CN101611028B - Substituted oxindole derivatives and their use as vasopressin receptor ligands - Google Patents

Substituted oxindole derivatives and their use as vasopressin receptor ligands Download PDF

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CN101611028B
CN101611028B CN 200780051459 CN200780051459A CN101611028B CN 101611028 B CN101611028 B CN 101611028B CN 200780051459 CN200780051459 CN 200780051459 CN 200780051459 A CN200780051459 A CN 200780051459A CN 101611028 B CN101611028 B CN 101611028B
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CN101611028A (en
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A·尼茨
T·乌斯特
H·格尼斯特
W·M·布拉杰
W·沃内特
L·昂杰
W·霍恩伯格
W·卢比希
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艾博特股份有限两合公司
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Abstract

本发明涉及新的通式(I)的羟吲哚衍生物,以及包含它们的药物以及它们用于预防和/或治疗加压素依赖性疾病的用途。 The present invention relates to novel oxindole derivatives of formula (I), and medicament containing them and their use for the prevention and / or treatment of vasopressin-dependent diseases.

Description

取代的羟吲哚衍生物、以及它们用作加压素受体配体的用 Substituted oxindole derivatives, and their use as vasopressin receptor ligands

way

[0001] 本发明涉及新的取代的羟吲哚衍生物,包含它们的药物以及它们治疗疾病的用途。 [0001] The present invention relates to novel substituted oxindole derivatives, medicaments containing them and their use in the treatment of diseases.

[0002] 加压素是ー种内源性激素,其对器官和组织具有广泛地不同的作用。 [0002] Vasopressin is ー endogenous sex hormones, having widely different effects on organs and tissues. 人们怀疑,加压素体系涉及多种病理状态,例如,心力衰竭和高血压。 It is suspected that the vasopressin system involves various pathological conditions, e.g., heart failure and hypertension. 目前已知三种受体(Via、Vlb或V3和V2),通过这些受体加压素调节它的许多作用。 Known three receptors (Via, Vlb or V3 and V2), these receptors by vasopressin adjust its many functions. 因此,研究这些受体的拮抗剂,以便尽可能地提供治疗疾病的新治疗方法(M.Thibonnier, Exp.0pin.1nvest.Drugsl998, 7 (5),729-740)。 Therefore, the study of these receptor antagonists, to provide a new method of treatment (M.Thibonnier, Exp.0pin.1nvest.Drugsl998, 7 (5), 729-740) the treatment of diseases as much as possible.

[0003] 本申请描述了在I位具有芳基磺酰基的新的取代羟吲哚。 [0003] The present application describes novel substituted oxindoles having arylsulfonyl group I bit. 1-苯磺酰基-1,3_ ニ氢-2H-吲哚-2-酮之前已经被描述为加压素受体的配体。 Benzenesulfonyl--1,3_ has been described as vasopressin receptor ligand before Ni hydrogen -2H- indol-2-one. 在WO 93/1505UW0 95/18105、WO 98/2590UW0 01/55130,W001/55134,WO 01/64668 和WO 01/98295 中描述了衍生物,所述衍生物源自于羟吲哚骨架并且在I位具有芳基磺酰基。 In WO 93 / 1505UW0 95/18105, WO 98 / 2590UW0 01/55130, W001 / 55134, WO 01/64668 and WO 01/98295 describes derivatives which are derived from the oxindole skeleton and I arylsulfonyl group having position. 这些化合物在3位的取代显著不同。 These compounds are significantly different substituents at the 3 position.

[0004]特别地,WO 93/15051 和WO 98/25901 描述了1-苯磺酰基_1,3_ ニ氢-2H-吲哚-2-酮作为加压素受体的配体,其中该羟吲哚结构在3位被两个烷基取代,所述烷基还可以一起形式环烷基(螺连接)。 [0004] In particular, WO 93/15051 and WO 98/25901 describes 1-benzenesulfonyl-Ni hydrogen _1,3_ -2H- indol-2-one as pressing a ligand-receptor, wherein the hydroxyl indole structure 3 is substituted with two alkyl groups, said alkyl groups may together form a cycloalkyl group (spiro-attached). 或者,所述螺环可以包含杂原子如氧和氮(任选具有取代基)。 Alternatively, the spiro rings may contain heteroatoms such as oxygen and nitrogen (optionally having a substituent group).

[0005] WO 95/18105描述了1-苯磺酰基_1,3_ ニ氢-2H-吲哚-2-酮作为加压素受体的配体,其在3位具有氣原子。 [0005] WO 95/18105 describes a 1-benzenesulfonyl-Ni hydrogen _1,3_ -2H- indol-2-one as a vasopressin receptor ligand, which has three atoms in the gas. 另外,选自烧基、环烧基、苯基和节基(在甸种情况下任选具有取代基)的基团在3位连接。 Further, the group is selected from burning, burn cycloalkyl group, a phenyl group, and the section (in the case Austin optionally having a substituent) group is attached at the 3 bits.

[0006] WO 03/008407`描述了1-苯基磺酰基羟吲哚类化合物,其中在3位吡啶基哌嗪通过氧羰基连接到羟吲哚上。 [0006] WO 03 / 008407` described hydroxyalkyl group of 1-phenylsulfonyl indoles, wherein the 3-pyridyl piperazine oxindole attached to the carbonyl group through an oxygen.

[0007] WO 2005/030755的实施例108描述了氨基甲酸酯化合物4-(1-甲基哌啶_4_基)哌嗪-1-羧酸5-氰基-1- (2,4- ニ甲氧基-苯磺酰基)-3- (2-甲氧基吡啶-3-基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基酷(根据IUPAC命名:5_氰基-1-[ (2,4-ニ甲氧基苯基)磺酰基]-3_ (2-甲氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基4-(1-甲基哌啶-4-基)哌嗪-1-羧酸酯)。 Example [0007] WO 2005/030755 describes a urethane compound 108 4- (1-methyl-piperidin _4_ yl) piperazine-1-carboxylic acid 5-cyano-1- (2,4 - ni methoxy - benzenesulfonyl) -3- (2-methoxy-3-yl) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl cool (according to IUPAC name: 5_-cyano-1- [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2-methoxy-3-yl) -2-oxo-2,3-ni hydrogen -1H- indol-3-yl 4- (1-methyl-piperidin-4-yl) piperazine-1-carboxylate).

[0008] WO 06/005609描述了所述2-こ氧基苯基脲类化合物N-[5-氰基-l-[(2,4-ニ甲氧基苯基)磺酰基]-3-(2-こ氧基苯基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺(作为实施例119)和N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3-(2-こ氧基苯基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺(作为实施例128)。 [0008] WO 06/005609 describes the 2- ko-phenyl urea compounds N- [5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl] -3- (2 ko) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine -1 - carboxamide (Example 119 a) and N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3- (2-ko-phenyl) -2 - oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide (Example 128 a).

[0009] 除对加压素Vlb受体的结合亲和力外,其它性质对治疗和/或预防加压素-依赖性疾病也可能是有利的,例如: [0009] In addition to pressing the binding affinity receptor Vlb element, the other properties for the treatment and / or prophylaxis of vasopressin - dependent diseases may also be advantageous, for example:

[0010] 1.)相对于加压素Vla受体来说,对加压素Vlb受体具有选择性,即对Vla受体的结合亲和力(Ki(Vla)(以单位"纳摩尔(nM)"測定)和对Vlb受体的结合亲和力(Ki(Vlb))(以单位"纳摩尔(nM)"測定)的商。商Ki (Via)/Ki (Vlb)越大,Vlb选择性越大; [0010] 1) with respect to the receptors for vasopressin Vla, Vlb selective for the vasopressin receptor, i.e. the receptor binding affinity of Vla (of Ki (Vla) (the unit "nanomolar (nM) "assays) and binding affinity for the receptor Vlb (of Ki (Vlb)) (the unit" nanomolar (nM) "assay) the quotient commercially Ki (Via) / Ki (Vlb), the greater the selectivity Vlb ;

[0011] 2.)相对于加压素V2受体来说,对加压素Vlb受体具有选择性,即对V2受体的结合亲和カ(Ki (V2)(以单位"纳摩尔(nM)"測定)和对Vlb受体的结合亲和力(Ki(Vlb))(以单位"纳摩尔(nM)"测定)的商。商Ki (V2)/Ki (Vlb)越大,Vlb选择性越大; [0011] 2) with respect to the vasopressin V2 receptor is selective for vasopressin Vlb receptors, binding affinity for V2 receptors and ka (of Ki (V2) (the unit "nanomolar ( nM) "assays) and binding affinity for the receptor Vlb (of Ki (Vlb)) (the unit" nanomolar (nM) "assay) the quotient quotient Ki (V2) / Ki (Vlb) larger, Vlb selective The greater;

[0012] 3.)相对于催产素OT受体来说,对加压素Vlb受体具有选择性,即对OT受体的结合亲和カ(Ki(OT)(以单位"纳摩尔(nM)"測定)和对Vlb受体的结合亲和力(Ki(Vlb))(以单位"纳摩尔(nM)"测定)的商。商Ki (OT)/Ki (Vlb)越大,Vlb选择性越大; [0012] 3.) Oxytocin OT receptor with respect to it, Vlb selective for vasopressin receptors, i.e. the OT receptor binding affinity and ka (of Ki (OT) (in the unit "nanomolar (nM ) "assay) and binding affinity for the receptor Vlb (of Ki (Vlb)) (the unit" nanomolar (nM) "assay) the quotient quotient Ki (OT) / Ki (Vlb) the larger, the more selective Vlb Big;

[0013] 4.)代谢稳定性,例如使用在各物种(例如大鼠或人)的肝脏微粒体中体外测得的半衰期进行确定; [0013] 4.) metabolic stability, for example, in various species (e.g., rat or human) liver microsomes measured in vitro half-life was determined;

[0014] 5.)即使有,也是较少的,细胞色素P450 (CYP)酶的抑制:细胞色素P450 (CYP)是具有酶(氧化酶)活性的血红素蛋白的超家族的名称。 [0014] 5) Even if there is less, cytochrome P450 (CYP) enzyme inhibition: cytochrome P450 (CYP) superfamily is the name of an enzyme (oxidase) heme protein activity. 它们对哺乳动物有机体内外来物质,例如药物或生物异源物质的降解(代谢)也是特别重要的。 Substances inside and outside thereof to a mammalian organism, such as degradation of the drug or xenobiotic substances (metabolic) also of particular importance. 人有机体中CYP型和亚型的最重要代表是:CYP 1A2、CYP 2C9、CYP 2D6和CYP 3A4。 The most important representative of the people organism CYP and subtypes are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. 当同时给予CYP 3A4抑制剂(例如葡萄柚汁、甲腈咪胍、红霉素)和通过这种酶系统降解并由此竞争该酶处相同结合位点的药物时,它们的降解可能被延迟,并且所给予的药物的作用和副作用可能以ー种不希望的方式増加; When administered simultaneously CYP 3A4 inhibitors (e.g., grapefruit juice, cimetidine, erythromycin) and degrades the same, and thus the drug binding site of the enzyme by the enzyme competitive system, their degradation may be delayed and the effect of a drug administered to and side effects may ー species to increase in an undesirable manner;

[0015] 6.)在水中合适的溶解度(以mg/ml表示); [0015] 6.) a suitable solubility in water (expressed in mg / ml);

[0016] 7.)适宜的药物动力学(在血浆或组织如脑中的本发明化合物浓度的时间曲线)。 [0016] 7.) suitable pharmacokinetics (concentrations of the compound of the present invention, such as brain tissue or in plasma-time curve). 药物动力学可以通过下列參数进行表述:半衰期、分布体积、血浆清除率、AUC ("曲线下面积",在浓度-时间曲线下的面积)、ロ服生物利用度、脑/血浆比例; Pharmacokinetics can be expressed by the following parameters: half-life, volume of distribution, plasma clearance, the AUC ( "area under the curve," concentration - area under the curve), ro service bioavailability, the brain / plasma ratio;

[0017] 8.)存在附着于血浆蛋白质的某一比例的活性物质(药物/血浆蛋白结合(PPB)值);` [0017] 8.) is present attached to a percentage of plasma proteins active substance (drug / plasma protein binding (PPB) values); '

[0018] 9.)没有或仅有少量的hERG通道阻滞:阻滞hERG通道的化合物可能延长QT时间间隔,由此导致严重的节律不齐(例如"扭转型室性心动过速")。 [0018] 9) no or only small amounts of hERG channel blockers: hERG channel blocking compound may prolong QT interval, resulting in severe uneven rhythm (e.g., "reverse ventricular tachycardia"). 使用在文献中所述的置换试验,使用放射活性标记的多菲菜德(GJDiaz等,Journal of Pharmacological andToxicologicalMethods,50 (2004),187-199),有可能测定阻滞hERG通道的化合物的潜力。 Using the displacement assay described in the literature, using radioactively labeled phenanthrene dish plurality Germany (GJDiaz the like, Journal of Pharmacological andToxicologicalMethods, 50 (2004), 187-199), it is possible to block the hERG channel potential of the compound was measured. 在此“多菲菜德试验"中的IC50越低,hERG阻滞越有效。 The lower the IC50 in this "Dauphine dish German test", the more effective hERG block. 此外,hERG通道的阻滞可以通过电物理实验,使用被hERG通道转染的细胞通过"全细胞膜片钳"进行測定(GJDiaz等,Journal ofPharmacological and Toxicological Methods,50(2004),187-199)。 Furthermore, blockade of the hERG channel by electro-physical experiments, the cells were transfected with the hERG channel were determined by "whole-cell patch-clamp" (GJDiaz the like, Journal ofPharmacological and Toxicological Methods, 50 (2004), 187-199).

[0019] 本发明的ー个目的是提供ー种具有高活性和选择性活性的化合物,优选特别是对于加压素vlb受体具有高活性和选择性活性,用于治疗或预防各种加压素-依赖性疾病。 [0019] ー object of this invention is to provide a compound having high activity and selectivity of the active species having ー, particularly preferably for vlb vasopressin receptor activity having high activity and selectivity for the treatment or prevention of various pressure hormone - dependent diseases. 此夕卜,本发明的物质将具有上述1.)-9.)中的ー个或多个优点,特别是相对于Vla受体对Vlb受体具有适宜的选择性。 Bu this evening, the substance of the present invention having the above 1) - 9) in one or more advantages ー, particularly with respect to appropriate Vla receptor selectivity Vlb receptors.

[0020] 本发明的目的通过通式(I)的化合物实现 [0020] The object of the present invention by the compounds of formula (I) is achieved

[0021] 其中 [0021] in which

[0022] [0022]

Figure CN101611028BD00111

[0023] Rl是こ氧基; [0023] Rl is ko group;

[0024] R2 是氢; [0024] R2 is hydrogen;

[0025] R3是氰基; [0025] R3 is cyano;

[0026] R4 是氢; [0026] R4 is hydrogen;

[0027] R5是氢、甲氧基或こ氧基; [0027] R5 is hydrogen, methoxy or ko group;

[0028] R6是氢或甲氧基; [0028] R6 is hydrogen or methoxy;

[0029] R7是氣、甲基、こ基、正丙基或异丙基; [0029] R7 is a gas, methyl, ko, n-propyl or isopropyl;

[0030] Xl 是_NH_ ; [0030] Xl is _NH_;

[0031] X2 是N 或CH; [0031] X2 is N or CH;

[0032] X3 是N 或CH ; [0032] X3 is N or CH;

[0033] 其中X2和X3不能同时是N(也就是说最多只有一个是氮原子);及其药学上可接受的盐、互变异构体形式和前药。 [0033] wherein X2 and X3 are not both N (that is to say at most one is a nitrogen atom); and pharmaceutically acceptable salts, tautomeric forms and prodrugs.

[0034] 因此,本发明涉及通式⑴的化合物(下文也称为"化合物⑴"),包括其互变异构体形式,以及化合物(I)的药学上可接受的盐和化合物(I)的前药。 [0034] Accordingly, the present invention relates to compounds of general formula ⑴ (hereinafter also referred to as "compound ⑴"), including tautomeric forms thereof, and a pharmaceutically acceptable compound (I) and a salt of Compound (I) prodrug.

[0035] 本发明的一个优选主题是通式(I)的化合物, [0035] A preferred subject of the invention is a compound of formula (I), and

[0036] 其中 [0036] in which

[0037] Rl是こ氧基; [0037] Rl is ko group;

[0038] R2 是氢; [0038] R2 is hydrogen;

[0039] R3是氰基; [0039] R3 is cyano;

[0040] R4 是氢; [0040] R4 is hydrogen;

[0041] R5是氢或甲氧基,特别是甲氧基; [0041] R5 is hydrogen or methoxy, especially methoxy;

[0042] R6是氢或甲氧基,特别是甲氧基; [0042] R6 is hydrogen or methoxy, especially methoxy;

[0043] R7是氣、甲基、こ基、正丙基或异丙基; [0043] R7 is a gas, methyl, ko, n-propyl or isopropyl;

[0044] Xl 是-NH-; [0044] Xl is -NH-;

[0045] X2 是N 或CH ; [0045] X2 is N or CH;

[0046] X3 是N 或CH ;[0047] 其中X2和X3不能同时是氮原子; [0046] X3 is N or CH; [0047] wherein X2 and X3 are not simultaneously a nitrogen atom;

[0048] 及其药学上可接受的盐、互变异构体形式和前药。 [0048] and pharmaceutically acceptable salts, tautomeric forms and prodrugs.

[0049] 本发明的一个特别优选主题是通式(I)的化合物, [0049] A particularly preferred subject matter of the present invention is a compound of formula (I), and

[0050] 其中 [0050] in which

[0051] Rl是こ氧基; [0051] Rl is ko group;

[0052] R2 是氢; [0052] R2 is hydrogen;

[0053] R3是氰基; [0053] R3 is cyano;

[0054] R4 是氢; [0054] R4 is hydrogen;

[0055] R5是氢或甲氧基,特别是甲氧基; [0055] R5 is hydrogen or methoxy, especially methoxy;

[0056] R6是氢或甲氧基,特别是甲氧基,特别是甲基或こ基; [0056] R6 is hydrogen or methoxy, especially methoxy, in particular methyl or ko-yl;

[0057] R7是氢、甲基或こ基; [0057] R7 is hydrogen, methyl or a ko-yl;

[0058] Xl 是-NH-; [0058] Xl is -NH-;

[0059] X2 是N ; [0059] X2 is N;

[0060] X3 是CH ;`[0061] 及其药学上可接受的盐、互变异构体形式和前药。 [0060] X3 is CH; `[0061] and pharmaceutically acceptable salts, tautomeric forms and prodrugs.

[0062] 本发明的另ー个特别优选主题是通式(I)的化合物, [0062] Another special ー subject of the present invention is preferably a compound of formula (I), and

[0063] 其中 [0063] in which

[0064] Rl是こ氧基; [0064] Rl is ko group;

[0065] R2 是氢; [0065] R2 is hydrogen;

[0066] R3是氰基; [0066] R3 is cyano;

[0067] R4 是氢; [0067] R4 is hydrogen;

[0068] R5是氢或甲氧基,特别是甲氧基; [0068] R5 is hydrogen or methoxy, especially methoxy;

[0069] R6是氢或甲氧基,特别是甲氧基; [0069] R6 is hydrogen or methoxy, especially methoxy;

[0070] R7是氢、甲基或こ基,特别是甲基或こ基; [0070] R7 is hydrogen, methyl or a ko-yl, especially methyl or a ko-yl;

[0071 ] Xl 是_NH_ ; [0071] Xl is _NH_;

[0072] X2 是CH ; [0072] X2 is CH;

[0073] X3 是N ; [0073] X3 is N;

[0074] 及其药学上可接受的盐、互变异构体形式和前药。 [0074] and pharmaceutically acceptable salts, tautomeric forms and prodrugs.

[0075] 本发明的另ー个特别优选主题是通式(I)的化合物, [0075] The present invention preferably further ー special topics are compounds of Formula (I), and

[0076] 其中 [0076] in which

[0077] Rl是こ氧基; [0077] Rl is ko group;

[0078] R2 是氢; [0078] R2 is hydrogen;

[0079] R3是氰基; [0079] R3 is cyano;

[0080] R4 是氢; [0080] R4 is hydrogen;

[0081] R5是氢或甲氧基,特别是甲氧基; [0081] R5 is hydrogen or methoxy, especially methoxy;

[0082] R6是氢或甲氧基,特别是甲氧基; [0082] R6 is hydrogen or methoxy, especially methoxy;

[0083] R7是氢、甲基或こ基,特别是甲基或こ基; [0083] R7 is hydrogen, methyl or a ko-yl, especially methyl or a ko-yl;

[0084] Xl 是_NH_ ; [0084] Xl is _NH_;

[0085] X2 是CH ;[0086] X3 是CH ; [0085] X2 is CH; [0086] X3 is CH;

[0087] 及其药学上可接受的盐、互变异构体形式和前药。 [0087] and pharmaceutically acceptable salts, tautomeric forms and prodrugs.

[0088] 本发明的另ー个特别优选主题是通式(I)的化合物, [0088] Another special ー subject of the present invention is preferably a compound of formula (I), and

[0089] 其中 [0089] in which

[0090] Rl是こ氧基; [0090] Rl is ko group;

[0091] R2 是氢; [0091] R2 is hydrogen;

[0092] R3是氰基; [0092] R3 is cyano;

[0093] R4 是氢; [0093] R4 is hydrogen;

[0094] R5是甲氧基; [0094] R5 is methoxy;

[0095] R6是甲氧基; [0095] R6 is methoxy;

[0096] R7是甲基或こ基; [0096] R7 is methyl or a ko-yl;

[0097] Xl 是_NH_ ; [0097] Xl is _NH_;

[0098] X2 是CH 和X3 是N ;或 [0098] X2 is CH and X3 is N; or

[0099] X2 是N 和X3 是CH ; [0099] X2 is N and X3 is CH;

[0100] 及其药学上可接受的盐、互变异构体形式和前药。 [0100] and pharmaceutically acceptable salts, tautomeric forms and prodrugs.

[0101] 本发明的优选实施方案的实例是通式(I)的化合物,及其药学上可接受的盐、互变异构体形式和前药,其中 [0101] Examples of preferred embodiments of the present invention is a compound of formula (I) and their pharmaceutically acceptable salts, tautomeric forms and prodrugs thereof, wherein

[0102] Rl是こ氧基, [0102] Rl is a group ko,

[0103] R2 是氢, [0103] R2 is hydrogen,

[0104] R3是氰基, [0104] R3 is cyano,

[0105] R4 是氢, [0105] R4 is hydrogen,

[0106] Xl 是NH, [0106] Xl is NH,

[0107] 以及其中基团X2、X3、R5、R6和R7在每种情况下具有下表I每列中所列的含义。 [0107] and wherein the groups X2, X3, R5, R6 and R7 have the meanings set forth in Table I for each column in each case.

[0108]表 1: [0108] Table 1:

[0109] [0109]

Figure CN101611028BD00131
Figure CN101611028BD00141
Figure CN101611028BD00151
Figure CN101611028BD00161
Figure CN101611028BD00171

[0111] 特别地,本发明涉及下列式Ia的化合物(其相当于表I的实施例1化合物) [0111] In particular, the present invention relates to the following compounds of formula Ia (which corresponds to the compound of Example I in Table 1)

[0112] [0112]

Figure CN101611028BD00172

[0113] 及Ia的药学上可接受的盐、互变异构体形式和前药。 [0113] Ia and pharmaceutically acceptable salts, tautomeric forms and prodrugs.

[0114] 特别地,本发明还涉及表I实施例7的化合物及其药学上可接受的盐、互变异构体形式和前药。 [0114] In particular, the present invention also relates to a compound in Table 7 in Example I, and pharmaceutically acceptable salts thereof embodiment, tautomeric forms and prodrugs.

[0115] 特别地,本发明还涉及表I实施例31的化合物及其药学上可接受的盐、互变异构体形式和前药。 [0115] In particular, the present invention also relates to a compound in Table 31 and pharmaceutically acceptable salts thereof Example I embodiment, tautomeric forms and prodrugs.

[0116] 特别地,本发明还涉及表I实施例37的化合物及其药学上可接受的盐、互变异构体形式和前药。 [0116] In particular, the present invention also relates to a compound in Table 37 and pharmaceutically acceptable salts thereof Example I embodiment, tautomeric forms and prodrugs. [0117] 本发明的化合物⑴或(Ia)在2-羟吲哚环的3位具有手性中心。 Compound [0117] The present invention ⑴ or (Ia) in three chiral center having a 2-oxindole ring. 因此,本发明的通式(I)或(Ia)化合物可以以对映异构体(外消旋体)的1:1混合物的形式存在,或可以以对映异构体的非外消旋混合物形式存在(其中两个对映异构体之一被富集,即或者是(左旋)对映异构体,其使线偏振光的偏振平面转向左(下称(-)_对映异构体),或是(右旋)对映异构体,其使线偏振光的偏振平面转向右(下称(+)_对映异构体)),或是以基本上对映异构体纯的化合物(对映异构体过量ee> 90%)的形式存在,即以基本上对映异构体纯的(-)_对映异构体或(+)_对映异构体的形式存在。 Thus, formula (I) of the present invention or (Ia) may be a compound of enantiomers (racemate): The presence of a mixture of Form 1, or may be non-racemic diastereomers the presence of a mixture (in which one of the two enantiomers is enriched, i.e. or (L) enantiomer which the polarization plane of linearly polarized light turning left (hereinafter referred to as (-) enantiomer isopropyl _ isomers), or (dextrorotatory) enantiomer which the polarization plane of linearly polarized light of the right turn (the (+) enantiomer _)), or to substantially enantiomerically in the form of pure compound body (enantiomeric excess ee> 90%) is present, i.e., substantially enantiomerically pure (-) enantiomer or _ (+) enantiomer _ form of existence. 优选地,所述化合物以基本上对映异构体纯的化合物的形式存在。 Preferably, the compound is present in the form of a substantially enantiomerically pure compound of. 特别优选的是基本上对映异构体纯的(ee > 90% )化合物。 Particularly preferred are substantially pure enantiomer (ee> 90%) compound.

[0118] 因此,本发明不仅提供纯的对映异构体以及它们的混合物,例如,一种对映异构体以富集形式存在的混合物,而且提供所述的外消旋体。 [0118] Accordingly, the present invention provides not only the pure enantiomers as well as mixtures thereof, e.g., a mixture of diastereomers in form of enrichment, but also provides the racemate. 本发明还提供(I)或(Ia)的纯的对映异构体的药学上可接受的盐、互变异构体和前药,以及以(I)或(Ia)的药学上可接受的盐、互变异构体和前药的形式存在的对映异构体混合物。 The present invention further provides acceptable (I) or (Ia) of pure pharmaceutically acceptable salts of enantiomers, tautomers and prodrugs thereof, and pharmaceutically acceptable in (I) or (Ia) is salts exist as tautomers and prodrugs of the enantiomer mixture.

[0119] 本发明的优选实施方案是如上所定义的通式(I)或(Ia)的化合物,其特征在于它们以旋光体存在,并且在每种情况下,它们都是游离碱形式的所述通式(I)化合物的对映异构体,或其药学上可接受的盐、互变异构体形式或前药,该对映异构体使偏振光的偏振平面向左旋(即左旋的对映异构体)。 [0119] Preferred embodiments of the present invention is a compound of formula (I) as defined above or (Ia), characterized in that they are present in optically active form, and in each case, they are in the form of the free base the polarization plane of enantiomers, or a pharmaceutically acceptable salt, tautomer or prodrug forms of the compound (I) of general formula enantiomer of left-handed polarized light (i.e., L the enantiomers). 下文中,化合物(I)或(Ia)的左旋对映异构体也被称为(-)_对映异构体。 Hereinafter, L-compound (I) or (Ia) of enantiomer is also referred to (-) enantiomer _.

[0120] 本发明的优选实施方案是如上所定义的通式(I)或(Ia)的化合物,其特征在于它们以旋光体形式存在,其中这些化合物的手性C-3环碳原子的绝对构型相当于游离碱形式的式(Ia)化合物的(-)_对映异构体的C-3处的绝对构型。 [0120] Preferred embodiments of the present invention is a compound of formula as defined above, (I) or (Ia), characterized in that they are present in optically active form, wherein the absolute of these chiral compounds C-3 ring carbon atoms, configuration corresponds to the free base form of the compound of formula (Ia) of (-) _ absolute configuration of the enantiomers of the C-3. 这种构型在下文中也被称为"优选的构型"。 This configuration is hereinafter also referred to as "preferred configuration." X-射线结构分析表明,相对于羟吲哚环3位碳原子处的不対称性中心,式(Ia)化合物的(-)_对映异构体具有S构型。 X- ray structure analysis shows that, with respect to the oxindole ring carbon atoms at 3, said compound not Dui center, of formula (Ia) (-) _ enantiomer having S configuration.

[0121] 根据本发明,优选如上所定义的通式(I)或(Ia)的化合物、其互变异构体、其药学上可接受的盐和其前药,其`中相应的(-)_对映异构体以光学纯度(对映异构体过量,ee)大于50%存在。 [0121] a compound of formula as defined according to the present invention, preferably the above (I) or (Ia), the tautomers, pharmaceutically acceptable salts and prodrugs thereof corresponding `(- ) _ enantiomer in an optical purity (enantiomeric excess, ee) of greater than 50% is present.

[0122] 根据本发明,优选如上所定义的通式(I)或(Ia)的化合物、其互变异构体、其药学上可接受的盐和其前药,其中在C-3环碳原子处具有优选绝对构型的对映异构体以大于50%的光学纯度(对映异构体过量,ee)存在。 [0122] a compound of formula as defined according to the present invention, preferably the above (I) or (Ia), the tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein the ring carbon at C-3 preferably atom having an absolute configuration of the enantiomer in greater than 50% optical purity (enantiomeric excess, ee) exists.

[0123] 根据本发明,优选如上所定义的通式(I)或(Ia)的化合物、其互变异构体、其药学上可接受的盐和其前药,其中相应的(-)_对映异构体以光学纯度(对映异构体过量,ee)大于90%存在。 [0123] a compound of formula as defined according to the present invention, preferably the above (I) or (Ia), the tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein the corresponding (-) _ enantiomeric optical purity (enantiomeric excess, ee) of greater than 90% is present.

