCN2016084691-appb-000030
将化合物LD486(0.50g，1.2mmol)溶于5mL无水NMP中，加入羟乙基哌嗪b5(0.31g，2.4mmol)，80℃反应2h。冷却至室温，倒入冰水中，抽滤、洗涤、烘干，得黄色固体0.62g，收率95.6％。乙醇重结晶，m.p.为284-285℃，记作JWX-A0728。
1H-NMR(400MHz,CDCl3)δ7.86(s,1H),7.55–7.31(m,3H),6.92(s,1H),3.86–3.59(m,6H),2.65–2.50(m,9H),2.25(s,3H).13C-NMR(101MHz,DMSO-d6)δ165.5,165.0,164.3,162.9,157.2,155.9,150.4,139.1,134.2,132.4,131.3,130.2,128.0,111.2,83.8,60.6,59.0,53.2,44.1,25.9,18.2.HRMS:m/z理论值C23H26ClN8O2S[M+H]+513.1583；实测值513.1592.
实施例21：制备6-(2-氯-6-甲基苯基)-2-(2-甲基-6-吗啉嘧啶-4-氨基)噻唑并[4,5-d]嘧啶-7(6H)酮(编号：JWX-A1012)
Figure PCTCN2016084691-appb-000031
合成方法同化合物JWX-A0728。白色固体，收率49.6％，m.p.为325-327℃，记作JWX-A1012。
1H-NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.34(s,1H),7.54(d,J＝7.3Hz,1H),7.45(dd,J＝18.8,7.1Hz,3H),6.06(s,1H),3.65(s,4H),3.49(s,4H),2.42(s,3H),2.10(s,3H).13C-NMR(101MHz,DMSO-d6)δ165.59,164.96,164.30,163.15,157.21,155.94,150.52,139.14,134.18,132.35,131.35,130.22,128.07,111.17,83.95,66.22,44.39,25.87,18.18.
实施例22：制备6-(2-氯-6-甲基苯基)-2-(2-甲基-6-(4-甲基哌嗪-1-嘧啶)-4-氨基)噻唑并[4,5-d]嘧啶-7(6H)酮(编号：JWX-A1022)
Figure PCTCN2016084691-appb-000032
合成方法同化合物JWX-A0728。白色固体，收率95.4％，m.p.为325-327℃，记作JWX-A1022。
1H-NMR(400MHz,DMSO-d6)δ12.08(s,1H),δ8.31(s,1H),7.51(d,J＝7.5Hz,1H),7.47–7.37(m,2H),6.04(s,1H),3.48(s,4H),2.38(s,3H),2.31(s,4H),2.15(s,3H),2.08(s,3H).13C-NMR(101MHz,DMSO-d6)δ165.55,165.00,164.31,162.88,157.19,155.93,150.48,139.14,134.18,132.35,131.33,130.21,128.06,111.15,83.87,54.58,46.18,43.94,25.88,18.18.
实施例23：制备6-(2,4,6-三甲基苯基)-2-苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LD252)
1、合成2-氯-N-(2,4,6-三甲基苯基)乙酰胺(B2)
Figure PCTCN2016084691-appb-000033
合成方法同化合物A2，得白色固体，收率57.0％，记作B2。粗品未经纯化，直接投下一步。
2、合成4-氨基-N-(2,4,6-三甲基苯基)-2-乙硫基噻唑-5-甲酰胺(B3)
Figure PCTCN2016084691-appb-000034
合成方法同化合物A3，得淡黄色固体，收率84.0％，记作B3。
3、合成6-(2,4,6-三甲基苯基)-2-乙磺酰基噻唑并[4,5-d]嘧啶-7(6H)-酮(B5)
Figure PCTCN2016084691-appb-000035
合成方法同化合物A5，得白色固体，收率77.0％，记作B5。粗品未经纯化，直接投下一步。
4、合成6-(2,4,6-三甲基苯基)-2-苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LD252)
Figure PCTCN2016084691-appb-000036
合成方法同化合物JWX-A0824。得白色固体，收率73.0％，m.p.为151-153℃，记作LD-252。
1H-NMR(400MHz,CDCl3)δ10.25(s,1H),7.91(s,1H),7.63(d,J＝7.8Hz,2H),7.32(t,J＝7.5Hz,2H),7.12(t,J＝7.1Hz,1H),6.98(s,2H),2.30(s,3H),2.08(s,6H).13C-NMR(101MHz,CDCl3)δ169.2,165.2,155.3,148.6,138.8,138.2,134.5,131.8,128.6,128.3,123.7,119.3,108.0,20.1,16.9.HRMS:m/z理论值C20H19N4OS[M+H]+363.1274；实测值363.1276.
实施例24：制备6-(2,4,6-三甲基苯基)-2-(吡啶-2-氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LD286)
Figure PCTCN2016084691-appb-000037
合成方法同化合物JWX-A0828，记作LD-286。
实施例25：制备6-(2,4,6-三甲基苯基)-2-(吡啶-4-氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LD293)
Figure PCTCN2016084691-appb-000038
合成方法同化合物JWX-A0828，记作LD-293。
实施例26：制备6-(2,6-二氯苯基)-2-甲硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LD493)
1、合成2-氯-N-(2,6-二氯苯基)乙酰胺(C2)
Figure PCTCN2016084691-appb-000039
合成方法同化合物A2，得白色鳞片状固体，收率98.0％，记作C2。粗品未经纯化，直接投下一步。
2、合成4-氨基-N-(2,6-二氯苯基)-2-甲硫基噻唑-5-甲酰胺(C3)
Figure PCTCN2016084691-appb-000040
合成方法同化合物A3，得橙红色固体，收率59.0％，记作C3。
3、合成6-(2,6-二氯苯基)-2-甲硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LD493)
Figure PCTCN2016084691-appb-000041
合成方法同化合物A4，得淡黄色固体，收率93.0％，m.p.为134-135℃。记作LD-493。
实施例27：制备6-(6-氯-2-甲基嘧啶-4-氨基)-3-(2-氯-6-甲基苯基)噻唑并[4,5-d][1,2,3]三嗪-4(3H)-酮(编号：JWX-A3N)
1、合成3-(2-氯-6-甲基苯基)-6-乙磺酰基噻唑并[4,5-d][1,2,3]三嗪-4(3H)-酮(A5’)
Figure PCTCN2016084691-appb-000042
将化合物A3(1.31g，4.0mmol)溶于4.0mL浓盐酸中，冷却至0℃。缓慢滴加NaNO2(0.35g，5.0mmol)的水溶液1.0mL。缓慢升至室温，反应2h。加水20mL，抽滤，水洗，烘干，得粉红色固体，记作A4’。
将化合物A4’(6.78g，20mmol)混悬于100mL乙醇中，加入Na2WO4·2H2O(1.0g，3.0mmol)。缓慢滴加30％双氧水15mL，室温反应1h，升温至50℃继续反应1h。反应结束后，加水未析出固体。加乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。浓缩得黄色泡沫状固体，收率70.0％，记作A5’。粗品未经纯化，直接投下一步。
2、合成6-(6-氯-2-甲基嘧啶-4-氨基)-3-(2-氯-6-甲基苯基)噻唑并[4,5-d][1,2,3]三嗪-4(3H)-酮(编号：JWX-A3N)
Figure PCTCN2016084691-appb-000043
将化合物A5’(370mg，1.0mmol)和2-甲基-4-氨基-6-氯嘧啶b1(287mg，2.0mmol)溶于3mL无水THF中，加入NaH(48mg，2.0mmol)，加干燥冷凝管，上方加气球。加热回流0.5h。停止反应，冷却至室温，倒入冰水中，滴加 稀盐酸调节pH至中性，析出大量固体。抽滤，洗涤，烘干。得黄色固体294mg，收率70.0％，m.p.为315-317℃，记作JWX-A3N。
1H-NMR(400MHz,DMSO-d6)δ13.19(s,1H),7.64–7.48(m,3H),7.06(s,1H),2.67(s,3H),2.14(s,3H).13C-NMR(101MHz,CDCl3)δ172.58,169.59,165.26,164.54,162.57,157.32,143.67,139.97,136.74,135.14,132.90,122.16,109.72,30.21,22.62.
