CN102558167A

CN102558167A - Thiazolidine derivant with GK and PPAR double excitation activity

Info

Publication number: CN102558167A
Application number: CN2010106124885A
Authority: CN
Inventors: 冯志强; 申竹芳; 卢建勋; 雷蕾; 金小锋; 环奕; 刘泉; 高丽辉
Original assignee: Institute of Materia Medica of CAMS and PUMC
Current assignee: Institute of Materia Medica of CAMS and PUMC
Priority date: 2010-12-29
Filing date: 2010-12-29
Publication date: 2012-07-11

Abstract

本发明公开了一类新的噻唑烷二酮衍生物、及其制法和药物组合物与用途。具体而言，涉及通式I和II所示的噻唑烷二酮衍生物，其可药用盐，其同样生物功能的前体或衍生物，及其制备方法，含有一个或多个这化合物的组合物，和该类化合物在治疗与葡萄糖激酶和过氧化物酶增殖体激活受体有关的疾病如糖尿病、肥胖症等方面的用途。

The invention discloses a new class of thiazolidinedione derivatives, its preparation method, pharmaceutical composition and application. Specifically, it relates to thiazolidinedione derivatives represented by general formulas I and II, their pharmaceutically acceptable salts, their precursors or derivatives with the same biological function, and their preparation methods, containing one or more of these compounds Composition, and the use of this type of compound in treating diseases related to glucokinase and peroxisome proliferator-activated receptors, such as diabetes and obesity.

Description

GK and the active thiazolidine diketone derivative of PPAR double excitations

Invention field

The present invention relates to the thiazolidine diketone derivative shown in general formula I and the II; Its pharmacologically acceptable salt; The precursor of its same biological function or verivate; And preparation method thereof, contain one or more these compound compositions and this compounds purposes at treatment and gk and px vegetation activated receptor diseases associated such as aspects such as mellitus, obesity.

Background of invention

Sugar is organism important energy and carbon source.The sugar decomposition generate energy can be supplied with the needs of organism vital movement, and glycometabolic intermediate product can be transformed into other carbon compound again, like amino acid, lipid acid, nucleosides etc.Carbohydrate metabolism can be divided into the decomposition of sugar and synthetic two aspects of sugar.Catabolism of carbohydrate comprises glycolysis-, i.e. the common decomposition approach of sugar; And tricarboxylic acid cycle, the i.e. last oxidative pathway of sugar.Glycolysis is that enzyme becomes pyruvic acid with glucose degradation and is accompanied by the process that generates ATP.It is the energy-producing common metabolic approach of breakdown of glucose in animal, plant, the microorganism cells.In the oxygen consumption organism, the pyruvic acid that glycolysis generates gets into plastosome, is become CO through tricarboxylic acid cycle by exhaustive oxidation ₂And water; The NADH that glycolysis generates produces ATP and water through the respiratory chain oxidation.So glycolysis is the prelude of oxidative phosphorylation and tricarboxylic acid cycle.Gk (GK) is one of four kinds of HKs finding on one's body Mammals [Cofowick, S.P.The Enzymes, Vol.9 (P.Boyer ' ed.) Academic Press; New York, N bifurcation .1-48 page or leaf, 1973]; It is first key enzyme in the glycolytic pathway; It can become the 6-glucose 1-phosphate1-with glucose phosphorylation under the condition that ATP exists, get into the metabolic process in downstream.Therefore, this step is first rate-limiting step of whole carbohydrate metabolism process, and GK is first rate-limiting enzyme in the carbohydrate metabolism process, plays important biological action.