[0124] 根据本发明,优选如上所定义的通式(I)或(Ia)的化合物、其互变异构体、其药学上可接受的盐和其前药,其中在C-3环碳原子处具有优选绝对构型的对映异构体以大于90%的光学纯度(对映异构体过量,ee)存在。 [0124] a compound of formula as defined according to the present invention, preferably the above (I) or (Ia), the tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein the ring carbon at C-3 preferably atom having an absolute configuration of the enantiomer in greater than 90% optical purity (enantiomeric excess, ee) exists.

[0125] 本发明的同样优选实施方案是如上所定义的通式(I)或(Ia)的化合物,其特征在于它们以非旋光体形式存在,也就是以外消旋体的形式存在,或者以该外消旋体的药学上可接受的盐、互变异构体形式或前药的形式存在。 [0125] Also preferred embodiment of the present invention is a compound of formula as defined above, (I) or (Ia), characterized in that they are present in a non-optically active form, i.e. other than the form of racemates, or in pharmaceutically acceptable salts of the racemate, exist in tautomeric forms or prodrug thereof.

[0126] 本发明的另ー主题涉及包含至少ー种如上所定义的通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的药物。 Another theme ー [0126] The present invention relates to seed comprising at least ー formula (I) as defined above or (Ia) compounds and / or a pharmaceutically acceptable salt thereof, or a pharmaceutical prodrug.

[0127] 本发明的另ー主题涉及如上所定义的通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药用作药物。 Another ー [0127] The present invention relates to the subject matter of general formula (I) or (Ia) as defined above compounds and / or a pharmaceutically acceptable salt thereof as a pharmaceutical acceptable before.

[0128] 本发明的另ー主题涉及如上所定义的式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药用于治疗或预防疾病,所述疾病特别是加压素依赖性疾病或在本文中提及的疾病。 [0128] Another subject of the invention relates ー of formula (I) or (Ia) as defined above compounds and / or a pharmaceutically acceptable salt or prodrug thereof for the treatment or prevention of diseases in particular plus vasopressin-dependent diseases or disorders mentioned herein.

[0129] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗和/或预防至少ー种加压素依赖性疾病和/或用于制备用于治疗和/或预防至少ー种加压素依赖性疾病的药物。 [0129] Another subject of the invention relates ー as defined above ー least of the general formula (I) or (Ia) compounds and pharmaceutically acceptable use / or a salt or prodrug, for the treatment and / or prevention least ー species vasopressin-dependent diseases and / or and / or prevention of a medicament for for the treatment of at least ー species vasopressin-dependent diseases. 加压素-依赖性疾病是那些,其中疾病的发展至少在某种程度上取决于加压素,即这样的疾病,其中加压素水平升高,加压素可以直接或间接地促成疾病像(disease picture)。 Vasopressin - dependent diseases are those in which at least some degree of progression of the disease depends on vasopressin, i.e., a disease in which elevated levels of vasopressin, vasopressin can contribute directly or indirectly to diseases like (disease picture).

[0130] 本发明还涉及本发明的化合物(I)或(Ia)和/或其药学上可接受的盐或前药用于治疗和/或预防疾病的用途,其中所述疾病的发展至少在某种程度上取决于加压素,即这样的疾病,其中加压素水平升高,加压素可以直接或间接地促成疾病像。 [0130] The present invention further relates to compounds (I) of the present invention or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof for the treatment and / or prophylaxis of diseases, wherein the development of the disease in at least vasopressin somewhat dependent, i.e., a disease in which elevated levels of vasopressin, vasopressin can contribute directly or indirectly to diseases like. 本发明还涉及本发明的化合物(I)或(Ia)和/或其药学上可接受的盐或前药在制备用于治疗和/或预防这样的疾病的药物中的用途。 The present invention further relates to compounds of the present invention (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof for the treatment and / or prophylaxis of such diseases in use.

[0131] 本发明特别涉及至少ー种如上所定义的通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药用于治疗和/或预防至少ー种疾病的用途,所述疾病选自糖尿病,特别是尿崩症、胰岛素抗性、夜遗尿、失禁、出现凝血障碍的疾病和/或延迟排尿的疾病,以及在制备用于治疗和/或预防至少ー种所述疾病的药物中的用途。 [0131] The present invention relates in particular at least ー of the general formula (I) as defined above or (Ia) is a compound and / or a pharmaceutically acceptable salt or prodrug thereof for the treatment and / or prevention of diseases of the at least ーthe use, the disease is selected from diabetes, particularly diabetes insipidus, insulin resistance, nocturnal enuresis, incontinence, diseases appear coagulopathy and / or delaying micturition disorders, and for the treatment and / or prophylaxis of at least ー species the use of the pharmaceutical disease.

[0132] 本发明特别涉及至少ー种如上所定义的通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药用于治疗和/或预防至少ー种疾病的用途,所述疾病选自高血压、肺动脉高血压、心カ衰竭、心肌梗死、冠状动脉痉挛、不稳定心绞痛、PTCA(经皮腔内冠状动脉成形木)、心脏缺血、肾脏体系紊乱、浮肿、肾血管痉挛、肾皮质坏死、低钠血症、低钾血症、Schwartz-Bartter综合`征、胃肠道紊乱、胃炎性血管疫挛(gestritic vasospasm)、肝硬化、胃肠溃疡、呕吐、化疗期间的呕吐和/或旅行病(travel sickness),以及在制备用于治疗和/或预防至少ー种所述疾病的药物中的用途。 [0132] The present invention relates in particular at least ー of the general formula (I) as defined above or (Ia) is a compound and / or a pharmaceutically acceptable salt or prodrug thereof for the treatment and / or prevention of diseases of the at least ーthe use, the disease is selected from hypertension, pulmonary hypertension, heart failure ka, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty wood), cardiac ischemia, renal system disorders, edema , renal vasospasm, necrosis of the renal cortex, hyponatraemia, hypokalaemia, Schwartz-Bartter syndrome `comprehensive, gastrointestinal disturbances, gastritis Phytophthora vascular spasms (gestritic vasospasm), cirrhosis of the liver, gastrointestinal ulcers, vomiting, vomiting during chemotherapy and / or travel sickness (travel sickness), and and / or prophylaxis in the preparation of medicament for the treatment of at least the species ー diseases.

[0133] 本发明的化合物(I)或(la)、它们的盐、它们的互变异构体和它们的前药还能够用于治疗各种加压素-依赖性疾病,其表现出中枢性神经病因或HPA轴(下丘脑脑垂体肾上腺轴)改变,例如用于治疗情感障碍如抑郁症和双相性精神障碍。 [0133] Compound (I) or (La) of the present invention, their salts, their tautomers and prodrugs thereof can also be used in the treatment of various vasopressin - dependent diseases which exhibit central neuropathy or due to the HPA axis (hypothalamus-pituitary-adrenal axis) changes, for example, for the treatment of affective disorders such as depression and bipolar disorder. 这些包括例如精神抑郁症(dythymicdisorders)、恐怖症、创伤后精神紧张性(精神)障碍、一般焦虑症、惊恐性障碍、季节性抑郁症和睡眠障碍。 These include, for example dysthymia (dythymicdisorders), phobias, post-traumatic stress (mental) disorder, generalized anxiety disorder, panic disorder, seasonal depression and sleep disorders.

[0134] 本发明的化合物⑴或(la)、它们的盐、它们的互变异构体和它们的前药同样能够用于治疗焦虑症和与应激反应有关的焦虑症,例如,一般焦虑症、恐怖症、外伤后的焦虑症、惊恐性焦虑症、強迫性焦虑症、与急性应激反应有关的焦虑症和社交恐怖症。 [0134] Compounds of the invention or ⑴ (La), their salts, their tautomers and prodrugs thereof can likewise be used in the treatment of anxiety and stress-related anxiety disorders, e.g., generalized anxiety disorder, phobias, post-traumatic anxiety disorder, panic anxiety, obsessive compulsive anxiety disorder, acute stress-related anxiety disorders and social phobia. 本发明的化合物还能够用于治疗记忆缺陷、阿尔茨海默氏病、精神病、精神障碍、睡眠障碍和/或库兴综合征以及所有与应激反应相关的疾病。 The compounds of this invention can also be useful in treating memory impairment, Alzheimer's disease, psychosis, psychotic disorders, sleep disorders and / or Cushing's syndrome, and all stress-related diseases.

[0135] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗情感障碍和/或用于制备用于治疗情感障碍的药物。 [0135] Another subject of the invention relates to ー ー least of the general formula (I) or (Ia) compound and / or a pharmaceutically acceptable use as defined above or a salt or prodrug, for the treatment of affective disorders and / or for the preparation of medicaments for the treatment of affective disorders.

[0136] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗焦虑症和/或与应激反应有关的焦虑症和/或用于制备用于治疗焦虑症和/或与应激反应有关的焦虑症的药物。 [0136] Another subject of the invention relates to ー ー least of the general formula (I) or (Ia) compounds and pharmaceutically acceptable use as defined above / or a salt or prodrug, for the treatment of anxiety and / or stress associated with anxiety and / or anxiety and / or anxiety for the preparation of a drug for the treatment of stress-related.

[0137] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗记忆缺陷和/或阿尔茨海默氏病和/或用于制备用于治疗记忆缺陷和/或阿尔茨海默氏病的药物。 [0137] Another subject of the invention relates to ー ー least of the general formula (I) or (Ia) compound and / or a pharmaceutically acceptable use as defined above or a salt or prodrug, for the treatment of memory impairment and / or Alzheimer's disease and / or memory impairments, and / or for the preparation of a medicament for the treatment of Alzheimer's disease.

[0138] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗精神病和/或精神障碍和/或用于制备用于治疗精神病和/或精神障碍的药物。 [0138] Another subject of the invention relates ー as defined above of at least ー compound of the general formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof, for the treatment of psychosis and / or mental disorders and / or for the preparation for the treatment of mental illness and / or mental disorders drugs.

[0139] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗库兴综合征或其它与应激反应有关的疾病和/或用于制备用于治疗库兴综合征或其它与应激反应有关的疾病的药物。 [0139] Another subject of the invention relates ー as defined above ー least of the general formula (I) or (Ia) compounds and pharmaceutically acceptable use / or a salt or prodrug, for the treatment of Cushing Comprehensive intrinsic or other stress related diseases and / or for preparing a medicament for the treatment of Cushing's syndrome or other diseases associated with the stress response.

[0140] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗睡眠障碍和/或用于制备用于治疗睡眠障碍的药物。 [0140] Another subject of the invention relates to ー ー least of the general formula (I) or (Ia) compounds and pharmaceutically acceptable use as defined above / or a salt or prodrug, for the treatment of sleep disorders and Drug treatment of sleep disorders and / or for the preparation.

[0141] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗抑郁症和/或用于制备用于治疗抑郁症的药物。 [0141] Another subject of the invention relates ー as defined above ー least of the general formula (I) or (Ia) and a compound or a pharmaceutically acceptable use / salt or prodrug thereof, for the treatment of depression and / or for the manufacture of a medicament for the treatment of depression.

[0142] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗儿童期起病的心境障碍和/或用于制备用于治疗儿童期起病的心境障碍的药物。 [0142] Another subject of the invention relates to ー ー least a compound of the general formula (I) or (Ia) and / or a pharmaceutically acceptable use as defined above or a salt or prodrug, for the treatment of childhood from mood disorders disease and / or mood disorders for the treatment of childhood-onset drug. 术语"儿童期起病的心境障碍"被理解为是指早在儿童期就开始的心境障碍和抑郁症。 The term "childhood onset mood disorders" is understood to mean mood disorders and depression in early childhood it began.

`[0143] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗血管舒缩症状和/或体温调节功能障碍,例如,"热潮紅"症状。 `[0143] Another subject of the invention relates ー as defined above ー least of the general formula (I) or (Ia) compounds and pharmaceutically acceptable use / or a salt or prodrug, for treating vasodilation reduction of symptoms and / or thermoregulatory disorders, e.g., "hot flashes" symptoms.

[0144] 本发明的另ー主题涉及如上所定义的至少ー种通式⑴或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗和/或预防精神作用物质依赖(drugdependencies)、药物依赖(medicamentdependencies),和/或由其它因素介导的依赖性,用于治疗和/或预防由调节依赖性的一种或多种因素的戒除所引起的应激反应,和/或用于治疗和/或预防应激反应引起的精神作用物质依赖、药物依赖和/或由其它因素介导的依赖性的复发。 [0144] Another subject of the invention relates ー as defined above or ⑴ ー least one compound (Ia) and / or the use of formula the pharmaceutically acceptable salt or prodrug thereof for the treatment and / or prophylaxis of psychotic effect of substance dependence (drugdependencies), drug dependence (medicamentdependencies), and / or mediated by other factors dependent, stress for the treatment and / or prevention of one or more factors regulating the dependence caused by withdrawal psychotropic effects induced reactions, and / or for the treatment and / or prevention of stress substance dependence, drug dependence, and / mediated by other factors dependent or relapse.

[0145] 本发明的另ー主题涉及如上所定义的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药的用途,用于治疗和/或预防精神分裂症和/或精神病。 [0145] Another subject of the invention relates ー as defined above ー least of the general formula (I) or (Ia) compounds and pharmaceutically acceptable use / or a salt or prodrug, for the treatment and / or prevention of schizophrenia and / or psychosis.

[0146] 本发明的另ー主题涉及在患者中治疗和/或预防下面至少ー种疾病的方法,所述疾病选自糖尿病,特别是尿崩症(diabetes insipidus)、胰岛素抗性、夜遗尿、失禁、出现凝血障碍的疾病和延迟排尿,其特征在于给予所述患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0146] Another subject of the invention relates ー treatment in a patient and / or prevention of disease in at least the following ー species, the disease is selected from diabetes, particularly diabetes insipidus (diabetes insipidus), insulin resistance, nocturnal enuresis, incontinence, and diseases appear coagulopathy delay urination, wherein administering to said patient an effective amount of at least ー of the general formula (I) or (Ia) compounds and / or a pharmaceutically acceptable salt or prodrug thereof.

[0147] 本发明的另ー主题涉及在患者中治疗和/或预防下面至少ー种疾病的方法,所述疾病选自高血压、肺动脉高血压、心カ衰竭、心肌梗死、冠状动脉痉挛、不稳定心绞痛、PTCA(经皮腔内冠状动脉成形木)、心脏缺血、肾脏体系紊乱、浮肿、肾血管痉挛、肾皮质坏死、低钠血症、低钾血症、Schwartz-Bartter综合征、胃肠道紊乱、胃炎性血管疫挛、肝硬化、胃肠溃疡、呕吐、化疗期间的呕吐和旅行病,其特征在于给予所述患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0147] Another subject of the invention ー relates to a method of treating in a patient and / or prophylaxis of the following diseases ー least, the disease is selected from hypertension, pulmonary hypertension, heart failure ka, myocardial infarction, coronary artery spasm, not stable angina, PTCA (percutaneous transluminal coronary angioplasty wood), cardiac ischemia, renal system disorders, edema, renal vasospasm, necrosis of the renal cortex, hyponatraemia, hypokalaemia, Schwartz-Bartter syndrome, stomach intestinal disorders, gastritis Phytophthora vascular spasms, cirrhosis of the liver, gastrointestinal ulcers, vomiting, emesis during chemotherapy and travel sickness, wherein administering to said patient an effective amount of at least ー of the general formula (I) or (Ia) is compound and / or a pharmaceutically acceptable salt or prodrug thereof.

[0148] 本发明的另ー主题涉及在患者中治疗和/或预防情感障碍的方法,其特征在于给予所述患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0148] Another subject of the invention ー relates to a method of treating in a patient and / or prevention of an affective disorder, wherein administering to said patient an effective amount of at least ー of the general formula (I) or (Ia) compounds and / or a pharmaceutically acceptable salt or prodrug thereof.

[0149] 本发明的另ー主题涉及在患者中治疗和/或预防焦虑症和/或与应激反应有关的焦虑症的方法,其特征在于给予所述患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0149] Another subject of the invention relates ー treatment in a patient and / or anxiety and / or stress related to the prevention of anxiety disorders, wherein administering to said patient an effective amount of at least ー species of formula ( I) or (Ia) compounds and / or a pharmaceutically acceptable salt or prodrug thereof.

[0150] 本发明的另ー主题涉及在患者中治疗和/或预防记忆缺陷和/或阿尔茨海默氏病的方法,其特征在于给予所述患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0150] Another subject of the invention relates ー treatment in a patient and / or memory impairment or Alzheimer's disease and methods / prophylaxis, wherein administering to said patient an effective amount of at least ー of the general formula (I) or (Ia) compounds and / or a pharmaceutically acceptable salt or prodrug thereof.

[0151] 本发明的另ー主题涉及在患者中治疗和/或预防精神病和/或精神障碍的方法,其特征在于给予所述患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0151] Another subject of the invention ー relates to a method of treating in a patient and / or prophylaxis of psychotic disorders and / or mental disorder, wherein administering to said patient an effective amount of at least ー of the general formula (I) or (Ia) is compound and / or a pharmaceutically acceptable salt or prodrug thereof.

[0152] 本发明的另ー主题涉及在患者中治疗库兴综合征的方法,其特征在于给予该患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0152] Another subject of the invention ー relates to a method of treating Cushing's syndrome in a patient, comprising administering to the patient an effective amount of at least ー of the general formula (I) or (Ia) compounds and / or pharmaceutically acceptable salt or prodrug thereof.

[0153] 本发明的另ー主题涉及在患者中治疗睡眠障碍的方法,其特征在于给予该患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0153] Another ー subject of the present invention relates to a method of treating sleep disorders in a patient, comprising administering a pharmaceutically and / or its pharmaceutically acceptable to the patient an effective amount of at least ー compound of the general formula (I) or (Ia) is salt or prodrug thereof.

[0154] 本发明的另ー主题涉及在患者中治疗抑郁症的方法,其特征在于给予该患者有效量的至少ー种通式(I)或(Ia`)的化合物和/或其药学上可接受的盐或前药。 May be [0154] Another subject of the invention ー relates to a method of treating depression in a patient, comprising administering to the patient an effective amount of at least ー compound of the general formula (I) or (Ia`) and / or pharmaceutically acceptable salt or prodrug thereof.

[0155] 本发明的另ー主题涉及在患者中治疗和/或预防血管舒缩症状和/或温度调节功能障碍例如"热潮紅"症状的方法,其特征在于给予该患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0155] Another subject of the invention relates ー treatment in a patient and / or prevention of vasomotor symptoms and / or dysfunctions such as temperature adjustment "hot flashes" symptoms method, wherein administering to the patient an effective amount of at least ー species a compound of formula (I) or (Ia) and / or a pharmaceutically acceptable salt or prodrug thereof.

[0156] 本发明的另ー主题涉及在患者中治疗和/或预防精神作用物质依赖、药物依赖和/或由其它因素介导的依赖性的方法,用于治疗和/或预防由调节依赖性的ー种或多种因素的戒除所引起应激反应的方法,和/或用于治疗和/或预防在精神作用物质依赖、药物依赖和/或由其它因素介导的依赖性中由应激反应引起的复发的方法,其特征在于给予所述患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0156] Another subject of the invention relates ー treatment in a patient and / or prevention of psychoactive substance dependence, drug dependence, and / or mediated by other factors dependent methods for the treatment and / or prevention of dependency adjustment method ー withdrawal or more kinds of factors caused by the stress response, and / or for the treatment and / or prevention of the psychoactive substance dependence, drug dependence, and / or by other factors mediated by stress-dependent recurrence by a reaction, wherein administering to said patient an effective amount of at least ー of the general formula (I) or (Ia) compounds and / or a pharmaceutically acceptable salt or prodrug thereof.

[0157] 本发明的另ー主题涉及在患者中治疗和/或预防精神分裂症和/或精神病的方法,其特征在于给予所述患者有效量的至少ー种通式(I)或(Ia)的化合物和/或其药学上可接受的盐或前药。 [0157] Another subject of the invention relates ー treatment in a patient and / or methods and or prevention of schizophrenia / psychosis, characterized by administering to said patient an effective amount of at least ー of the general formula (I) or (Ia) compound and / or a pharmaceutically acceptable salt or prodrug thereof.

[0158] 本发明的另ー主题涉及如上所定义的方法,其特征在于所述患者是哺乳动物,优选是人或非人类哺乳动物或非人类转基因哺乳动物。 [0158] Another subject of the invention ー relates to a method as defined above, wherein said patient is a mammal, preferably a human or non-human mammal or non-human transgenic mammal.

[0159] 如上所定义的通式(I)或(Ia)的化合物,它们的药学上可接受的盐和前药可以由本领域技术人员根据本发明的技术教导在本身已知的方法步骤的设备和/或类似设备中进行制备。 [0159] a compound of formula (I) or (Ia) as defined above, and their pharmaceutically acceptable salts and prodrugs can be in a device known per se method steps taught by the present art in the art in accordance with the techniques of the present invention and / or similar device prepared. [0160] 另ー优选实施方案涉及如上所述的通式(I)或(Ia)的化合物、它们的互变异构体、它们的前药和它们的药学上可接受的盐,其特征在于它们对加压素受体亚型Vlb相对于至少一种密切相关的加压素/催产素受体亚型(例如加压素via,加压素V2和/或催产素)是选择性的。 [0160] Another preferred embodiment relates to compounds ー above formula (I) or (Ia), and pharmaceutically tautomers thereof, prodrugs thereof and pharmaceutically acceptable salts thereof, wherein they Vlb vasopressin receptor subtypes are closely related with respect to at least one of the vasopressin / oxytocin receptor subtypes (e.g. vasopressin via, V2 vasopressin and / or oxytocin) is selective.

[0161] 另ー优选实施方案涉及如上所述的通式(I)或(Ia)的化合物、它们的互变异构体、它们的前药和它们的药学上可接受的盐,其特征在于它们具有改善的代谢稳定性。 [0161] Another preferred embodiment relates to compounds ー above formula (I) or (Ia), and pharmaceutically tautomers thereof, prodrugs thereof and pharmaceutically acceptable salts thereof, wherein they have improved metabolic stability.

[0162] 化合物的代谢稳定性可以被測定,例如,将此化合物的溶液与特定物种(例如大鼠、狗或人类)的肝微粒体一起培养,然后在这些条件下測定所述化合物的半衰期(RSObach, Curr Opin Drug Discov Devel.2001,4, 36-44)。 [0162] Metabolic stability of compounds can be measured, for example, a solution of this compound with a particular species (e.g. rat, dog or human) cultured with liver microsomal half-life of the compound under these conditions was measured ( RSObach, Curr Opin Drug Discov Devel.2001,4, 36-44). 观察到较长的半衰期有可能得出该化合物的代谢稳定性得到改善的结论。 Observed longer half-life is possible to derive the metabolic stability of the compound is improved results. 在人肝微粒体存在下的稳定性是特别使人感兴趣的,因为它能够预测在人肝脏中该化合物的代谢分解。 Stability in the presence of human liver microsomes is of particular interest, since it is possible to predict the metabolic breakdown in human liver of the compound. 因此,具有増加代谢稳定性的化合物(在肝微粒体测试中进行測定)或许在肝脏中也会更慢地分解。 Thus, compounds to increase in metabolic stability (measured in the liver microsome test) may also have a slower decomposition in the liver. 在肝脏中的缓慢代谢分解可以导致化合物在体内的较高和/或更长时间保持的浓度(有效水平),由此提高本发明化合物的消除半衰期(elimination half-life)。 Slow metabolic breakdown in the liver and can lead to higher compound concentration (effective level) in vivo and / or longer maintained, thereby increasing the elimination half-life of the compounds of the present invention (elimination half-life). 提高的和/或更长时间持续的有效水平可以导致该化合物在治疗或预防各种与加压素相关的疾病中的更好效果。 Increased and / or long-lasting effective levels may lead to better results in the compound of various vasopressin-related disease treatment or prevention. 此外,改善的代谢稳定性还可以导致在ロ服给药后生物利用度提高,这是因为所述化合物在肠内吸收后在肝脏中发生较低的代谢分解(所谓的首过效应)。 In addition, the improved metabolic stability may also result in improved bioavailability after ro buccal administration, since the metabolic breakdown of the compound (a so-called first pass effect) in the liver occurred after the lower intestinal absorption. 因为该化合物的浓度(有效水平)提高了,提高的ロ服生物利用度可以导致ロ服给药后该化合物的效果更好。 Because the concentration of the compound (active level) increased, increased bioavailability ro service may result in the effect after buccal administration of the compound ro better.

[0163] 另ー优选实施方案涉及如上所述的通式(I)的化合物,其特征在于,与由现有技术已知的羟吲哚类化合物相比,所述化合物在患者中或者能够对治疗应用预测性报告的相关动物模型中,具有改善的药理学活性。 [0163] Another preferred embodiment relates to compounds ー above formula (I), characterized in that, as compared with the prior art known oxindole compound, the compound can be in a patient or for relevant animal model for therapeutic use predictive report, with improved pharmacological activity.

[0164] 所述这些变量的优选定义的每一个可与任何其它变量的定义组合。 [0164] defined for each combination of the preferred meanings of these variables may be combined with any other variable.

[0165] 本发明特别涉及选自下列实施例的通式(I)的化合物,1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、 [0165] The present invention relates in particular selected from the following examples of the general formula (I) compound, 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15 , 16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,

36、37、38、39、40、41`、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89和90,以及它们的互变异构体形式、它们的前药,特别是它们的生理学上可接受的盐和它们的非盐形式如水合物和/或溶剂合物。 36,37,38,39,40,41`, 42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60 , 61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85 , 86,87,88,89 and 90, and their tautomeric forms, their prodrugs, especially their physiologically acceptable salts and their non-salt form, such as a hydrate and / or solvate thereof. 特别优选游离碱形式或酸加成盐形式的上述化合物。 Or the above compounds in the form of a base addition salt form of the free acid is particularly preferred.

[0166] 本发明还特别涉及通式(I)的选自下列的实施例1-90化合物的(-)_对映异构体,1B、2B、3B、4B、5B、6B、7B、8B、9B、10B、11B、12B、13B、14B、15B、16B、17B、18B、19B、20B、21B、22B、23B、24B、25B、26B、27B、28B、29B、30B、31B、32B、33B、34B、35B、36B、37B、38B、39B、40B、41B、42B、43B、44B、45B、46B、47B、48B、49B、50B、51B、52B、53B、54B、55B、56B、57B、58B、59B、60B、61B、62B、63B、64B、65B、66B、67B、68B、69B、70B、71B、72B、73B、74B、75B、76B、77B、78B、79B、80B、81B、82B、83B、84B、85B、86B、87B、88B、89B 和90B,以及式(I)化合物的互变异构体形式、前药,特别是它们的生理学上可接受的盐和非盐形式如水合物和/或溶剂合物。 [0166] The present invention is also particularly directed to selected embodiments of formula (I) compound 1-90 (-) enantiomer _, 1B, 2B, 3B, 4B, 5B, 6B, 7B, 8B , 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B , 34B, 35B, 36B, 37B, 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B, 52B, 53B, 54B, 55B, 56B, 57B, 58B , 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, 77B, 78B, 79B, 80B, 81B, 82B, 83B , 84B, 85B, 86B, 87B, 88B, 89B tautomeric forms of the compounds and 90B, and the formula (the I), prodrugs, especially their physiologically acceptable salts and non-salt forms such as hydrates and / or solvate thereof. 特别优选游离碱形式或酸加成盐形式的上述化合物。 Or the above compounds in the form of a base addition salt form of the free acid is particularly preferred.

[0167] 术语"前药"被理解为是指那些化合物,其在体内被代谢为本发明的化合物。 [0167] The term "prodrug" is understood to refer to those compounds which are metabolized in vivo to a compound of the present invention. 前药的典型例子描述在CGWermeth (Ed.):The Practice ofMedicinal Chemistry,Academic Press, San Diego, 1996,第671-715页中。 Typical examples of prodrugs are described in CGWermeth (Ed.): The Practice ofMedicinal Chemistry, Academic Press, San Diego, 1996, pp. 671-715 in. 它们包括,例如,磷酸酯、氨基甲酸酉旨或氨基酸、酷等。 They include, for example, phosphate esters, amino acid or amino acid unitary purpose, cool the like. 在本发明中,式I化合物的适宜前药是式I的化合物,其中携帯R7的氮原子是酰胺/肽基团的一部分,即所述氮携带酰基如C1-C4-烷基羰基如こ酰基、丙酰基、正丁酰基(正丙基羰基)、异丁酰基、正丁基羰基或叔丁基羰基(新戊酰基)、苯甲酰基、来源于氨基酸的CO结合基团例如来源于甘氨酸、丙氨酸、丝氨酸、苯丙氨酸等的CO结合基团。 In the present invention, suitable prodrugs of the compounds of formula I are compounds of formula I, wherein R7 carrying Bands nitrogen atom is part of an amide / peptide groups, i.e., as the nitrogen carries the acyl group C1-C4- alkylcarbonyl group such as a ko , propionyl, n-butyryl (n-propyl carbonyl group), an isobutyryl group, n-butylcarbonyl or t-butylcarbonyl (pivaloyl), benzoyl, CO derived from the amino acid glycine binding group derived from e.g., alanine, serine, phenylalanine binding a CO group. 适宜的前药还包括烷基羰氧基烷基氨基甲酸酷,其中式I中的基团R7是式-C(=O) -O-CHRa-OC ( = O)-Rb部分,其中Ra和Rb互相独立地选自C1-C4-烷基。 Further comprising a suitable prodrug alkylcarbonyloxyalkyl cool amino acid, wherein in formula I and R7 is a group of formula -C (= O) -O-CHRa-OC (= O) -Rb moiety, wherein Ra and each Rb is independently selected from C1-C4- alkyl. 这些氨基甲酸酯已经由J.Alexander, R.Cargill, SRMichelson, H.Schwam, J.Medicinal Chem.1988,31 (2) ,318-322作了概括性描述。 These carbamates have, 318-322 been described by the general J.Alexander, R.Cargill, SRMichelson, H.Schwam, J.Medicinal Chem.1988,31 (2). 这些基团在代谢条件下被裂解,得到式I的化合物,其中R7是氧。 These groups are cleaved under metabolic conditions, to give compounds of formula I, wherein R7 is oxygen.

