WO2015043111A1 - 作为糖原磷酸化酶抑制剂的苯并氮杂卓酮类化合物、其制备方法及医药用途 - Google Patents

作为糖原磷酸化酶抑制剂的苯并氮杂卓酮类化合物、其制备方法及医药用途 Download PDF

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WO2015043111A1
WO2015043111A1 PCT/CN2014/000861 CN2014000861W WO2015043111A1 WO 2015043111 A1 WO2015043111 A1 WO 2015043111A1 CN 2014000861 W CN2014000861 W CN 2014000861W WO 2015043111 A1 WO2015043111 A1 WO 2015043111A1
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substituted
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independently
branched alkyl
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张丽颖
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承德医学院
张丽颖
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Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a novel class of benzazepine glucosinolate phosphorylase inhibitors.
  • the compounds can be used for preparing anti-diabetes and its complications drugs, anti-ischemic drugs, anti-cardiovascular drugs, hypolipidemic drugs, weight loss drugs, anti-atherosclerotic drugs, metabolic syndrome drugs or anti-tumor drugs.
  • the invention also relates to methods of synthesizing such compounds and combinations of medicaments containing the same.
  • Glycogen metabolism is an important component of glucose metabolism, especially in certain disease states, abnormal glycogen metabolism becomes an important pathological factor. Studies have shown that insulin regulation of hepatic glycogen metabolism is one of the key mechanisms for maintaining blood glucose balance in the body. Myocardial ischemic injury has a clear correlation with abnormal cardiac glycogen metabolism, abnormal brain glycogen metabolism and cerebral ischemic injury There is a certain correlation (Journal of China Pharmaceutical University, 2006, 37, 1).
  • glycogen metabolism signal transduction molecules and receptor proteins have become potential drug targets for the treatment of type 2 diabetes, ischemic cardiovascular diseases, tumors and psoriasis, such as glycogen synthase kinase-3. , glycogen phosphorylase, protein kinase B and glucagon receptor, etc. (Med. Res. Rev., 2002, 22, 373; Curr. Protein. Pep. Sci., 2002, 3, 561; Cancer Res. , 2006, 66, 5130; Expert Opinion Therap. Pat., 1999, 9, 701).
  • Glycogen phosphorylase is a key enzyme in glycogen metabolism.
  • the enzyme catalyzes the phosphorylation of glycogen, and the produced glucose-1-phosphate is converted to glucose-6-phosphate by catalysis of phosphoglucomutase, which is either catalyzed by glucose-6-phosphatase to produce glucose.
  • the tissue provides glucose or goes directly into the anaerobic and aerobic metabolic pathways to participate in the energy supply. Since glycogen phosphorylase is a key factor in glycogen metabolism, its pharmacological inhibition may be used to treat diseases associated with excessive glycogen degradation, such as diabetes, ischemic myocardial injury, and tumors ( Curr. Protein. Pept. Sci., 2002, 3, 561; Am. J. Physiol. Heart. Girc. Physiol., 2004, 286, H1177).
  • hypertension and its associated pathological changes such as atherosclerosis, hyperlipidemia, and hypercholesterolemia are associated with elevated insulin levels.
  • Inhibition of glycogen phosphorylase can effectively reduce insulin levels, and thus can be used for the treatment of diseases such as hypercholesterolemia, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia.
  • the present invention discloses for the first time the benzodiazepine compound having the medicinal value represented by the formula (I), a preparation method thereof and a medical use thereof, including a medicament for preparing anti-diabetes and its complications, an anti-ischemic drug, and an anti-diabetic agent.
  • Cardiovascular disease drugs blood reduction
  • lipid drugs weight loss drugs
  • anti-atherosclerotic drugs drugs for the treatment of metabolic syndrome and anti-tumor drugs.
  • the compound of formula (I) is a novel glycogen phosphorylase inhibitor and can therefore be used to treat diseases associated with abnormal glycogen metabolism, including: diabetes (especially type 2 diabetes) and its complications.
  • Ischemic cardio-cerebral vascular disease especially myocardial infarction, angina pectoris, arrhythmia, coronary heart disease, stroke, cerebral infarction or ischemic neurodegenerative diseases
  • hyperinsulinemia especially insulin resistance, metabolic syndrome, obesity Fasting hyperglycemia and tumors.