The cell distribution of GK is limited, is mainly seen in pancreas beta cell and hepatic tissue cell.In addition, GK is playing the part of important role in controlling blood sugar balance and metabolism, regulates on the one hand the glycogen metabolism, and when on an empty stomach or blood sugar when low, GK is active low, and glycogen output increases, to guarantee the energy supply of vitals; After the meal or blood sugar when high, the GK increased activity, thus promote liver starch synthetic, suppress the liver glyconeogenesis, to keep glycaemic homeostasis.Regulate and control secretion of insulin as the susceptor of glucose on the other hand.When blood sugar concentration was higher than normal value in the body, the glucose in the blood got into beta Cell of islet by glucose transporter 2 (GLUT2) transhipment, and phosphorylation generates the 6-glucose 1-phosphate1-under the GK effect.The glycolysis of glucose, oxidative metabolism increase ATP/ADP ratio; The K+ ionic channel is closed, film depolarize, voltage susceptibility Ca2+ channel opener; Stream in the Ca2+; Regular Insulin storage vesica and plasma membrane merge, and make Regular Insulin discharge into blood, and get into the adjusting that liver, fat and muscle cell are participated in blood sugar with blood circulation.Glucose in liver phosphoric acid under the effect of GK turns to-6 glucose 1-phosphate1-s, then synthetic liver starch under insulin action.At fat and muscle cell, Regular Insulin triggers glucose transporter 4 (GLUT4) and in cell, stores picked-up and the metabolism that vesica migrates to plasma membrane promotion glucose.GK discharges and glycogen metabolism double action mechanism lowering blood glucose through regulating Regular Insulin, and [Al-Hasani H plays a significant role in keeping the glycaemic homeostasis process; Tschopl M H.Mol Interv, 2003,3 (7), 367-370].[Chipkin, S.R., Kelly, K.L. and Ruderrnam, N.B. are shown in Joslin ' Diabetes (C.R.Khan and G.C.Wier compile), Lea and Febiger, Philadelphia, PA, 97-115 page or leaf, 1994].

It is to be caused by afunction after the GK transgenation that young type is early sent out mellitus (MODY), shows that GK also plays glucose sensor Liang in human body, Y, Kesavan, P., Wang, people such as L., Biochem.J.309,167-173,1995).Except that MODY, also ubiquity GK is active in the general diabetic individual descends.Pathogenesis to diabetes B discovers that further the active reduction of liver GK possibly participated in insulin resistant mechanism, causes blood sugar increasing, and islet function is impaired to be increased the weight of with insulin resistant.Can increase the active medicine of GK to stop or to delay advancing of disease so seek, might open up a new way for early prevention and treatment mellitus.

Recognize in recent years: pancreatic beta type glucokinase is confined to the brain of rat, wherein particularly expresses in the feeding center (ventromedial nucleus of hypothalamus, VMH).The neurocyte of the about twenty percent among the VMH is known as glucose response property neurone (glucose-responsive neutrons), is considered to aspect management of body weight, play a significant role in the past.In the brain of rat, give glucose, then food ration reduces, and if analogue one glycosamine that gives glucose in the brain suppresses glucose metabolism, many foods then take place.The electrophysiology experiment shows: glucose response property neurone and physiological glucose concn change (5-20mM) and are activated accordingly, but through inhibition glucose metabolisms such as glycosamines, then its activity is suppressed.Can infer the glucose concn sensory perceptual system of VHM and the insulin secretion of pancreatic beta cell is the mechanism via glucokinase equally.Therefore, except that liver, pancreatic beta cell, the active material of glucokinase that activates VHM not only has the effect of blood sugar regulation, also possibly regulate the worried obesity of a lot of diabetes B patients.Can know by above-mentioned record; Compound with glucokinase activation can be used as treatment of diabetes medicine and/or prophylactic agent; Perhaps the chronic complicating diseases of mellitus such as retinopathy, ephrosis, neurosis, ischemic heart disease, arteriosclerosis treat and/or prevent medicine, further can be used as the fat medicine that treats and/or prevents.

It has been found that many GK small molecules acvators; Has the various structure characteristic: like substituted phenylacetamides (WO0058293 WO0185706 WO0208209 WO0185707 WO0183465 WO0246173WO2004072066 WO0246173); Substituted hydantoins (WO0183478), substituted azole class (WO2006112549), substituent indole (US0067939 WO031179); The substituted Propionamides of isoindoline (WO0248106); Substituted anthranilamide-based (WO03080585), substituted α phenylacryloyl amine (WO0214312) etc., wherein phenylacetamides is that research is done many one type.Though above-mentioned GK acvator research has been made very big contribution to this area, and is active for improving compound structure and GK acvator, research is still being continued in this area.

Px vegetation activated receptor (PPARs) belongs to the nuclear hormone receptor superfamily, has three kinds of hypotypes (PPAR α, PPAR γ, PPAR δ).Three kinds of acceptors are exercised the function of lipid transmitter, and important organism metabolism is regulated in the expression of coordinated regulation several genes sequence.PPARs has multiple biological effect, can promote adipocyte differentiation and steatogenesis, and enhancing body is to the susceptibility of Regular Insulin, and sugared balance in the mediation body is the drug targets of effectively treating metabolic disease (like type ii diabetes and atherosclerosis).And generation of the inflammation-inhibiting factor and inflammatory reaction, influence tumor growth, to cardiovascular generation protective effect.Research in recent years shows that PPARs also has neuroprotective, can alleviate nerve cell damage in the nerve degenerative diseases such as A Ercaimo disease, Parkinson's disease, cerebral ischemia and multiple sclerosis.