[0168] 此外,本发明涉及式I化合物的药学上可接受的盐,其也被称为生理学上可接受的盐。 [0168] Further, the present invention relates to pharmaceutically acceptable salts of the compounds of Formula I, which is also known as a physiologically acceptable salt thereof. 所述盐通常可由本发明化合物(I)的游离碱与适宜的酸反应获得。 The salt is usually obtained by the present compound (I) free acid with a suitable base. 适宜的酸例如夕丨」在Fortschritte derArzneimittelforschung" [Advances in Drug Research], 1966, Suitable acids such as evening Shu "in Fortschritte derArzneimittelforschung" [Advances in Drug Research], 1966,

Birkhauser Verlag, Vol.10, pp.224-285中。 Birkhauser Verlag, Vol.10, pp.224-285 in. 它们包括,例如,盐酸、梓檬酸、酒石酸、乳 They include, for example, hydrochloric acid, citric acid Zi, tartaric acid, lactic

酸、磷酸、甲磺酸、こ酸、甲酸、马来酸和富马酸。 Acid, phosphoric acid, methanesulfonic acid, ko acid, formic acid, maleic acid and fumaric acid.

[0169] 本发明的化合物通过各种途径给药后都是有效的。 Compound [0169] of the present invention after administration by various routes are valid. 所述给药途径例如可以是静脉内、肌内、皮下、局部、气管内、鼻内、经皮、阴道、直肠、舌下、口腔或ロ服,并且通常可以是静脉内、肌内或特别是ロ服。 For example, the route of administration may be intravenous, intramuscular, subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal, rectal, sublingual, buccal or ro clothing, and generally may be intravenous, intramuscular, or especially ro is served.

[0170] 本发明还涉及药物组合物,其包含本发明的化合物(I)和/或其互变异构体和/或其药学上可接受的盐和/或其前药以及适宜的制药载体(药物载体)。 [0170] The present invention further relates to pharmaceutical compositions comprising a compound of the present invention (I) and / or a tautomer thereof and / or a pharmaceutically acceptable salt and / or prodrug thereof together with a suitable pharmaceutical carrier (Drug carrier). 化合物I在药物组合物中的数量可以取决于该组合物的剂型并且例如可以在0.0001mg/g-lg/g该组合物的范围,特别是可以在范围0.001mg/g-0.5g/g该组合物。 Number of Compound I in the pharmaceutical composition may depend on the dosage form of the composition and may be, for example, 0.0001mg / g-lg / g of the composition range, which can in particular range 0.001mg / g-0.5g / g combination.

[0171] 这些药物载体根据药物形式和所期望的给药方式进行选择。 [0171] The pharmaceutical carrier selected according to the pharmaceutical form and the desired mode of administration.

`[0172] 本发明的通式(I)化合物或,如果合适的话,这些化合物的适宜的盐能够用于制备ロ服、舌下、口腔、皮下、肌内、静脉内、局部、气管内、鼻内、经皮、阴道或直肠给药的药物组合物,所述药物组合物可以以单位剂型的形式与常规药物载体混合给予动物或人,用于预防或治疗上述障碍或疾病。 `[0172] The compounds of the invention of formula (I) or, if appropriate, suitable salts of these compounds can be used for the preparation ro service, the sublingual, buccal, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal pharmaceutical composition, vaginal or rectal administration, the pharmaceutical composition may be in unit dosage form with conventional pharmaceutical carriers administering to an animal or human, for the prevention or treatment of the above disorders or diseases.

[0173] 适宜的ー贯的给药形式(单位剂型)包括用于ロ服给药的形式,例如片剂、胶囊、粉剂、粒剂、ロ服摄取的溶液或悬浮液,用于舌下、口腔、气管内或鼻内给药的形式,气雾剂,植入物,皮下、肌内或静脉内给药的形式以及直肠给药的形式。 [0173] Suitable administration forms ー coherent (unit dosage form) comprising means for ro service administration forms such as tablets, capsules, powders, granules, ro serving uptake solutions or suspensions, forms for sublingual, oral, intratracheal, intranasal administration forms, aerosols, in the form of implants, subcutaneous, intramuscular or intravenous administration and forms of rectal administration or.

[0174] 对于局部给药,本发明的化合物能够以乳剤、膏剂或洗剂的形式使用。 [0174] For topical administration, the compounds of the present invention can be used in the form of milk Ji, ointments or lotions.

[0175] 为了达到所需的预防或治疗效果,该活性化合物的剂量可以在0.01至50mg/kg体重/日的范围内变化。 [0175] In order to achieve the desired prophylactic or therapeutic effect, the dose of the active compound may vary within a range of 0.01 to 50mg / kg body weight / day.

[0176] 每单位剂量可以包含0.05至5000mg,优选Ι-lOOOmg的活性化合物和药物载体。 [0176] Each dosage unit may contain 0.05 to 5000mg, preferably the active compound and a pharmaceutical carrier of Ι-lOOOmg. 此单位剂量可以每日给药1-5次,这样给予0.5-25000mg,优选l_5000mg的日剂量。 This unit dose can be administered 1 to 5 times daily, so that given 0.5-25000mg, the daily dose is preferably l_5000mg.

[0177] 如果制备的是片剂形式的固体组合物,那么将该活性化合物与药物载体如明胶、 [0177] If the preparation is a solid composition in tablet form, then the active compound with a pharmaceutical carrier such as gelatin,

淀粉、乳糖、硬脂酸镁、滑石、ニ氧化硅等混合。 Starch, lactose, magnesium stearate, talc, silica and the like Ni.

[0178] 所述片剂可以用蔗糖、纤维素衍生物或其它合适物质包衣或者进行其它处理,以使其具有持久或延迟的活性,并使得连续释放出预定量的活性化合物。 [0178] The tablets may be sugar, a cellulose derivative or other suitable materials or coatings for other processing, so as to have sustained or delayed activity and continuously release a predetermined amount such that the active compound. [0179] 胶囊形式制剂通过将活性化合物与增量剂混合并将所得混合物容纳在软或硬胶 [0179] Formulation in the form of capsules by mixing the active compounds with extenders and the resulting mixture was housed in a soft or hard gelatin

囊中获得。 Bag available.

[0180] 糖浆或酏剂形式的制剂或者以滴剂形式给药的制剂可以含有活性化合物以及甜味剂,优选不含卡路里的甜味剂、作为防腐剂的对羟基苯甲酸甲酯或对羟基苯甲酸丙酷、调味剂和适宜的着色剂。 [0180] A syrup or elixir form preparations or formulations for administration in the form of drops may contain the active compound, a sweetener, preferably calorie-free sweetener, methylparaben as preservatives or hydroxy cool propionic acid, flavoring and a suitable colorant.

[0181] 水可分散性粉剂或粒剂可以包含与分散剂、润湿剂或悬浮剂如聚こ烯吡咯烷酮以及甜味剂或矫味剂混合的活性化合物。 [0181] water-dispersible powders or granules can contain mixed with dispersants, wetting agents, or suspending agents such as polyvinylpyrrolidone and polyethylene ko sweetening or flavoring agents active compound.

[0182] 直肠或阴道给药通过使用栓剂实现,栓剂使用在肛温融化的粘合剂进行制备,所述粘合剂例如是可可脂或聚こニ醇。 [0182] rectal or vaginal administration by suppositories using, suppositories melt at rectal temperature adhesive be prepared, for example, the adhesive cocoa butter or polyethylene ko ni alcohol. 肠胃外给药通过使用含水悬浮液、等渗盐溶液或无菌和可注射溶液起作用,其包含药理学适宜的分散剂和/或润湿剂,例如丙ニ醇或聚こニ醇。 Parenteral administration by using aqueous suspensions, isotonic saline solutions and sterile injectable solutions or function, comprising a pharmacologically suitable dispersants and / or wetting agents, for example propan-ni ni ko alcohol or poly alcohol.

[0183] 所述活性化合物还能够配制成微胶囊或中心体(centrosomes)的形式,如果适宜的话,与一种或多种载体或添加剂一起进行配制。 The [0183] The active compounds can also be formulated as microcapsules or central body (centrosomes) is, if appropriate, with one or more carriers or additives be formulated together.

[0184] 除通式(I)的化合物或它们的药学上可接受的盐或前药外,本发明的组合物可以包含其它活性化合物,所述其它活性化合物对治疗如上所述的损害或疾病是有益的。 [0184] In addition to a compound of formula (I) or a pharmaceutically acceptable salt thereof or prodrug thereof, compositions of the invention may comprise further active compound, the other active compound for the treatment of damage or diseases as described above It is beneficial.

[0185] 因此,本发明还涉及药物组合物,其包含多种活性化合物,其中这些活性化合物中的至少ー种是本发明的化合物(I)或其互变异构体、盐或前药。 [0185] Accordingly, the present invention also relates to a pharmaceutical composition comprising the active compound, wherein the active compound is at least ー species is a compound of the invention (I) or a tautomer, salt or prodrug thereof.

[0186] 本发明化合物的制备 Preparation of the compounds of the present invention, [0186]

[0187] 制备本发明的羟吲哚衍生物的合成路线的例子描述如下。 [0187] Examples of synthetic routes oxindole derivative prepared according to the present invention are described below.

[0188] 本发明的羟吲哚的制备能够通过如合成方案I和2中所示的不同途径进行。 [0188] Preparation of oxindole of the present invention can be synthesized via different routes as shown in Scheme I and 2, such as. 在这些合成方案中,所述变量`具有如通式(I)中相同的含义。 In these synthetic schemes, the variables have the same meaning as' general formula (I).

[0189] 所述3-羟基-1,3- ニ氢吲哚-2-酮IV可以通过将金属化的杂环III加入到靛红(isatins)ll的3-酮基中得到。 [0189] The 3-hydroxy-1,3-Ni hydrogen-indol-2-one IV can be added to the resulting 3-keto isatin (isatins) ll by the metallization heterocycle III. 该金属化的杂环,例如,相应的格利雅(Mg)化合物或有机锂化合物,可以以常规方式由卤素或烃化合物获得。 The metallization heterocycle, for example, the corresponding Grignard (Mg) compound or an organic lithium compound, can be obtained from halogen or hydrocarbon compounds in a conventional manner. 示范性的方法可以在Houben-Weyl,Methoden derOrganischen しhemie[Methods of organic chemistry」,Vol.13,1-2, Chap.Mg和Li化合物中找到。 Exemplary methods of organic chemistry can be "in Houben-Weyl, Methoden derOrganischen shi hemie [Methods, Vol.13,1-2, Chap.Mg Li compound and found. 所述靛红II或者是市场上可买到的或者以类似于文献(Advancesin Heterocyclic Cnemistry,ARKatritzky和AJBoulton,Academic Press,New York,1975,18,2-58 ;J.Brazil.Chem.Soc.12,273-324,2001)中所述的方法制备。 The isatin II are either commercially available or in analogy to the literature (Advancesin Heterocyclic Cnemistry, ARKatritzky and AJBoulton, Academic Press, New York, 1975,18,2-58; J.Brazil.Chem.Soc.12 , prepared 273-324,2001) above.

[0190] 使用KCN或Zn(CN)2以及Pd(O)催化剂在溶剂如ニ甲基甲酰胺或四氢呋喃中,如果合适的话还加入碱例如K2CO3或其它碳酸盐和胺,在高温下,有可能将在6-元芳族环中含有碘取代基,例如基团R3或R4的3-羟基羟吲哚IV转化为类似的含氰基-的3-羟基-羟吲哚IV。 [0190] using KCN or Zn (CN) 2 and Pd (O) catalyst in a solvent such as tetrahydrofuran, dimethylformamide or Ni, if appropriate also added K2CO3 or other bases such as carbonates and amines, at elevated temperatures, there is the iodine may contain a substituent at the 6-membered aromatic ring, for example, groups R3 or 3-hydroxy-oxindole IV R4 is converted to the cyano group-containing similar - 3-hydroxy - oxindole IV. 适合作为Pd(O)盐使用的是,例如,由PdCl2或PdOAc2通过加入膦,例如三(邻甲苯基)膦,原位制得的过渡金属配合物。 Suitable (O) Pd salt is used as, for example, by the addition of PdCl2 PdOAc2 or a phosphine, such as tri (o-tolyl) phosphine, prepared in situ of the transition metal complex. 还可能使用商业的钯配合物,例如,催化剂四(三苯基膦)钯(0)和/或附加的膦配体。 Also possible to use a commercial palladium complex, e.g., the catalyst tetrakis (triphenylphosphine) palladium (0) and / or an additional phosphine ligand.

[0191] 所述3-羟基羟吲哚IV能够转化为在3位携带离去基团LG'的化合物V,其中所述离去基团LG'可以是常规离去基团,例如,卤化物、甲磺酸酯基(mesylate)或甲苯磺酸酯基(tosylate)。 [0191] The 3-hydroxy-oxindole IV can be converted into the 3-position carrying a leaving group LG 'compound V, wherein the leaving group LG' may be a conventional leaving group, e.g., a halide , mesylate (mesylate) or tosylate group (tosylate). 所述中间体V其中,例如,LG' =氯,能够通过醇IV用亚硫酰氯在碱如卩比唳存在下处理进行制备。 The intermediate V wherein, e.g., LG '= chloro, can be a base such as Jie Li ratio presence treatment with thionyl chloride prepared by alcohol IV. 或者,使用甲磺酰氯在碱如三こ胺存在下通过转化成甲磺酸酯,可能获得醇IV。 Alternatively, using methanesulfonyl chloride in the presence of a base such as triethyl amine ko by conversion into the mesylate, it is possible to obtain the alcohol IV. 随后,化合物V与胺如氨水反应,在取代反应后,得到类似的胺VI。 Subsequently, the compound V with an amine such as aqueous ammonia, after the substitution reaction, to give a similar amine VI. 然后,通过用磺酰氯VII处理,化合物如VI在用强碱如叔丁醇钾或氢化钠在DMF中脱质子化反应后,被转化为产物VIII。 Then, by treatment with a sulfonyl chloride VII, VI compound such as potassium tert-butoxide, after sodium hydride or deprotonation with a strong base in DMF, the product is converted to VIII. 所使用的磺酰氯VII或者是市场上可买到的,或者能够以与已知方法类似的方式进行制备(參见,例如,J.Med.Chem.40,1149(1997))。 Sulfonyl chloride VII can be used either a commercially available or can be prepared (see, e.g., J.Med.Chem.40,1149 (1997)) in a similar manner to known methods.

[0192] 通过与衍生氨基的试剂如氯甲酸酷、异氰酸酯或氨基甲酰氯通过常规方法进行反应,化合物VIII 被转化为化合物IX(參见J.March, Advanced Organic Chemistry, 1992,4th版,Wiley, New York, p.417-421 ;499 ;903)。 [0192], isocyanate or carbamoyl chloride by reagents such as an amino group derived chloroformate cool the reaction by a conventional method, compound VIII is converted to compound IX (see J.March, Advanced Organic Chemistry, Edition 1992,4th, Wiley, new York, p.417-421; 499; 903). 例如,作为离去基团的LG在化合物IX中可以是O苯基,其通过VIII与氯甲酸苯酯在碱如吡啶存在下反应获得。 For example, the leaving group LG in compound IX may be O-phenyl, which is obtained in the presence of a base such as pyridine VIII by reaction with phenyl chloroformate.

[0193] 随后与胺X反应,如果合适的话在高温下并加入辅助的碱如三こ胺或ニ异丙基こ胺,得到本发明通式(I)的化合物。 [0193] X is then reacted with the amine, if appropriate at elevated temperature and the addition of an auxiliary base such as triethyl amine or Ni ko ko isopropyl amine, to give a compound of the invention of formula (I) is. 该胺X或者是市场上可买到的或者可以通过參考文献中已知的方法制备。 The amine X are either commercially available or can be prepared by methods known references.

[0194] 制备胺X的另ー种方法是胺与醛或酮在还原剂如氰基硼氢化钠或こ酰氧基硼氢化钠存在下反应,即进行还原性胺化反应(J.March, AdvancedOrganic Chemistry, 1992,4th版,Wiley, New York,第411 ;898 页)。 [0194] Another method is to ー amine with an aldehyde or ketone, such as sodium cyanoborohydride or sodium borohydride ko acyloxy amine X under the presence of a reducing agent of the reaction, i.e. a reductive amination reaction (J. March, AdvancedOrganic Chemistry, 1992,4th Edition, Wiley, New York, 411; 898).

[0195] 合成方案I [0195] Synthetic Scheme I

[0196]` [0196] `

Figure CN101611028BD00261

[0197] 如合成方案2中所述,类似于上面的合成方案I,制备本发明的化合物I的合成步骤的顺序可以重新安排。 [0197] The synthesis scheme 2 in the order similar to the above synthesis scheme I, the synthetic steps of the preparation of compounds I of the present invention may be rearranged. 因此,首先,化合物VI中的氨基例如使用氯甲酸苯酯进行衍生化反应,得到化合物XIa和/或Xlb。 Therefore, first, the amino group in compound VI for example using phenyl chloroformate derivatized to give compound XIa, and / or Xlb. 在过量胺X存在下或借助于辅助碱,可以制得脲衍生物XII,该脲衍生物XII在随后的反应中,在常规条件下通过使用强碱如氢化钠或叔丁醇钾使化合物XII脱质子化,井随后用在DMF中的磺酰氯VII处理,可以转化为本发明的化合物I。 X in the presence of excess amine or by means of an auxiliary base, urea derivatives XII can be obtained, the urea derivative XII in subsequent reactions, under conventional conditions with a strong base such as sodium hydride or potassium tert-butoxide Compound XII deprotonation, followed by the well treated with a sulfonyl chloride VII in DMF, the present invention can be converted into a compound I.

[0198] 合成方案2 [0198] Scheme 2 Synthesis of

[0199] [0199]

Figure CN101611028BD00271

` I `I

[0200] 下面,本发明使用实施例进行更详细地说明,所述实施例不构成对本发明范围的限制。 [0200] Hereinafter, the embodiments of the present invention in more detail, the embodiment does not limit the scope of the present invention.

[0201] 本发明的化合物能够通过多种合成途径制备。 Compound [0201] of the present invention can be prepared by a variety of synthetic routes. 因此,在合成方案I和2中所述的方法,仅基于所提及的实施例进行更详细地举例说明,而不受合成途径I或2或所提及的类似方法的限制。 Thus, in the process of Scheme I and in the synthesis of 2, just-mentioned embodiment is based be exemplified in more detail, without synthetic routes I or 2, or the like and limit mentioned of.

[0202] 实验部分 [0202] Experimental Part

[0203] 实施例1 [0203] Example 1

[0204] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺 [0204] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide

[0205] Ia) 3- (2-こ氧基吡啶_3_基)~3~羟基_5_碘-1,3_ ニ氢_2H_吲哚_2_酮 [0205] Ia) 3- (2- ko oxypyridin _3_ yl) ~ hydroxy-3 ~ ni _5_ hydrogen iodide -1,3_ one _2H_ indol _2_

[0206] 在冰浴冷却下,将20.86g(76.40mmol)5-碘靛红在400ml无水四氢呋喃(THF)中进行搅拌,接着加入3.22g(80.50mmol,60% w/w)氢化钠,每次加入少许,将温度保持在0-10°C之间。 [0206] Under ice cooling, 20.86g (76.40mmol) 5- iodo-isatin was stirred in 400ml of anhydrous tetrahydrofuran (THF), followed by addition of 3.22g (80.50mmol, 60% w / w) of sodium hydride, every time a little added, maintaining the temperature between 0-10 ° C. 在冰浴冷却下,将所述悬浮液搅拌I小时,在此期间,制得吡啶格氏试剂。 Under ice-cooling, the suspension was stirred for I h, during which the pyridine Grignard reagent was prepared. 在室温下,20g(80.30mmol)2-こ氧基-3-碘吡啶溶于400ml无水THF中,接着用5_10分钟的时间,冷却下,在22至15°C之间将95.6ml (在THF中的IM溶液,95.60mmol)溴化こ基镁加入到此溶液中。 At room temperature, 20g (80.30mmol) 2- ko-3-iodopyridine were dissolved in 400ml of anhydrous THF, followed by 5_10 minutes, with cooling, at between 22 to 15 ° C 95.6ml (in IM solution in THF, 95.60mmol) ko-yl magnesium bromide was added to this solution. 将所述溶液搅拌20分钟,在此期间,溶液颜色从无色变为轻微浅黄色。 The solution was stirred for 20 minutes, during which the color of the solution changed from colorless to pale yellow slightly.

[0207] 然后,用5-10分钟时间,将所述吡啶格氏试剂的溶液加入到在冰浴中冷却的该5-碘靛红钠盐的溶液中,所述温度在5至18°C之间波动。 [0207] Then, 5-10 minutes, the pyridine Grignard reagent was added to a cooled in an ice bath, the sodium salt of 5-iodo-isatin solution, the temperature 5 to 18 ° C fluctuations between. 所述格氏试剂加毕后,除去冰浴,接着再将反应混合物在室温下搅拌2小吋。 After the Grignard reagent addition was completed, the ice bath was removed, and the reaction mixture was then stirred for 2 hours at room temperature inch. 加入过量饱和氯化铵溶液,随后加入こ酸こ酯,将该混合物再搅拌5分钟。 Excess saturated ammonium chloride solution was added, followed by addition of ko ko acid ester, and the mixture was stirred for an additional 5 minutes. 移出水相并用こ酸こ酯萃取(2x)。 The aqueous phase was removed and extracted with ko ko acid ester (2x). 将合并的有机相用水(2x)洗涤,接着在减压下除去溶剤。 The combined organic phases were washed with water (2x), dried and then the solvent removed under reduced pressure Ji. 首先,未反应的5-碘靛红从稀溶液中沉淀析出并被除去,进ー步浓缩后,产物也结晶析出。 First, the unreacted 5-iodo-isatin precipitated from a dilute solution and removed, into ー further concentration, the product is also crystallized. 将该悬浮液储存在5°C冰箱中2小吋,然后滤出略浅黄色的固体并用少量こ酸こ酯洗涤。 The suspension was stored in a refrigerator between 5 ° C for 2 inches, then filtered off and slightly pale yellow solid was washed with a small amount ko ko acid ester. 在40°C干燥后,分离得到所需的3-(2-こ氧基吡啶-3-基)-3-羟基-5-碘-1,3-ニ氢-2H-吲哚-2-酮(17.1g, 43.16mmol,57% )。 After drying at 40 ° C, to give the desired separation of 3- (2-ko-3-yl) -3-hydroxy-5-iodo-1,3-Ni hydrogen -2H- indol-2-one (17.1g, 43.16mmol, 57%).

[0208] ES1-MS [M+H+] = 397.05 计算值C15H13IN2O3 = 396.19 [0208] ES1-MS [M + H +] = 397.05 Calculated for C15H13IN2O3 = 396.19

[0209] Ib) 5-氰基-3-羟基-3- (2-こ氧基吡啶_3_基)-1,3_ ニ氢吲哚_2_酮 [0209] Ib) 5- cyano-3-hydroxy-3- (2-pyridinyl group _3_ ko-yl) indoline _2_ -1,3_ Ni-one

[0210] 在氣气氛中,将7.1g(17.92mmol) 3-(2-こ氧基卩比淀_3~基)-3-轻基-5-鹏-1,3- ニ氢-2H-吲哚-2-酮在IOOml无水THF中在室温下进行搅拌。 [0210] In the gas atmosphere, 7.1g (17.92mmol) 3- (2- ko ~ _3 alkoxy Jie ratio of starch-yl) -3-5- Peng light -2H- 1,3-Ni hydrogen indol-2-one IOOml anhydrous THF was stirred at rt. 加入2.1g(17.92mmol)氰化锌,接着加入0.51g(0.45mmol)四(三苯基膦)钯(O)。 Was added 2.1g (17.92mmol) of zinc cyanide, followed by addition of 0.51g (0.45mmol) of tetrakis (triphenylphosphine) palladium (O). 将所述反应混合物直接转移到在100°C预热的油浴中。 The reaction mixture was transferred directly into the preheated 100 ° C oil bath. 将所述混合物在100°C (油浴温度)搅拌30分钟后,加入另外 After the mixture was 100 ° C (oil bath temperature) for 30 minutes, additional

0.51g(0.45mmol)的催化剂。 0.51g (0.45mmol) of the catalyst. 将所述混合物总共搅拌2小时。 The mixture was stirred for a total of 2 hours. 将反应混合物冷却至室温,并加入过量的水。 The reaction mixture was cooled to room temperature, and excess water was added. 所述混合物用こ酸こ酯(3x)萃取,将合并的有机相用水(3x)洗涤。 The mixture was ko ko acid ester (3x), the combined organic phases were washed with water (3x) and washed. 在减压下将溶剂蒸发至干,接着用少量的こ酸こ酷使残余物变成淤浆。 The solvent was evaporated under reduced pressure to dryness, followed by a small amount of an acid ko ko Cool the residue was slurried. 过滤出略浅黄色的固体,用こ酸こ酯洗涤并在真空烘箱中干燥。 Slightly filtered off as a pale yellow solid was washed with ko ko acid ester and dried in a vacuum oven. 能分离得到3.7g(12.44mmol,69.4% )所需产物5-氰基-3-羟基-3-(2-こ氧基吡啶-3-基)-1,3- ニ氢吲哚-2-酮。 Can be isolated as the hydrogen-indole 3.7g (12.44mmol, 69.4%) of the desired product 5-cyano-3-hydroxy-3- (2-ko-3-yl) -1,3-ni -2- ketone.

[0211] ES1-MS [M+H+] = 296.05 计算值C16H13N3O3 = 295.30 [0211] ES1-MS [M + H +] = 296.05 Calculated for C16H13N3O3 = 295.30

[0212] Ic) 3-氣-3- (2~こ氧基卩比淀_3~基)~2~氧代_■氧卩引噪_5-臆 [0212] Ic) 3- gas -3- (2 ~ ko ~ _3 alkoxy group Jie than starch) ~ 2 ~ _ ■ oxo oxygen Jie chest lead noise _5-

[0213] 在氣气氛中,将6.0Og(2`0.32mmol) 5-氛基-3-轻基-3-(2-こ氧基卩比淀_3-基)-1,3_ ニ氢吲哚-2-酮悬浮在60ml无水ニ氯甲烷(分子筛干燥过)中。 [0213] In the gas atmosphere, 6.0Og (2`0.32mmol) 5- atmosphere light-3-yl 3- (2-yloxy Jie than starch _3- ko-yl) indole hydrogen -1,3_ ni 2-one was suspended in 60ml of anhydrous Ni chloride (dried over molecular sieve) was. 然后,加入 Then,

2.30ml (28.45mmol)吡啶。 2.30ml (28.45mmol) of pyridine. 将反应混合物冷却至(TC,然后滴加2.06ml (28.45mmol)纯的亚硫酰氯(放热反应)。将所述混合物在室温下搅拌I小吋。观察到生成ー种黄色悬浮液。反应进程通过薄层层析(TLC)监测(硅胶,95: 5的ニ氯甲烷/甲醇)。将所述反应混合物小心地倾倒到冰-水中。搅拌15分钟后,移出有机相。水相用ニ氯甲烷(2x)萃取。合并所有的有机相,用硫酸镁干燥,过滤,并在减压下除去溶剤。得到无定形固体形式的5.70g (18.17mmol, 89 % )广物3-氣-3- (2-こ氧基卩比淀_3~基)~2~氧代_■氧卩引噪_5~月青,其在没有进ー步提纯的情况下就用于下ー步反应中。 The reaction mixture was cooled to (TC, then a solution of 2.06 ml (28.45 mmol) of pure thionyl chloride (exothermic reaction). The mixture was stirred at room temperature for I inch small. ー species observed to generate a yellow suspension. The reaction process monitoring (silica gel, 95: 5 ni chloride / methanol) by thin layer chromatography (TLC) the reaction mixture was carefully poured into ice - water and after stirring for 15 minutes, the organic phase was removed with the aqueous phase Ni... chloride (2x) and extracted. All combined organic phase was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure Ji. to give amorphous solid of 5.70g (18.17mmol, 89%) was widely -3 gas 3- - (2-yloxy Jie ratio ko ~ _3 precipitate yl) ~ 2 ~ _ ■ oxo oxygen Jie primer _5 ~ ilicifolia noise, which without further purification ー feed was used in the next reaction step ー.

[0214] ES1-MS [M+H+] = 314.1 计算值C16H12ClN3O2 = 313.75 [0214] ES1-MS [M + H +] = 314.1 Calculated for C16H12ClN3O2 = 313.75

[0215] Id) 3-氨基-3- (2-こ氧基吡啶-3-基)_2_氧代ニ氢吲哚_5_腈 [0215] Id) 3- amino-3- (2-ko-3-yl) oxo _2_ Ni indoline _5_ carbonitrile

[0216] 将5.70g (18.17mmol) 3-氣-3- (2-こ氧基卩比淀_3~基)~2~氧代_■氢!卩引噪_5-臆溶于50ml ニ氯甲烷中。 [0216] A 5.70g (18.17mmol) 3- gas -3- (2-yloxy Jie ratio ko ~ _3 precipitate yl) ~ 2-oxo ~ _ ■ hydrogen! Jie noise _5- chest lead dissolved in 50ml ni chloromethane. 在氮气氛中,将14ml (98.llmmol)7N甲醇氨溶液缓慢滴加到冷却的反应溶液中。 In a nitrogen atmosphere, 14ml (98.llmmol) 7N methanolic ammonia solution was slowly added dropwise to the reaction solution was cooled. 溶液的顔色变为淡黄色,接着将所述溶液在室温下搅拌过夜,在此期间产物缓慢地结晶出来。 Color of the solution changed to pale yellow, and the solution was stirred at room temperature overnight, during which the product slowly crystallized out. 反应进程通过TLC监测(硅胶,9: I的ニ氯甲烷/甲醇)。 The reaction was monitored by TLC (silica gel, 9: I ni of dichloromethane / methanol). 在减压下除去溶剂,将残余物再一次导出并溶于ニ氯甲烷中。 The solvent was removed, the residue was again exported under reduced pressure and dissolved in dichloromethane ni. 然后,混合物用水萃取。 Then, the mixture was extracted with water. 分离相,接着将在相之间生成的油脂相加入到水相中。 The phases were separated, then the resulting phase between the fat phase is added to the aqueous phase. 水相用こ酸こ酯萃取,直到油脂相溶解为止。 The aqueous phase was extracted ester ko ko acid, fat phase until dissolved. 合并获得的所有有机相,接着在减压下除去溶剤。 All combined organic phases were obtained, and then the solvent was removed under reduced pressure Ji. 所述残余物用こ醚研制,形成ー种固态物质,将该固态物质滤出并在真空烘箱中在中等温度(35°C )进行干燥。 The residue was triturated with ether ko formed ー solid-state material, the solid material was filtered off and dried at moderate temperatures (35 ° C) in a vacuum oven. 得到4.54g(15.43mmol,85% )固体形式的3-氨基-3-(2-こ氧基卩比唳-3-基)-2_氧代ニ氢Π引哚-5-臆。 To give 4.54g (15.43mmol, 85%) of 3- amino-3- (2-yloxy ko Jie Li ratio of 3-yl) -2_ Ni hydrogen-oxo-5-Π primer addiction.