  • the present invention provides a pharmaceutical preparation comprising the compound of the formula (I).
  • the present invention relates to a compound of the formula (I): and a pharmaceutically acceptable salt or ester thereof:
  • X 1 , X 2 , X 3 and X 4 are all C or one of X 1 , X 2 , X 3 and X 4 is N and the others must be C;
  • R 1 and R 1 ' are each independently H, halogen, hydroxy, cyano, C 0-4 alkyl, C 1-4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, vinyl Ethynyl group;
  • R 2 and R 2 ' are each independently H, halogen, hydroxy, cyano, C 0-4 alkyl, C 1-4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, vinyl Ethynyl group;
  • R 3 is H, an unsubstituted or X-substituted linear or branched alkyl group of 1 to 20 carbons, an alkene group, an alkyne group, a substituted or X-substituted aryl group, a substituted or X-substituted heteroaryl group;
  • R 4 and R 5 are each independently H, an unsubstituted or X-substituted straight or branched alkyl, alkene or alkyne group of 1 to 20 carbons;
  • Y is CHR 6 , NH, O, S;
  • R 6 is H, an unsubstituted or X-substituted linear or branched alkyl group of 1 to 20 carbons, an alkene group, an alkyne group, a phenyl group, a benzyl group, a naphthyl group, a nitrile group;
  • X represents H, F, Cl, Br, I, CN, NO 2 , NH 2 , CF 3 , SH, OH, OCH 3 , OC 2 H 5 , COOH, a linear or branched alkyl group of 1 to 10 carbons An alkene group, an alkyne group, an aryl group, a heteroaryl group.
  • Preferred compounds among the above compounds are:
  • X 1 , X 2 , X 3 and X 4 are all C;
  • R 1 and R 1 ' are each independently H, halogen, cyano;
  • R 2 and R 2 ' are each independently H;
  • R 3 is H, 1-2 carbon unsubstituted or X-substituted straight or branched alkyl, substituted or X substituted aryl, substituted or X substituted heteroaryl;
  • R 4 and R 5 are each independently H;
  • Y is CH 2 , NH, O;
  • X represents H, F, Cl, Br, I, CN, NO 2 , NH 2 , CF 3 , SH, OH, OCH 3 , OC 2 H 5 , COOH, a linear or branched alkyl group of 1 to 10 carbons An alkene group, an alkyne group, an aryl group, a heteroaryl group.
  • More preferred compounds are:
  • the compounds of the present invention can be prepared by the reported process or by the following methods:
  • Solvents are generally selected as inert solvents, especially aprotic solvents, including acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, toluene, n-hexane, cyclohexane, tetrahydrofuran.
  • the condensation reagent may be a conventional amidation condensation reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), N,N'-dicyclohexylcarbodiimide.
  • EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • N,N'-dicyclohexylcarbodiimide N,N'-dicyclohexylcarbodiimide.
  • the inorganic base used is sodium carbonate, sodium hydrogencarbonate, potassium carbonate or potassium hydrogencarbonate, and the organic base used is N,N-diisopropylethylamine or triethylamine.
  • the present invention also encompasses a pharmaceutical preparation comprising as an active agent a compound of the formula (I) or a pharmaceutically acceptable salt, ester thereof, Or a pharmaceutically acceptable carrier.
  • the above pharmaceutically acceptable carrier means a conventional pharmaceutical carrier in the pharmaceutical field, and means one or several inert, non-toxic solid or liquid fillers, diluents, auxiliaries, etc., which are not reversed with the active compound or the patient. It works.
  • the dosage form of the composition of the present invention may be a pharmaceutically acceptable dosage form such as a tablet, a capsule, a pill, a suppository, a soft capsule, an oral solution, a suspension, or an injection.
  • Tablets and capsules for oral use contain conventional excipients such as fillers, diluents, lubricants, dispersing agents, and binders.
  • compositions of the invention can be prepared according to methods well known in the art of pharmacy.
  • the dosage of the above active agents will vary from formulation to formulation.