PPAR γ is different with classical nuclear receptor; After it is combined to activate by sepcific ligands; Still can not Direct Recognition combine special DNA regulating and controlling sequence, must be through (retinoid X receptor RXR) forms heterodimer with vitamin A acid x acceptor; Under the effect of many auxiliary adjustment factors (cofactors), regulate special genetic transcription.The PPAR γ part that activated gene is transcribed in early stage research calls the PPAR gamma agonist, is called suppressor factor and suppressor gene is transcribed.Latest Progress shows that PPAR γ combines the special conformation of formation with different ligands, determined the selective binding effect of PPAR γ one RXR heterodimer and special cofactor, has further determined heterogeneic alternative transcription regulating effect.Just because of this structure and interactional selectivity, make different PPAR γ parts through the selected gene transcriptional control, produce different biological effects.With regard to the complicacy of gene regulating; Same PPAR γ part is to the activation of transcribing of target gene; The inhibition that has, therefore, more and more scholars is with the unilateral definition of " regulator " replacement " agonist/suppressor factor "; And then the known selectively acting of research in some PPAR γ part of specific gene transcriptional control call " selective PPAR gamma modulators " (selective PPAR γ modulator, SPPARM).If any micromolecular compound activate PPAR γ; Then with the interaction of different cofactors; Can fatty atomization and glycolipid metabolism process be separated in the gene regulating level, promptly some promotes the not induced lipolysis differentiation of PPAR gamma agonist of glycolipid metabolism.

Research to PPA № regulator at present mainly concentrates on two problems: the one, and we need PPAR γ part to have great activation activity, activate PPAR γ to reach appropriateness, regulate the purpose that target gene is transcribed; The 2nd, can the fat differentiation be separated with insulin-sensitizing effect in the gene regulating level? The compound or the material that align under study for action should deeply be inquired into the molecular mechanism that its PPAR γ regulates, and screening existing insulin-sensitizing effect does not influence the fat differentiation again even promote lipometabolic PPAR gamma modulators.

Because PPAR α/δ participates in regulating lipid metabolism, improves hyperlipidaemia, alleviate the fat differentiation of PPAR γ activation-inducing to a certain extent; PPAR δ is also more extensive than PPAR α on tissue distribution; Research to PPAR δ in recent years also receives publicity; Many investigators are devoted to develop PPAR alpha/gamma double agonists or α/δ/γ three agonists; Expect that this type of medicine can reach the hypoglycemic effect of bringing into play regulating blood fat simultaneously, specific aim treatment obesity, insulin resistant, metabolic syndrome.Point out in the result of study of animal and clinical experiment at present; PPAR alpha/gamma double agonists or α/δ/γ three agonists really can improve insulin resistant; Improve hyperlipemia, but owing to still lack drug safety and toxicity test foundation, the application prospect of this compounds is still waiting to observe.

Mellitus are a kind of whole body chronic metabolic disease, and its pathological characters mainly is a hyperglycemia.It has been generally acknowledged that the main pathological change that causes hyperglycemia comprises the weakening and the metabolic imbalance of glycogen (being also referred to as three big pathological changes) of minimizing, effect of insulin secretion.The activation energy of gk (GK) promotes insulin secretion and glycogen metabolism simultaneously; The activation energy of px vegetation activated receptor (PPAR) increases the susceptibility of body cell to Regular Insulin.Therefore; Three big pathological changes to the mellitus hyperglycemia; Structure and pharmacological action based on known GK and PPAR small molecules agonist; Make up and synthetic GK and the two target spot ligand compounds of PPAR, research and develop a kind of many target spots of ' one medicine that can improve insulin secretion, glycogen metabolism and promotion peripheral tissues simultaneously the susceptibility of Regular Insulin ' medicine, will become the new way of seeking general efficacious therapy Glucovance.