[0217] ES1-MS [M+H+] = 295.3 计算值C16H14N4O2 = 294.32 [0217] ES1-MS [M + H +] = 295.3 Calculated for C16H14N4O2 = 294.32

[0218] Ie) 3-氨基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_ (2-こ氧基吡啶_3_基)-2_氧代ニ氢吲哚-5-腈 [0218] Ie) 3- amino-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2-pyridinyl group _3_ ko-yl) oxo -2_ Ni indoline 5-carbonitrile

[0219] 将3.54g (12.03mmol) 3-氣基-3- (2-こ氧基卩比淀_3~基)_2_氧代_■氧卩引噪_5-臆溶于80ml无水ニ甲基甲酰胺(分子筛干燥过)中。 [0219] A 3.54g (12.03mmol) 3- gas-3- (2-yloxy Jie ratio ko ~ _3 precipitate yl) ■ _ _2_ oxo oxygen dissolved Jie primer 80ml of anhydrous addictive noise _5- ni dimethylformamide (dried over molecular sieve) was. 在氮气氛中并使用冰浴冷却下,每次少量地加入1.49g(13.23mmol)叔丁醇钾。 In a nitrogen atmosphere and cooled using an ice bath, was added in small portions 1.49 g (13.23 mmol) of potassium tert-butoxide. 反应混合物的颜色发生变化,将该棕色溶液在0°C下再搅拌I小时以确保脱质子化反应完全。 The reaction mixture color changed, and the brown solution was stirred at 0 ° C for another I hour to ensure complete deprotonation. 在低温下,加入3.16g(13.23mmol)2,4-ニ甲氧基苯磺酰氯,将该混合物在0°C下再搅拌2小吋。 At low temperature, was added 3.16g (13.23mmol) 2,4- Ni-methoxybenzenesulfonyl chloride, the mixture was stirred for 2 inches at 0 ° C. 反应进程通过TLC监测(硅胶,9: I的ニ氯甲烷/甲醇)。 The reaction was monitored by TLC (silica gel, 9: I ni of dichloromethane / methanol). 将所述反应混合物倾倒到冰-水中,然后用こ酸こ酯萃取。 The reaction mixture was poured into ice - water, and then extracted with an acid ester ko ko. 有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥,蒸除溶剤。 The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate, the solvent was distilled Ji. 将残余物悬浮在こ醚中,搅拌直到析出固体形式的产物为止,并可通过过滤移出。 Ko The residue was suspended in ether, stirred until a solid product was precipitated, and was removed by filtration. 除去溶剂后,母液再次用こ醚(2x)处理直到最终为止,干燥后,得到4.67g(9.44mmol, 79% )所需的固体形式的3-氨基_1_[ (2,4-ニ甲氧基苯基)磺酰基]-3-(2-こ氧基吡啶-3-基)-2-氧代ニ氢吲哚-5-腈。 After removal of solvent, the mother liquor ko again treated with ether (2x) until the final date, and dried to give (9.44mmol, 79%) as a solid of the desired amino _1_ 4.67g 3- [(4-methoxy Ni phenyl) sulfonyl] -3- (2-ko-3-yl) -2-oxo-indole-5-carbonitrile hydrogen ni.

[0220] ES1-MS [M+H+] = 495.15 计算值C24H22N4O6S = 494.53 [0220] ES1-MS [M + H +] = 495.15 Calculated for C24H22N4O6S = 494.53

[0221] If) [5-氛基-1-[ (2,4-_■甲氧基苯基)横酸基]-3-(2-こ氧基卩比淀-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]氨基甲酸苯酯 [0221] If) [5- yl atmosphere -1- [(2,4-_ ■ methoxyphenyl) an acid cross-yl] -3- (2-yloxy Jie than starch ko-yl) -2 - oxo-2,3-Ni hydrogen -1H- indol-3-yl] carbamate

[0222] 将4.678(9.44臟01)3-氨基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2-こ氧基吡啶-3-基)-2-氧代ニ氢吲哚-5-腈溶于120ml吡啶中并使用冰浴冷却至O °C。 [0222] A 4.678 (9.44 dirty 01) 3-amino-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2-ko-3-yl) -2 Generation ni indoline-5-carbonitrile was dissolved in 120ml of pyridine, and was cooled using an ice bath to O ° C. 加入1.30ml (10.39mmol)纯的氯甲酸苯酷,并将反应混合物在0°C下搅拌2小时。 Was added 1.30ml (10.39mmol) of pure phenyl chloroformate cool, and the reaction mixture was stirred at 0 ° C 2 hours. 反应进程通过TLC监测(硅胶,95: 5的ニ氯甲烷/甲醇)。 The reaction was monitored by TLC (silica gel, 95: 5 Ni chloride / methanol). 在减压下除去溶剂,尤其是吡啶,将残余物用水稀释并用こ酸こ酯(3x)萃取。 The solvent was removed under reduced pressure, especially pyridine, the residue diluted with water and extracted with ko ko acid ester (3x). 将合并的有机相用饱和氯化钠溶液洗涤,用硫酸镁干燥并过滤,接着在减压下除去溶剂。 The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered, then the solvent was removed under reduced pressure. 通过反复加入甲苯并在旋转蒸发仪上蒸发,除去痕量的吡啶。 By repeated addition of toluene and evaporation on a rotary evaporator to remove traces of pyridine. 将こ醚加入到分离的残`余物中,固体结晶过夜,得到5.62g(9.14mmol,97% )所需产物[5-氛基-1-[ (2,4- _■甲氧基苯基)横酸基]-3_(2-こ氧基卩比淀_3~基)-2-氧代-2,3- _.氢-1H-吲哚-3-基]氨基甲酸苯酷。 Ether was added to separate the residue ko `residue, the solid crystallized overnight to give 5.62g (9.14mmol, 97%) of the desired product [5-yl atmosphere -1- [(2,4- _ ■ methoxybenzene yl) acid cross-yl] -3_ (2-yloxy Jie ratio ko ~ _3 precipitate yl) -2-oxo-2,3-_. hydrogen -1H- indol-3-yl] carbamate cool.

[0223] ES1-MS [M+H+] = 615.15 计算值C31H26N4O8S = 614.64 [0223] ES1-MS [M + H +] = 615.15 Calculated for C31H26N4O8S = 614.64

[0224] Ig) N-[5-氰基-l-[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶_4_基)哌嗪-1-羧酰胺 [0224] Ig) N- [5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2-oxo -2,3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin _4_ yl) piperazine-1-carboxamide

[0225] 将1.0Og(1.63mmol) [5-氛基-1-[ (2,4-_■甲氧基苯基)横酸基]-3-(2-こ氧基批啶-3-基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基]氨基甲酸苯酷,596mg (3.25mmol) 1-(1-甲基哌啶-4-基)哌嗪和8ml干燥THF混合,并将该混合物在室温下搅拌24小吋。 [0225] The 1.0Og (1.63mmol) [5- yl atmosphere -1- [(2,4-_ ■ methoxyphenyl) an acid cross-yl] -3- (2-ko-3-yloxy Batch yl) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] carbamate cool, 596mg (3.25mmol) 1- (1- methyl-piperidin-4-yl) piperazine 8ml of dry THF and mixed, and the mixture was stirred at room temperature for 24 hours inch. 借助于分析HPLC(RP,洗脱液こ腈/水,0.01% TFA)检测反应是否结束。 Analysis by means of HPLC (RP, ko eluent acetonitrile / water, 0.01% TFA) detecting the reaction is finished. 除去溶剂,残余物用制备性HPLC在Chromolith柱(正相,来自默克)上提纯,使用ニ氯甲烷和6 %甲醇作为洗脱液。 The solvent was removed purification, the residue was purified by preparative HPLC on a Chromolith column (normal phase, from Merck) using Ni and 6% methanol in methylene chloride as eluent. 重复柱色谱后,可以分离230mg(0.33mmol, 21 % )N_[5_氰基-1_[ (2,4- ニ甲氧基苯基)磺酰基]-3_ (2-こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4_(1_甲基哌啶-4-基)哌嗪-1-羧酰胺。 After repeated column chromatography, can be isolated 230mg (0.33mmol, 21%) N_ [5_ cyano -1_ [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2-pyridin-3 yloxy ko - yl) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4_ (1_ methyl-piperidin-4-yl) piperazine-1-carboxamide.

[0226] 或者,反应结束后,可以如下进行后处理和提纯:除去溶剤。 [0226] Alternatively, after the completion of the reaction, post-processing may be as follows and purification: Ji solvent was removed. 将粗物质溶于こ酸こ酷中,并用IN HCl萃取。 The crude material was dissolved in cool ko ko acid, and extracted with IN HCl. 在有机相中检测出杂质,产物在酸性水相中。 Impurities detected in an organic phase, acidic aqueous product phase. 因此,水相用2N NaOH溶液中和并用こ酸こ酯萃取。 Thus, the aqueous phase with 2N NaOH solution and extracted with ko ko acid ester. 用硫酸镁干燥后,过滤并在减压下除去こ酸こ酷,所述产物可以用こ醚结晶。 Dried over magnesium sulfate, filtered and removed under reduced pressure to cool ko ko acid, the product can be crystallized ko ether. 获得收率> 50%的N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3- (2-乙氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4- (1-甲基哌啶-4-基)哌嗪-1-羧酰胺。 Obtained yields> 50% of N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3- (2-ethoxy-3-yl) -2 - oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide.

[0227] ES1-MS [M+H+] = 704.2 计算值C35H41N7O7S = 703.82 [0227] ES1-MS [M + H +] = 704.2 Calculated for C35H41N7O7S = 703.82

[0228] 1H-NMR ([D6] -DMS0,400ΜΗζ) δ [ppm] = 8.12 (d, 1H, J = 4.8Hz),7.88 (d, 1H, J =8.8Hz),7.87 (d, 1H, J = 8.7Hz) ,7.81 (d, 1H, J = 8.5Hz),7.72 (d, 1H, J = 7.6Hz),7.67 (s,1H),7.64 (s, 1H),7.02 (dd, 1H, J = 5.0Hz, J = 7.5Hz),6.69 (d, 1H, J = 8.9Hz),6.65 (s,1H), 4.15(m,2H),3.85(s,3H),3.44(s,3H),3.20 (m, 4H), 2.76 (m, 2H, J = 11.1Hz),2.34 (m,4H),2.ll(m,4H),1.81(m,2H,J = 11.3Hz),1.64 (m,2H,J = 10.7Hz),1.37 (m,2H),1.06 (t,1H, J = 7.0Hz)。 [0228] 1H-NMR ([D6] -DMS0,400ΜΗζ) δ [ppm] = 8.12 (d, 1H, J = 4.8Hz), 7.88 (d, 1H, J = 8.8Hz), 7.87 (d, 1H, J = 8.7Hz), 7.81 (d, 1H, J = 8.5Hz), 7.72 (d, 1H, J = 7.6Hz), 7.67 (s, 1H), 7.64 (s, 1H), 7.02 (dd, 1H, J = 5.0Hz, J = 7.5Hz), 6.69 (d, 1H, J = 8.9Hz), 6.65 (s, 1H), 4.15 (m, 2H), 3.85 (s, 3H), 3.44 (s, 3H) , 3.20 (m, 4H), 2.76 (m, 2H, J = 11.1Hz), 2.34 (m, 4H), 2.ll (m, 4H), 1.81 (m, 2H, J = 11.3Hz), 1.64 ( m, 2H, J = 10.7Hz), 1.37 (m, 2H), 1.06 (t, 1H, J = 7.0Hz).

[0229] 实施例5: [0229] Example 5:

[0230] N- [5-氰基-3- (2-こ氧基吡啶_3_基)-1- [ (4_甲氧基苯基)磺酰基]_2_氧代_2, [0230] N- [5- cyano-3- (2-pyridinyl group _3_ ko-yl) -1- [(4_ methoxyphenyl) sulfonyl] _2 _2_ oxo,

3- ニ氢-1H-吲哚-3-基}-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺 3- ni hydrogen -1H- indol-3-yl} -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide

[0231 ] 5a) 5-氰基-3- (2_こ氧基卩比唳-3-基)~2~氧代-3-[(苯氧擬基)氨基]ニ氢ロ引哚-2-羧酸苯酯 [0231] 5a) 5- cyano-3- (2_ than ko Jie Li 3-yloxy) ~ 2 ~ oxo-3 - [(phenoxy quasi-yl) amino] -2 indole ni ro hydrogen - carboxylic acid benzyl ester

[0232] 将2.78g (9.43mmol) 3-氣基-3- (2-こ氧基卩比淀_3~基)~2~氧代_■氧卩引噪_5-臆(根据实施例1,方法步骤la)-lc)制备)悬浮在25ml ニ氯甲烷中,并用冰浴冷却至0°C。 [0232] A 2.78g (9.43mmol) 3- gas-3- (2-yloxy Jie ratio ko ~ _3 precipitate yl) ~ 2 ~ _ ■ oxo oxygen Jie noise _5- chest lead (according to Example 1, step la) -lc) prepared) was suspended in 25ml Ni methyl chloride, and cooled with an ice bath to 0 ° C. 加入7.63ml (94.34mmol)吡啶,然后缓慢滴加2.37ml (18.87mmol)氯甲酸苯酷,以便温度不超过5-10°C。 Was added 7.63ml (94.34mmol) of pyridine, followed by slow dropwise addition of 2.37ml (18.87mmol) phenyl chloroformate cool, so that the temperature did not exceed 5-10 ° C. 在冰浴融化的情况下,将反应在室温下搅拌过夜,然后沉淀析出略带颜色的固体。 In the case where the melting ice bath, and the reaction was stirred at room temperature overnight, then the precipitated solid was slightly colored. 反应混合物用ニ氯甲烷稀释,加入水后,固体返回到溶液中。 The reaction mixture was diluted with methylene chloride ni After adding water, the solid is returned to the solution. 分离相,水相再次用ニ氯甲烷(Ix)萃取。 The phases were separated, the aqueous phase was extracted again with dichloromethane Ni (Ix). 合并的有机相首先用水(3x)洗涤,然后用饱和氯化钠溶液(Ix)洗涤。 The combined organic phases were washed first with water (3x), dried and then washed with saturated sodium chloride solution (Ix). 用硫酸镁干燥后,过滤并在`减压下蒸除溶剂,将残余物溶解在こ醚中,加入10倍数量的戊烷。 Dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure 'and the residue was dissolved in ether ko, 10 times the amount of added pentane. 生成ー种白色沉淀,将该沉淀抽吸滤出,用戊烷洗涤,并在真空烘箱中在40°C干燥。ー species generated white precipitate, and the precipitate was filtered off with suction, washed with pentane, and dried in a vacuum oven at 40 ° C. 分级结晶后,总共分尚得到4.46g(8.35mmol, 89% ) 5-氛基_3_(2-こ氧基卩比唳_3_基)-2-氧代-3_ [(苯氧羰基)氨基]ニ氢吲哚-1-羧酸苯酷。 After fractional crystallization, to give a total of points still 4.46g (8.35mmol, 89%) 5- yl _3_ atmosphere (2-yloxy ko than Jie Li _3_ yl) -2-oxo -3_ [(phenoxycarbonyl) amino] ni indoline-carboxylic acid benzyl cool.

[0233] ES1-MS [M+H+] = 535.15 计算值C30H22N4O6 = 534.53 [0233] ES1-MS [M + H +] = 535.15 Calculated for C30H22N4O6 = 534.53

[0234] 5b) N-[5-氰基-3-(2-こ氧基吡啶_3_ 基)-2_ 氧代_2,3_ ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺 [0234] 5b) N- [5- cyano-3- (2-pyridinyl group _3_ ko-yl) oxo _2,3_ -2_ Ni hydrogen -1H- indol-3-yl] -4- ( 1-methyl-piperidin-4-yl) piperazine-1-carboxamide

[0235] 在室温下,首先将760mg (1.42mmol) 5_氛基_3_ (2-こ氧基卩比卩定-3-基)~2~氧代-3_[(苯氧羰基)氨基]ニ氢吲哚-1-羧酸苯酯加入到5ml THF中,并在未稀释下加入1.42g(5.69mmol)l-(l-甲基哌啶-4-基)哌嗪。 [0235] At room temperature, first 760mg (1.42mmol) 5_ _3_ atmosphere yl (2-yloxy Jie ko given ratio Jie-3-yl) -3-oxo ~ 2 ~ _ [(phenoxycarbonyl) amino] ni indoline-carboxylic acid benzyl ester were added to 5ml THF and added 1.42g (5.69mmol) l- (l- methylpiperidin-4-yl) piperazine undiluted. 将反应混合物搅拌过夜,反应通过TLC检测(硅胶,ニ氯甲烷/甲醇15: 5)以确定反应进程。 The reaction mixture was stirred overnight, the reaction by TLC (silica gel, Ni chloride / methanol 15: 5) to determine the progress of the reaction. 该反应用こ酸こ酯稀释并用水(Ix)和饱和氯化钠溶液(Ix)洗涤。 The reaction was ko ko acid ester was diluted with water (Ix is) and saturated sodium chloride solution (Ix is) washed. 将有机相用硫酸镁干燥并过滤,并在减压下除去溶剤。 The organic phase was dried over magnesium sulfate and filtered, and the solvent removed under reduced pressure Ji. 将残余物导入少量こ醚中,加入6倍数量的环己烷。 The residue was introduced into a small amount of ether ko, 6 times the amount of cyclohexane was added. 沉淀析出一种无色固体,其包含615mg (1.22mmol, 86% )纯的N- [5-氛基_3- (2~ こ氧基卩比淀_3~ 基)~2~ 氧代-2,3- _.氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺。 A colorless solid precipitated out, which comprises 615mg (1.22mmol, 86%) of pure N- [5- yl atmosphere _3- (2 ~ ko ~ _3 alkoxy group Jie than starch) ~ 2 ~ oxo - 2,3 _ hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide.

[0236] ES1-MS [M+H+] = 504.25 计算值C27H33N7O3 = 503.61[0237] 5c) N-[5-氰基-3-(2-こ氧基吡啶-3-基)-1-[(4-甲氧基苯基)磺酰基]-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺 [0236] ES1-MS [M + H +] = 504.25 Calculated for C27H33N7O3 = 503.61 [0237] 5c) N- [5- cyano-3- (2-ko-3-yl) -1 - [( 4-methoxyphenyl) sulfonyl] -2_ oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine l-carboxamide

[0238] 80.0mg (0.16mmol) N- [5—氛基—3— (2—乙氧基B比淀—3—基)~2~ 氧代~2, 3— _.氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺溶于ニ甲基甲酰胺中,并在0°C下加入7.63mg(0.19mmol, 60% w/w)氢化钠。 [0238] 80.0mg (0.16mmol) N- [5- atmosphere-3- (2-ethoxy-3-yl Lake B ratio) ~ 2 ~ oxo ~ 2, 3- _. -1H- indazol hydrogen 3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide was dissolved Ni dimethylformamide, was added 7.63mg (0.19mmol at 0 ° C, 60% w / w) of sodium hydride. 为使I, 3-ニ氢-2H-卩引哚-2-酮衍生物脱质子化,将混合物搅拌10分钟,然后加入39.4mg (0.19mmol)4-甲氧基苯磺酰氯。 For I, 3- Ni Jie hydrogen -2H- indol-2-one derivatives deprotonation, the mixture was stirred for 10 minutes and then 39.4mg (0.19mmol) 4- methoxybenzenesulfonyl chloride. 然后,将混合物温热至室温并搅拌30分钟。 The mixture was then allowed to warm to room temperature and stirred for 30 min. 反应进程通过TLC监测(硅胶,ニ氯甲烷/甲醇1:1)。 The reaction was monitored by TLC (silica gel, Ni chloride / methanol 1: 1). 将饱和碳酸氢钠溶液和こ酸こ酯加入到该反应混合物中,然后分离相。 A saturated sodium bicarbonate solution and ko ko acid ester was added to the reaction mixture, and the phases were separated. 水相再用こ酸こ酯(Ix)萃取。 The aqueous phase was ko ko acid ester (Ix is) extracted. 合并的有机相用水(Ix)和饱和氯化钠溶液(Ix)洗涤,用硫酸镁干燥,过滤,并在减压下除去溶剤。 Washed (Ix is) The combined organic phases were washed with water (Ix is) and saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure Ji. 残余物用制备性MPLCdSCO Companion, 4g NP柱)使用移动相ニ氯甲烷/甲醇(5-20%)提纯。 Ni with dichloromethane / methanol (5-20%) and the residue was purified by preparative mobile MPLCdSCO Companion, 4g NP column). 分离得到27.311^(0.04臟01,23%收率,90%纯度)的N-[5-氰基-3-(2-こ氧基吡啶-3-基)-1-[(4-甲氧基苯基)磺酰基]-2-氧代-2,3-ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺。 Isolated 27.311 ^ (0.04 dirty 01,23% yield, 90% purity) of N- [5- cyano-3- (2-ko-3-yl) -1 - [(4-methoxy phenyl) sulfonyl] -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxylic amide.

[0239] ES1-MS [M+H+] = 674.2 计算值C34H39N7O6S = 673.80 [0239] ES1-MS [M + H +] = 674.2 Calculated for C34H39N7O6S = 673.80

[0240] 粗混合物结晶的可供选择的提纯方法包括正相常规柱色谱(NP-SiO2柱,Chromabond)使用流动相ニ氯甲烷/甲醇进行提纯,或者通过制备性HPLC(RP,流动相こ腈/水,0.01% TFA或0.01%こ酸)进行提纯。 [0240] The method for purifying a crude mixture of the alternative crystalline phase comprises a conventional positive column chromatography (NP-SiO2 column, Chromabond) ni mobile phase dichloromethane / methanol and purified either by preparative HPLC (RP, mobile phase ko-carbonitrile / water, 0.01% TFA ko acid or 0.01%) was purified.

[0241] 实施例2-4 和6-30: [0241] Example 2-4 and 6-30:

[0242] 实施例2-4和6-30的化合物能够以与实施例1和/或实施例5类似的制备方式使用适宜的起始原料进行制备。 The compounds of Examples 2-4 and 6-30 [0242] embodiment can be prepared as in Example 1 and / or prepared in a similar manner as Example 5 using appropriate starting materials Example embodiment.

[0243] 实施例2: [0243] Example 2:

[0244] N- {5-氰基-3- (2-こ氧基吡啶_3_基)-1- [ (2_甲氧基苯基)磺酰基]_2_氧代_2,3- ニ氢-1H-吲哚-3-`基}-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺 [0244] N- {5- cyano-3- (2-pyridinyl group _3_ ko-yl) -1- [(2_-methoxyphenyl) sulfonyl] _2_ oxo _2,3- ni hydrogen -1H- indol-3-yl} `-4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide

[0245] ES1-MS [M+H+] = 674.05 计算值C34H39N7O6S = 673.80 [0245] ES1-MS [M + H +] = 674.05 Calculated for C34H39N7O6S = 673.80

[0246] 实施例3: [0246] Example 3:

[0247] N-[5-氛基-1-[ (2-こ氧基苯基)横酸基]-3_(2~こ氧基卩比淀_3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺三氟こ酸盐 [0247] N- [5- atmosphere-1- [(2-methoxyphenyl ko) an acid cross-yl] -3_ (2 ~ ko Jie than starch _3- alkoxy-yl) -2-oxo-2 3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide trifluoroacetic acid salt ko

[0248] ES1-MS [M+H+] = 688.3 计算值C35H41N7O6S = 687.82 [0248] ES1-MS [M + H +] = 688.3 Calculated for C35H41N7O6S = 687.82

[0249] 实施例4: [0249] Example 4:

[0250] N- [5-氰基-3- (2-こ氧基吡啶_3_基)_2_氧代_1_ (苯磺酰基)_2,3_ ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺 [0250] N- [5- cyano-3- (2-pyridinyl group _3_ ko-yl) oxo _1_ _2_ (phenylsulfonyl) -1H- _2,3_ Ni hydrogen-indol-3-yl ] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide

[0251] ES1-MS [M+H+] = 644.2 计算值C33H37N7O5S = 643.77 [0251] ES1-MS [M + H +] = 644.2 Calculated for C33H37N7O5S = 643.77

[0252] 实施例31: [0252] Example 31:

[0253] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺 [0253] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide

[0254] 首先将100mg(0.16mmol) [5-氰基-1-[(2,4_ ニ甲氧基苯基)磺酰基]-3-(2-こ氧基吡啶-3-基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基]氨基甲酸苯酯(根据实施例1,方法步骤la)_lf)制备)加入到8ml无水四氢呋喃(分子筛干燥过)中,并加入44.7mg(0.24mmol) 1-甲基-4-(哌啶-4-基)哌嗪。 [0254] First, 100mg (0.16mmol) [5- cyano-1 - [(2,4_ Ni-methoxyphenyl) sulfonyl] -3- (2-ko-3-yl) -2 - oxo-2,3-Ni hydrogen -1H- indol-3-yl] carbamate prepared _lf) (Example 1, la according to the method steps)) was added to 8ml of anhydrous tetrahydrofuran (dried over molecular sieves) in , and was added 44.7mg (0.24mmol) 1- methyl-4- (piperidin-4-yl) piperazine. 将反应混合物在室温下搅拌过夜。 The reaction mixture was stirred at room temperature overnight. 反应进程通过TLC (硅胶,9: I的ニ氯甲烷/甲醇)和LCMS (RP,こ臆/水作为洗脱液和0.01%TFA)监测。 Reaction progress was monitored by TLC (silica gel, 9: I ni of dichloromethane / methanol) and LCMS (RP, addiction ko / water as eluent and 0.01% TFA) monitoring. 在减压下除去溶剂,将残余物导入到ニ氯甲烷中并用2N氢氧化钠溶液(Ix)萃取。 The solvent was removed under reduced pressure, the residue was introduced into a Ni chloride and extracted with 2N sodium hydroxide solution (Ix). 将合并的有机相用硫酸镁干燥并过滤,并在减压下除去溶剤。 The combined organic phases were dried over magnesium sulfate and filtered, and the solvent removed under reduced pressure Ji. 所述粗混合物用柱色谱(5g NP-SiO2柱体Chromabond)提纯两次,使用99: 1-80: 20的ニ氯甲烷/甲醇作为洗脱液。 The crude mixture was purified by column chromatography (5g NP-SiO2 cartridge Chromabond) was purified twice using 99: 20 Ni chloride / methanol as eluent: 1-80. 分离得到53.8mg(0.08mmol,47% )纯的N_[5_氰基_1_[ (2,4-ニ甲氧基苯基)磺酰基]-3_(2-こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4_甲基哌嗪-1-基)哌啶-1-羧酰胺。 Isolated as 53.8mg (0.08mmol, 47%) of pure N_ [5_ cyano _1_ [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2-oxy-3-yl ko ) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (4_ methylpiperazin-1-yl) piperidine-1-carboxamide.

[0255] ES1-MS [M+H+] = 704.25 计算值C35H41N7O7S = 703.82 [0255] ES1-MS [M + H +] = 704.25 Calculated for C35H41N7O7S = 703.82

[0256] 1H-NMR ([D6] -DMS0,400ΜΗζ) δ [ppm] = 8.13 (dd, 1H, J = 1.4Hz, J = 4.8Hz),7.88 (d, 1H, J = 8.5Hz),7.87 (d, 1H, J = 8.8Hz),7.81 (dd, 1H, J= 1.6Hz, J = 8.6Hz),7.71 (dd, 1H, J=L 4Hz, J = 7.6Hz),7.68 (d, 1H, J=L 3Hz),7.65 (s, 1H),7.02 (dd, 1H, J =4.9Hz, J = 7.6Hz),6.68 (d, 1H, J = 8.9Hz),6.65 (s, 1H),4.17 (m, 2H),3.85 (s, 3H),3.80 (m,2H), 3.44(s,3H),2.62 (m,2H),2.41-2.12(m,9H),2.12(s,3H),1.61 (m, 2H),1.16(m,2H),1.09(t,3H,J = 7.0Hz).[0257]实施例 32-36: [0256] 1H-NMR ([D6] -DMS0,400ΜΗζ) δ [ppm] = 8.13 (dd, 1H, J = 1.4Hz, J = 4.8Hz), 7.88 (d, 1H, J = 8.5Hz), 7.87 (d, 1H, J = 8.8Hz), 7.81 (dd, 1H, J = 1.6Hz, J = 8.6Hz), 7.71 (dd, 1H, J = L 4Hz, J = 7.6Hz), 7.68 (d, 1H , J = L 3Hz), 7.65 (s, 1H), 7.02 (dd, 1H, J = 4.9Hz, J = 7.6Hz), 6.68 (d, 1H, J = 8.9Hz), 6.65 (s, 1H), 4.17 (m, 2H), 3.85 (s, 3H), 3.80 (m, 2H), 3.44 (s, 3H), 2.62 (m, 2H), 2.41-2.12 (m, 9H), 2.12 (s, 3H) , 1.61 (m, 2H), 1.16 (m, 2H), 1.09 (t, 3H, J = 7.0Hz) [0257] Example 32-36:

[0258] 实施例32-36的化合物能够以与实施例1、5和/或31类似的制备方式使用适宜的起始原料进行制备。 The compound of Example 32-36 [0258] embodiment can be prepared in a similar manner as in Example 1, 5 and / or 31 using the appropriate starting materials prepared.