  • advantageous amounts have been demonstrated to achieve a desired result in a total amount of the compound of formula (1) administered per kilogram per 24 hours of from about 0.01 to 800 mg, preferably in a total amount of from 0.1 to 100 mg/kg. If necessary, it is administered in several single doses. However, if necessary, it is also possible to deviate from the above dosage, that is, depending on the type and weight of the subject to be treated, the behavior of the individual on the drug, the nature and severity of the disease, the type of preparation and administration, and the administration time. And spacing.
  • Figure 1 is a diagram showing the preparation process of a partial derivative of the present invention.
  • X 1 , X 2 , X 3 , X 4 , R 1 , R 1 ', R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , X and Y are as defined above. Defined in formula (I).
  • Preparation of reagents 1) Preparation of coloring solution: Weigh 5g of ammonium molybdate, dissolve in 500ml of 1M HCl, stir with a stirrer, add 190mg of malachite green after all dissolved, continue stirring until all dissolved, and use tin foil 2) Buffer preparation: 1 Weigh 0.5656g of Hepes accurately, dissolve it in 5ml H 2 O, adjust the pH to 7.2 with 10M NaOH, and prepare Hepes with a final concentration of 0.5M; 2 Precision Weigh KCl 0.3728g , dissolved in 5ml H 2 O, formulated into a final concentration of 1M KCl; 3 precision weighing MgCl 2 0.0255g, dissolved in 1ml H 2 O, formulated into a final concentration of 125mM MgCl 2 ; 4 precision weighing EGTA 0.0476g, dissolved in 5ml H 2 O, adjusted to pH 7.0 with 10M NaOH, formulated into a final concentration of
  • a dose-response curve for measuring rabbit muscle glycogen phosphorylase activity was determined by reading the OD value at 655 nm after adding different concentrations of GPa to the color developing solution.
  • the amount of GPa can be selected from the dose-effect curve to be 250 ng.