实施例28：制备3-(2,6-二氯苯基)-6-甲硫基噻唑并[4,5-d][1,2,3]三嗪-4(3H)-酮(编号：LD496)
Figure PCTCN2016084691-appb-000044
合成方法同化合物A4’，得红褐色固体，收率84.0％，记作LD496。
实施例29：制备6-(2-氯-6-甲基苯基)-2-羟基噻唑并[4,5-d]嘧啶-7(6H)酮(编号：JWX-A0903)
Figure PCTCN2016084691-appb-000045
将化合物A5(0.37g，1mmol)溶于7mL乙酸中，110℃反应2h。加水，析出固体，抽滤，烘干，得白色固体0.218g，收率74.2％，m.p.为230-233℃，记作JWX-A0903。
1H-NMR(400MHz,DMSO-d6)δ13.05(s,1H),δ8.46(s,1H),7.61–7.54(m,1H),7.48(dt,J＝14.7,7.3Hz,2H),2.14(s,3H).13C-NMR(101MHz,DMSO-d6)δ169.57,153.89,153.71,151.96,138.99,133.60,132.10,131.60,130.28,128.07,101.68,18.13.
实施例30：制备6-(2-氯-6-甲基苯基)-2-苄基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1223)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-苄基硫基噻唑-5-甲酰胺(A3-1)
Figure PCTCN2016084691-appb-000046
将化合物A2(10.9g，50mmol)溶于100mL丙酮，室温下将溶有氰胺二硫代甲酸二钾盐(9.7g，50mmol)水溶液100mL加到体系中，加入2mol/LLNaOH水溶液25mL，室温搅拌2h，再加热到80℃反应0.5h，冷却至室温。滴加苄溴(8.55g，50mmol)，很快出现大量黄色固体，室温反应1h后倒入冰水中，抽滤、水洗、烘干，得黄色固体16.2g，收率83.1％，记作A3-1。
2、合成6-(2-氯-6-甲基苯基)-2-苄基硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1223)
Figure PCTCN2016084691-appb-000047
将化合物A3-1(1.17g，3mmol)溶于2mL甲酸中，加热回流1h，冷却至室温。加水，静置，弃去水层。加入乙酸乙酯，溶解后加入无水硫酸钠干燥，浓缩拌样，经柱层析分离纯化(PE:EA＝10:1)得黄色固体255mg，收率21.3％，m.p.为134-138℃，记作JWX-A1223。
1H-NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.44(m,8H),4.70(s,2H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.72,166.23,155.04,151.27,139.06,136.22,133.57,130.31,129.62,129.15,128.90,128.30,128.10,116.81,37.54,18.15.
实施例31：制备6-(2-氯-6-甲基苯基)-2-苄基氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1228)
Figure PCTCN2016084691-appb-000048
将化合物A5(0.37g，1mmol)溶于5mL四氢呋喃中，加入苄胺a16(0.321g，3mmol)及0.5mL三乙胺，50℃反应过夜。浓缩拌样，经柱层析分离纯化 (CH2Cl2:MeOH＝150:1)得白色固体0.127g，收率33.2％，m.p.为155-161℃，记作JWX-A1228。
1H-NMR(400MHz,DMSO-d6)δ9.44(s,1H),8.28(s,1H),7.62–7.21(m,8H),4.65(s,2H),2.12(s,3H).13C-NMR(101MHz,DMSO-d6)δ172.04,166.93,155.00,150.43,139.12,138.27,134.18,132.38,131.25,130.12,128.99,128.03,127.99,127.83,107.36,48.13,18.17.
实施例32：制备6-(2-氯-6-甲基苯基)-2-正丙基氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A1229)
Figure PCTCN2016084691-appb-000049
合成方法同化合物JWX-A1228。淡黄色固体，收率60.7％，m.p.为193-196℃，记作JWX-A1229。
1H-NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.27(s,1H),7.73–7.23(m,3H),3.35(m,2H),2.12(s,3H),1.81–1.48(m,2H),0.94(t,J＝7.3Hz,3H).13C-NMR(101MHz,DMSO-d6)δ172.00,167.12,154.94,150.37,139.12,134.21,132.37,131.23,130.11,127.98,106.78,46.66,22.19,18.15,11.78,11.30.
实施例33：制备6-(2-氯-6-甲基苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0108)
Figure PCTCN2016084691-appb-000050
合成方法同化合物JWX-A0824。白色固体，收率91.3％，m.p.为222-226℃，记作JWX-A0108。
1H-NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.41(s,1H),7.74(d,J＝12.6Hz,1H),7.57(dd,J＝7.7,1.0Hz,1H),7.53–7.43(m,2H),7.34–7.28(m,2H),2.22(s,3H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.47,166.30,162.18,159.78,155.15,150.85,139.22,139.09,133.99,132.38,132.28, 131.42,130.23,128.06,119.28,119.11,114.76,108.51,106.03,105.75,18.17,14.13.
实施例34：制备N-(6-(2-氯-6甲基苯基)-7-氧代-6,7-二氢噻唑并[4,5-d]嘧啶-2-基)苯甲酰胺(编号：JWX-A0121)
Figure PCTCN2016084691-appb-000051
合成方法同化合物JWX-A0828。淡黄色固体，收率45.5％，m.p.为253-256℃，记作JWX-A0121。
1H-NMR(400MHz,DMSO-d6)δ13.49(s,1H),8.50(s,1H),8.18(d,J＝7.5Hz,2H),7.70(t,J＝7.2Hz,1H),7.60(t,J＝7.1Hz,3H),7.55–7.45(m,2H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ166.95,165.01,163.81,156.13,151.04,139.13,133.97,133.85,132.31,131.64,131.49,130.29,129.27,128.97,128.10,111.68,18.2
实施例35：制备N-(6-(2-氯-6甲基苯基)-7-氧代-6,7-二氢噻唑并[4,5-d]嘧啶-2-基)-4-甲基苯甲酰胺(编号：JWX-A0310)
Figure PCTCN2016084691-appb-000052
合成方法同化合物JWX-A0828。白色固体，收率47.0％，m.p.为272-274℃，记作JWX-A0310。
1H-NMR(400MHz,DMSO-d6)δ13.41(s,1H),8.49(s,1H),8.08(d,J＝8.0Hz,2H),7.61–7.43(m,3H),7.37(d,J＝8.0Hz,2H),2.38(s,3H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ166.63,164.96,163.81,156.14,150.98,144.30,139.13,133.98,132.32,131.45,130.26,129.79,129.00,128.71,128.09,111.70,21.63,18.21.