[0259] 实施例32: [0259] Example 32:

[0260] N- [5-氰基-3- (2-こ氧基吡啶_3_基)-1- [ (2_甲氧基苯基)磺酰基]_2_氧代_2,3- ニ氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺 [0260] N- [5- cyano-3- (2-pyridinyl group _3_ ko-yl) -1- [(2_-methoxyphenyl) sulfonyl] _2_ oxo _2,3- ni hydrogen -1H- indol-3-yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide

[0261] ES1-MS [M+H+] = 674.8 计算值C34H39N7O6S = 673.80 [0261] ES1-MS [M + H +] = 674.8 Calculated for C34H39N7O6S = 673.80

[0262] 实施例33: [0262] Example 33:

[0263] N-[5-氛基-`1-[ (2-こ氧基苯基)横酸基]-3_(2-こ氧基卩比淀_3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺三氟こ酸盐 [0263] N- [5- yl atmosphere -`1- [(2-methoxyphenyl ko) an acid cross-yl] -3_ (2-yloxy Jie than starch _3- ko-yl) -2-oxo - 2,3-Ni hydrogen -1H- indol-3-yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide trifluoroacetic acid salt ko

[0264] ES1-MS [M+H+] = 688.2 计算值C35H41N7O6S = 687.82 [0264] ES1-MS [M + H +] = 688.2 Calculated for C35H41N7O6S = 687.82

[0265] 实施例34: [0265] Example 34:

[0266] N- [5-氰基-3- (2-こ氧基吡啶_3_基)_2_氧代_1_ (苯磺酰基)_2,3_ ニ氢-1H-吲哚-3-基]-4- (4-甲基哌嗪-1-基)哌啶-1-羧酰胺 [0266] N- [5- cyano-3- (2-pyridinyl group _3_ ko-yl) oxo _1_ _2_ (phenylsulfonyl) -1H- _2,3_ Ni hydrogen-indol-3-yl ] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide

[0267] ES1-MS [M+H+] = 644.7 计算值C33H37N7O5S = 643.77 [0267] ES1-MS [M + H +] = 644.7 Calculated for C33H37N7O5S = 643.77

[0268] 实施例35: [0268] Example 35:

[0269] N- [5-氰基-3- (2-こ氧基吡啶_3_基)-1- [ (4_甲氧基苯基)磺酰基]_2_氧代_2,3- ニ氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺三氟こ酸盐 [0269] N- [5- cyano-3- (2-pyridinyl group _3_ ko-yl) -1- [(4_ methoxyphenyl) sulfonyl] _2_ oxo _2,3- ni hydrogen -1H- indol-3-yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide trifluoroacetic acid salt ko

[0270] ES1-MS [M+H+] = 674.2 计算值C34H39N7O6S = 673.80 [0270] ES1-MS [M + H +] = 674.2 Calculated for C34H39N7O6S = 673.80

[0271] 实施例37: [0271] Example 37:

[0272] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4-こ基哌嗪-1-基)哌啶-1-羧酰胺 [0272] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4- (4-ko-l-yl) piperidine-1-carboxamide

[0273] 首先加入溶于8ml无水四氢呋喃(分子筛干燥过)中的IOOmg (0.16mmol)[5-氛基-l-[ (2,4_ ニ甲氧基苯基)横酸基]-3- (2-こ氧基卩比卩定-3-基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基]氨基甲酸苯酯(根据实施例1,方法步骤la)-lf)制备)。 [0273] First, dissolved in 8ml of dry tetrahydrofuran (dried over molecular sieve) was IOOmg (0.16mmol) [5- yl atmosphere -l- [(2,4_ Ni-methoxyphenyl) an acid cross-yl] -3- (2-yloxy Jie ko given ratio Jie-3-yl) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] carbamate (according to Example 1, step Example la ) -LF) prepared). 将74.9mg(0.24mmol) 1-こ基-4-哌啶_4_基哌嗪和0.07ml三こ胺一起加入到反应混合物中,然后将其在室温下搅拌过夜。 Added 74.9mg (0.24mmol) 1- ko-yl-4-piperidinyl _4_ piperazine and 0.07ml three ko to the reaction mixture with an amine, which was then stirred at room temperature overnight. 为了加速反应和实现完全的转化,将所述混合物再次加热到50°C。 In order to accelerate the reaction and to achieve complete conversion, the mixture is heated again to 50 ° C. 反应进程通过TLC(硅胶,9: I的ニ氯甲烷/甲醇)和LCMS (RP,こ臆/水作为洗脱液和0.01% TFA)监测。 Reaction progress was monitored by TLC (silica gel, 9: I ni of dichloromethane / methanol) and LCMS (RP, addiction ko / water as eluent and 0.01% TFA) monitoring. 在减压下除去溶剂,将残余物导入到ニ氯甲烷中并用2N氢氧化钠溶液(Ix)萃取。 The solvent was removed under reduced pressure, the residue was introduced into a Ni chloride and extracted with 2N sodium hydroxide solution (Ix). 将合并的有机相用硫酸镁干燥并过滤,并在减压下除去溶剂。 The combined organic phases were dried over magnesium sulfate and filtered, and the solvent removed under reduced pressure. 粗混合物首先用硅胶柱色谱提纯(柱子20X200mm),使用ニ氯甲烷和2%甲醇作为洗脱液。 The crude mixture was first purified by silica gel column chromatography (column 20X200mm), the use of Ni and 2% methanol in methylene chloride as eluent. 将合并的、稍微有点杂质的产物馏分用制备性HPLC在Chromolith柱(正相,来自Merck)上进行再次提纯,使用ニ氯甲烧和甲醇(用15min甲醇的梯度0-10%体积)洗脱。 The combined, a little impurity product fractions by preparative HPLC on a Chromolith column (normal phase, from Merck) was purified on again, the use of Ni for methane and chlorine methanol (15min with a gradient of 0-10% methanol by volume) to afford . 得到20mg(0.03mmol, 17% )所需的N-[5-氰基-l-[ (2,4- ニ甲氧基苯基)横酸基]-3_ (2-こ氧基卩比唳-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4-こ基哌嗪-1-基)哌啶-1-羧酰胺。 To give the desired 20mg (0.03mmol, 17%) N- [5- cyano -l- [(2,4- Ni-methoxyphenyl) an acid cross-yl] -3_ (2-yloxy ko than Jie Li 3-yl) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (4-ko-l-yl) piperidine-1-carboxamide.

[0274] ES1-MS [M+H+] = 718.25 计算值C36H43N7O7S = 717.85 [0274] ES1-MS [M + H +] = 718.25 Calculated for C36H43N7O7S = 717.85

[0275] 1H-NMR ([D6] -DMS0,400ΜΗζ) δ [ppm] = 8.13 (dd, 1H, J = 1.2Hz, J = 4.6Hz),7.88 (d, 1H, J = 8.2Hz),7.87 (d, 1H, J = 8.7Hz),7.81 (dd, 1H, J= 1.4Hz, J = 8.6Hz),7.72 (dd, 1H, J=L 3Hz, J = 7.6Hz),7.68 (d, 1H, J=L 1Hz),7.66 (s, 1H),7.02 (dd, 1H, J =4.9Hz, J = 7.6Hz),6.68 (dd, 1H, J = 2.0Hz, J = 8.8Hz),6.65 (d, 1H, J = 2.2Hz),4.17 (m,2H),3.85 (s,3H) ,3.81 (m, 2H),3.44 (s,3H),2.62 (m, 2H),2.43-2.29 (m,11H),1.61 (m, 2H), [0275] 1H-NMR ([D6] -DMS0,400ΜΗζ) δ [ppm] = 8.13 (dd, 1H, J = 1.2Hz, J = 4.6Hz), 7.88 (d, 1H, J = 8.2Hz), 7.87 (d, 1H, J = 8.7Hz), 7.81 (dd, 1H, J = 1.4Hz, J = 8.6Hz), 7.72 (dd, 1H, J = L 3Hz, J = 7.6Hz), 7.68 (d, 1H , J = L 1Hz), 7.66 (s, 1H), 7.02 (dd, 1H, J = 4.9Hz, J = 7.6Hz), 6.68 (dd, 1H, J = 2.0Hz, J = 8.8Hz), 6.65 ( d, 1H, J = 2.2Hz), 4.17 (m, 2H), 3.85 (s, 3H), 3.81 (m, 2H), 3.44 (s, 3H), 2.62 (m, 2H), 2.43-2.29 (m , 11H), 1.61 (m, 2H),

1.15 (m, 2H),1.09 (t, 3H, J = 7.0Hz),0.97 (t, 3H, J = 7.1Hz).[0276]实施例 38-90: 1.15 (m, 2H), 1.09 (t, 3H, J = 7.0Hz), 0.97 (t, 3H, J = 7.1Hz) [0276] Example 38-90:

[0277] 实施例38-90的化合物能够以与实施例1、5、31、37、55、61和/或67类似的制备方式使用适宜的起始原料进行制备。 The compound of Example 38-90 [0277] In the embodiment can be implemented 1,5,31,37,55,61 and / or a similar manner to Example 67 using appropriate starting materials prepared.

[0278] 实施例40: [0278] Example 40:

[0279] N- [5-氰基-3- (2-こ氧基吡啶_3_基)_2_氧代_1_ (苯磺酰基)_2,3_ ニ氢-1H-吲哚-3-基]-4- (4-こ基哌嗪-1-基)哌啶-1-羧酰胺 [0279] N- [5- cyano-3- (2-pyridinyl group _3_ ko-yl) oxo _1_ _2_ (phenylsulfonyl) -1H- _2,3_ Ni hydrogen-indol-3-yl ] -4- (4-ko-l-yl) piperidine-1-carboxamide

[0280] ES1-MS [`M+H+] = 658.25 计算值C34H39N7O5S = 657.79 [0280] ES1-MS [ `M + H +] = 658.25 Calculated for C34H39N7O5S = 657.79

[0281] 实施例43: [0281] Example 43:

[0282] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4- (4-丙基哌嗪-1-基)哌啶-1-羧酰胺 [0282] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4- (4-propyl-piperazin-1-yl) piperidine-1-carboxamide

[0283] ES1-MS [M+H+] = 732.3 计算值C37H45N7O7S = 731.88 [0283] ES1-MS [M + H +] = 732.3 Calculated for C37H45N7O7S = 731.88

[0284] 实施例55: [0284] Example 55:

[0285] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4-哌嗪-1-基哌啶-1-羧酰胺 [0285] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4-piperazin-1-yl piperidine-1-carboxamide

[0286] 55a)4-[l_({[5-氰基-l-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]氨基}羰基)哌啶-4-基]哌嗪-1-羧酸叔丁酯 [0286] 55a) 4- [l _ ({[5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) - oxo-2,3-Ni hydrogen -1H- indol-3-yl] amino} carbonyl) piperidin-4-yl] piperazine-1-carboxylate

[0287] 首先将100mg(0.16mmol) [5-氰基-l-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基]氨基甲酸苯酯(根据实施例1,方法步骤la)_lf)制备)加入到8ml无水四氢呋喃(分子筛干燥过)中,并加入65.8mg(0.24mmol)4-哌唳~4~基哌嗪-1-羧酸叔丁酷。 [0287] First, 100mg (0.16mmol) [5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2 - oxo-2,3-Ni hydrogen -1H- indol-3-yl] carbamate prepared _lf) (Example 1, la according to the method steps)) was added to 8ml of anhydrous tetrahydrofuran (dried over molecular sieves) in , and was added 65.8mg (0.24mmol) 4- ~ 4 Li ~ piperidin-l-carboxylic acid tert-butyl cool. 然后,混合物在室温下搅拌过夜。 Then, the mixture was stirred at room temperature overnight. 反应进程通过TLC(硅胶,CH2Cl2/MeOH 9: I)和LCMS (RP,移动相こ臆/水和0.01 %TFA)监测。 Reaction progress was monitored by TLC (silica gel, CH2Cl2 / MeOH 9: I) and LCMS (RP, Mobile phase addiction ko / water and 0.01% TFA) monitoring. 在减压下除去溶剂,将残余物导入到ニ氯甲烷中并用2N氢氧化钠溶液(Ix)萃取。 The solvent was removed under reduced pressure, the residue was introduced into a Ni chloride and extracted with 2N sodium hydroxide solution (Ix). 将合并的有机相用硫酸镁干燥并过滤,并在减压下除去溶剤。 The combined organic phases were dried over magnesium sulfate and filtered, and the solvent removed under reduced pressure Ji. 粗混合物用柱色谱提纯(5g NP-SiO2柱,Chromabond)使用98: 2的ニ氯甲烧/甲醇作为流动相。 The crude mixture was purified by column chromatography (5g NP-SiO2 column, Chromabond) using 98: 2 Ni burning chloroformate / methanol as the mobile phase. 得到55.3mg(0.07mmol,43% )所需产物,其直接用于下ー步反应中进行Boc脱保护。 To give 55.3mg (0.07mmol, 43%) of the desired product, which was used directly in the next step ー Boc deprotection reaction.

[0288] ES1-MS [M+H+] = 790.30 计算值C39H47N7O9S = 789.91 [0288] ES1-MS [M + H +] = 790.30 Calculated for C39H47N7O9S = 789.91

[0289] 55b) N-[5-氰基-1_[(2,4_ ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-哌嗪-1-基哌啶-1-羧酰胺 [0289] 55b) N- [5- cyano-1 _ [(2,4_ Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2-oxo-2 3-Ni hydrogen -1H- indol-3-yl] -4-piperazin-1-yl piperidine-1-carboxamide

[0290] 首先,将55.3mg(0.07mmol)4-[ト({[5-氰基-ト[(2,4_ ニ甲氧基苯基)磺酰基]-3- (2-こ氧基卩比卩定-3-基)-2-氧代-2, 3- 二氧-1H- Π引噪-3-基]氛基}擬基)喊啶-4-基]哌嗪-1-羧酸叔丁酯加入到4ml甲醇中,并加入1.0ml5-6M在异丙醇中的盐酸。 [0290] First, 55.3mg (0.07mmol) 4- [Suites ({[5-cyano - Suites [(2,4_ Ni-methoxyphenyl) sulfonyl] -3- (2-yloxy ko Jie Jie than fixed-3-yl) -2-oxo-2,3-dioxo-3-noise primer -1H- Π] yl} atmosphere quasi-yl) call-4- yl] piperazine-1-carboxylic acid tert-butyl ester was added to 4ml of methanol, and added 1.0ml5-6M hydrochloric acid in isopropanol. 将所述混合物在室温下搅拌。 The mixture was stirred at room temperature. 反应进程通过TLC监测(硅胶,CH2Cl2/MeOH 9:1)。 The reaction was monitored by TLC (silica gel, CH2Cl2 / MeOH 9: 1). 完全转化后,除去醇溶剂,接着将残余物导入到ニ氯甲烷中,使用IN氢氧化钠水溶液通过萃取将PH值调节到9。 After complete conversion, removing the alcohol solvent, the residue was then introduced into the Ni chloride, and the PH value is adjusted to 9 by extraction using IN aqueous sodium hydroxide. 有机相与水相分离,水相用ニ氯甲烷再萃取(2x)。 The organic phase and the aqueous phase was separated, the aqueous phase was re-extracted with dichloromethane (2x) Ni. 将合并的有机相用硫酸镁干燥,并在减压下除去溶剤。 The combined organic phases were dried over magnesium sulfate, and the solvent removed under reduced pressure Ji. 将残余物用こ醚結晶。 The residue was crystallized from ether ko. 或者,该残余物还可以通过正相常规柱色谱(NP-SiO2柱,ChiOmabond)使用ニ氯甲烷/甲醇作为移动相进行提纯,或者通过制备性HPLC(RP,移动相こ臆/水,0.01% TFA)进行提纯。 Alternatively, the residue may be used Ni chloride by normal-phase HPLC column chromatography (NP-SiO2 column, ChiOmabond) / methanol as the mobile phase purification, or by preparative HPLC (RP, Mobile phase ko chest / water, 0.01% TFA) purification. 结晶后,分离得到15.9mg(0.023mmol,33 % ) N- [5-氛基_1- [ (2,4- _■甲氧基苯基)横酸基]-3- (2-こ氧基卩比淀_3~基)~2~氧代-2,3- ニ氢-1H-吲哚-3-基]-4-哌嗪-1-基哌啶-1-羧酰胺。 After crystallization, separation to give 15.9mg (0.023mmol, 33%) N- [5- yl atmosphere _1- [(2,4- _ ■ methoxyphenyl) an acid cross-yl] -3- (2-oxo ko Jie-yl ~ _3 than starch yl) ~ 2 ~ oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4-piperazin-1-yl piperidine-1-carboxamide.

[0291] ES1-MS [M+H+] = 690.45 计算值C34H39N7O7S = 689.80 [0291] ES1-MS [M + H +] = 690.45 Calculated for C34H39N7O7S = 689.80

[0292]实施例 25-30 和56-60 和85-90: [0292] Example 25-30 and 56-60 and 85-90:

[0293] 实施例25-30和56-60和85-90的化合物还能够以与实施例1、5、31、37和/或55制备方法类似的方式使用适宜的起始原料进行制备。 The compounds of Examples 25-30 and 56-60 and 85-90 of the [0293] embodiment is also possible in a similar manner and / or 1,5,31,37 method of Example 55 was prepared using the appropriate starting materials prepared.

`[0294] 实施例25: `[0294] Example 25:

[0295] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4-哌啶-4-基哌嗪-1-羧酰胺ニ(三氟こ酸盐) [0295] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4-piperazin-1-yl-4-carboxamide ni (ko trifluoroacetic acid salt)

[0296] ES1-MS [M+H+] = 690.15 计算值C34H39N7O7S = 689.80 [0296] ES1-MS [M + H +] = 690.15 Calculated for C34H39N7O7S = 689.80

[0297] 实施例85: [0297] Example 85:

[0298] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4,4' -联哌啶-1-羧酰胺ニ(三氟こ酸盐) [0298] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4,4 '- piperidine-1-carboxamide with Ni (ko trifluoroacetic acid salt)

[0299] ES1-MS [M+H+] = 689.25 计算值C35H4tlN6O7S = 688.81 [0299] ES1-MS [M + H +] = 689.25 Calculated for C35H4tlN6O7S = 688.81

[0300] 在本发明的化合物⑴中,还可以根据合成方案I或2,随后通过还原性胺化反应引入取代基R7,其以举例的方式使用实施例61和67进行举例说明: [0300] In the compounds of the present invention ⑴ may also be I or 2, followed by reductive amination synthesis scheme is introduced according to the substituents R7, which is cited by way of example described in Examples 61 and 67:

[0301] 实施例61: [0301] Example 61:

[0302] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3-ニ氢-1H-吲哚-3-基]-1' -甲基-4,4' -联哌啶-1-羧酰胺 [0302] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -1 '--4,4' - bipiperidine-carboxamide

[0303]首先将 IOOmg (0.138mmol) 4_[1_ ({[5_ 氰基_1_[ (2,4_ ニ甲氧基苯基)磺酰基]-3- (2-こ氧基卩比卩定-3-基)-2-氧代-2, 3- 二氧-1H- Π引噪-3-基]氛基}擬基)喊啶-4-基]氯化哌啶(相当于实施例85的氯化物盐)(根据实施例1,方法步骤la)-1f)和实施例55,方法步骤55a)-55b)制备)加入到IOml ニ氯甲烷中。 [0303] First IOOmg (0.138mmol) 4_ [1_ ({[5_ cyano _1_ [(2,4_ Ni-methoxyphenyl) sulfonyl] -3- (2-yloxy ko Jie Jie predetermined ratio - 3- yl) -2-oxo-2,3-dioxo-3-noise primer -1H- Π] yl} atmosphere quasi-yl) call-4-yl] piperidinium chloride (corresponding to Example 85 chloride salt) (according to Example 1, step la) -1f) and Example 55, step 55a) -55b) prepared) was added to a Ni IOml chloromethane. 加入20 μ I (0.207mmol)甲醛水溶液(37%浓度),并将反应混合物搅拌5分钟。 Add 20 μ I (0.207mmol) aqueous formaldehyde solution (37% strength) was added and the reaction mixture was stirred for 5 minutes. 该溶液变得稍微混浊。 The solution became slightly cloudy. 加入98mg(0.69mmol)硫酸钠和20 μ I (0.279mmol)冰こ酸,并将该混合物搅拌1.5h。 Was added 98mg (0.69mmol) of sodium sulfate and 20 μ I (0.279mmol) ice ko acid, and the mixture was stirred for 1.5h. 每次少量加入48.7mg(0.207mmol)氢化试剂こ酰氧基硼氢化钠,15分钟后,该反应混合物变得澄清,然后不久反应混合物再次变得混浊。 Little by little added 48.7mg (0.207mmol) hydrogenating agent ko acyloxy sodium borohydride after 15 minutes, the reaction mixture became clear, and soon the reaction mixture became turbid again. 将混合物在室温下搅拌过夜并温热至40°C又I小吋。 The mixture was stirred at room temperature overnight and allowed to warm to 40 ° C and less I inch. 反应混合物首先用30ml ニ氯甲烷稀释,然后用饱和碳酸氢钠溶液(3x)萃取。 The reaction mixture was first diluted with 30ml Ni chloride, and then extracted with saturated sodium bicarbonate solution (3x). 将合并的有机相用硫酸镁干燥并过滤,并在减压下蒸发溶剤。 The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure Ji. 分离得到75mg粗产物,该粗产物用制备性HPLC在Chromolith柱(RP_18e,来自Merck,移动相こ腈/水,0.01%こ酸)上提纯。 The crude product was isolated to give 75mg of the crude product was purified by preparative HPLC on a Chromolith column (RP_18e, from Merck, mobile phase ko acetonitrile / water, 0.01% acid ko) was purified on. 分离得到5mg(0.007mmol, 5% )所需的N-[5-氛基-1-[ (2,4-_■甲氧基苯基)横酸基]-3-(2-こ氧基吡啶-3-基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基]-1'-甲基-4,4'-联哌啶-1-羧酰胺(相应地以こ酸盐的形式存在)。 Isolated 5mg (0.007mmol, 5%) of the desired N- [5- yl atmosphere -1- [(2,4-_ ■ methoxyphenyl) an acid cross-yl] -3- (2-yloxy ko pyridin-3-yl) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4,4'-1'-methyl-piperidine-l-carboxamide (corresponding ko be in the form of salt).

[0304] ES1-MS [M+H+] = 703.2 计算值C36H42N6O7S = 702.83 [0304] ES1-MS [M + H +] = 703.2 Calculated for C36H42N6O7S = 702.83

[0305] 实施例67: [0305] Example 67:

[0306] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3-ニ氢-1H-吲哚-3-基]-1' -こ基-4,4' -联哌啶-1-羧酰胺三氟こ酸盐 [0306] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -1 '- ko-4,4' - bipiperidine ko-carboxamide trifluoroacetic acid salt

[0307] ES1-MS [M+H+] = 717.30 计算值C37H44N6O7S = 716.86 [0307] ES1-MS [M + H +] = 717.30 Calculated for C37H44N6O7S = 716.86

[0308] 实施例1-90的外消旋化合物的外消旋体拆分: Racemate racemate [0308] Example 1-90 Split:

[0309] 在一种示范性方式中,使用实施例1,通过在制备性手性柱上分离,所述外消旋体如下述被分离成它的对映异构体(实施例1A和1B): [0309] In an exemplary embodiment, in Example 1, was prepared by chiral separation column, as described below the racemate was separated into its enantiomers (Examples 1A and 1B ):

[0310] A.)实施例1的外消旋化合物的外消旋体拆分: Racemate racemate [0310] A.) split Example 1:

[0311] IOOmg (0.14mmol)外消旋的N-[5-氰基-1-[(2,4_ ニ甲氧基苯基)磺酰基]-3- (2-こ氧基吡啶`-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4- (1-甲基哌啶-4-基)哌嗪-1-羧酰胺(实施例1)在手性制备柱上(Chiralcell 0D,流速55ml/min)使用正庚烷/こ醇(700: 300)作为洗脱液进行分离。 [0311] IOOmg (0.14mmol) of racemic N- [5- cyano-1 - [(2,4_ Ni-methoxyphenyl) sulfonyl] -3- (pyridin-2- yloxy ko `-3 - yl) -2-oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide (Example separator 300 as eluent): 1) using n-heptane / ko-ol (700 chiral preparative column (Chiralcell 0D, flow rate 55ml / min). 能够分离得到19mg(0.03mmol, 19%)首先洗脱出的对映异构体,具有正旋光度(实施例1A),和随后的8mg(0.0lmmol, 8% )具有负旋光度的对映异构体(实施例1B)。 Can be separated to give 19mg (0.03mmol, 19%) is first eluted enantiomer, it has a positive optical rotation (Example. 1A), and subsequent 8mg (0.0lmmol, 8%) having a negative optical rotation of the enantiomer isomer (Example 1B).

[0312] 实施例1A: [0312] Example 1A:

[0313] (+)-N-[5-氰基-l-[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶_4_基)哌嗪-1-羧酰胺 [0313] (+) - N- [5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2- oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin _4_ yl) piperazine-1-carboxamide

[0314] ES1-MS [M+H+] = 704.25 计算值C35H41N7O7S = 703.82 [0314] ES1-MS [M + H +] = 704.25 Calculated for C35H41N7O7S = 703.82

[0315] HPLC(Chiralcel OD 0.46cmX 25cm ;正庚烧/ こ醇7: 3) Rf = 9.04min [0315] HPLC (Chiralcel OD 0.46cmX 25cm; n-heptyl burning / ko alcohol 7: 3) Rf = 9.04min

[0316]旋光度 a (22°C,589nm, CHCl3, lmg/ml)=右旋 [0316] Optical rotation a (22 ° C, 589nm, CHCl3, lmg / ml) = dextrorotatory

[0317] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.13 (dd, 1Η, J = 1.6Hz, J = 4.9Hz),7.89 (d, 1Η, J = 8.9Ηζ),7.88 (d, 1Η, J = 8.6Ηζ),7.82 (dd, 1Η, J= 1.7Hz, J = 8.6Ηζ),7.72 (dd, 1Η, J= 1.5Hz, J = 7.7Ηζ),7.68 (d, 1Η, J=L 6Ηζ),7.65 (s,1Η),7.02 (dd, 1Η,J = 4.9Hz, J = 7.6Ηζ),6.69 (dd, 1Η, J = 2.2Hz, J = 8.9Ηζ),6.66 (d, 1Η, J = 2.1Hz),4.17(m,2H),3.86(s,3H),3.45 (s,3Η),3.21 (m,4Η),2.77 (m, 2Η, J = 11.0Hz), 2.34(m,4H), [0317] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.13 (dd, 1Η, J = 1.6Hz, J = 4.9Hz), 7.89 (d, 1Η, J = 8.9Ηζ), 7.88 (d, 1Η, J = 8.6Ηζ), 7.82 (dd, 1Η, J = 1.7Hz, J = 8.6Ηζ), 7.72 (dd, 1Η, J = 1.5Hz, J = 7.7Ηζ), 7.68 (d, 1Η , J = L 6Ηζ), 7.65 (s, 1Η), 7.02 (dd, 1Η, J = 4.9Hz, J = 7.6Ηζ), 6.69 (dd, 1Η, J = 2.2Hz, J = 8.9Ηζ), 6.66 ( d, 1Η, J = 2.1Hz), 4.17 (m, 2H), 3.86 (s, 3H), 3.45 (s, 3Η), 3.21 (m, 4Η), 2.77 (m, 2Η, J = 11.0Hz), 2.34 (m, 4H),

2.12 (m, 4Η),1.82 (m, 2Η, J = 10.9Ηζ),1.64 (m, 2Η, J = 10.8Ηζ),1.37 (m, 2Η),1.08 (t, 3Η, J=7.0Hz).[0318] 实施例1B: 2.12 (m, 4Η), 1.82 (m, 2Η, J = 10.9Ηζ), 1.64 (m, 2Η, J = 10.8Ηζ), 1.37 (m, 2Η), 1.08 (t, 3Η, J = 7.0Hz). [0318] Example 1B:

[0319] (-) -N-[5-氰基-1_[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(1-甲基哌啶_4_基)哌嗪-1-羧酰胺 [0319] (-) -N- [5- cyano-1 _ [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2 2,3 ni hydrogen -1H- indol-3-yl] -4- (1-methyl-piperidin _4_ yl) piperazine-1-carboxamide

[0320] ES1-MS [M+H+] = 704.25 计算值C35H41N7O7S = 703.82 [0320] ES1-MS [M + H +] = 704.25 Calculated for C35H41N7O7S = 703.82

[0321] HPLC(Chiralcel OD 0.46cmX 25cm ;正庚烷/ こ醇7: 3) Rf = 25.73min [0321] HPLC (Chiralcel OD 0.46cmX 25cm; n-heptane / ko alcohol 7: 3) Rf = 25.73min

[0322]旋光度 a (22°C,589nm, CHCl3, lmg/ml)=左旋 [0322] Optical rotation a (22 ° C, 589nm, CHCl3, lmg / ml) = L

[0323] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.13 (dd, 1Η, J = 1.2Hz, J = 4.7Hz),7.88 (d, 1Η, J = 8.9Ηζ),7.87 (d, 1Η, J = 8.5Ηζ),7.81 (dd, 1Η, J= 1.5Hz, J = 8.5Ηζ),7.72 (dd, 1Η, J=L IHzjJ = 7.6Ηζ),7.68 (s,1Η),7.64 (s,1Η) ,7.01 (dd, 1Η, J = 4.9Hz,J =7.6Ηζ),6.69 (dd, 1Η, J=L 9Hz, J = 9.0Hz),6.66 (d, 1Η, J=L 9Ηζ),4.16 (m, 2Η),3.85 (S,3Η),3.45(s,3H),3.20(m,4H),2.77 (m, 2Η, J=Il.5Ηζ),2.34(m,4H),2.12(m,4H),1.82 (m,2Η, J=Il.3Ηζ),1.64(m,2H,J=Il.5Ηζ),1.37 (m, 2Η),1.07(t,3H,J = 7.0Hz)。 [0323] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.13 (dd, 1Η, J = 1.2Hz, J = 4.7Hz), 7.88 (d, 1Η, J = 8.9Ηζ), 7.87 (d, 1Η, J = 8.5Ηζ), 7.81 (dd, 1Η, J = 1.5Hz, J = 8.5Ηζ), 7.72 (dd, 1Η, J = L IHzjJ = 7.6Ηζ), 7.68 (s, 1Η), 7.64 (s, 1Η), 7.01 (dd, 1Η, J = 4.9Hz, J = 7.6Ηζ), 6.69 (dd, 1Η, J = L 9Hz, J = 9.0Hz), 6.66 (d, 1Η, J = L 9Ηζ), 4.16 (m, 2Η), 3.85 (S, 3Η), 3.45 (s, 3H), 3.20 (m, 4H), 2.77 (m, 2Η, J = Il.5Ηζ), 2.34 (m, 4H) , 2.12 (m, 4H), 1.82 (m, 2Η, J = Il.3Ηζ), 1.64 (m, 2H, J = Il.5Ηζ), 1.37 (m, 2Η), 1.07 (t, 3H, J = 7.0 Hz).