  • test results show that the compound of Example 1 has an IC 50 ⁇ 0.1 ⁇ m, and the pharmacological data shows that the compound of the formula (I) of the present invention has an inhibitory effect on glycogen phosphorylase, and thus can be used for preparing an antidiabetic drug and an anti-brain.

Abstract

本发明涉及药物化学领域，具体涉及一类新型的苯并氮杂卓酮类衍生物（I）、其制备方法及其医药用途。该类化合物具有糖原磷酸化酶抑制作用，可用于制备抗糖尿病及其并发症药物、抗脑缺血药物、抗心血管疾病药物、降血脂药物、减肥药物、抗动脉粥样硬化药物、治疗代谢综合症药物或抗肿瘤药物。本发明还涉及这类化合物的制备方法以及含有它们的药物制剂。

Description

作为糖原磷酸化酶抑制剂的苯并氮杂卓酮类化合物、其制备方法及医药用途 技术领域
本发明涉及药物化学领域，具体涉及一类新型的苯并氮杂卓酮类糖原磷酸化酶抑制剂。该类化合物可用于制备抗糖尿病及其并发症药物、抗脑缺血药物、抗心血管疾病药物、降血脂药物、减肥药物、抗动脉粥样硬化药物、治疗代谢综合症药物或抗肿瘤药物。本发明还涉及这类化合物的合成方法以及含有它们的药物组合。
背景技术
糖原代谢是糖代谢的一个重要组成部分，尤其是在某些疾病状态下，糖原代谢异常成为重要的病理因素。研究表明，胰岛素对肝脏糖原代谢的调控是其维持周身血糖平衡的关键机制之一，心肌缺血损伤与心脏糖原代谢异常有明确的相关性，脑糖原代谢异常与脑缺血损伤也存在着一定的关联(中国药科大学学报，2006，37，1)。
目前，一些糖原代谢的信号转导分子和受体蛋白已成为治疗2型糖尿病、缺血性心血管疾病、肿瘤和银屑病等的潜在药物靶点，如：糖原合成酶激酶-3、糖原磷酸化酶、蛋白激酶B和胰高血糖素受体等(Med.Res.Rev.，2002，22，373；Curr.Protein.Pep.Sci.，2002，3，561；Cancer Res.，2006，66，5130；Expert Opinion Therap.Pat.，1999，9，701)。
其中，糖原磷酸化酶(Glycogen phosphorylase，GP)是糖原代谢的一个关键酶。该酶催化糖原的磷酸解，产生的葡萄糖-1-磷酸在磷酸葡萄糖变位酶催化下转变为葡萄糖-6-磷酸，后者或是在葡萄糖-6-磷酸酶催化下生成葡萄糖，为机体组织提供葡萄糖，或是直接进入无氧代谢和有氧代谢途径以参与能量供应。由于糖原磷酸化酶是糖原代谢中的一个关键因子，因此，对它的药理性抑制有可能用于治疗与糖原过度降解相关的疾病，如糖尿病、缺血性心肌损伤和肿瘤等(Curr.Protein.Pept.Sci.，2002，3，561；Am.J.Physiol.Heart.Girc.Physiol.，2004，286，H1177)。
此外，高血压及其相关的病理改变例如动脉粥样硬化、高脂血症以及高胆固醇血症等都与升高的胰岛素水平有关。抑制糖原磷酸化酶可有效降低胰岛素水平，因此可用于治疗高胆固醇血症、高胰岛素血症、高脂血症、动脉粥样硬化及心肌缺血等疾病。
近年来，研发新型糖原磷酸化酶抑制剂这一领域已受到广泛关注。例如，美国专利申请No.6,297,269和欧洲专利申请No.EP0832066记载了作为糖原磷酸化酶抑制剂的取代的N-(吲哚-2-羰基)酰胺及其衍生物，美国专利申请No.6,107,329记载了作为糖原磷酸化酶抑制剂的取代的N-(吲哚-2-羰基)甘氨酰胺及其衍生物，欧洲专利申请No.WO2006059163记载了作为糖原磷酸化酶抑制剂的吡咯并吡啶-2-甲酸酰胺衍生物。
发明内容
本发明首次公开了式(I)所示的具有药用价值的苯并氮杂卓酮化合物、其制备方法及医药用途，包括在制备抗糖尿病及其并发症药物、抗脑缺血药物、抗心血管疾病药物、降血 脂药物、减肥药物、抗动脉粥样硬化药物、治疗代谢综合症药物和抗肿瘤药物方面的用途。尤其是式(I)所示的化合物是新型糖原磷酸化酶抑制剂，因此可以用于治疗与糖原代谢异常相关的疾病，这些疾病包括：糖尿病(特别是2型糖尿病)及其并发症、缺血性心脑血管疾病(特别是心肌梗死、心绞痛、心律失常、冠心病、中风、脑梗死或缺血性神经退行性疾病等)、高胰岛素血症、胰岛素抵抗、代谢综合征、肥胖、禁食高血糖症和肿瘤。此外，本发明还提供一种含有式(I)所示化合物的药物制剂。
本发明涉及式(I)所示的化合物及其药学上可接受的盐或酯：
Figure PCTCN2014000861-appb-000001
其中：
X1、X2、X3和X4全为C或者X1、X2、X3和X4之一为N而其他的必须为C；
R1和R1’各自独立为H、卤素、羟基、氰基、C0-4烷基、C1-4烷氧基、氟代甲基、二氟甲基、三氟甲基、乙烯基、乙炔基；
R2和R2’各自独立为H、卤素、羟基、氰基、C0-4烷基、C1-4烷氧基、氟代甲基、二氟甲基、三氟甲基、乙烯基、乙炔基；