实施例36：制备6-(2-氯-6-甲基苯基)-2-苯基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-C1200)
Figure PCTCN2016084691-appb-000053
将化合物A4(100mg，0.3mmol)溶于5mL四氢呋喃中，加入苯硼酸(73mg，0.6mmol)、CuTC(190mg，1mmol)及三苯基膦钯(34mg，0.015mmol)，110℃反应过夜。硅藻土过滤后用乙酸乙酯与NaHCO3水溶液萃取三次，取乙酸乙酯层旋干拌样，经柱层析分离纯化(PE:EA＝10:1)得白色固体148mg，收率84.0％，m.p.为135-136℃，记作JWX-C1200。
1H-NMR(400MHz,CDCl3)δ8.16(dd,J＝8.1,1.5Hz,1H),8.03(s,1H),7.59–7.50(m,2H),7.46(d,J＝7.0Hz,1H),7.40(t,J＝7.8Hz,1H),7.33(d,J＝7.6Hz,1H),2.24(s,2H).13C-NMR(101MHz,CDCl3)δ175.28,166.9,155.99,149.43,138.51,133.44,132.81,132.54,132.33,130.97,129.70,129.30,128.15,127.53,118.30,18.32.HRMS:m/z理论值C18H13ClN3OS[M+H]+354.04624；实测值354.04635。
实施例37：制备6-(2-甲基苯基)-2-对甲基苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0414)
1、合成2-氯-N-(2-甲基苯基)乙酰胺(D2)
Figure PCTCN2016084691-appb-000054
合成方法同化合物A2，得白色固体，收率33.1％，记作D2。粗品未经纯化，直接投下一步。
2、合成4-氨基-N-(2-甲基苯基)-2-乙硫基噻唑-5-甲酰胺(D3)
Figure PCTCN2016084691-appb-000055
合成方法同化合物A3，得白色固体，收率87.6％，记作D3。
3、合成6-(2-甲基苯基)-2-乙磺酰基噻唑并[4,5-d]嘧啶-7(6H)-酮(D5)
Figure PCTCN2016084691-appb-000056
合成方法同化合物A5，得白色固体，收率77.5％，记作D5。粗品未经纯化，直接投下一步。
4、合成6-(2-甲基苯基)-2-对甲基苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0414)
Figure PCTCN2016084691-appb-000057
合成方法同化合物JWX-A0824。得白色固体，收率34.7％，记作JWX-A0414。
1H-NMR(400MHz,DMSO-d6)δ11.06(s,1H),8.32(s,1H),7.62(d,J＝8.2Hz,2H),7.51–7.31(m,4H),7.21(d,J＝8.2Hz,2H),2.29(s,3H),2.10(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.70,166.45,155.81,150.69,137.63,136.89,136.05,133.06,131.23,130.07,129.96,128.84,127.47,119.23,108.15,20.93,17.67.
实施例38：制备6-(2-氯苯基)-2-对甲基苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0415)
1、合成2-氯-N-(2-氯苯基)乙酰胺(E2)
Figure PCTCN2016084691-appb-000058
合成方法同化合物A2，得白色固体，收率75.5％，记作E2。粗品未经纯化，直接投下一步。
2、合成4-氨基-N-(2-氯苯基)-2-乙硫基噻唑-5-甲酰胺(E3)
Figure PCTCN2016084691-appb-000059
合成方法同化合物A3，得黄色固体，收率77.2％，记作E3。
3、合成6-(2-氯苯基)-2-乙磺酰基噻唑并[4,5-d]嘧啶-7(6H)-酮(E5)
Figure PCTCN2016084691-appb-000060
合成方法同化合物A5，得黄色固体，收率63.4％，记作E5。粗品未经纯化，直接投下一步。
4、合成6-(2-氯苯基)-2-对甲基苯氨基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0415)
Figure PCTCN2016084691-appb-000061
合成方法同化合物JWX-A0824。得黄色固体，收率49.8％，记作JWX-A0415。
1H-NMR(400MHz,DMSO-d6)δ11.07(s,1H),8.40(s,1H),7.79–7.66(m,2H),7.65–7.51(m,4H),7.22(d,J＝8.1Hz,2H),2.29(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.85,166.42,155.50,150.62,137.55,135.11,133.17,132.01,131.80,131.14,130.48,130.09,128.82,119.30,107.92,20.94.
实施例39：制备6-(2-氯-6-甲基苯基)-2-(2-氟苄基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150309-2F)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-(2-氟苄基)硫基噻唑-5-甲酰胺(A3-2)
Figure PCTCN2016084691-appb-000062
合成方法同A3-1，得黄色固体，收率65.8％，记作A3-2。
2、合成6-(2-氯-6-甲基苯基)-2-(2-氟苄基)硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150309-2F)
Figure PCTCN2016084691-appb-000063
合成方法同JWX-A1223，得黄色固体，收率44.1％，记作LYH150309-2F。
1H-NMR(400MHz,DMSO-d6)δ8.54(s,1H),7.65(td,J＝7.7,1.4Hz,1H),7.58(d,J＝6.8Hz,1H),7.55–7.44(m,2H),7.39(tt,J＝5.2,2.6Hz,1H),7.32–7.18(m,2H),4.74(s,2H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.04,166.18,159.78,155.08,151.34,139.06,133.54,132.16,132.01,131.97,131.63,130.82,130.74,130.34,128.11,125.20,125.17,123.36,123.22,116.97,116.19,115.98,31.24,18.13.
实施例40：制备6-(2-氯-6-甲基苯基)-2-(3-氟苄基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150310-3F)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-(3-氟苄基)硫基噻唑-5-甲酰胺(A3-3)
Figure PCTCN2016084691-appb-000064
合成方法同A3-1，得黄色固体，收率84.5％，记作A3-3。
2、合成6-(2-氯-6-甲基苯基)-2-(3-氟苄基)硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150310-3F)
Figure PCTCN2016084691-appb-000065
合成方法同JWX-A1223，得黄色固体，收率32.2％，记作LYH150310-3F。
1H-NMR(400MHz,DMSO-d6)δ8.53(s,1H),7.61–7.54(m,1H),7.53–7.35(m,5H),7.15(ddd,J＝9.4,6.9,2.1Hz,1H),4.72(s,2H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.39,166.17,163.75,161.32,155.06,151.33,139.41,139.33,139.06,133.54,132.17,131.62,131.15,131.07,130.33,128.11,125.77,116.91,116.51,116.29,115.27,115.06,36.79,18.14.
实施例41：制备6-(2-氯-6-甲基苯基)-2-(4-氟苄基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150312-4F)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-(4-氟苄基)硫基噻唑-5-甲酰胺(A3-4)
Figure PCTCN2016084691-appb-000066
合成方法同A3-1，得黄色固体，收率73.5％，记作A3-4。
2、合成6-(2-氯-6-甲基苯基)-2-(4-氟苄基)硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150312-4F)
Figure PCTCN2016084691-appb-000067
合成方法同JWX-A1223，得黄色固体，收率25.6％，记作LYH150312-4F。
1H-NMR(400MHz,DMSO-d6)δ8.53(s,1H),7.64–7.54(m,3H),7.53–7.42(m,2H),7.26–7.16(m,2H),4.70(s,2H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.55,166.20,163.34,155.05,151.31,139.06,133.55,132.66,132.63,132.17,131.77,131.69,131.62,130.33,128.11,116.82,116.08,115.87,36.65,18.13.