[0324] B.)实施例31的外消旋化合物的外消旋体拆分: Racemate racemate [0324] B.) Example 31 Split:

[0325] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺 [0325] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide

[0326](实施例31)在手性制备柱上(Chiralcell 0D,流速55ml/min)使用正庚烷/乙醇(700: 300)作为洗脱液进行分离。 [0326] (Example 31) was prepared in a chiral column (Chiralcell 0D, flow rate 55ml / min) using n-heptane / ethanol (700: 300) as an eluent for separation. 首先洗脱出的对映异构体具有正旋光度(实施例31A),以及随后洗脱出的对映异构体具有负旋光度(实施例31B)。 Eluted first has a positive optical rotation of the enantiomer (Example 31A), and subsequently eluted with negative optical rotation (Example 31B) enantiomer.

[0327]实施例 `3IA: [0327] Example `3IA:

[0328] (+)-N-[5-氰基-l-[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4-甲基哌嗪_1_基)哌啶-1-羧酰胺 [0328] (+) - N- [5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2- oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (4-methylpiperazin-_1_ yl) piperidine-1-carboxamide

[0329] ES1-MS [M+H+] = 704.80 计算值C35H41N7O7S = 703.82 [0329] ES1-MS [M + H +] = 704.80 Calculated for C35H41N7O7S = 703.82

[0330] HPLC(Chiralcel OD 0.46cmX 25cm ;正庚烷/ こ醇7: 3) Rf = 9.60min [0330] HPLC (Chiralcel OD 0.46cmX 25cm; n-heptane / ko alcohol 7: 3) Rf = 9.60min

[0331]旋光度 a (22°C,589nm, CHCl3, lmg/ml)=右旋 [0331] Optical rotation a (22 ° C, 589nm, CHCl3, lmg / ml) = dextrorotatory

[0332] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ.[ppm] = 8.12 (dd, 1Η, J = 1.6Hz, J = 4.8Hz),7.87 (d, 1Η, J = 8.5Ηζ),7.86 (d, 1Η, J = 8.8Ηζ),7.81 (dd, 1Η, J= 1.7Hz, J = 8.6Ηζ),7.73 (dd, 1Η, J=L 5Hz, J = 7.7Ηζ),7.69 (s,1Η),7.67 (d, 1Η, J=L 5Ηζ),7.02 (dd, 1Η, J =4.9Hz, J = 7.6Ηζ),6.67 (dd, 1Η, J = 2.2Hz, J = 8.9Ηζ),6.65 (d, 1Η, J = 2.1Hz),4.14 (m,2Η),3.83 (s,3Η),3.80 (m, 2Η),3.42 (s,3H),2.60 (m, 2Η),2.39-2.10 (m, 9Η),2.10 (s,3H),1.60 (m, 2Η),1.12 (m, 2Η),1.06 (t, 3Η, J = 7.0Hz).[0333]实施例 3IB: [0332] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ. [Ppm] = 8.12 (dd, 1Η, J = 1.6Hz, J = 4.8Hz), 7.87 (d, 1Η, J = 8.5Ηζ), 7.86 (d, 1Η, J = 8.8Ηζ), 7.81 (dd, 1Η, J = 1.7Hz, J = 8.6Ηζ), 7.73 (dd, 1Η, J = L 5Hz, J = 7.7Ηζ), 7.69 (s, 1Η), 7.67 (d, 1Η, J = L 5Ηζ), 7.02 (dd, 1Η, J = 4.9Hz, J = 7.6Ηζ), 6.67 (dd, 1Η, J = 2.2Hz, J = 8.9Ηζ), 6.65 (d, 1Η, J = 2.1Hz), 4.14 (m, 2Η), 3.83 (s, 3Η), 3.80 (m, 2Η), 3.42 (s, 3H), 2.60 (m, 2Η), 2.39-2.10 ( m, 9Η), 2.10 (s, 3H), 1.60 (m, 2Η), 1.12 (m, 2Η), 1.06 (t, 3Η, J = 7.0Hz) [0333] Example 3IB.:

[0334] (-)-Ν-[5-氰基-1_[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4-甲基哌嗪_1_基)哌啶-1-羧酰胺 [0334] (-) - Ν- [5- cyano-1 _ [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2 2,3 ni hydrogen -1H- indol-3-yl] -4- (4-methylpiperazin-_1_ yl) piperidine-1-carboxamide

[0335] ES1-MS [Μ+Η+] = 704.80 计算值C35H41N7O7S = 703.82 [0335] ES1-MS [Μ + Η +] = 704.80 Calculated for C35H41N7O7S = 703.82

[0336] HPLC(Chiralcel OD 0.46cmX 25cm ;正庚烷/ こ醇7: 3) Rf = 34.31min [0336] HPLC (Chiralcel OD 0.46cmX 25cm; n-heptane / ko alcohol 7: 3) Rf = 34.31min

[0337]旋光度 a (22°C,589nm, CHCl3, lmg/ml)=左旋[0338] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.12 (dd, 1H, J = 1.6Hz, J = 4.9Hz),7.86 (d, 1H, J = 8.7Hz),7.85 (d, 1H, J = 8.8Hz),7.81 (dd, 1H, J= 1.6Hz, J = 8.6Hz),7.72 (dd, 1H, J=L 4Hz, J = 7.6Hz),7.69 (s, 1H),7.67 (d, 1H, J=L 6Hz),7.02 (dd, 1H, J =4.9Hz, J = 7.6Hz),6.67 (dd, 1H, J = 2.2Hz, J = 8.9Hz),6.64 (d, 1H, J = 2.0Hz),4.13 (m,2H),3.83 (s,3H),3.80 (m, 2H),3.42 (s,3H),2.60 (m, 2H),2.42-2.10 (m, 9H),2.10 (s,3H),1.60 (m, 2H),1.12 (m, 2H),1.06 (t, 3H, J = 7.0Hz).[0339] C.)实施例37的外消旋化合物的外消旋体拆分: [0337] Optical rotation a (22 ° C, 589nm, CHCl3, lmg / ml) = L [0338] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.12 (dd, 1H, J = 1.6 hz, J = 4.9Hz), 7.86 (d, 1H, J = 8.7Hz), 7.85 (d, 1H, J = 8.8Hz), 7.81 (dd, 1H, J = 1.6Hz, J = 8.6Hz), 7.72 (dd, 1H, J = L 4Hz, J = 7.6Hz), 7.69 (s, 1H), 7.67 (d, 1H, J = L 6Hz), 7.02 (dd, 1H, J = 4.9Hz, J = 7.6Hz ), 6.67 (dd, 1H, J = 2.2Hz, J = 8.9Hz), 6.64 (d, 1H, J = 2.0Hz), 4.13 (m, 2H), 3.83 (s, 3H), 3.80 (m, 2H ), 3.42 (s, 3H), 2.60 (m, 2H), 2.42-2.10 (m, 9H), 2.10 (s, 3H), 1.60 (m, 2H), 1.12 (m, 2H), 1.06 (t, 3H, J = 7.0Hz) [0339] C.) racemate resolution of racemic compounds according to Example 37:

[0340] N-[5-氰基-1-[(2,4-ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶_3_基)-2_氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(4-こ基哌嗪-1-基)哌啶-ト羧酰胺(实施例37)在手性制备柱上(Chiralcell 0D,流速55ml/min)使用正庚烷/こ醇(700: 300)作为洗脱液进行分离。 [0340] N- [5- cyano-1 - [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ _3_ ko oxypyridin-yl) -2-oxo--2_ 3-Ni hydrogen -1H- indol-3-yl] -4- (4-ko-l-yl) piperidine - Suites carboxamide (Example 37) was prepared in a chiral column (Chiralcell 0D , flow rate 55ml / min) using n-heptane / ko-ol (700: 300) as an eluent for separation. 首先洗脱出的对映异构体具有正旋光度(实施例37A),以及随后洗脱出的对映异构体具有负旋光度(实施例37B)。 Eluted first has a positive optical rotation of the enantiomer (Example 37A), and subsequently eluted with negative optical rotation (Example 37B) enantiomer.

[0341]实施例 37A: [0341] Example 37A:

[0342] (+)-N-[5-氰基-l-[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4- (4-こ基哌嗪_1_基)哌啶-1-羧酰胺 [0342] (+) - N- [5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2- oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (4-piperazin-ko _1_ yl) piperidine-1-carboxamide

[0343] ES1-MS [M+H+] = 718.30 计算值C36H43F3N7O7S = 717.85 [0343] ES1-MS [M + H +] = 718.30 Calculated for C36H43F3N7O7S = 717.85

[0344] HPLC(Chiralcel OD 0.46cmX 25cm ;正庚烷/ こ醇7: 3) Rf = 7.29min [0344] HPLC (Chiralcel OD 0.46cmX 25cm; n-heptane / ko alcohol 7: 3) Rf = 7.29min

[0345]旋光度 a (22°C,589nm, CHCl3, lmg/ml)=右旋 [0345] Optical rotation a (22 ° C, 589nm, CHCl3, lmg / ml) = dextrorotatory

[0346] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.13 (dd, 1Η, J = 1.7Hz, J = 4.9Hz),7.89 (d, 1Η, J = 8.6Ηζ),7.88 (d, 1Η, J = 8.8Ηζ),7.82 (dd, 1Η, J= 1.8Hz, J = 8.6Ηζ),7.72 (dd, 1Η, J=L 7Hz, J = 7.7Ηζ),7.69 (d, 1Η, J=L 7Ηζ),7.67 (s,1Η),7.02 (dd, 1Η, J =4.9Hz, J = 7.7Ηζ)`,6.69 (dd, 1Η, J = 2.2Hz, J = 8.9Ηζ),6.66 (d, 1Η, J = 2.2Ηζ),4.18 (m,2Η),3.85 (s,3Η) ,3.81 (m, 2Η),3.44 (s,3H),2.62 (m, 2Η),2.42-2.24 (m, 11Η),1.62 (m, 2Η),1.15 (m, 2Η),1.09 (t, 3Η, J = 7.1Hz),0.96 (t, 3Η, J = 7.2Ηζ).[0347]实施例 37Β: [0346] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.13 (dd, 1Η, J = 1.7Hz, J = 4.9Hz), 7.89 (d, 1Η, J = 8.6Ηζ), 7.88 (d, 1Η, J = 8.8Ηζ), 7.82 (dd, 1Η, J = 1.8Hz, J = 8.6Ηζ), 7.72 (dd, 1Η, J = L 7Hz, J = 7.7Ηζ), 7.69 (d, 1Η , J = L 7Ηζ), 7.67 (s, 1Η), 7.02 (dd, 1Η, J = 4.9Hz, J = 7.7Ηζ) `, 6.69 (dd, 1Η, J = 2.2Hz, J = 8.9Ηζ), 6.66 (d, 1Η, J = 2.2Ηζ), 4.18 (m, 2Η), 3.85 (s, 3Η), 3.81 (m, 2Η), 3.44 (s, 3H), 2.62 (m, 2Η), 2.42-2.24 ( m, 11Η), 1.62 (m, 2Η), 1.15 (m, 2Η), 1.09 (t, 3Η, J = 7.1Hz), 0.96 (t, 3Η, J = 7.2Ηζ) [0347] Example 37Β.:

[0348] (-)-Ν-[5-氰基-1_[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4- (4-こ基哌嗪_1_基)哌啶-1-羧酰胺 [0348] (-) - Ν- [5- cyano-1 _ [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2 2,3 ni hydrogen -1H- indol-3-yl] -4- (4-piperazin-ko _1_ yl) piperidine-1-carboxamide

[0349] ES1-MS [Μ+Η+] = 718.25 计算值C36H43F3N7O7S = 717.85 [0349] ES1-MS [Μ + Η +] = 718.25 Calculated for C36H43F3N7O7S = 717.85

[0350] HPLC(Chiralcel OD 0.46cmX 25cm ;正庚烷/ こ醇7: 3) Rf = 12.41min [0350] HPLC (Chiralcel OD 0.46cmX 25cm; n-heptane / ko alcohol 7: 3) Rf = 12.41min

[0351]旋光度 a (22°C,589nm, CHCl3, lmg/ml)=左旋 [0351] Optical rotation a (22 ° C, 589nm, CHCl3, lmg / ml) = L

[0352] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.12 (dd, 1Η, J = 1.6Hz, J = 4.9Hz),7.88 (d, 1Η, J = 8.5Ηζ),7.87 (d, 1Η, J = 8.8Ηζ),7.80 (dd, 1Η, J= 1.7Hz, J = 8.6Ηζ),7.71 (dd, 1Η, J=L 5Hz, J = 7.7Ηζ),7.68 (d, 1Η, J=L 5Ηζ),7.66 (s,1Η),7.00 (dd, 1Η, J =4.9Hz, J = 7.6Ηζ),6.67 (dd, 1Η, J = 2.2Hz, J = 8.9Ηζ),6.65 (d, 1Η, J = 2.1Hz),4.16 (m,2Η),3.84(s,3H),3.80 (m,2Η),3.44(s,3H),2.61 (m,2H),2.41-2.23(m,11Η),1.60 (m,2H),1.14 (m, 2Η),1.08 (t, 3Η, J = 7.1Hz),0.95 (t, 3Η, J = 7.2Hz).[0353] D.)外消旋化合物2-30、21-36和38_90的外消旋体拆分:[0354] 以与外消旋化合物1、31和37的外消旋体拆分类似的方式,可以进行外消旋体2-30、32-36 和38-90 的分离,得到相应的(+)_ 对映异构体2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A,10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A,29A,30A 和32A,33A,34A,35A 和38A,39A,40A,41A,42A,43A,44A,45A,46 [0352] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 8.12 (dd, 1Η, J = 1.6Hz, J = 4.9Hz), 7.88 (d, 1Η, J = 8.5Ηζ), 7.87 (d, 1Η, J = 8.8Ηζ), 7.80 (dd, 1Η, J = 1.7Hz, J = 8.6Ηζ), 7.71 (dd, 1Η, J = L 5Hz, J = 7.7Ηζ), 7.68 (d, 1Η , J = L 5Ηζ), 7.66 (s, 1Η), 7.00 (dd, 1Η, J = 4.9Hz, J = 7.6Ηζ), 6.67 (dd, 1Η, J = 2.2Hz, J = 8.9Ηζ), 6.65 ( d, 1Η, J = 2.1Hz), 4.16 (m, 2Η), 3.84 (s, 3H), 3.80 (m, 2Η), 3.44 (s, 3H), 2.61 (m, 2H), 2.41-2.23 (m , 11Η), 1.60 (m, 2H), 1.14 (m, 2Η), 1.08 (t, 3Η, J = 7.1Hz), 0.95 (t, 3Η, J = 7.2Hz). [0353] D.) racemic rotary compound racemate resolution of 2-30,21-36 and 38_90: [0354] compound 1, 31 and similar to racemate resolution with racemic way 37 may be made racemate 2-30,32-36 and 38-90 separated to give the corresponding (+) enantiomer _ 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A and 32A, 33A, 34A, 35A and 38A, 39A, 40A, 41A, 42A, 43A, 44A, 45A, 46 A,47A,48A,49A,50A,51A,52A,53A,54A,55A,56A,57A,58A,59A,60A,61A,62A,63A,64A,65A,66A,67A,68A,69A,70A,71A,72A,73A,74A,75A,76A,77A,78A,79A,80A,81A,82A,83A,84A,85A,86A,87A,88A,89A 和90A A, 47A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, 73A, 74A, 75A, 76A, 77A, 78A, 79A, 80A, 81A, 82A, 83A, 84A, 85A, 86A, 87A, 88A, 89A and 90A

[0355] 以及相应的(-)-对映异构体2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, I IB, 12B, 13B, 14B,15B, 16B,17B,18B,19B,20B,21B,22B,23B,24B,25B,26B,27B,28B,29B,30B 和32B,33B,34B,35B 和38B,39B,40B,41B,42B,43B,44B,45B,46B,47B,48B,49B,50B,51B,52B,53B,54B, 55B, 56B, 57B,58B,59B,60B,61B,62B,63B,64B,65B,66B,67B,68B,69B,70B,71B,72B,73B,74B,75B,76B,77B,78B,79B,80B,81B,82B,83B,84B,85B,86B,87B,88B,89B 和90B。 [0355] and the corresponding (-) - enantiomer 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, I IB, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B and 32B, 33B, 34B, 35B and 38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, 77B, 78B, 79B, 80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B.

[0356] 对映异构体A和B也能够使用对映异构体纯的前体和中间体进行制备,例如类似于合成方案I或2,优选通过合成方案I。 [0356] Enantiomer A and B can be used enantiomerically pure precursors and intermediates prepared, for example, analogous to the synthesis scheme I or 2, preferably by a synthetic scheme I. 外消旋混合物分离成(+)_对映异构体和(-)_对映异构体可以通过手性制备色谱进行,优选通过相应的胺结构単元VI。 Racemic mixture was separated into (+) enantiomer and _ (-) _ enantiomer may be prepared by chiral chromatography, preferably by radiolabeling Element structures corresponding amine VI.

[0357] 实施例7B: [0357] Example 7B:

[0358] (-)-N-[5-氰基-l-[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-4-(1-こ基哌啶_4_基)哌嗪-1-羧酰 [0358] (-) - N- [5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2- oxo-2,3-Ni hydrogen -1H- indol-3-yl] -4- (1-piperidinyl group _4_ ko-yl) piperazine-1-carboxylic acid

胺三氟こ酸盐 Ko amine trifluoroacetic acid salt

[0359] ES1-MS [M+H+] = 718.25 计算值C36H43N7O7S = 717.85 [0359] ES1-MS [M + H +] = 718.25 Calculated for C36H43N7O7S = 717.85

[0360]实施例 40B: [0360] Example 40B:

[0361] (-) -N-[5-氰基-3-(2-こ氧基吡啶_3_基)-2_氧代-1-(苯磺酰基)-2,3_ ニ氢-1H-吲哚-3-基]-4- (4`-こ基哌嗪-1-基)哌啶-1-羧酰胺 [0361] (-) -N- [5- cyano-3- (2-pyridyl _3_ ko-yl oxy) -2_ oxo-1- (phenylsulfonyl) -1H hydrogen -2,3_ ni - indol-3-yl] -4- (4`- ko-l-yl) piperidine-1-carboxamide

[0362] ES1-MS [M+H+] = 658.25 计算值C34H39N7O5S = 657.79 [0362] ES1-MS [M + H +] = 658.25 Calculated for C34H39N7O5S = 657.79

[0363]实施例 6IB: [0363] Example 6IB:

[0364] (-)-N-[5-氰基-l-[(2,4- ニ甲氧基苯基)磺酰基)-3-(2-こ氧基吡啶-3-基)-2-氧代-2,3- ニ氢-1H-吲哚-3-基]-1' -甲基-4,4' -联哌啶-1-羧酰胺三氟こ酸盐 [0364] (-) - N- [5- cyano -l - [(2,4- Ni-methoxyphenyl) sulfonyl) -3- (2-ko-3-yl) -2 - oxo-2,3-Ni hydrogen -1H- indol-3-yl] -1 '--4,4' - bipiperidine ko-carboxamide trifluoroacetic acid salt

[0365] ES1-MS [M+H+] = 703.30 计算值C36H42N6O7S = 702.83 [0365] ES1-MS [M + H +] = 703.30 Calculated for C36H42N6O7S = 702.83

[0366] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 9.26 (1H, TFA 的质子化,8.12 (dd, 1H, J=1.7Hz, J = 4.9Hz),7.87 (dd, 2H, J= 1.3Hz, J = 8.7Hz),7.80 (dd, 1H, J= 1.8Hz, J=8.5Hz), 7.80 (m, 2H), 7.66 (s, 1H), 7.00 (dd, 1H, J = 4.9Hz, J = 7.6Hz) ,6.68 (dd, 1H,J = 2.2Hz, J = 8.9Hz),6.65 (d, 1H, J = 2.1Hz),4.16 (m, 2H),3.85 (s,6H),3.44-3.41 (m,5H),2.85 (m, 2H),2.73 (m, 2H),2.57 (m, 2H) ,1.81 (m, 2H),1.55 (m, 2H),1.34-1.22 (m, 4H), [0366] 1H-NMR ([D6] -DMS0, 500ΜΗζ) δ [ppm] = 9.26 (1H, protonation of TFA, 8.12 (dd, 1H, J = 1.7Hz, J = 4.9Hz), 7.87 (dd, 2H, J = 1.3Hz, J = 8.7Hz), 7.80 (dd, 1H, J = 1.8Hz, J = 8.5Hz), 7.80 (m, 2H), 7.66 (s, 1H), 7.00 (dd, 1H, J = 4.9Hz, J = 7.6Hz), 6.68 (dd, 1H, J = 2.2Hz, J = 8.9Hz), 6.65 (d, 1H, J = 2.1Hz), 4.16 (m, 2H), 3.85 (s , 6H), 3.44-3.41 (m, 5H), 2.85 (m, 2H), 2.73 (m, 2H), 2.57 (m, 2H), 1.81 (m, 2H), 1.55 (m, 2H), 1.34- 1.22 (m, 4H),

1.08 (t, 3H, J = 7.0Hz),0.92 (m, 2H).[0367]实施例 67B: . 1.08 (t, 3H, J = 7.0Hz), 0.92 (m, 2H) [0367] Example 67B:

[0368] (-)-N-[5-氰基-1_[(2,4- ニ甲氧基苯基)磺酰基]-3_(2_こ氧基吡啶-3-基)-2-氧代-2,3-ニ氢-1H-吲哚-3-基]-1'-こ基-4,4'-联哌啶-1-羧酰胺 [0368] (-) - N- [5- cyano-1 _ [(2,4-Ni-methoxyphenyl) sulfonyl] -3_ (2_ ko-3-yl) -2 2,3 ni hydrogen -1H- indol-3-yl] -1'-yl ko -4,4'-piperidine-1-carboxamide

三氟こ酸盐[0369] ES1-MS [M+H+] = 717.35 计算值C37H44N6O7S = 716.86 Ko trifluoroacetic acid salt [0369] ES1-MS [M + H +] = 717.35 Calculated for C37H44N6O7S = 716.86

[0370] 通式X的胺能够根据合成方案I或2通过还原性胺化反应进行制备。 [0370] The amine of general formula X can be synthesized Scheme I or 2 are prepared by reductive amination according to. 在下文中,使用胺化合物1-こ基-4-哌啶-4-基哌嗪的制备作为例子进行说明: Hereinafter, the use of amine compound 1 ko-4-piperidin-4-yl piperazine is described as an example:

[0371] 实施例91:1_乙某-4-哌啶-4-某哌嗪 [0371] Example 91: 1_ -4- piperidin-4-acetate a certain piperazine

[0372] 91a) 4-(4-こ基哌嗪_1_基)哌啶_1_羧酸叔丁酯 [0372] 91a) 4- (4- piperazin-ko _1_ yl) piperidine-carboxylate _1_

[0373] 在冰冷却下,首先将29.2g(256mmol)N-こ基喊嚷和50.0g(256mmol) 4-氧代哌唳-1-羧酸叔丁酯(相当于l-Boc-4-哌唳酮)加入到800mlこ醇中,并加入15.4g(256mmol)冰こ酸。 [0373] Under ice-cooling, first, 29.2g (256mmol) N- group Hanrang ko and 50.0g (256mmol) 4- Li-oxopiperidine-l-carboxylate (corresponding to l l-Boc-4- Li ketone) was added to a 800ml ko alcohol, was added 15.4g (256mmol) of ice ko acid. 然后,毎次少量地将16.1g(256mmol)的こ酰氧基硼氢化钠加入到冷却的反应混合物中。 Then, every time the small amounts 16.1g (256mmol) of ko acyloxy sodium borohydride was added to the cooled reaction mixture. 开始,稍微有气体放出,在加入2/3的还原剂后,可以观察到泡沫。 Start, little gas evolution, after addition of 2/3 of the reducing agent, the foam can be observed. 将反应混合物在室温下搅拌过夜。 The reaction mixture was stirred at room temperature overnight. 对于后处理,冷却下将200ml 2N氢氧化钠水溶液加入到反应溶液中,蒸除溶剂こ醇,然后将剩余的反应混合物用水稀释。 For the workup, 200ml 2N aqueous solution under cooling to the reaction solution of sodium hydroxide was added, solvent was distilled off ko alcohol, and then the remaining reaction mixture was diluted with water. 所述混合物用こ醚(2x)萃取并用饱和氯化钠溶液洗涤(Ix),合并的有机相用硫酸镁干燥,过滤,并在减压下除去溶剤。 Ko The mixture was extracted with ether (2x) and washed with saturated sodium chloride solution (Ix is) and the combined organic phases were dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure Ji. 获得黄色油状的所需产物,其随后在填充有硅胶的41 Nutsche过滤器上进行色谱分离,使用ニ氯甲烷和10%甲醇作为洗脱液。 To obtain the desired product as a yellow oil, which is then chromatographed on silica gel packed with 41 Nutsche filter, using Ni and 10% methanol in methylene chloride as eluent. 总共得到4(^(135臟01,53% )4-(4-こ基哌嗪-1-基)哌唳-1-羧酸叔丁酷。 In total 4 (^ (dirty 01,53 135%) of 4- (4-ko-l-yl) piperidine 1-carboxylic acid tert-butyl Li cool.

[0374] 91b)氯化物盐形式的1-こ基-4-哌啶-4-基哌嗪: [0374] 91b) in the form of chloride salts of 1 ko-4-piperidin-4-yl piperazine:

[0375] 为了除去保护基,首先将40g(135mmol)4-(4_こ基哌嗪-1-基)哌唳_1_羧酸叔丁酷加入到200ml甲醇和1.8L ニ氯甲烷中,并加入IOOml在异丙醇中的5_6M HCl溶液。 [0375] For removal of the protecting group, first, 40g (135mmol) 4- (4_ ko-l-yl) piperidine carboxylic acid tert-butyl Li _1_ cool and 1.8L of methanol were added to 200ml of Ni chloride, and adding IOOml 5_6M HCl solution in isopropanol. 所述溶液变成ー种悬浮液,并观察到有轻微气体放出。 The solution became a suspension ー species, and slight gas evolution was observed. 将反应混合物在40°C (水浴温度)搅拌I小时,接着在室温下搅拌过周末。 The reaction mixture was stirred at 40 ° C (water bath temperature) I h, followed by stirring at room temperature over the weekend. 为了完成脱保护以获得所需产物,加入另外50ml的在异丙醇中的5-6M HCl溶液,接着将该混合物在40°C进行搅拌。 In order to complete the deprotection to obtain the desired product, an additional 50ml of 5-6M HCl solution in isopropanol, then the mixture was stirred at 40 ° C. 在旋转蒸发仪上蒸出ニ氯甲烷,加入另外200ml甲醇和30ml在异丙醇中的5_6M HCl溶液。 Ni chloride was distilled off on a rotary evaporator and an additional 200ml of methanol and 30ml 5_6M HCl solution in isopropanol. 在回流下搅拌I小时后,在强气体放出下`生成ー种白色悬浮液。 After stirring at reflux for I hour, under strong gas evolution generated ー species `white suspension. 随后,生成ー种低粘性的悬浮液,将其冷却至室温。 Subsequently, the generated ー kinds of low viscosity suspension which was cooled to room temperature. 抽吸滤出沉淀,用甲醇和こ醚洗涤。 The precipitate was filtered off with suction, washed with methanol and ether ko. 干燥后,分离得到氯化物盐形式的36g(117mm0l,87% )1-こ基-4-哌啶-4-基哌嗪。 After drying, the chloride salt form was isolated 36g (117mm0l, 87%) 1- ko-4-piperidin-4-yl piperazine.

[0376] 1H-匪R (D20,400MHz) δ [ppm] = 3.74-3.47 (m,11H),3.28 (q,2H,J = 7.3Hz), [0376] 1H- bandit R (D20,400MHz) δ [ppm] = 3.74-3.47 (m, 11H), 3.28 (q, 2H, J = 7.3Hz),

3.06 (dt, 2Η, J = 2.2Hz, J = 13.2Ηζ),2.38 (m, 2Η, J = 13.6Ηζ),1.89 (dq, 2Η, J = 4.1Hz,J = 13.3Ηζ),1.30 (t, 3Η, J = 7.3Ηζ).[0377] 实施例1-90化合物(外消旋体)和相应的右旋(+)-对映异构体(实施例号1-90并附有字母"A"例如,1A、2A等)和相应的左旋(-)_对映异构体(实施例号1-90并附有字母"B",例如1B、2B等)的化学结构表示在下表2中: 3.06 (dt, 2Η, J = 2.2Hz, J = 13.2Ηζ), 2.38 (m, 2Η, J = 13.6Ηζ), 1.89 (dq, 2Η, J = 4.1Hz, J = 13.3Ηζ), 1.30 (t, 3Η, J = 7.3Ηζ) [0377] 1-90 compound (racemate) and Example respective dextrorotatory (+) - enantiomer (Example No. 1-90 together with the letter "a "for example, 1A, 2A, etc.) and the corresponding L (-) enantiomer _ (example No. 1-90 together with the letter" B ", e.g. 1B, 2B, etc.) chemical structures represented in table 2 below :

Figure CN101611028BD00401
Figure CN101611028BD00411
Figure CN101611028BD00421
Figure CN101611028BD00431
Figure CN101611028BD00441
Figure CN101611028BD00451
Figure CN101611028BD00461
Figure CN101611028BD00471
Figure CN101611028BD00481
Figure CN101611028BD00491
Figure CN101611028BD00501
Figure CN101611028BD00511
Figure CN101611028BD00521
Figure CN101611028BD00531
Figure CN101611028BD00541
Figure CN101611028BD00551
Figure CN101611028BD00561
Figure CN101611028BD00571
Figure CN101611028BD00581
Figure CN101611028BD00591
Figure CN101611028BD00601
Figure CN101611028BD00611
Figure CN101611028BD00621
Figure CN101611028BD00631
Figure CN101611028BD00641
Figure CN101611028BD00651
Figure CN101611028BD00661
Figure CN101611028BD00671
Figure CN101611028BD00681
Figure CN101611028BD00691
Figure CN101611028BD00701

[0411]物质: [0411] substances:

[0412] 将试验物质以1(Γ2Μ的浓度溶于DMSO中,并在DMSO中进一步稀释到5 X 1(Γ4Μ至5Χ IO-9M的浓度。这些DMSO预稀释系列用试验缓冲液以1: 10稀释。在试验混合物(2%DMSO在该混合物中)中,将物质浓度再次以1: 5稀释。 [0412] The test substance at a concentration of 1 (Γ2Μ dissolved in DMSO and further diluted to a concentration of IO-9M 5 X 1 (Γ4Μ 5Χ in DMSO to these pre-dilution series with DMSO in assay buffer at 1: 10 dilution (the mixture 2% DMSO), the substance concentration in the test mixture was again 1: 5 dilution.