R3为H，1-20个碳的非取代的或X取代的直链或支链烷基、烯烃基、炔烃基，取代或X取代的芳基，取代或X取代的杂芳基；
R4和R5各自独立为H，1-20个碳的非取代的或X取代的直链或支链烷基、烯烃基、炔烃基；
Y为CHR6，NH，O，S；
R6为H，1～20个碳的非取代的或X取代的直链或支链烷基、烯烃基、炔烃基、苯基、苄基、萘基、腈基；
X代表H、F、Cl、Br、I、CN、NO2、NH2、CF3、SH、OH、OCH3、OC2H5、COOH、1～10个碳的直链或支链烷基、烯烃基、炔烃基、芳基、杂芳基。
上述化合物中优选的化合物为：
X1、X2、X3和X4全为C；
R1和R1’各自独立为H、卤素、氰基；
R2和R2’各自独立为H；
R3为H，1-2个碳的非取代的或X取代的直链或支链烷基，取代或X取代的芳基，取代 或X取代的杂芳基；
R4和R5各自独立为H；
Y为CH2，NH，O；
X代表H、F、Cl、Br、I、CN、NO2、NH2、CF3、SH、OH、OCH3、OC2H5、COOH、1～10个碳的直链或支链烷基、烯烃基、炔烃基、芳基、杂芳基。
更为优选的化合物是：
Figure PCTCN2014000861-appb-000002
本发明所述的化合物可采用已报道的工艺方法制备，也可以采用下述方法制备得到：
将取代的吲哚羧酸或吡咯并吡啶-2-羧酸，与苯并氮杂卓酮化合物溶解在有机溶剂中，加入缩合试剂与有机胺或无机碱，反应1-72小时，温度为0℃至45℃。溶剂一般选择惰性溶剂，特别是非质子性溶剂，包括乙腈、氯仿、二氯甲烷、1，2-二氯乙烷、N，N-二甲基甲酰胺、甲苯、正己烷、环己烷、四氢呋喃、叔丁基甲基醚或上述溶剂的混合溶剂，优先采用二氯甲烷、1，2-二氯乙烷或、N，N-二甲基甲酰胺。缩合试剂可以采用常规的酰胺化缩合试剂，如1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(EDCI)、N，N′-二环己基碳二亚胺(DCC)、O-苯并三氮唑-N，N，N′，N′-四甲基脲四氟硼酸(TBTU)、2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(HATU)、1-丙基磷酸三环酸酐(T3P)。所采用的无机碱为碳酸钠、碳酸氢钠、碳酸钾或碳酸氢钾，所采用的有机碱为N，N-二异丙基乙胺或三乙胺。
本发明还包括药物制剂，该制剂包含作为活性剂的通式(I)化合物或其药用盐、酯、 或药学上可接受的载体。
上述药学上可接受的载体是指药学领域常规的药物载体，是指一种或几种惰性的、非毒性的固体或液体填充物、稀释剂，助剂等，它们不逆向与活性化合物或病人发生作用。
本发明组合物的剂型可以是片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬剂、注射液等药剂学上常用的剂型。
口服用药片和胶囊含有传统的赋形剂如填充物、稀释剂、润滑剂、分散剂以及粘合剂。
本发明药物组合物的各种剂型可以按照药学领域中熟知的方法进行制备。
以上活性剂的剂量将因配方而异。
一般地，已证明有利的量，为达到所需结果，每千克每24小时给药的式(1)化合物的总量为约0.01-800mg，优选的总量为0.1-100mg/kg。如果必要，以几次单剂量的形式给药。然而，如果必要，也可以偏离上述用量，即这取决于待治疗的受试者的类型和体重、个体对药物的行为、疾病的性质和严重性、制剂和给药的类型、以及给药时间和间隔。
附图说明
下面结合附图和实施例对本发明做进一步说明。
图1是表示本发明部分衍生物的制备过程。
在图1中，X1、X2、X3、X4、R1、R1’、R2、R2’、R3、R4、R5、R6、X和Y的定义如上述式(I)中所定义。
具体实施方式：
下面通过实施例具体说明本发明的内容。在本发明中，以下所述的实例是为了更好的阐述本发明，并不是用来限制本发明的范围。
以下通过实施例进一步说明本发明的实施
实施例1
7-(5-氯-1H-吲哚-2-酰胺)-3，4-二氢苯并[f][1，4]氧氮杂卓-5(2H)-酮
将5-氯-1H-吲哚-2-甲酸(593mg，3.03mmol)和7-氨基-3，4-二氢苯并[f][1，4]氧氮杂卓-5(2H)-酮(450mg，2.53mmol)溶解于干燥的二氯甲烷(10.0ml)中，缓慢加入1-丙基磷酸三环酸酐的乙酸乙酯溶液(T3P，50wt.％，3.02mL，10.12mmol)和N，N-二异丙基乙胺(DIPEA，1.3mL，7.59mmol)。加毕，氮气保护下室温搅拌2小时。反应结束后，反应液中依次以1N盐酸水溶液，饱和NaHCO3水溶液和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，残渣经反相HPLC分离(流动相：ACN---H2O(0.1％TFA)，梯度：40％-70％)，得白色固体(70mg，16％)。
ESI-MS m/z：354.1[M-H]-.