实施例42：制备6-(2-氯-6-甲基苯基)-2-(4-甲基苄基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150318-4Me)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-(4-甲基苄基)硫基噻唑-5-甲酰胺(A3-5)
Figure PCTCN2016084691-appb-000068
合成方法同A3-1，得黄色固体，收率77.8％，记作A3-5。
2、合成6-(2-氯-6-甲基苯基)-2-(4-甲基苄基)硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150318-4Me)
Figure PCTCN2016084691-appb-000069
合成方法同JWX-A1223，得黄色固体，收率63.8％，记作LYH150318-4Me。
1H-NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.62–7.56(m,1H),7.54–7.39(m,4H),7.18(d,J＝7.9Hz,2H),4.65(s,2H),2.28(s,3H),2.12(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.83,175.75,166.23,155.04,151.29,139.05,137.65,133.55,133.03,132.17,131.62,130.33,129.72,129.56,128.11,116.71,37.33,21.19,18.13.
实施例43：制备6-(2-氯-6-甲基苯基)-2-(3-甲基苄基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150324-3Me)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-(3-甲基苄基)硫基噻唑-5-甲酰胺(A3-6)
Figure PCTCN2016084691-appb-000070
合成方法同A3-1，得黄色固体，收率85.3％，记作A3-6。
2、合成6-(2-氯-6-甲基苯基)-2-(3-甲基苄基)硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150324-3Me)
Figure PCTCN2016084691-appb-000071
合成方法同JWX-A1223，得黄色固体，收率30.2％，记作LYH150324-3Me。
1H-NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.58(d,J＝7.8Hz,1H),7.47(s,1H),7.33(d,J＝8.6Hz,2H),7.27(d,J＝7.5Hz,1H),7.13(d,J＝7.4Hz,1H),4.65(s,2H),2.30(s,3H),2.12(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.80,166.23,151.32,139.05,138.36,135.97,133.54,130.12,129.00,128.10,116.74,21.41,18.12.
实施例44：制备6-(2-氯-6-甲基苯基)-2-(2-甲基苄基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150325-2Me)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-(2-甲基苄基)硫基噻唑-5-甲酰胺(A3-7)
Figure PCTCN2016084691-appb-000072
合成方法同A3-1，得黄色固体，收率78.9％，记作A3-7。
2、合成6-(2-氯-6-甲基苯基)-2-(2-甲基苄基)硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150325-2Me)
Figure PCTCN2016084691-appb-000073
合成方法同JWX-A1223，得黄色固体，收率63.9％，记作LYH150325-2Me。
1H-NMR(400MHz,DMSO-d6)δ8.54(s,1H),7.58(d,J＝7.7Hz,1H),7.55–7.44(m,3H),7.28–7.17(m,3H),4.71(s,2H),2.42(s,3H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.52,166.23,155.07,151.32,139.06,137.49,133.53,132.16,131.63,131.02,130.55,130.34,128.74,128.11,126.73,116.81,36.11,19.32,18.13.
实施例45：制备6-(2-氯-6-甲基苯基)-2-(4-甲氧基苄基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150326-4OCH3)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-(4-甲氧基苄基)硫基噻唑-5-甲酰胺(A3-8)
Figure PCTCN2016084691-appb-000074
合成方法同A3-1，得黄色固体，收率52.8％，记作A3-8。
2、合成6-(2-氯-6-甲基苯基)-2-(4-甲氧基苄基)硫基噻唑并[4,5-d]嘧啶 -7(6H)-酮(编号：LYH150326-4OCH3)
Figure PCTCN2016084691-appb-000075
合成方法同JWX-A1223，得黄色固体，收率47.0％，记作LYH150326-4OCH3。
1H-NMR(400MHz,DMSO-d6)δ8.52(s,1H),7.58(d,J＝7.2Hz,1H),7.54–7.44(m,4H),6.94(d,J＝8.6Hz,2H),4.64(s,2H),3.74(s,3H),2.12(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.87,166.24,159.38,155.05,151.30,139.06,133.57,132.17,131.62,130.96,130.34,128.11,127.79,116.68,114.57,55.59,37.17,18.13.
实施例46：制备6-(2-氯-6-甲基苯基)-2-(4-三氟甲基苄基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150409-4CF3)
1、合成4-氨基-N-(2-氯-6-甲基苯基)-2-(4-三氟甲基苄基)硫基噻唑-5-甲酰胺(A3-9)
Figure PCTCN2016084691-appb-000076
合成方法同A3-1，得黄色固体，收率58.9％，记作A3-9。
2、合成6-(2-氯-6-甲基苯基)-2-(4-三氟甲基苄基)硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150409-4CF3)
Figure PCTCN2016084691-appb-000077
合成方法同JWX-A1223，得黄色固体，收率52.4％，记作LYH150409-4CF3。
1H-NMR(400MHz,DMSO-d6)δ8.53(s,1H),7.77(q,J＝8.6Hz,4H),7.58(dd,J＝7.8,1.0Hz,1H),7.54–7.43(m,2H),4.80(s,2H),2.12(s,3H).13C-NMR(101MHz,DMSO-d6)δ175.25,166.17,155.05,151.35,141.69,139.06,133.53,132.16,131.63,130.42,130.34,128.11,126.02,125.98, 116.96,36.70,18.13.
实施例47：制备6-(2-氯-6-甲基苯基)-2-(2-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0602)
Figure PCTCN2016084691-appb-000078
合成方法同化合物JWX-A0824。白色固体，收率75.5％，m.p.为268-270℃，记作JWX-A0602。
1H-NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.33(s,1H),7.69(d,J＝7.8Hz,1H),7.56(dd,J＝7.7,1.2Hz,1H),7.51–7.41(m,2H),7.37–7.26(m,2H),7.22(dd,J＝10.7,4.0Hz,1H),2.30(s,3H),2.12(s,3H).13C-NMR(101MHz,DMSO-d6)δ171.28,166.73,155.03,150.65,139.11,137.99,134.09,132.57,132.33,131.51,131.34,130.18,128.03,127.37,126.92,124.98,107.91,18.20,18.17.
实施例48：制备6-(2-氯-6-甲基苯基)-2-(2-氟苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A0611)
Figure PCTCN2016084691-appb-000079
合成方法同化合物JWX-A0824。白色固体，收率74.7％，m.p.为181-183℃，记作JWX-A0611。
1H-NMR(400MHz,DMSO-d6)δ10.97(s,1H),8.38(s,1H),8.32(dd,J＝11.7,4.5Hz,1H),7.57(dd,J＝7.8,1.3Hz,1H),7.52–7.43(m,2H),7.39–7.26(m,2H),7.25–7.18(m,1H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ168.77,166.08,155.20,154.73,152.29,150.74,139.09,134.01,132.29,131.40,130.22,128.05,125.84,125.77,125.38,125.34,123.16,116.30,116.11,109.15,18.16.