Summary of the invention

The invention provides a kind of glucokinase activators that promptly can be used as and can be used as the general structure I of px vegetation activated receptor agonist and the thiazolidine diketone derivative of II again:

The object of the present invention is to provide a kind of GK of having and the active novel thiazole alkane of PPAR double excitations derovatives, its pharmacologically acceptable salt, its solvolyte, its prodrug, its polycrystalline or eutectic.

Another object of the present invention is to provide a kind of method for preparing novel thiazole alkane derovatives.

A purpose more of the present invention is to provide a kind of pharmaceutical composition that contains one or more this compounds.

Another purpose of the present invention is based on GK and PPAR biological function, proposes the new ideas of many target drugs combined therapy mellitus.

Another again purpose of the present invention provides GK and two ligand compounds of PPAR and the purposes of this compounds in treatment and GK and PPAR diseases related medicine.

The present invention relates to have the thiazolidine diketone derivative of following general formula I and II:

In the formula

R1 is selected from hydrogen, nitro, amino, cyanic acid, hydroxyl, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, halogen, C1-6 alkyl amido.

R1 more preferably is a hydrogen, nitro, amino, cyanic acid, hydroxyl, C1-4 alkyl, halogen.

R1 is hydrogen more preferably, nitro, amino, cyanic acid, hydroxyl, C1-4 alkyl.

R1 spy is preferably nitro, amino, hydroxyl, methyl.

R1 most preferably is nitro, amino, hydroxyl.

R2 is selected from-C (O) NHR1 ,-C (NH) R1, and-C (S) NHR1 and the hetero-aromatic ring that is connected through ring carbon atom: it contains 5-6 annular atoms, wherein has 1-4 to be selected from nitrogen, the heteroatoms of sulphur or oxygen; Or it contains 9-10 annular atoms, is condensed by aromatic ring that contains 6 annular atomses or hetero-aromatic ring and the hetero-aromatic ring that contains 5-6 annular atoms to form, and 1-5 heteroatoms that is selected from nitrogen, oxygen or sulphur arranged in the ring; At least one nitrogen-atoms is arranged in the ortho position of heterocycle shack carbon atom in the said hetero-aromatic ring; Said aromatic ring or hetero-aromatic ring do not replace for having, single replacement or polysubstituted; Substituting group is selected from R3, and R3 comprises following groups: halogen, amino, C1-6 alkylamino, C1-6 alkyl amido, carboxyl, ester group, 2-(methoxyimino) acetic ester-2-base, 2-(2-fluorine ethoxy imino) acetic ester-2-base, nitro, cyanic acid, methanesulfonamido, C1-6 alkyl, C1-6 alkoxyl group, perfluor replace the substituted C1-6 alkylamino of heteroaryl, R3, the substituted C1-6 alkyl amido of R3, the substituted C1-6 alkoxyl group of R3, the substituted C1-6 alkylthio of R3 that C1-4 alkyl, C1-6 alkylthio, perfluor replacement C1-4 alkyl sulphonyl, the substituted phenyl of R3 or 5-6 unit ring contain 1-5 heteroatoms (nitrogen, oxygen, sulphur).

R2 more preferably is-C (O) NHCH3 that-C (NH) CH3 and the hetero-aromatic ring that is connected through ring carbon atom: it contains 5-6 annular atoms, wherein has 1-4 to be selected from nitrogen, the heteroatoms of sulphur or oxygen; Or it contains 9-10 annular atoms, is condensed by aromatic ring that contains 6 annular atomses or hetero-aromatic ring and the hetero-aromatic ring that contains 5-6 annular atoms to form, and 1-5 heteroatoms that is selected from nitrogen, oxygen or sulphur arranged in the ring; At least one nitrogen-atoms is arranged in the ortho position of heterocycle shack carbon atom in the said hetero-aromatic ring; Said aromatic ring or hetero-aromatic ring do not replace for having, single replacement or polysubstituted.Substituting group is selected from R3, comprises following groups: halogen, amino, C1-6 alkylamino, C1-6 alkyl amido, carboxyl, ester group, 2-(methoxyimino) acetic ester-2-base, 2-(2-fluorine ethoxy imino) acetic ester-2-base, cyanic acid, methanesulfonamido, C1-6 alkyl, C1-6 alkoxyl group, perfluor replace the substituted C1-6 alkylamino of heteroaryl, R3, the substituted C1-6 alkyl amido of R3, the substituted C1-6 alkoxyl group of R3, the substituted C1-6 alkylthio of R3 that C1-4 alkyl, C1-6 alkylthio, perfluor replacement C1-4 alkyl sulphonyl, the substituted phenyl of R3 or 5-6 unit ring contain 1-5 heteroatoms (nitrogen, oxygen, sulphur).