[0413] 膜制备: [0413] Preparation of films:

[0414] 采集具有稳定表达的人加压素Vlb受体(克隆3Η2)的CH0-K1细胞,并在50mMTris-HCl中和在蛋白酶抑制剂(Roche complete Mini#1836170)存在下使用Polytron勻浆器在中间位置匀化2X 10秒,随后以40000xg离心lh。 Al [0414] have acquired stable expression of vasopressin Vlb receptor (clone 3Η2) of CH0-K1 cells were homogenized using a Polytron homogenizer, and protease inhibitors at (Roche complete Mini # 1836170) in the presence of 50mMTris-HCl in the intermediate position homogenized 2X 10 seconds, followed by centrifugation at 40000xg lh. 所述膜沉淀再次如上所述进行匀化和离心,然后导入到50mM Tris-HCl, pH 7.4中,匀化并在_190°C等份冷冻保存在液氮中。 The membrane pellet was re-homogenized and centrifuged as described above, and then introduced into 50mM Tris-HCl, pH 7.4, the homogenized _190 ° C and aliquots were kept frozen in liquid nitrogen.

[0415] 结合试验: [0415] Binding Assay:

[0416]结合试验基于 Tahara 等人(Tahara A 等人,Brit.J.Pharmacol.125,1463-1470(1998))的方法进行。 [0416] Binding Assay method based Tahara et al. ((1998) Tahara A, et al., Brit.J.Pharmacol.125,1463-1470). 该培养缓冲液是:50mM Tris, IOmMMgCl2,0.1% BSA, pH7.4。 The incubation buffer is: 50mM Tris, IOmMMgCl2,0.1% BSA, pH7.4.

[0417] 在该试验混合物(250 μ I)中,具有稳定表达人Vlb受体(细胞系hVlb_3H2_CH0)的CHO-Kl细胞的膜(50μ g/ml蛋白在培养缓冲液中)与在培养缓冲液(50mMTris,IOmMMgCl2,0.1% BSA, pH7.4)中的1.5nM 3H-AVP (8_Arg_ 加压素,PerkinElmer#18479)(完全结合)一起进行培养`,或者另外加入增加浓度的试验物质(顶替实验)进行培养。 [0417] In the assay mixture (250 μ I) having a film CHO-Kl cells (50μ g / ml protein in incubation buffer) in the incubation buffer Vlb stably expressing human receptor (cell line hVlb_3H2_CH0) of (50mMTris, IOmMMgCl2,0.1% BSA, pH7.4) 1.5nM 3H-AVP (8_Arg_ vasopressin, PerkinElmer # 18479) (fully engaged) with the `cultured, or otherwise increasing the concentration of added test substance (replacement experiment ) were cultured. 非特异性结合用ΙμΜ AVP (Bachem #Η1780)测定。 Nonspecific binding was determined using ΙμΜ AVP (Bachem # Η1780). 全部测定一式三份。 All measured in triplicate. 培养(在室温下60分钟)后,通过真空过滤(Skatron细胞收集器7000)穿过Wathman GF/B玻璃纤维滤纸垫过滤出游离的放射性配体,并将滤纸转移到闪烁管中。 Culture (at room temperature for 60 min), passed through by vacuum filtration (a Skatron cell harvester 7000) Wathman GF / B glass fiber filter mat was filtered free radioligand, and the filters transferred to a scintillation vial. 液体闪烁测定在Tricarb型2000或2200CA仪(Packard)中进行。 Tricarb liquid scintillation measurement was performed in a Model 2000 or 2200CA instrument (Packard) in. 借助于标准粹灭系列将测得的cpm转化为dpm。 By means of a series of standard pure off the measured cpm into dpm.

[0418]评价: [0418] Evaluation:

[0419] 结合参数通过SAS中的非线性回归分析进行计算。 Analysis calculated by nonlinear regression in SAS [0419] binding parameters. 程序算法类似于LIGAND分析程序进行(Munson PJ 和Rodbard D,AnalyticalBiochem.107, 220-239 (1980))。 Program algorithm similar to the LIGAND analysis program (Munson PJ and Rodbard D, AnalyticalBiochem.107, 220-239 (1980)). 对于重组体人Vlb受体的3H-AVP的Kd是0.4nM,其用于确定Ki值。 For recombinant human Vlb 3H-AVP receptor of Kd is 0.4nM, for Ki values ​​were determined.

[0420] 该试验表明,本发明的化合物通常对Vlb受体具有高的亲合力,其以KiQ1-Vlb)值表示,并且通常低于150nM,特别是至多50nM,尤其是至多ΙΟηΜ。 [0420] This experiment shows that the compounds of the present invention generally have a high affinity receptor for Vlb, which is KiQ1-Vlb) value represents, and typically less than 150 nM, in particular at most 50 nM, in particular up ΙΟηΜ. 结果在表3中给出。 The results are given in Table 3.

[0421] 加压素Vla受体结合试验: [0421] vasopressin Vla receptor binding test:

[0422]物质: [0422] substances:

[0423] 该测试物质以KT2M浓度溶于DMSO中。 [0423] The test substance dissolved in DMSO at a concentration of KT2M. 这些DMSO溶液在培养缓冲液(50mM Tris,IOmM MgCl2,0.1% BSA, pH 7.4)中进一步稀释。 These solutions in DMSO incubation buffer (50mM Tris, IOmM MgCl2,0.1% BSA, pH 7.4) was further diluted.

[0424] 膜制备: [0424] Preparation of films:

[0425] 采集具有稳定表达的人加压素Vla受体(克隆5)的CH0-K1细胞,并在50mMTris-HCl中和在蛋白酶抑制剂(Roche complete Mini#1836170)存在下使用Polytron勻浆器在中间位置匀化2X 10秒,随后以40000xg离心lh。 Al [0425] have acquired stable expression vasopressin Vla receptor (clone 5) of CH0-K1 cells were homogenized using a Polytron homogenizer, and protease inhibitors at (Roche complete Mini # 1836170) in the presence of 50mMTris-HCl in the intermediate position homogenized 2X 10 seconds, followed by centrifugation at 40000xg lh. 所述膜沉淀再次如上所述进行匀化和离心,然后导入到50mM Tris-HCl, pH 7.4中,匀化并在_190°C等份冷冻保存在液氮中。 The membrane pellet was re-homogenized and centrifuged as described above, and then introduced into 50mM Tris-HCl, pH 7.4, the homogenized _190 ° C and aliquots were kept frozen in liquid nitrogen.

[0426] 结合试验: [0426] Binding Assay:

[0427] 结合试验基于Tahara等人的方法进行(Tahara A等人,Brit.J.Pharmacol.125,1463-1470(1998))。 [0427] Binding Assay based Tahara et al. (Tahara A, et al., Brit.J.Pharmacol.125,1463-1470 (1998)). [0428]该培养缓冲液是:50mM Tris, IOmM MgCl2,0.1% BSA, pH 7.4。 [0428] The incubation buffer is: 50mM Tris, IOmM MgCl2,0.1% BSA, pH 7.4.

[0429] 在该试验混合物(250 μ I)中,具有稳定表达人Vla受体(细胞系hVla_5_CH0)的CHO-Kl细胞的膜(20μ g/ml蛋白在培养缓冲液中)与在培养缓冲液(50mM Tris, IOmMMgCl2,0.1% BSA, pH7.4)中的0.04nM 1251-AVP(8_Arg_ 加压素,NEX 128)(完全结合)一起进行培养,或者另外加入增加浓度的试验物质(顶替实验)进行培养。 [0429] In the assay mixture (250 μ I) having a film CHO-Kl cells (20μ g / ml protein in incubation buffer) in incubation buffer and stably expressing human Vla receptor (cell line hVla_5_CH0) of (50mM Tris, IOmMMgCl2,0.1% BSA, pH7.4) 0.04nM 1251-AVP (8_Arg_ vasopressin, NEX 128) (fully integrated) is incubated with or otherwise added increasing concentrations of the test substance (replacement experiment) cultured. 非特异性结合用ΙμΜ AVP(Bachem #H1780)进行测定。 Non-specific binding was measured by ΙμΜ AVP (Bachem # H1780). 一式三份进行测定。 It was measured in triplicate.

[0430] 培养(在室温下60分钟)后,通过真空过滤(Skatron细胞收集器7000)穿过Wathman GF/B玻璃纤维滤纸垫过滤出游离的放射性配体,并将滤纸转移到闪烁管中。 [0430] culture (at room temperature for 60 min), passed through by vacuum filtration (a Skatron cell harvester 7000) Wathman GF / B glass fiber filter mat was filtered free radioligand, and the filters transferred to a scintillation vial.

[0431] 液体闪烁测定在Tricarb型2000或2200CA仪(Packard)中进行。 [0431] Tricarb liquid scintillation measurement in the Model 2000 or 2200CA instrument (Packard) in. 借助于标准猝灭系列将测得的cpm转化为dpm。 By means of standard quench series the measured cpm into dpm.

[0432]评价: [0432] Evaluation:

[0433] 结合参数通过SAS中的非线性回归分析进行计算。 Analysis calculated by nonlinear regression in SAS [0433] binding parameters. 程序算法类似于LIGAND分析程序进行(Munson PJ 和Rodbard D,AnalyticalBiochem.107, 220-239 (1980))。 Program algorithm similar to the LIGAND analysis program (Munson PJ and Rodbard D, AnalyticalBiochem.107, 220-239 (1980)). 针对重组体hVla受体的1251-AVP的Kd在饱和实验中进行测定。 Measured at saturation experiments against Kd 1251-AVP recombinant hVla receptor. 1.33nM的Kd用来确定Ki值。 The Kd 1.33nM to determine Ki values.

[0434] 该试验表明,与Vla受体相比,本发明的化合物对Vlb受体通常具有选择性,其,以Ki (h-Vla) /Ki (h-Vlb)值表示,通常超过10,并且经常至少15,特别是至少50,以及尤其是至少100。 [0434] This experiment showed that compared with Vla receptor, the compounds of the present invention typically has a selectivity Vlb receptors, which, in order to Ki (h-Vla) / Ki (h-Vlb) value, which normally exceeds 10, and often at least 15, especially at least 50, and in particular at least 100. 结果在表3中给出。 The results are given in Table 3.

[0435] 加压素V2受体结合试验: [0435] vasopressin V2 receptor binding test:

[0436]物质:`[0437] 该测试物质以10_2M浓度溶于DMSO中。 [0436] Substances: `[0437] The test substance dissolved in DMSO at a concentration of 10_2M. 这种DMSO溶液在培养缓冲液(50mM Tris,IOmM MgCl2,0.1% BSA, pH 7.4)中进一步稀释。 This DMSO solution in incubation buffer (50mM Tris, IOmM MgCl2,0.1% BSA, pH 7.4) was further diluted.

[0438] 膜制备: [0438] Preparation of films:

[0439] 采集具有稳定表达的人加压素V2受体(克隆23)的CHO-Kl细胞,并在50mMTris-HCl中和在蛋白酶抑制剂(Roche complete Mini#1836170)存在下使用Polytron勻浆器在中间位置匀化2X 10秒,随后以40000xg离心lh。 Al [0439] have acquired stable expression vasopressin V2 receptor (clone 23) in CHO-Kl cells were homogenized using a Polytron homogenizer, and in the protease inhibitor (Roche complete Mini # 1836170) in the presence of 50mMTris-HCl in the intermediate position homogenized 2X 10 seconds, followed by centrifugation at 40000xg lh. 所述膜沉淀再次如上所述进行匀化和离心,然后导入到50mM Tris-HCl, pH 7.4中,匀化并在_190°C等份冷冻保存在液氮中。 The membrane pellet was re-homogenized and centrifuged as described above, and then introduced into 50mM Tris-HCl, pH 7.4, the homogenized _190 ° C and aliquots were kept frozen in liquid nitrogen.

[0440] 结合试验: [0440] Binding Assay:

[0441] 结合试验基于Tahara等人的方法进行(Tahara A等人,Brit.J.Pharmacol.125,1463-1470(1998))。 [0441] Binding Assay based Tahara et al. (Tahara A, et al., Brit.J.Pharmacol.125,1463-1470 (1998)).

[0442]该培养缓冲液是:50mM Tris, IOmM MgCl2,0.1% BSA, pH 7.4。 [0442] The incubation buffer is: 50mM Tris, IOmM MgCl2,0.1% BSA, pH 7.4.

[0443] 在该试验混合物(250 μ I)中,具有稳定表达人V2受体(细胞系hV2_23_CH0)的CHO-Kl细胞的膜(50μ g/mi蛋白在培养缓冲液中)与在培养缓冲液(50mM Tris, IOmMMgCl2,0.1% BSA, pH7.4)中的l_2nM 3H-AVP (8_Arg_ 加压素,PerkinElmer #1别79)(完全结合)一起进行培养,或者另外加入增加浓度的试验物质(顶替实验)进行培养。 [0443] In the assay mixture (250 μ I) having a film CHO-Kl cells (50μ g / mi protein in incubation buffer) stably expressing human V2 receptor (cell line hV2_23_CH0) in incubation buffer and (50mM Tris, IOmMMgCl2,0.1% BSA, pH7.4) l_2nM 3H-AVP (8_Arg_ vasopressin, PerkinElmer # 1 do 79) (fully integrated) is incubated with or otherwise added increasing concentrations of the test substance (replacement experiments) were cultured. 非特异性结合用ΙμΜ AVP(Bachem #H1780)测定。 Nonspecific binding was determined using ΙμΜ AVP (Bachem # H1780). 全部测定一式三份。 All measured in triplicate.

[0444] 培养(在室温下60分钟)后,通过真空过滤(Skatron细胞收集器7000)穿过Wathman GF/B玻璃纤维滤纸垫过滤出游离的放射性配体,并将滤纸转移到闪烁管中。 [0444] culture (at room temperature for 60 min), passed through by vacuum filtration (a Skatron cell harvester 7000) Wathman GF / B glass fiber filter mat was filtered free radioligand, and the filters transferred to a scintillation vial.

[0445] 液体闪烁测定在Tricarb型2000或2200CA仪(Packard)中进行。 [0445] Tricarb liquid scintillation measurement in the Model 2000 or 2200CA instrument (Packard) in. 借助于标准猝灭系列将测得的cpm转化为dpm。 By means of standard quench series the measured cpm into dpm. [0446]评价: [0446] Evaluation:

[0447] 结合参数通过SAS中的非线性回归分析进行计算。 [0447] Analysis calculated by nonlinear regression in SAS binding parameters. 程序算法类似于LIGAND分析程序进行(Munson PJ 和Rodbard D,AnalyticalBiochem.107, 220-239 (1980))。 Program algorithm similar to the LIGAND analysis program (Munson PJ and Rodbard D, AnalyticalBiochem.107, 220-239 (1980)). 对于重组体hV2受体的3H-AVP的Kd是2.4nM,其用于确定Ki值。 For recombinant hV2 3H-AVP receptor of Kd is 2.4nM, for Ki values ​​were determined.

[0448] 该试验表明,与V2受体相比,本发明的化合物对Vlb受体通常具有选择性,其,以Ki(K^)Ai (h-Vlb)值表示,通常超过10,并且经常至少15,特别是至少25,以及尤其是至少50。 [0448] This experiment showed that, compared with the V2 receptor, the compounds of the present invention typically has a selectivity Vlb receptors, which, in order to Ki (K ^) Ai (h-Vlb) value, which normally more than 10, and often at least 15, especially at least 25, and in particular at least 50.

[0449] 催产素受体结合试验 [0449] Oxytocin receptor binding test

[0450]物质: [0450] substances:

[0451] 将物质以KT2M的浓度溶于DMSO中并用培养缓冲液(50mMTris,IOmM MgCl2,0.1%BSA,pH 7.4)稀释。 [0451] The material was dissolved at a concentration of KT2M DMSO and diluted with incubation buffer (50mMTris, IOmM MgCl2,0.1% BSA, pH 7.4).

[0452] 细胞制备: [0452] Cell Preparation:

[0453] 具有瞬时表达的重组人催产素受体的融合HEK-293细胞以750xg在室温下离心5分钟。 [0453] transiently expressed human recombinant oxytocin receptor in HEK-293 cells fused centrifuged at 750xg at room temperature for 5 minutes. 将残余物导出到冰冷的溶胞缓冲液(50mMTris-HCl,10%甘油,pH 7.4和RocheComplete蛋白酶抑制剂)中,并在4°C经历渗透压休克20分钟。 The residue was exported to ice-cold lysis buffer (50mMTris-HCl, 10% glycerol, pH 7.4 and RocheComplete protease inhibitors), and osmotic shock experienced at 4 ° C for 20 min. 然后,将溶胞中的细胞以750xg在4°C离心20分钟,将残余物导出到培养缓冲液中,制得107细胞/ml的等分试样。 Then, the lysis of the cells by centrifugation 750xg at 4 ° C for 20 minutes, the residue was exported to the incubation buffer, aliquoted to obtain 107 cells / ml. 该等分试样在使用前冷冻于-80°C下。 Aliquot before use in frozen at -80 ° C.

[0454] 结合试验: [0454] Binding Assay:

[0455] 在实验的当天`,将细胞解冻,用培养缓冲液稀释并使用MultipetteCombitip (`Eppendorf,Hamburg)勻化。 [0455] 'day of the experiment, the cells were thawed, diluted with buffer and culture using MultipetteCombitip ( `Eppendorf, Hamburg) homogenized. 0.250ml 的反应混合物由2-5X104 重组细胞、3-4nM 3H-催产素(PerkinElmer,NET 858)在测试物质(抑制图)存在下或仅仅在培养缓冲液(全部结合)存在下组成。 The reaction mixture was 0.250ml by recombinant 2-5X104 cells, 3-4nM 3H- oxytocin (PerkinElmer, NET 858) in the test substance (inhibition FIG.) Or simply in the presence of incubation buffer (total binding) in the presence of the composition. 非特异性结合用10_6M催产素(Bachem AG,H2510)进行测定。 Non-specific binding was measured using 10_6M oxytocin (Bachem AG, H2510). 测定一式三份进行。 Determination was performed in triplicate. 结合的和游离的放射性配体通过真空过滤使用Skatron细胞收集器7000用Whatman GF/B玻璃纤维滤纸过滤进行分离。 Bound and free radioligand by filtration using Skatron cell harvester with 7000 by vacuum Whatman GF / B glass fiber filter paper separated by filtration. 结合放射性通过Tricarb β计数器2000型或2200CA(Packard)的液体闪烁测定。 Tricarb β bound radioactivity by a liquid counter type 2000 or 2200CA (Packard) scintillation measurement.

[0456]评价: [0456] Evaluation:

[0457] 结合参数通过非线性回归分析(SAS)进行计算,类似于Munson和Rodbard的LIGAND 程序(Analytical Biochem 1980;107:220-239)。 [0457] binding parameters calculated by nonlinear regression analysis (SAS), similar to the LIGAND program of Munson and Rodbard (Analytical Biochem 1980; 107: 220-239). 对于重组体hOT 受体的3H-催产素的Kd是7.6nM,其用于确定Ki值。 For hOT recombinant oxytocin receptor 3H- Kd is 7.6nM, for Ki values ​​were determined.

[0458] 该试验表明,与催产素受体相比,本发明的化合物对Vlb受体通常具有选择性,其,以KiO1-OTVKiG1-Vlb)值表示,通常超过10,并且经常至少15,特别是至少25,以及尤其是至少50。 [0458] This experiment showed that, compared to oxytocin receptors, the compounds of the present invention typically has a selectivity Vlb receptors, which, in KiO1-OTVKiG1-Vlb) value, which normally more than 10, and often at least 15, in particular It is at least 25, and in particular at least 50. 结果在表3中给出。 The results are given in Table 3.

[0459]表 3 [0459] TABLE 3

[0460] [0460]

Figure CN101611028BD00731
Figure CN101611028BD00741

[0461] Ki (h-Vlb) Ki (h_Vla)/Ki (h_Vlb) Ki (h-OT) /Ki (h-Vlb) [0461] Ki (h-Vlb) Ki (h_Vla) / Ki (h_Vlb) Ki (h-OT) / Ki (h-Vlb)

[0462] + > 50-150nM 15-50 15-25 [0462] +> 50-150nM 15-50 15-25

[0463] ++ 10-50nM > 50-100 > 25-50 [0463] ++ 10-50nM> 50-100> 25-50

[0464] +++ < IOnM > 100 > 50 [0464] +++ <IOnM> 100> 50

[0465] 微粒体半衰期的测定: [0465] microsomal half-life assay:

[0466] 本发明化合物的代谢稳定性在下面试验中进行测定。 Metabolic stability [0466] The compounds of the present invention is measured in the following assay. [0467] 试验物质以0.5 μ M浓度如下培养: [0467] In the test substance concentration 0.5 μ M cultured as follows:

[0468] 0.5 μ M试验物质与各种物种(大鼠、人或其它物种)的肝微粒体(0.25mg微粒体蛋白/ml)在0.05M磷酸钾缓冲液pH 7.4中在微量滴定板中于37°C—起预培养5min。 [0468] 0.5 μ M of the test substance with various species (rat, human or other species) liver microsomes (microsomal protein 0.25mg / ml) 0.05M potassium phosphate buffer, pH 7.4 in the microtiter plate from 37 ° C- preculture 5min. 通过加入NADPH(lmg/ml)开始反应。 The reaction was started by the addition of NADPH (lmg / ml). 在0、5、10、15、20和30min之后,取出50 μ I等分试样,并立即经等体积的乙腈终止反应并冷却。 0,5,10,15,20 and after 30min, then aliquots of 50 μ I, and the like immediately by volume of acetonitrile and cooled to terminate the reaction. 将样品冷冻直到进行分析为止。 The samples were frozen until analysis carried out so far. 使用MSMS,测定未分解试验物质的剩余浓度。 Using MSMS, measured undecomposed residual concentration of the test substance. 由试验物质信号/时间单位曲线的增加测定半衰期(Τ1/2),其中假定一级动力学,由随时间化合物浓度的减少可以计算试验物质的半衰期。 Signal from the test substance / unit of time measurement curve increases half-life (Τ1 / 2), assuming first-order kinetics, the compound concentrations decreased over time may be calculated half-life of the test substance. 微粒体清除率(mCl) WmCl = 1η2/Τ1/2/(微粒体蛋白的含量mg/ml) X 1000 [ml/min/mg]的形式计算(根据参考文献进行修改:Di,The Society for BiomoleculaurScreening, 2003,453-462 ;Obach,DMD,1999 vol 27.N 11,1350-1359)。 Microsomal clearance (mCl) WmCl = 1η2 / Τ1 / 2 / (content mg ​​microsomal protein / ml) X 1000 [ml / min / mg] calculated in the form (modified in accordance with Reference: Di, The Society for BiomoleculaurScreening , 2003,453-462; Obach, DMD, 1999 vol 27.N 11,1350-1359).

[0469] 该试验表明,本发明的化合物通常具有高的代谢稳定性,其导致人微粒体清除率值通常至多220 μ Imirr1Iiig4,经常120 μ lmin_1mg_1,以及特别是至多60 μ ImirT1Iiig'结果在表4中给出。 [0469] This experiment shows that the compounds of the present invention generally have a high metabolic stability, which results in human microsomes clearance values ​​generally up to 220 μ Imirr1Iiig4, often 120 μ lmin_1mg_1, and in particular at most 60 μ ImirT1Iiig 'results in Table 4 given.

[0470]表 4 [0470] TABLE 4

[0471] [0471]

Figure CN101611028BD00751

[0472] [0472]

Figure CN101611028BD00761

[0473] 人微粒体清除率 [0473] human microsomal clearance

[0474] + > 120-220 μ ImirT1Iiig-1 [0474] +> 120-220 μ ImirT1Iiig-1

[0475] ++ 60-120 μ Imin 1Iiig 1 [0475] ++ 60-120 μ Imin 1Iiig 1

[0476] +++ < 60 μ Imin 1Iiig 1 [0476] +++ <60 μ Imin 1Iiig 1

[0477] 通过平衡透析法测定血浆蛋白结合(PPB): [0477] Determination of plasma protein binding by equilibrium dialysis (PPB):

[0478] 将加入I或10 μ M试验物质的150 μ I大鼠或人血浆移入到96孔透析室的一侧,将150 μ I PPS缓冲液移入到该96孔透析室的另一侧。 [0478] I added 10 μ M or 150 μ I of the test substance rat or human plasma move to one side of the dialysis chamber 96, the buffer 150 μ I PPS moved to the other side of the dialysis chamber 96. 所述透析室通过6-8000道尔顿截留分子量的透析膜进行分离。 The dialysate chamber is separated by a dialysis membrane 6-8000 dalton molecular weight cutoff.

[0479] 将该96孔透析室盖上并轻轻地摇动过夜。 [0479] The dialysis chamber 96 covered and gently shaken overnight.

[0480] 第二天早上,移取10 μ I血浆并用90 μ I PPS缓冲液稀释,接着使用200 μ I乙腈析出蛋白。 [0480] The next morning, 10 μ I plasma was pipetted and diluted with 90 μ I PPS buffer using 200 μ I of acetonitrile followed by precipitation of proteins. 离心除去该析出的蛋白,100 μ I上清液用于MSMS分析。 The precipitated protein was removed by centrifugation, 100 μ I supernatant was used for MSMS analysis. 从缓冲液一侧移取100 μ I进行MSMS 分析。 Sway taken from a buffer 100 μ I for MSMS analysis. 还参见下列参考文献:Banker, Journal of Pharmaceutical SciencesVol.92,5,967-974,2003。 See also the following references: Banker, Journal of Pharmaceutical SciencesVol.92,5,967-974,2003.

[0481] 细胞色素P450 (CYP)抑制的体外测定方法 [0481] In vitro method for measuring cytochrome P450 (CYP) inhibition

[0482] 2C9和3A4的荧光底物: [0482] 2C9 and 3A4 fluorogenic substrate:

[0483] 将0.4mg/ml人肝微粒体与待试验物质(0_20 μ Μ)、CYP特异性底物一起在0.05Μ磷酸钾缓冲液PH 7.4中在37°C预培养10分钟。 [0483] The 0.4mg / ml human liver microsomes and the substance to be tested (0_20 μ Μ), in 0.05Μ potassium phosphate buffer PH 7.4 were preincubated for 10 minutes at 37 ° C CYP specific substrates together. CYP2C9的Cyp-特异性底物是荧光素H,CYP 3A4的Cyp-特异性底物是荧光素BE。 Cyp- specific substrates of CYP2C9 fluorescein H, CYP 3A4 is specific substrates Cyp- fluorescein BE. 通过加入NADPH开始反应。 The reaction was started by the addition of NADPH. 于RT培养30min后,加入突光素检测试剂,并测定所得突光信号(根据参考文献进行修改:Promega, TechnicalBulletin P450-GL0™ Assays)。 After culturing at RT for 30min, the light projecting element detection reagent was added, and the resultant projection light measurement signal (modified according References: Promega, TechnicalBulletin P450-GL0 ™ Assays).

[0484] 咪达唑仑CYP 3A4与时间有关的抑制 [0484] CYP 3A4 Midazolam time-dependent inhibition

[0485] 该试验由两部分组成。 [0485] The test consists of two parts. 在第一部分中,该试验物质与肝微粒体(含NADPH) —起进行预培养=预培养,接着加入所述底物;在第二部分中,底物和试验物质同时加入=共培养。 In the first part, the test substance with liver microsomes (with NADPH) - from preculture = pre-culture, followed by addition of the substrate; in the second portion, the substrate and the test substance added simultaneously = coculture.

[0486] 预培养: [0486] Pre-culture:

[0487] 将0.05mg/ml微粒体蛋白(人肝微粒体)与0-10 μ M (或50 μ M)试验物质一起在50mM磷酸钾缓冲液中预培养5min。 [0487] A 0.05mg / ml microsomal protein (human liver microsomes) and 0-10 μ M (or 50 μ M) pre-incubated with the test substance 5min in 50mM potassium phosphate buffer. 使用NADPH开始反应。 NADPH is used to start the reaction. 30min后,加入4 μ M咪达唑仑(最终浓度),将该混合物再培养lOmin。 After 30min, was added 4 μ M midazolam (final concentration), and the mixture was incubated for lOmin. IOmin后,移取75 μ I反应溶液并用150 μ I乙腈溶液淬灭。 After IOmin, pipetting the reaction solution was 75 μ I and treated with 150 μ I of acetonitrile was quenched.

[0488] 共培养: [0488] co-culture:

[0489] 将0.05mg/ml微粒体蛋白(人肝微粒体)、4 μ M咪达唑仑(最终浓度)和0-10 μ M(或50 μ Μ)试验物质在50mM磷酸钾缓冲液中预培养5min。 [0489] A 0.05mg / ml microsomal protein (human liver microsomes), 4 μ M midazolam (final concentration) and 0-10 μ M (or 50 μ Μ) of the test substance in 50mM potassium phosphate buffer pre-culture 5min. 使用NADPH开始反应。 NADPH is used to start the reaction. IOmin后,移取75 μ I反应溶液并用150 μ I乙腈溶液淬灭。 After IOmin, pipetting the reaction solution was 75 μ I and treated with 150 μ I of acetonitrile was quenched. 用MSMS分析前将样品一直冷冻(根据参考文献改变: Samples were analyzed by MSMS before been frozen (according to reference changes:

[0490] Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol316,I,336-348,2006 ;ffalsky, Drug Metabolism and Disposition Vol 32,6,647-660,2004)。 [0490] Obdach, Journal of Pharmacology & Experimental Therapeutics, Vol316, I, 336-348,2006; ffalsky, Drug Metabolism and Disposition Vol 32,6,647-660,2004).