实施例49：制备6-(2-氯-6-甲基苯基)-2-(4-三氟甲氧基苯氨基)噻唑并[4,5-d] 嘧啶-7(6H)-酮(编号：JWX-A-C0901)
Figure PCTCN2016084691-appb-000080
合成方法同化合物JWX-A0824。白色固体，收率82.8％，m.p.为213-215℃，记作JWX-A-C0901。
1H-NMR(400MHz,DMSO-d6)δ11.39(s,1H),8.41(s,1H),7.93–7.79(m,2H),7.57(dd,J＝7.8,1.4Hz,1H),7.54–7.41(m,4H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.56,166.27,155.18,150.87,144.02,139.18,139.10,133.99,132.29,131.44,130.25,128.08,122.63,120.35,108.77,18.19.
实施例50：制备6-(2-氯-6-甲基苯基)-2-(3-三氟甲氧基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0907)
Figure PCTCN2016084691-appb-000081
合成方法同化合物JWX-A0824。白色固体，收率68.8％，m.p.为247-249℃，记作JWX-A-C0907。
1H-NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.42(s,1H),8.00(s,1H),7.76–7.33(m,5H),7.09(d,J＝8.0Hz,2H),2.14(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.36,166.11,155.19,150.89,149.30,141.56,139.08,133.95,132.27,131.43,131.38,130.23,128.06,121.86,119.31,117.62,115.55,111.05,18.15.
实施例51：制备6-(2-氯-6-甲基苯基)-2-(3,4-二氟苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0915)
Figure PCTCN2016084691-appb-000082
合成方法同化合物JWX-A0824。白色固体，收率67.7％，m.p.为255-258 ℃，记作JWX-A-C0915。
1H-NMR(400MHz,DMSO-d6)δ11.35(s,1H),8.42(s,1H),7.99(ddd,J＝12.9,7.2,2.5Hz,1H),7.57(dd,J＝7.8,1.3Hz,1H),7.52–7.37(m,4H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.45,166.15,155.15,150.88,148.50,148.37,146.99,144.59,144.46,139.07,133.95,132.27,131.42,130.22,128.06,118.47,118.29,115.44,108.76,108.25,108.04,18.16.
实施例52：制备6-(2-氯-6-甲基苯基)-2-(2,4-二甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C1017)
Figure PCTCN2016084691-appb-000083
合成方法同化合物JWX-A0824。白色固体，收率95.4％，m.p.为152-154℃，记作JWX-A-C1017。
1H-NMR(400MHz,DMSO-d6)δ11.03(s,1H),8.37(s,1H),7.57(d,J＝7.6Hz,1H),7.52–7.41(m,2H),7.32(s,2H),6.78(s,1H),2.30(s,6H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ168.05,166.47,155.11,150.70,139.84,139.10,138.87,134.05,132.31,131.37,130.20,128.04,125.78,117.04,108.08,21.61,18.16.
实施例53：制备6-(2-氯-6-甲基苯基)-2-(3-氯-4-氟苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0104)
Figure PCTCN2016084691-appb-000084
合成方法同化合物JWX-A0824。白色固体，收率94.5％，m.p.为265-267℃，记作JWX-A-C0104。
1H-NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.42(s,1H),8.13(dd,J＝6.5,2.4Hz,1H),7.60–7.54(m,2H),7.52–7.43(m,3H),2.13(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.47,166.17,155.17,154.82,152.40,150.92,139.09,137.21,133.96,132.29,131.46,130.25,128.08,120.36,120.19,120.01, 119.46,119.39,117.99,117.77,108.84,18.19.
实施例54：制备N-(6-(2-氯-6-甲基苯基)-7-氧代-6,7-二氢噻唑并[4,5-d]嘧啶-2-基)-4-甲氧基苯甲酰胺(编号：JWX-A0312)
Figure PCTCN2016084691-appb-000085
合成方法同化合物JWX-A0828。黄色固体，收率74.4％，m.p.为261-264℃，记作JWX-A0312。
1H-NMR(400MHz,DMSO-d6)δ13.29(s,1H),8.47(s,1H),8.17(d,J＝8.8Hz,2H),7.61–7.40(m,3H),7.09(d,J＝8.8Hz,2H),3.85(s,3H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ166.03,165.08,163.83,163.77,156.15,150.89,139.13,133.98,132.32,131.43,131.15,130.24,128.07,123.52,114.54,111.64,56.06,18.19.
实施例55：制备N-(6-(2-氯-6-甲基苯基)-7-氧代-6,7-二氢噻唑并[4,5-d]嘧啶-2-基)-4-氟苯甲酰胺(编号：JWX-A0617)
Figure PCTCN2016084691-appb-000086
合成方法同化合物JWX-A0828。白色固体，收率42.9％，m.p.为335-337℃，记作JWX-A0617。
1H-NMR(400MHz,DMSO-d6)δ13.54(s,1H),8.50(s,1H),8.32–8.08(m,2H),7.59(d,J＝7.3Hz,1H),7.55–7.39(m,4H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ165.80,164.86,163.74,156.12,151.07,139.12,133.93,132.29,132.02,131.93,131.50,130.28,128.10,116.49,116.27,111.74,18.19.
实施例56：制备N-(6-(2-氯-6-甲基苯基)-7-氧代-6,7-二氢噻唑并[4,5-d]嘧啶-2-基)-4-氯苯甲酰胺(编号：JWX-A-C1020)
Figure PCTCN2016084691-appb-000087
合成方法同化合物JWX-A0828。白色固体，收率33.6％，m.p.为312-314℃，记作JWX-A-C1020。
1H-NMR(400MHz,DMSO-d6)δ13.60(s,1H),8.50(s,1H),8.18(d,J＝8.6Hz,2H),7.67(d,J＝8.6Hz,2H),7.59(dd,J＝7.8,1.3Hz,1H),7.50(dt,J＝7.5,7.1Hz,2H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ165.95,164.79,163.74,156.11,151.10,139.12,138.79,133.93,132.29,131.50,130.90,130.43,130.29,129.39,128.10,111.79,18.19.
实施例57：制备N-(6-(2-氯-6-甲基苯基)-7-氧代-6,7-二氢噻唑并[4,5-d]嘧啶-2-基)-4-溴苯甲酰胺(编号：JWX-A-C1122)
Figure PCTCN2016084691-appb-000088
合成方法同化合物JWX-A0828。白色固体，收率59.5％，m.p.为335-337℃，记作JWX-A-C1122。
1H-NMR(400MHz,DMSO-d6)δ13.58(s,1H),8.50(s,1H),8.10(d,J＝7.7Hz,2H),7.81(d,J＝7.6Hz,2H),7.59(d,J＝6.8Hz,1H),7.54–7.39(m,2H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ166.12,164.77,163.74,156.11,151.08,139.12,133.93,132.32,131.49,130.99,130.80,130.28,128.09,127.91,110.00,18.19.
实施例58：制备N-(6-(2-氯-6-甲基苯基)-7-氧代-6,7-二氢噻唑并[4,5-d]嘧啶-2-基)-4-三氟甲基苯甲酰胺(编号：JWX-A-C1128)
Figure PCTCN2016084691-appb-000089
合成方法同化合物JWX-A0828。白色固体，收率87.3％，m.p.为282-285 ℃，记作JWX-A-C1128。
1H-NMR(400MHz,DMSO-d6)δ13.77(s,1H),8.51(s,1H),8.35(d,J＝7.4Hz,2H),7.97(d,J＝7.3Hz,2H),7.59(d,J＝7.1Hz,1H),7.55–7.43(m,2H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ165.98,164.74,163.70,156.16,151.17,139.16,135.51,133.95,133.68,133.36,133.04,132.73,132.33,131.54,130.33,129.97,128.14,126.19,125.58,122.87,111.93,18.23.