1H-NMR(d6-DMSO，400MHz)：11.94(s，1H)，10.39(s，1H)，8.37(t，J＝4.4Hz，1H)，8.13(d，J＝2.0Hz，1H)，7.97(dd，J＝2.4，8.8Hz，1H)，7.94(dd，J＝2.4，8.8Hz，1H)，7.78(s，1H)，7.48(d， J＝8.8Hz，1H)，7.43(s，1H)，7.23(d，J＝8.4Hz，1H)，7.05(d，J＝8.8Hz，1H)，4.28(t，J＝4.4Hz，2H)，3.33-3.35(m，2H).
体外糖原磷酸化酶抑制活性试验：
试剂的配制：1)显色液的配制：称量钼酸铵5g，溶解于500ml 1M HCl中，用搅拌器搅拌，至全部溶解后在加入孔雀绿190mg，继续搅拌至全部溶解，并用锡箔纸避光；2)缓冲液的配制：①精密称量Hepes 0.5958g，溶于5ml H2O中，用10MNaOH调PH至7.2，配制成终浓度为0.5M的Hepes；②精密称量KCl 0.3728g，溶于5ml H2O中，配制成终浓度为1M的KCl；③精密称量MgCl20.0255g，溶于1ml H2O中，配制成终浓度为125mM的MgCl2；④精密称量EGTA 0.0476g，溶于5ml H2O中，用10M NaOH调PH至7.0，配制成终浓度为25mM的EGTA；⑤精密称量G-1-P 0.0152g，溶于10ml H2O中，配制成终浓度为5mM的G-1-P；⑥精密称量glycogen 10mg，溶于1ml H2O中，配制成终浓度为10mg/ml的glycogen；3)阳性药caffeine溶液的配制：将caffeine溶于10ml H2O配制0.5、5、50和500μM的溶液；4)配制GPa溶液：取1μl的GPa加入到100μl反应体系中，终浓度为250ng/100μl；5)待测试化合物溶液的配制：将待测试化合物溶于DMSO配制成浓度为10mM溶液，取适量化合物溶液加入到反应体系中至不同终浓度。
测定rabbit肌糖原磷酸化酶活性的量效曲线：通过读取不同浓度的GPa加入显色液后的在655nm下的OD值，来测定其量效曲线。由量效曲线可选择GPa的量为250ng。
实验步骤：1)设计PC(阳性对照)、Blank(空白对照)、阳性药(咖啡因)；2)加反应buffer52μl；3)加测试化合物至终浓度；4)加酶1μl，终浓度为250ng/100μl；5)加显色液150μl；6)30摄氏度条件下反应20分钟；7)在波长655nm条件下比色；8)数据的读取及抑制率的计算：抑制率＝[阳性对照-待测样品]/[阳性对照-空白对照]。
测试结果显示，实施例1中的化合物IC50＜0.1μm，该药理学数据显示，本发明通式(I)化合物具有糖原磷酸化酶的抑制作用，因此可用于制备抗糖尿病药物、抗脑缺血药物、抗心血管疾病药物、降血脂药物、减肥药物、抗动脉粥样硬化药物或抗肿瘤药物。

Claims (10)

  1. 本发明涉及式(I)所示的化合物及其药学上可接受的盐或酯：
    Figure PCTCN2014000861-appb-100001
    其中：
    X1、X2、X3和X4全为C或者X1、X2、X3和X4之一为N而其他的必须为C；
    R1和R1’各自独立为H、卤素、羟基、氰基、C0-4烷基、C1-4烷氧基、氟代甲基、二氟甲基、三氟甲基、乙烯基、乙炔基；
    R2和R2’各自独立为H、卤素、羟基、氰基、C0-4烷基、C1-4烷氧基、氟代甲基、二氟甲基、三氟甲基、乙烯基、乙炔基；