[0491] 水溶解度(mg/ml)的测定方法 [0491] Water solubility (mg / ml) of the assay method

[0492] 本发明化合物的水溶解度例如可以根据所谓的"shake flask"方法(根据ASTM International:E 1148—02,Standard test methods formeasurement of aqueoussolubility, Book of Standards Volume 11.05.)进行测定。 [0492] Water solubility of the compound of the present invention may, for example, a so-called "shake flask" method (in accordance with ASTM International: E 1148-02, Standard test methods formeasurement of aqueoussolubility, Book of Standards Volume 11.05.) Was measured. 在此,将过量固体化合物加入到具有某一pH值(例如磷酸盐缓冲液pH 7.4)的缓冲溶液中,并将所得混合物摇动或搅拌直到达到稳定状态为止(典型地24或48小时,有时甚至直至7天)。 Here, the excess solid compound was added to a buffer solution having a pH (e.g. a phosphate buffer pH 7.4) in, and the resulting mixture was stirred or shaken until it reaches a steady state until the (typically 24 or 48 hours, sometimes even up to 7 days). 然后,过滤或离心除去不溶固体,通过UV光`谱或高压液相色谱分析(HPLC)使用适宜的校准曲线测定溶解化合物的浓度。 Then, insoluble solid was removed by filtration or centrifugation, dissolved concentration of the compound was measured using an appropriate calibration curve by UV light spectrum or `HPLC analysis (HPLC).

Claims (41)

1.通式⑴的化合物 1. The compounds of formula ⑴
Figure CN101611028BC00021
其中Rl是乙氧基;R2是氢;R3是氰基;R4是氢;R5是氢、甲氧基或乙氧基;R6是氢或甲氧基;R7是氢、甲基、乙基、正丙基或异丙基;Xl 是_NH_ ;X2是N或CH ;X3是N或CH ;其中X2和X3不同时是N;及其药学上可接受的盐、和互变异构体形式。 Wherein Rl is ethoxy; R2 is hydrogen; R3 is cyano; R4 is hydrogen; R5 is hydrogen, methoxy or ethoxy; R6 is hydrogen or methoxy; R7 is hydrogen, methyl, ethyl, n-propyl or isopropyl; Xl is _NH_; X2 is N or CH; X3 is N or CH; wherein X2 and X3 are not simultaneously N; and pharmaceutically acceptable salts thereof, and tautomeric forms .
2.权利要求1的化合物,其中R5是氢或甲氧基。 2. The compound of claim 1, wherein R5 is hydrogen or methoxy.
3.权利要求1的化合物,其中R7是氢、甲基或乙基。 3. The compound of claim 1, wherein R7 is hydrogen, methyl or ethyl.
4.权利要求1-3任一项的化合物,其中R5是氢或甲氧基;R7是氧、甲基或乙基;Xl 是_NH_ ;X2是N ;和X3 是CH。 4. The compound according to any one of claims 1-3, wherein R5 is hydrogen or methoxy; R7 is oxygen, methyl or ethyl; Xl is _NH_; X2 is N; and X3 is CH.
5.权利要求1-3任一项的化合物,其中R5是氢或甲氧基;R7是氧、甲基或乙基;Xl 是_NH_ ;X2是CH ;和X3 是N。 5. The compound according to any one of claims 1-3, wherein R5 is hydrogen or methoxy; R7 is oxygen, methyl or ethyl; Xl is _NH_; X2 is CH; and X3 is N.
6.权利要求1-3任一项的化合物,其中R5是甲氧基; R6是甲氧基; R7是甲基或乙基; Xl 是_NH_ ; X2是CH和X3是N ;或X2是N和X3是CH。 6. The compound of any one of claim 1-3, wherein R5 is methoxy; R6 is methoxy; R7 is methyl or ethyl; Xl is _NH_; X2 is CH and X3 is N; or X2 is a N and X3 is CH.
7.权利要求1-3任一项的化合物,其中R5是甲氧基; R6是甲氧基; R7是甲基; Xl 是_NH_ ; X2是N ;和X3 是CH。 7. The compound according to any one of claims 1-3, wherein R5 is methoxy; R6 is methoxy; R7 is methyl; Xl is _NH_; X2 is N; and X3 is CH.
8.权利要求1-3任一项的化合物,其中R5是甲氧基; R6是甲氧基; R7是甲基; Xl 是_NH_ ; X2是CH ;和X3 是N。 8. The compound according to any one of claims 1-3, wherein R5 is methoxy; R6 is methoxy; R7 is methyl; Xl is _NH_; X2 is CH; and X3 is N.
9.权利要求1-3任一项的化合物,其中R5是甲氧基; R6是甲氧基; R7是乙基; Xl 是_NH_ ; X2是CH ;和X3 是N。 9. The compound of any one of claims 1-3, wherein R5 is methoxy; R6 is methoxy; R7 is ethyl; Xl is _NH_; X2 is CH; and X3 is N.
10.权利要求1-3任一项的通式(I)的化合物,其特征在于它们以旋光体形式存在并且它们是游离碱形式的所述通式(I)化合物的左旋的(-)-对映异构体,该左旋的(-)-对映异构体使线偏振光的偏振平面向左旋,及其药学上可接受的盐、和/或互变异构体形式。 Compound of formula 1-3 according to any one of (I) as claimed in claim 10, characterized in that they exist in optically active forms thereof and the compound is levorotatory (I) of the free base form of formula (-) - enantiomer, the levorotatory (-) - enantiomer so that the polarization plane of the linearly polarized light L, and pharmaceutically acceptable salts thereof, and / or the tautomeric form.
11.权利要求1-3任一项的通式(I)的化合物,其特征在于它们以旋光体形式存在,其中手性C-3环碳原子的绝对构型相当于游离碱形式的式(Ia)化合物的左旋的(-)_对映异构体的C-3处的绝对构型, 11. A compound of formula 1-3 according to any one of (I) as claimed in claim, characterized in that they are present in optically active form, wherein the absolute configuration of a chiral C-3 ring carbon atoms, corresponding to the free base of formula ( levorotatory (Ia) compounds -) _ absolute configuration of the enantiomers of the C-3,
Figure CN101611028BC00041
该左旋的(-)-对映异构体使线偏振光的偏振平面向左旋,及其药学上可接受的盐、和互变异构体形式。 The levorotatory (-) - acceptable enantiomers make the polarization plane of the linearly polarized light L, and pharmaceutically acceptable salts thereof, and tautomeric forms.
12.权利要求10的通式(I)的化合物,其是旋光体形式的,其特征在于该相应的左旋的(-)_对映异构体以大于50%的光学纯度(对映异构体过量,ee)存在,及其药学上可接受的盐、和互变异构体形式。 12. A compound of formula (I) as claimed in claim 10, which is an optically active form, characterized in that the respective levorotatory (-) enantiomer _ to greater than 50% optical purity (enantiomeric excess, EE) is present, and pharmaceutically acceptable salts and tautomeric forms.
13.权利要求11的通式(I)的化合物,其是旋光体形式的,其特征在于在C-3环碳原子处具有优选绝对构型的对映异构体以大于50%的光学纯度(对映异构体过量,ee)存在,及其药学上可接受的盐、和互变异构体形式。 13. A compound of formula (I) as claimed in claim 11, which is an optically active form, characterized in that the absolute configuration having preferably enantiomers greater than 50% optical purity at C-3 carbon atom ring (enantiomeric excess, EE) is present, and pharmaceutically acceptable salts and tautomeric forms.
14.权利要求10的通式(I)的化合物,其是旋光体形式的,其特征在于相应的左旋的(-)_对映异构体以大于90%的光学纯度(对映异构体过量,ee)存在,及其药学上可接受的盐、和互变异构体形式。 14. A compound of formula (I) as claimed in claim 10, which is an optically active form, characterized in that the respective levorotatory (-) enantiomer _ to greater than 90% optical purity (enantiomer excess, EE) is present, and pharmaceutically acceptable salts and tautomeric forms.
15.权利要求11的通式(I)的化合物,其是旋光体形式的,其特征在于在C-3环碳原子处具有优选绝对构型的对映异构体以大于90%的光学纯度(对映异构体过量,ee)存在,及其药学上可接受的盐、和互变异构体形式。 15. A compound of formula (I) as claimed in claim 11, which is an optically active form, characterized in that the absolute configuration having preferably enantiomers greater than 90% optical purity at C-3 carbon atom ring (enantiomeric excess, EE) is present, and pharmaceutically acceptable salts and tautomeric forms.
16.权利要求1-3任一项的通式(I)的化合物,其是外消旋体形式的,及通式(I)化合物的外消旋体的药学上可接受的盐、和互变异构体形式。 16. A compound of formula 1-3 according to any one of (I) as claimed in claim, which is a pharmaceutically acceptable racemate compound racemic form outer and Formula (I) salts, and interoperability tautomeric forms.
17.权利要求1的通式⑴的化合物,其选自以下的化合物: (1) N-[5-氰基-1-[(2,4- 二甲氧基苯基)磺酰基]-3- (2-乙氧基吡啶_3_基)_2_氧代-2,3- 二氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺; (2) (+)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(1-甲基哌啶_4_基)哌嗪-1-羧酰胺; (3) (-)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(1-甲基哌啶_4_基)哌嗪-1-羧酰胺; (4) N- [5-氰基-3- (2-乙氧基吡啶-3-基)-1- [ (4-甲氧基苯基)磺酰基]-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺; (5) N- [5-氰基-3- (2-乙氧基吡啶-3-基)-1- [ (2-甲氧基苯基)磺酰基]-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺; (6) N-[5-氛基-l-[ (2-乙氧基苯基)横酸基]-3- (2-乙氧基卩比唳 - [(2,4-dimethoxyphenyl) sulfonyl] -3 (1) N- [5- cyano-1: the compound of Formula 1 is chosen from the following ⑴ compound as claimed in claim 17, - (pyridin-2-ethoxy _3_ yl) -1H- _2_ oxo-2,3-dihydro-indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine 1-carboxamide; (2) (+) - N- [5- cyano -l - [(2,4- dimethoxyphenyl) sulfonyl] -3- (pyridin-ethoxy 2_ 3-yl) -2-oxo-2,3-dihydro -1H- indol-3-yl] -4- (1-methyl-piperidin _4_ yl) piperazine-1-carboxamide; (3) (-) - N- [5- cyano -l - [(2,4- dimethoxyphenyl) sulfonyl] -3- (2_-ethoxy-pyridin-3-yl) -2 - oxo-2,3-dihydro -1H- indol-3-yl] -4- (1-methyl-piperidin _4_ yl) piperazine-1-carboxamide; (4) N- [5 - cyano-3- (2-ethoxy-3-yl) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro-indazol -1H- 3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide; (5) N- [5- cyano-3- (pyridin-2-ethoxy - 3- yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro -1H- indol-3-yl] -4- (1-methyl piperidin-4-yl) piperazine-1-carboxamide; (6) N- [5- atmosphere -L-yl [(2-ethoxyphenyl) an acid cross-yl] -3- (2-ethoxyethyl Jipianpangbili -3-基)~2~氧代-2,3- 二氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺; (7) N- [5-氰基-3- (2-乙氧基吡啶-3-基)-2-氧代-1-(苯磺酰基)_2,3- 二氢-1H-吲哚-3-基]-4-(1-甲基哌啶-4-基)哌嗪-1-羧酰胺; (8) N-[5-氰基-1-[(2,4- 二甲氧基苯基)磺酰基]-3-(2-乙氧基吡啶_3_基)_2_氧代-2,3- 二氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺; (9) (+)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(4-甲基哌嗪_1_基)哌啶-1-羧酰胺; (10) (-)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(4-甲基哌嗪_1_基)哌啶-1-羧酰胺; (11)N-[5-氰基-3-(2-乙氧基吡啶-3-基)-1-[ (2-甲氧基苯基)磺酰基]-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺; (12) N-[5_氛基-1-[ (2-乙氧基苯基)横酸基]_3_ (2-乙氧基卩比 3-yl) ~ 2 ~ oxo-2,3-dihydro -1H- indol-3-yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide; (7) N- [5- cyano-3- (2-ethoxy-3-yl) -2-oxo-1- (phenylsulfonyl) -1H- indol _2,3- dihydro - 3- yl] -4- (1-methyl-piperidin-4-yl) piperazine-1-carboxamide; (8) N- [5- cyano-1 - [(2,4-dimethoxy phenyl) sulfonyl] -3- (pyridin-2-ethoxy _3_ yl) -1H- _2_ oxo-2,3-dihydro-indol-3-yl] -4- (4-methyl piperazin-1-yl) piperidine-1-carboxamide; (9) (+) - N- [5- cyano -l - [(2,4- dimethoxyphenyl) sulfonyl] -3 - (2_-ethoxy-pyridin-3-yl) -2-oxo-2,3-dihydro -1H- indol-3-yl] -4- (4-methylpiperazin-_1_ yl) piperidine-1-carboxamide; (10) (-) - N- [5- cyano -l - [(2,4- dimethoxyphenyl) sulfonyl] -3- (ethoxy 2_ pyridin-3-yl) -2-oxo-2,3-dihydro -1H- indol-3-yl] -4- (4-methylpiperazin-_1_ yl) piperidine-1-carboxamide ; (11) N- [5- cyano-3- (2-ethoxy-3-yl) -1 - [(2-methoxyphenyl) sulfonyl] -2-oxo-2, 3- dihydro -1H- indol-3-yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide; (12) N- [5_ atmosphere-1- [(2-ethoxyphenyl) an acid cross-yl] _3_ (2-ethoxy than Jie _3_基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺; (13) N- [5-氰基-3- (2-乙氧基吡啶-3-基)-2-氧代-1-(苯磺酰基)_2,3- 二氢-1H-吲哚-3-基]-4- (4-甲基哌嗪-1-基)哌啶-1-羧酰胺; (14) N- [5-氰基-3- (2-乙氧基吡啶-3-基)-1- [ (4-甲氧基苯基)磺酰基]-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(4-甲基哌嗪-1-基)哌啶-1-羧酰胺; (15) N-[5-氰基-1-[(2,4- 二甲氧基苯基)磺酰基]-3- (2-乙氧基吡啶-3-基)_2_氧代-2,3- 二氢-1H-吲哚-3-基]-4-(4-乙基哌嗪-1-基)哌啶-1-羧酰胺; (16) (+)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4- (4-乙基哌嗪_1_基)哌啶-1-羧酰胺; (17) (-)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4- (4-乙基哌嗪_1_基)哌啶-1-羧酰胺;` (18) N- [5-氰基-3- (2-乙氧基吡啶-3-基)-2-氧代-1-( _3_-yl) -2-oxo-2,3-dihydro -1H- indol-3-yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide; ( 13) N- [5- cyano-3- (2-ethoxy-3-yl) -2-oxo-1- (phenylsulfonyl) -1H- indol-3-dihydro-_2,3- - yl] -4- (4-methyl-piperazin-1-yl) piperidine-1-carboxamide; (14) N- [5- cyano-3- (2-ethoxy-3-yl ) -1 - [(4-methoxyphenyl) sulfonyl] -2-oxo-2,3-dihydro -1H- indol-3-yl] -4- (4-methylpiperazine - 1- yl) piperidine-1-carboxamide; (15) N- [5- cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (2-ethoxy pyridin-3-yl) -1H- _2_ oxo-2,3-dihydro-indol-3-yl] -4- (4-ethyl-piperazin-1-yl) piperidine-1-carboxamide; (16) (+) - N- [5- cyano -l - [(2,4- dimethoxyphenyl) sulfonyl] -3- (2_-ethoxy-pyridin-3-yl) -2 - oxo-2,3-dihydro -1H- indol-3-yl] -4- (4-ethyl-piperazin-_1_ yl) piperidine-1-carboxamide; (17) (-) - N- [5- cyano -l - [(2,4- dimethoxyphenyl) sulfonyl] -3- (2_-ethoxy-pyridin-3-yl) -2-oxo-2,3 - dihydro -1H- indol-3-yl] -4- (4-ethyl-piperazin-_1_ yl) piperidine-1-carboxamide; `(18) N- [5- cyano-3- (2-ethoxy-3-yl) -2-oxo-1- ( 磺酰基)_2,3- 二氢-1H-吲哚-3-基]-4- (4-乙基哌嗪-1-基)哌啶-1-羧酰胺; (19) (-)-N-[5-氰基-3-(2-乙氧基吡啶-3-基)-2-氧代-1-(苯磺酰基)-2,3_ 二氢-1H-吲哚-3-基]-4- (4-乙基哌嗪-1-基)哌啶-1-羧酰胺; (20) N-[5-氛基-l-[ (2,4- 二甲氧基苯基)横酸基]_3_ (2-乙氧基卩比卩定_3_基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(4-丙基哌嗪-1-基)哌啶-1-羧酰胺; (21) N-[5-氛基-l-[ (2,4- 二甲氧基苯基)横酸基]-3- (2-乙氧基卩比唳-3-基)~2~氧代-2,3- 二氢-1H-吲哚-3-基]-4-哌嗪-1-基哌啶-1-羧酰胺;(22) N-[5-氛基-l-[ (2,4- 二甲氧基苯基)横酸基]_3_ (2-乙氧基卩比卩定_3_基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-哌啶-4-基哌嗪-1-羧酰胺; (23) N-[5-氛基-l-[ (2,4- 二甲氧基苯基)横酸基]_3_ (2-乙氧基卩比卩定_3_基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4,4' -联哌啶-1-羧酰胺; (24) N-[5-氰基-1-[(2,4- 二甲氧基苯基)磺酰基]-3- (2-乙氧基吡啶_3_ Sulfonyl) -1H- _2,3- dihydro-indol-3-yl] -4- (4-ethyl-piperazin-1-yl) piperidine-1-carboxamide; (19) (-) - N - [5-cyano-3- (2-ethoxy-pyridin-3-yl) -2-oxo-1- (phenylsulfonyl) -1H- -2,3_ dihydro-indol-3-yl] 4- (4-ethyl-piperazin-1-yl) piperidine-1-carboxamide; (20) N- [5- yl atmosphere -l- [(2,4- dimethoxyphenyl) cross acid-yl] _3_ (2-ethoxy-Jie Jie ratio given _3_ yl) -2-oxo-2,3-dihydro -1H- indol-3-yl] -4- (4-propyl-piperazine l-yl) piperidine-1-carboxamide; (21) N- [5- yl atmosphere -l- [(2,4- dimethoxyphenyl) an acid cross-yl] -3- (2- Jie Li ratio ethoxy-3-yl) ~ 2 ~ oxo-2,3-dihydro -1H- indol-3-yl] -4-piperazin-1-yl piperidine-1-carboxamide; (22) N- [5- yl atmosphere -l- [(2,4- dimethoxyphenyl) an acid cross-yl] _3_ (2-ethoxy-Jie Jie ratio given _3_ yl) -2 dihydro -1H- indol-3-yl] -4-piperazin-1-yl-4-carboxamide; (23) N- [5- atmosphere -L-yl [( 2,4-dimethoxyphenyl) an acid cross-yl] _3_ (2-ethoxy-Jie Jie ratio given _3_ yl) -2-oxo-2,3-dihydro -1H- indol-3 - yl] -4,4 '- bipiperidinyl-carboxamide; (24) N- [5- cyano-1 - [(2,4-dimethoxyphenyl) sulfonyl] -3- (pyridin-2-ethoxy _3_ )_2_氧代-2,3-二氢-1H-吲哚-3-基]-1' -甲基_4,4' -联哌啶-1-羧酰胺; (25) (-)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-1' -甲基-4,4' -联哌啶_1_羧酰胺; (26) N-[5-氛基-l-[ (2,4- 二甲氧基苯基)横酸基]_3_ (2-乙氧基卩比卩定_3_基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-1' -乙基-4,4' -联哌啶_1_羧酰胺; (27) (-)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3-二氢-1H-吲哚-3-基]-1' -乙基_4,4' -联哌啶_1_羧酰胺; (28) (-)-N-[5-氰基-l-[(2,4- 二甲氧基苯基)磺酰基]-3-(2_乙氧基吡啶-3-基)-2-氧代-2,3- 二氢-1H-吲哚-3-基]-4-(1-乙基哌啶_4_基)哌嗪-1-羧酰胺; 或其至少一种药学上可接受的盐或一种互变异构体形式。 ) -1H- _2_ oxo-2,3-dihydro-indol-3-yl] -1 '- methyl _4,4' - bipiperidinyl-carboxamide; (25) (-) - N- [5- cyano -l - [(2,4- dimethoxyphenyl) sulfonyl] -3- (2_-ethoxy-pyridin-3-yl) -2-oxo-2,3 - dihydro -1H- indol-3-yl] -1 '--4,4' - bipiperidine _1_ carboxamide; (26) N- [5- yl atmosphere -l- [(2 , 4-dimethoxyphenyl) an acid cross-yl] _3_ (2-ethoxy-Jie Jie ratio given _3_ yl) -2-oxo-2,3-dihydro -1H- indol-3 yl] -1 '- ethyl-4,4' - bipiperidine _1_ carboxamide; (27) (-) - N- [5- cyano -l - [(2,4- dimethoxyphenyl phenyl) sulfonyl] -3- (2_-ethoxy-pyridin-3-yl) -2-oxo-2,3-dihydro -1H- indol-3-yl] -1 '- ethyl _ 4,4 '- bipiperidine _1_ carboxamide; (28) (-) - N- [5- cyano -l - [(2,4- dimethoxyphenyl) sulfonyl] -3- (2_-ethoxy-pyridin-3-yl) -2-oxo-2,3-dihydro -1H- indol-3-yl] -4- (1-ethyl-piperidin _4_ yl) piperazine 1-carboxamide; or a pharmaceutically acceptable salt or at least one tautomeric form.
18.药物,包含至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式。 18. A pharmaceutical compound, as claimed in claim comprising at least one formula (I) according to any of 1-16 or at least one of a pharmaceutically acceptable salt or one tautomeric forms cross, or at least one claim It requires at least 17 or a compound of a pharmaceutically acceptable salt or one tautomeric form.
19.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:至少一种加压素-依赖性疾病。 At least one pharmaceutically acceptable salt or one tautomeric forms of the compounds of formula 1-16 or 19. At least one of any one of claims (I) or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of: at least one vasopressin - dependent diseases.
20.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:至少一种疾病,所述疾病选自糖尿病、胰岛素抗性、夜遗尿、失禁、出现凝血障碍的疾病和/或延迟排尿。 At least one pharmaceutically acceptable salt or one tautomeric forms of the compounds of formula 1-16 or 20. At least one of any one of claims (I) or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of: at least one disease, the disease is selected from diabetes, insulin resistance, nocturnal enuresis, incontinence, diseases appear coagulopathy and / or delay of urination.
21.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:至少一种疾病,所述疾病选自高血压、心力衰竭、心肌梗死、冠状动脉痉挛、不稳定心绞痛、PTCA(经皮腔内冠状动脉成形术)、心脏缺血、肾脏体系紊乱、浮肿、肾血管痉挛、肾皮质坏死、低钠血症、低钾血症、Schwartz-Bartter综合征、胃肠道紊乱、胃炎性血管疫挛、肝硬化、胃肠溃疡、呕吐和/或旅行病。 At least one pharmaceutically acceptable salt or one tautomeric forms of the compounds of formula 1-16 or 21. At least one of any one of claims (I) or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of: at least one disease, the diseases selected from hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), cardiac ischemia, renal system disorders, edema, renal vasospasm, renal cortex necrosis, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, gastrointestinal disorders, vascular Phytophthora twin gastritis, liver cirrhosis, gastrointestinal ulcers, vomiting and / or travel sickness.
22.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:肺动脉高血压。 At least one pharmaceutically acceptable salt or one tautomeric forms thereof 22. A compound of formula 1-16 according to at least of claims (I) of the, or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of diseases: pulmonary hypertension.
23.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:化疗期间的呕吐。 At least one pharmaceutically acceptable salt or one tautomeric forms of the compounds of formula 1-16 or 23. At least one of any one of claims (I) or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of diseases: vomiting during chemotherapy.
24.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:情感障碍。 At least one pharmaceutically acceptable salt or one tautomeric forms thereof 24. A compound of formula 1-16 according to any one of at least one of claims (I) of the, or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of diseases: affective disorders.
25.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:焦虑症。 At least one pharmaceutically acceptable salt or one tautomeric forms thereof 25. A compound of formula 1-16 according to any one of at least one of claims (I) of the, or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of diseases: anxiety.
26.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:记忆缺陷和/或阿尔茨海默氏病。 At least one pharmaceutically acceptable salt or one tautomeric forms thereof 26. A compound of formula 1-16 according to any one of at least one of claims (I) of the, or at least one of claims 17 compound or at least a pharmaceutically acceptable salt or one tautomeric form for the preparation of a patient for the treatment and / or prophylaxis of the following diseases: memory deficits and / or Alzheimer Alzheimer's disease.
27.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:精神障碍。 At least one pharmaceutically acceptable salt or one tautomeric forms thereof 27. A compound of formula 1-16 according to any one of at least one of claims (I) of the, or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of diseases: mental disorders.
28.至少一种权利`要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:库兴综合征。 28. at least one compound as claimed in claim `formula (I) according to any of 1-16 or at least one of a pharmaceutically acceptable salt or one tautomeric forms cross, as claimed in claim 17 or at least one compound or at least a pharmaceutically acceptable salt or one tautomeric form for the preparation of a patient for the treatment and / or prophylaxis of the following diseases: Cushing's syndrome.
29.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:睡眠障碍。 At least one pharmaceutically acceptable salt or one tautomeric forms of the compounds of formula 1-16 or 29. The at least any one of claims (I) of the, or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of diseases: sleep disorders.
30.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:抑郁症。 At least one pharmaceutically acceptable salt or one tautomeric forms thereof 30. A compound of formula 1-16 at least any one of claims (I) of the, or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or prophylaxis of drug treatment in: depression.
31.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:儿童期发病的心境障碍。 At least one pharmaceutically acceptable salt or one tautomeric forms thereof 31. A compound of formula 1-16 according to any one of at least one of claims (I) of the, or at least one of claims 17 a compound or a pharmaceutically acceptable salt or at least one tautomeric form for the preparation of a patient for use and / or treatment of prophylaxis of: mood disorders in childhood onset.
32.至少一种权利要求1-16任一项的通式(I)的化合物或其至少一种药学上可接受的盐或一种互变异构体形式,或至少一种权利要求17的化合物或其至少一种药学上可接受的盐或一种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:血管舒缩症状和/或温度调节功能障碍。 At least one pharmaceutically acceptable salt or one tautomeric forms thereof 32. A compound of formula 1-16 at least any one of claims (I) of the, or at least one of claims 17 compound or at least a pharmaceutically acceptable salt or one tautomeric form for the preparation of a patient for the treatment and / or prophylaxis of the following diseases: vasomotor symptoms and / or temperature adjustment dysfunction.
33.至少ー种权利要求1-16任一项的通式(I)的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式,或至少ー种权利要求17的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:"热潮紅"症状。 33. A compound as claimed in claim species ー least any one of Formula 1-16 (I) or a pharmaceutically ー least kind ー acceptable salt or tautomeric form thereof, or at least a kind of claim ー 17 the use and / or prophylaxis of the following diseases or at least a compound or a pharmaceutically acceptable salt species ー ー tautomeric forms for the preparation of a patient for the treatment of: "hot flashes" symptoms.
34.至少ー种权利要求1-16任一项的通式(I)的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式,或至少ー种权利要求17的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:精神作用物质依赖和/或药物依赖,由调节依赖性的一种或多种因素的戒除所引起应激反应,和/或精神作用物质依赖和/或药物依赖中由应激反应引起的复发。 34. A compound as claimed in claim species ー least any one of Formula 1-16 (I) or a pharmaceutically ー least kind ー acceptable salt or tautomeric form thereof, or at least a kind of claim ー 17 compound tautomeric forms or at least ー species or a pharmaceutically acceptable salt thereof for the manufacture of ー and / or medicament for treating a patient in prophylaxis: psychoactive substance dependence and / or drug dependence, recurrent stress, and / or psychoactive substance dependence and / or drug dependence caused by the stress-dependent regulation by the withdrawal of one or more factors caused.
35.至少ー种权利要求1-16任一项的通式(I)的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式,或至少ー种权利要求17的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:精神分裂症。 35. A compound as claimed in claim species ー least any one of Formula 1-16 (I) or a pharmaceutically ー least kind ー acceptable salt or tautomeric form thereof, or at least a kind of claim ー 17 a compound or a pharmaceutically acceptable salt or species least ー ー tautomeric forms for the preparation of a patient for use and / or treatment of prophylaxis of diseases: schizophrenia.
36.至少ー种权利要求1-16任一项的通式(I)的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式,或至少ー种权利要求17的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:与应激反应有关的焦虑症。 36. A compound as claimed in claim species ー least any one of Formula 1-16 (I) or a pharmaceutically ー least kind ー acceptable salt or tautomeric form thereof, or at least a kind of claim ー 17 a compound or a pharmaceutically acceptable salt or species least ー ー tautomeric forms for the preparation of a patient for the treatment and / or prophylaxis of the following diseases: anxiety and stress-related disease.
37.至少ー种权利要求1-16任一项的通式(I)的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式,或至少ー种权利要求17的化合物或其至少ー种药学上可接受的盐或ー种互变异构体形式在制备用于患者的用于治疗和/或预防下述疾病的药物中的用途:精神病。 37. A compound as claimed in claim species ー least any one of Formula 1-16 (I) or a pharmaceutically ー least kind ー acceptable salt or tautomeric form thereof, or at least a kind of claim ー 17 a compound or a pharmaceutically acceptable salt or species least ー ー tautomeric forms for the preparation of a patient for use and / or treatment of prophylaxis of diseases: psychosis.
38.权利要求19-37任ー项的用途,其特征在于所述患者是ー种哺乳动物。 The use according to any of items 19-37 ー claimed in claim 38., wherein said patient is ー mammals.
39.权利要求19-37任ー项的用途,其特征在于所述患者是人。 The use according to any of items 19-37 ー claimed in claim 39., wherein said patient is a human.
40.权利要求19-30和32-37任ー项的用途,其特征在于所述患者是非人类哺乳动物。 The use of any of 32-37 19-30 and 40. The term ー claim, wherein said patient is a non-human mammal.
41.权利要求19 -30和32-37任ー项的用途,其特征在于所述患者是非人类转基因哺乳动物。 The use of any of 32-37 19-30 and 41. The term ー claim, wherein the patient is a non-human transgenic mammal.
CN 200780051459 2006-12-30 2007-12-28 Substituted oxindole derivatives and their use as vasopressin receptor ligands CN101611028B (en)

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