实施例59：制备N-(6-(2-氯-6-甲基苯基)-7-氧代-6,7-二氢噻唑并[4,5-d]嘧啶-2-基)-4-三氟甲氧基苯甲酰胺(编号：JWX-A-C1205)
Figure PCTCN2016084691-appb-000090
合成方法同化合物JWX-A0828。白色固体，收率73.6％，m.p.为134-136℃，记作JWX-A-C1205。
1H-NMR(400MHz,DMSO-d6)δ13.64(s,1H),8.51(s,1H),8.30(d,J＝8.8Hz,2H),7.58(dd,J＝6.7,4.7Hz,3H),7.53–7.45(m,2H),2.15(s,3H).13C-NMR(101MHz,DMSO-d6)δ165.70,164.81,163.77,156.17,152.15,151.13,139.18,133.98,132.35,131.59,131.53,130.63,130.32,128.14,121.71,121.31,119.15,111.88,18.22.
实施例60：制备6-(2-甲基苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C1026)
Figure PCTCN2016084691-appb-000091
合成方法同化合物JWX-A0824。黄色固体，收率47.8％，m.p.为252-254℃，记作JWX-A-C1026。
1H-NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.35(s,1H),7.75(d,J＝12.7Hz,1H),7.50–7.36(m,4H),7.30(s,2H),2.21(s,3H),2.10(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.14,166.17,159.78,155.85,150.84,139.38,139.27,136.83,136.02,132.34,132.27,131.24,130.01,128.84,127.49,119.11, 118.93,114.58,108.61,105.88,105.61,17.64,14.14.
实施例61：制备6-(2-氯苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0831)
Figure PCTCN2016084691-appb-000092
合成方法同化合物JWX-A0824。白色固体，收率72.4％，m.p.为251-253℃，记作JWX-A-C0831。
1H-NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.43(s,1H),7.72(dd,J＝15.6,8.1Hz,3H),7.64–7.52(m,2H),7.30(s,2H),2.22(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.32,166.14,162.17,159.78,155.53,150.76,139.32,139.22,135.04,132.37,132.30,131.97,131.84,131.12,130.48,128.84,119.23,119.06,114.70,108.40,105.98,105.71,14.14.
实施例62：制备6-(2-溴-6-甲基苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0106)
1、合成2-氯-N-(2-溴-6-甲基苯基)乙酰胺(F2)
Figure PCTCN2016084691-appb-000093
合成方法同化合物A2，得白色固体，收率50.3％，记作F2。粗品未经纯化，直接投下一步。
2、合成4-氨基-N-(2-溴-6-甲基苯基)-2-乙硫基噻唑-5-甲酰胺(F3)
Figure PCTCN2016084691-appb-000094
合成方法同化合物A3，得黄色固体，收率80.4％，记作F3。
3、合成6-(2-溴-6-甲基苯基)-2-乙磺酰基噻唑并[4,5-d]嘧啶-7(6H)-酮(F5)
Figure PCTCN2016084691-appb-000095
合成方法同化合物A5，得白色固体，收率69.9％，记作F5。粗品未经纯化，直接投下一步。
4、合成6-(2-溴-6-甲基苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0106)
Figure PCTCN2016084691-appb-000096
合成方法同化合物JWX-A0824。白色固体，收率65.8％，m.p.为262-264℃，记作JWX-A-C0106。
1H-NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.39(s,1H),7.73(dd,J＝16.2,10.1Hz,2H),7.48(d,J＝7.4Hz,1H),7.41(t,J＝7.8Hz,1H),7.30(s,2H),2.22(s,3H),2.14(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.45,166.32,162.20,159.80,155.11,150.88,139.32,139.21,139.14,135.56,132.40,132.34,131.78,131.24,130.80,123.01,119.31,119.13,114.76,108.59,106.03,105.76,18.51,14.18.
实施例63：制备6-(2-氟-6-甲基苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0111)
1、合成2-氯-N-(2-氟-6-甲基苯基)乙酰胺(G2)
Figure PCTCN2016084691-appb-000097
合成方法同化合物A2，得白色固体，收率95.0％，记作G2。粗品未经纯化，直接投下一步。
2、合成4-氨基-N-(2-氟-6-甲基苯基)-2-乙硫基噻唑-5-甲酰胺(G3)
Figure PCTCN2016084691-appb-000098
合成方法同化合物A3，得黄色固体，收率63.2％，记作G3。
3、合成6-(2-氟-6-甲基苯基)-2-乙磺酰基噻唑并[4,5-d]嘧啶-7(6H)-酮(G5)
Figure PCTCN2016084691-appb-000099
合成方法同化合物A5，得白色固体，收率78.6％，记作G5。粗品未经纯化，直接投下一步。
4、合成6-(2-氟-6-甲基苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0111)
Figure PCTCN2016084691-appb-000100
合成方法同化合物JWX-A0824。白色固体，收率92.9％，m.p.为260-263℃，记作JWX-A-C0111。
1H-NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.48(s,1H),7.74(d,J＝12.0Hz,1H),7.51(dd,J＝13.6,7.5Hz,1H),7.36–7.26(m,4H),2.21(s,3H),2.14(s,3H).13C-NMR(101MHz,DMSO-d6)δ167.47,166.27,162.20,159.80,159.32,156.85,155.33,151.07,139.32,139.21,138.97,132.38,132.32,131.61,131.53,127.00,124.28,124.14,119.29,119.11,114.73,114.37,114.17,108.52,106.01,105.74,17.43,14.17.
实施例64：制备6-(2-氯-4-甲基苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0229)
1、合成2-氯-N-(2-氯-4-甲基苯基)乙酰胺(H2)
Figure PCTCN2016084691-appb-000101
合成方法同化合物A2，得白色固体，收率83.3％，记作H2。粗品未经纯化，直接投下一步。
2、合成4-氨基-N-(2-氯-4-甲基苯基)-2-乙硫基噻唑-5-甲酰胺(H3)
Figure PCTCN2016084691-appb-000102
合成方法同化合物A3，得黄色固体，收率82.3％，记作H3。
3、合成6-(2-氯-4-甲基苯基)-2-乙磺酰基噻唑并[4,5-d]嘧啶-7(6H)-酮(H5)
Figure PCTCN2016084691-appb-000103
合成方法同化合物A5，得白色固体，收率63.8％，记作H5。粗品未经纯化，直接投下一步。
4、合成6-(2-氯-4-甲基苯基)-2-(3-氟-4-甲基苯氨基)噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：JWX-A-C0229)
Figure PCTCN2016084691-appb-000104
合成方法同化合物JWX-A0824。白色固体，收率64.4％，m.p.为254-256℃，记作JWX-A-C0229。
实施例65：制备6-(2-氯-6-甲基苯基)-2-苯硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH151120)
Figure PCTCN2016084691-appb-000105
将化合物A5(738mg，2mmol)溶于10mL四氢呋喃中，加入苯硫酚d1(330mg，3mmol)，再加入2mL三乙胺，65℃回流反应6h。旋干拌样经柱层析分离纯化(PE:EA＝10:1)得白色固体398mg，收率51.6％，记作 LYH151120。
1H-NMR(400MHz,CDCl3)δ7.94(s,1H),7.78(d,J＝6.7Hz,2H),7.64–7.52(m,3H),7.43(d,J＝7.3Hz,1H),7.37(t,J＝7.8Hz,1H),2.18(s,3H).13C-NMR(101MHz,CDCl3)δ180.44,166.82,155.04,149.35,138.44,135.86,133.37,132.73,131.55,130.91,130.58,129.65,128.31,128.10,77.38,77.07,76.75,18.21.HRMS:m/z理论值C18H13ClN3OS2[M+H]+386.0183；实测值386.0197.