    R3为H，1-20个碳的非取代的或X取代的直链或支链烷基、烯烃基、炔烃基，取代或X取代的芳基，取代或X取代的杂芳基；
    R4和R5各自独立为H，1-20个碳的非取代的或X取代的直链或支链烷基、烯烃基、炔烃基；
    Y为CHR6，NH，O，S；
    R6为H，1～20个碳的非取代的或X取代的直链或支链烷基、烯烃基、炔烃基、苯基、苄基、萘基、腈基；
    X代表H、F、Cl、Br、I、CN、NO2、NH2、CF3、SH、OH、OCH3、OC2H5、COOH、1～10个碳的直链或支链烷基、烯烃基、炔烃基、芳基、杂芳基。
  2. 权利要求1的化合物及其药学上可接受的盐或酯，其特征在于：
    X1、X2、X3和X4全为C；
    R1和R1’各自独立为H、卤素、氰基；
    R2和R2’各自独立为H；
    R3为H，1-2个碳的非取代的或X取代的直链或支链烷基，取代或X取代的芳基，取代或X取代的杂芳基；
    R4和R5各自独立为H；
    Y为CH2，NH，O；
    X代表H、F、Cl、Br、I、CN、NO2、NH2、CF3、SH、OH、OCH3、OC2H5、COOH、1～10个碳的直链或支链烷基、烯烃基、炔烃基、芳基、杂芳基。
  3. 权利要求1的化合物，其中化合物可以是下列任一化合物及其药用盐或酯：
    Figure PCTCN2014000861-appb-100002
  4. 权利要求1、2、3的化合物的制备方法，包括：
    将取代的吲哚羧酸或吡咯并吡啶-2-羧酸，与苯并氮杂卓酮化合物溶解在有机溶剂中，加入缩合试剂与有机胺或无机碱，反应1-72小时，温度为0℃至45℃。溶剂一般选择惰性溶剂，特别是非质子性溶剂，包括乙腈、氯仿、二氯甲烷、1，2-二氯乙烷、N，N-二甲基甲酰胺、甲苯、正己烷、环己烷、四氢呋喃、叔丁基甲基醚或上述溶剂的混合溶剂，优先采用二氯甲烷、1，2-二氯乙烷或、N，N-二甲基甲酰胺。缩合试剂可以采用常规的酰胺化缩合试剂，如1-乙基-3-(3-二甲胺丙基)碳二亚胺盐酸盐(EDCI)、N，N′-二环己基碳二亚胺(DCC)、O-苯并三氮唑-N，N，N′，N′-四甲基脲四氟硼酸(TBTU)、2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(HATU)、1-丙基磷酸三环酸酐(T3P)。所采用的无机碱为碳酸钠、碳酸氢钠、碳酸钾或碳酸氢钾，所采用的有机碱为N，N-二异丙基乙胺或三乙胺。
  5. 一种药物组合物，其中含有治疗有效量的通式(I)化合物、混旋体、光学异构体或其药学上可接受的盐或酯及药学上可接受的载体。
  6. 权利要求1至3的化合物，其特征在于：这些化合物是新型糖原磷酸化酶抑制剂。
  7. 权利要求6的用途，其特征在于：糖原磷酸化酶抑制剂是预防和治疗糖尿病及其并发症、高血脂症、肥胖、缺血性心脑血管疾病、高胰高血糖素症、胰岛素抵抗、禁食高血糖症、高血压及其并发症、动脉粥样硬化症、代谢综合征或肿瘤的药物。
  8. 权利要求7的用途，其特征在于：糖尿病是2型糖尿病，其并发症包括：糖尿病肾病、糖尿病足、糖尿病神经病变或糖尿病并发的心脑血管疾病。
  9. 权利要求7的用途，其特征在于：缺血性心脑血管疾病是心肌梗死、心绞痛、心律失常、冠心病、脑缺血、中风、脑梗死或缺血性神经退行性疾病。
  10. 权利要求7的用途，其特征在于：权利要求1至3的化合物可用于预防和治疗高血脂 症和动脉粥样硬化症。
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