实施例66：制备6-(2-氯-6-甲基苯基)-2-间氟苯硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH151215)
Figure PCTCN2016084691-appb-000106
合成方法同化合物LYH151120。白色固体，收率76.7％，记作LYH151215。
1H-NMR(400MHz,CDCl3)δ7.95(s,1H),7.60–7.47(m,3H),7.45–7.34(m,2H),7.33–7.26(m,2H),2.17(s,3H).13C-NMR(101MHz,CDCl3)δ178.56,166.70,164.36,161.86,155.00,149.47,138.42,133.28,132.70,131.92,131.84,131.44,131.40,130.97,129.90,129.82,129.68,128.13,122.67,122.44,118.87,118.66,77.38,77.07,76.75,18.23.
实施例67：制备6-(2-氯-6-甲基苯基)-2-对氟苯硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150908)
Figure PCTCN2016084691-appb-000107
合成方法同化合物LYH151120。白色固体，收率74.4％，记作LYH150908。
1H-NMR(400MHz,CDCl3)δ7.95(s,1H),7.77(dd,J＝8.8,5.1Hz,2H),7.43(d,J＝8.0Hz,1H),7.38(t,J＝7.8Hz,1H),7.33–7.22(m,3H),2.18(s,3H).13C-NMR(101MHz,CDCl3)δ180.11,166.82,166.00,163.48,154.99,149.46,138.42,138.29,138.20,133.29,132.70,130.96,129.68,128.12,123.57,123.54,118.06,118.00,117.84,77.40,77.08,76.76,18.22.
实施例68：制备6-(2-氯-6-甲基苯基)-2-对甲氧基苯硫基噻唑并[4,5-d]嘧啶-7(6H)-酮(编号：LYH150909)
Figure PCTCN2016084691-appb-000108
合成方法同化合物LYH151120。白色固体，收率65.6％，记作LYH150909。
1H-NMR(400MHz,CDCl3)δ7.93(s,1H),7.69–7.63(m,2H),7.45–7.39(m,1H),7.35(t,J＝7.8Hz,1H),7.29(dd,J＝5.2,2.3Hz,1H),7.09–7.01(m,2H),3.89(s,3H),2.17(s,3H).13C-NMR(101MHz,CDCl3)δ182.50,166.97,162.33,155.02,149.31,138.45,137.70,133.38,132.70,130.90,129.66,128.08,118.71,117.84,116.16,77.46,77.14,76.82,55.60,18.23.
活性实验
实验过程如下：
(1)向***中注射编码α7nAChR的cRNA，使其在细胞膜上成功表达α7nAChR；
(2)单独加入100μM ACh，记录其引起的α7nAChR特征性电流，作为对照；
(3)洗去ACh；
(4)单独加入10μM化合物，若化合物不诱发α7nAChR特征性电流，则认为其不结合于激动剂位点，可进行下一步操作；
(5)***经10μM化合物孵育1min后，同时加入10μM化合物和100μM ACh，记录此时由ACh引发的电流；
(6)比较两次电流在峰值强度和持续时间方面的差异，以前后两次电流峰值强度的比值表示调节效果(Enhance Rate)，判断化合物是否具有PAM活性，若活性较好，则进行后续测试；
(7)设置浓度梯度，评价不同浓度的化合物对100μM ACh引起的α7 nAChR特征性电流的影响，同一浓度多次测量，最终以“均值±标准差”形式呈现结果；
(8)采用Hill方程Inormalized＝Emax/(1+(EC50/C)nH)拟合量效曲线，得到 该化合物的EC50值(半数最大效应浓度)和Max mod值(最大程度可调节内源性激动剂乙酰胆碱引起的电流幅度)等活性数据。实验结果列于下表中：
Figure PCTCN2016084691-appb-000109
Figure PCTCN2016084691-appb-000110
Figure PCTCN2016084691-appb-000111
Figure PCTCN2016084691-appb-000112
Figure PCTCN2016084691-appb-000113
Figure PCTCN2016084691-appb-000114
Figure PCTCN2016084691-appb-000115
由上表中的实验结果可以看出，本申请的化合物均具有一定的α7 nAChR正向变构调节活性。
药效实施例(LD486)
1、LD486不影响内源性配体与放射性配体[3H]-Methyllycaconitine(美国Radiolabeled Chemicals公司)([3H]-MLA)的结合
利用放射性同位素配体结合实验(Wallace,T.L.,Callahan,P.M.,Tehim,A.,Bertrand,D.,Tombaugh,G.,Wang,S.,Xie,W.,Rowe,W.B.,Ong,V.,Graham,E.,Terry,A.V.,Jr.,Rodefer,J.S.,Herbert,B.,Murray,M.,Porter,R.,Santarelli,L.,Lowe,D.A.,The Journal of pharmacology and experimental therapeutics.2011,336,242-253)，在逐渐提高内源性配体拮抗剂PNU-282987(美国sigma公司)或LD486的浓度情况下取代结合于大鼠脑细胞膜的[3H]-Methyllycaconitine放射性配体的速率曲线，结果如图1所示。从图1可以看出，随着PNU-282987浓度逐渐增加，[3H]-MLA的结合量逐渐减少，Ki值为34.1±4.3nM；而对于化合物LD486，其浓度加至10μM时仍不会减少[3H]-MLA与大鼠海马区α7nAChR的结合，说明LD486与α7 nAChR的结合位点并不是目前认为激动剂在α7 nAChR结合位点。
2.利用双电极电压钳实验(Prickaerts,J.,van Goethem,N.P.,Chesworth,R.,Shapiro,G.,Boess,F.G.,Methfessel,C.,Reneerkens,O.A.,Flood,D.G.,Hilt,D.,Gawryl,M.,Bertrand,S.,Bertrand,D.,Konig,G.,Neuropharmacology 2012,62,1099-1110)发现LD486作为α7尼古丁乙酰胆碱受体正向变构调节剂的活性较强
图2表示的是100μM Ach(乙酰胆碱，美国sigma公司)在不添加LD486以及添加不同浓度的LD486下蛙***膜片钳响应强度。从图2可以看出，以单独加入100μM ACh引起的电流作为对照，可以看到只加入不同浓度的LD486(0.1-10μM)并不会诱发α7 nAChR特征性电流，但LD486孵育1min后再同时加入相同浓度的LD486和100μM ACh，可以观察到100μM ACh所诱发的电流幅度与对照组相比显著增加。
图3为LD486的浓度响应曲线。峰值电流幅值只通过100μM ACh与不同浓度LD486产生的振幅作出归一化曲线。EC50＝3.2μM,Emax＝320％,nHill＝1.4(所有数据测量次数为6次)。从图3可以看出，采用Hill方程拟合量效曲线并计算其动力学参数，结果显示LD486最大程度可调节内源性激动剂ACh电流幅度为3.2倍左右，EC50值为3.2±0.3μM,希尔系数为 1.4±0.2(n＝6)。
3.利用双电极电压钳实验(Prickaerts,J.,van Goethem,N.P.,Chesworth,R.,Shapiro,G.,Boess,F.G.,Methfessel,C.,Reneerkens,O.A.,Flood,D.G.,Hilt,D.,Gawryl,M.,Bertrand,S.,Bertrand,D.,Konig,G.,Neuropharmacology 2012,62,1099-1110),发现LD486不增强蛙***中α4β2和α3β4受体的电流强度
图4A、B左图分别显示的是只在10μM ACh刺激下的蛙***对α4β2、α3β4的响应强度曲线。图4A、B右图分别显示的是在10μM ACh以及10μM LD486刺激下的蛙***对α4β2、α3β4的响应强度曲线。蛙***预先被10μM LD486刺激60秒。
α4β2如今也被认为是AD的潜在治疗靶点，但本发明的目的是筛选α7nAChR靶向化合物，以利于研究α7nAChR在神经精神疾病中作用；靶向nAChR研发的药物目前在临床上发现普遍存在胃肠道不良反应，因此我们希望LD486对于nAChR家族范围内的靶点专一性较好，以减少作用于其它无关靶点而带来的不良反应。
以蛙卵作为外源表达***，以1：1比例注射不同的α亚基和β亚基。48h后检测通道是否表达，发现10μM ACh可分别激活α4β2、α3β4受体，但加入LD486对10μM ACh诱发电流的幅度无明显影响。
4.利用全自动膜片钳Qplate-16实验(Schmalhofer,W.A.,Swensen,A.M.,Thomas,B.S.,Felix,J.P.,Haedo,R.J.,Solly,K.,Kiss,L.,Kaczorowski,G.J.,Garcia,M.L.,Assay and drug development technologies 2010,8,714-726)，发现LD486对表达于CHO(中国仓鼠卵巢细胞)细胞株上的hERG(人类ether-a-go-go相关基因)通道没有抑制作用
hERG通道在不添加或添加不同浓度的LD486或cisapride(西沙必利，美国Sigma公司)药物相关的hERG钾通道抑制能够导致心室延迟复极(长QT间期综合征)，可能引发尖端扭转室速等致命性心律失常，甚至猝死的条件下的响应电流强度。结果显示，LD486对于hERG通道有轻微的抑制作用，但由于抑制效应较弱，仍可作为先导化合物，对其进行结构优化以期得到调节α7 nAChR能力更强的化合物。

Claims (9)

  1. 一种噻唑并嘧啶酮化合物，该化合物具有如化学式(I)所示的结构：
    Figure PCTCN2016084691-appb-100001
    其中，X＝O或S，Y＝C或N，
    当Y＝C时，R3选自H，C1-C12烃基，苯基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，和五元或六元杂环；
    R2选自H，C1-C12烃基，C1-C6烷氧基，C1-C6烷硫基，C1-C6烷氨基，苯基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苄基，被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄基，五元或六元杂环，和被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的五元或六元杂环；
    R1选自H，C1-C6烷基，C1-C6烷氧基，C1-C6烷硫基，C1-C6烷氨基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苯硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基，苄硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄硫基，芳氨基，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，和被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基。
  2. 根据权利要求1所述的噻唑并嘧啶酮化合物，其中，X＝O，Y＝C，R1选自C1-C6烷硫基，C1-C6烷氨基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苯硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基，苄硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄 硫基，芳氨基，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，和被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基；R2选自被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基；R3为H。
  3. 权利要求1或2所述的噻唑并嘧啶酮化合物的制备方法，该方法包括以下步骤：
    Figure PCTCN2016084691-appb-100002
    (1)将氯乙酰氯与R2-NH2反应生成化合物II；
    (2)将化合物II与氰胺二硫代甲酸二钾，以及碘甲烷，或碘乙烷，或卤代的C1-C6烷基，或卤代的C1-C6烷基胺，或被卤素、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，或芳胺，或被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳胺，或被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄基卤反应生成化合物III；
    (3)将化合物III与甲酸或NaNO2反应，生成合环产物IV，
    当制备R1为C1-C6烷硫基或被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄硫基时，上述合环产物IV即为式(I)所示的化合物；或
    当制备R1为C1-C6烷氨基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苯硫基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫基，芳氨基，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，或被卤素、 C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基时，将化合物IV进行步骤(4)，或者将化合物IV在氧化剂作用下生成化合物V再进行步骤(4)；
    (4)化合物IV或V与C1-C6烷基胺，苯硼酸，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硼酸，苯硫酚，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯硫酚，芳胺，被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳胺，芳甲酰胺，或被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰胺反应生成式(I)所示的化合物；
    其中，化合物III、IV、V中的R1’选自C1-C6烷基，苯基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苯基，苄基，被卤素、酯基、羧基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的苄基，五元或六元杂环，或被卤素、羟基、羧基、酯基、C1-C4烷基和C1-C4烷氧基中的一个或多个取代的五元或六元杂环。
  4. 根据权利要求3所述的制备方法，其中，所述制备方法包括以下四种合成路线：
    合成路线一：
    Figure PCTCN2016084691-appb-100003
    其中，取代基
    Figure PCTCN2016084691-appb-100004
    表示C1-C6烷氨基，芳氨基，被卤素、C1-C4烷基、 C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳氨基，芳甲酰氨基，或被卤素、C1-C4烷基、C1-C4烷氧基、五元或六元杂环和被C1-C4烷基或羟基取代的五元或六元杂环中的一个或多个取代的芳甲酰氨基，或-NH-R2；
    合成路线二：
    Figure PCTCN2016084691-appb-100005
    合成路线三：
    Figure PCTCN2016084691-appb-100006
    合成路线四：
    Figure PCTCN2016084691-appb-100007
  5. 权利要求1或2所述的噻唑并嘧啶酮化合物或者按照权利要求3或4所述制备方法制得的噻唑并嘧啶酮化合物在制备用于治疗中枢神经***疾病的药物中的应用。
  6. 一种治疗中枢神经***疾病的方法，其包括给予需要的受试者权利要求1或2所述的噻唑并嘧啶酮化合物或者按照权利要求3或4所述制备方法制得的噻唑并嘧啶酮化合物。
  7. 权利要求1或2所述的噻唑并嘧啶酮化合物或者按照权利要求3或4所述制备方法制得的噻唑并嘧啶酮化合物，其用于治疗中枢神经***疾病。
  8. 权利要求1或2所述的噻唑并嘧啶酮化合物或者按照权利要求3或4所述制备方法制得的噻唑并嘧啶酮化合物在制备α7尼古丁乙酰胆碱受体正向变构调节剂中的应用。
  9. 权利要求1或2所述的噻唑并嘧啶酮化合物或者按照权利要求3或4所述制备方法制得的噻唑并嘧啶酮化合物，其作为α7尼古丁乙酰胆碱受体正向变构调节剂。
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