R2 more preferably from-C (O) NHCH3 ,-C (NH) CH3, thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base, 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, 5-ethoxycarbonyl thiazol-2-yl, 5-(2-(methoxyimino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-(2-(2-fluorine ethoxy imino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-methyl-isoxazole-3-base, pyridine-2-base, 5-picoline-2-base, 5-carboxyl pyridine-2-base, 5-chloropyridine-2-base, 5-fluorine pyridine-2-base, 5-methoxycarbonyl yl pyridines-2-base, 5-ethoxycarbonyl yl pyridines-2-base, the different third oxygen formyl radical pyridine of 5--2-base, 5-carbamyl yl pyridines-2-base, pyrazole-3-yl, basic, the 3-methyl isophthalic acid of N-methylpyrazole-3-; 2; 4-thiadiazoles-5-base, 3-methoxyl group-1; 2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid; 3; 4-thiadiazoles-2-base, 1H-tetrazolium-5-base, 5-methoxycarbonyl base-1; 2; 4-triazole-3-base, 5-ethoxycarbonyl-1; 2,4-triazole-3-base, pyrido thiazol-2-yl, 6-methylamino pyrido thiazol-2-yl, pyridine-imidazole-2-base, benzothiazole-2-base, pyrimidine-4-base, pyrimidine-2-base, methylamine formyl radical, NSC 158269 formyl radical, a chlorobenzylamine formyl radical, carboxylic ethamine formyl radical, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base, pyridazine-3-base, 6-methyl pyridazine-3-base, 6-chlorine pyridazine-3-base, quinoline-2-base, isoquinolyl-1; R2 special preferred from-C (O) NHCH3 ,-C (NH) CH3, thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base, 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, 5-ethoxycarbonyl thiazol-2-yl, 5-(2-(methoxyimino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-(2-(2-fluorine ethoxy imino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-methyl-isoxazole-3-base, pyridine-2-base, 5-picoline-2-base, 5-carboxyl pyridine-2-base, 5-chloropyridine-2-base, 5-fluorine pyridine-2-base, 5-methoxycarbonyl yl pyridines-2-base, 5-ethoxycarbonyl yl pyridines-2-base, the different third oxygen formyl radical pyridine of 5--2-base, 5-carbamyl yl pyridines-2-base, pyrazole-3-yl, basic, the 3-methyl isophthalic acid of N-methylpyrazole-3-; 2; 4-thiadiazoles-5-base, 3-methoxyl group-1; 2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid; 3; 4-thiadiazoles-2-base, 1H-tetrazolium-5-base, 5-methoxycarbonyl base-1; 2; 4-triazole-3-base, 5-ethoxycarbonyl-1; 2,4-triazole-3-base, pyrido thiazol-2-yl, 6-methylamino pyrido thiazol-2-yl, pyridine-imidazole-2-base, benzothiazole-2-base, pyrimidine-4-base, pyrimidine-2-base, methylamine formyl radical, NSC 158269 formyl radical, a chlorobenzylamine formyl radical, carboxylic ethamine formyl radical, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base, pyridazine-3-base, 6-methyl pyridazine-3-base, 6-chlorine pyridazine-3-base, quinoline-2-base, isoquinolyl-1.R2 most preferably from-C (O) NHCH3 ,-C (NH) CH3, thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base, 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, 5-ethoxycarbonyl thiazol-2-yl, 5-(2-(methoxyimino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-(2-(2-fluorine ethoxy imino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-methyl-isoxazole-3-base, pyridine-2-base, 5-picoline-2-base, 5-carboxyl pyridine-2-base, 5-chloropyridine-2-base, 5-fluorine pyridine-2-base, 5-methoxycarbonyl yl pyridines-2-base, 5-ethoxycarbonyl yl pyridines-2-base, the different third oxygen formyl radical pyridine of 5--2-base, 5-carbamyl yl pyridines-2-base, pyrazole-3-yl, basic, the 3-methyl isophthalic acid of N-methylpyrazole-3-; 2; 4-thiadiazoles-5-base, 3-methoxyl group-1; 2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid; 3; 4-thiadiazoles-2-base, 1H-tetrazolium-5-base, 5-methoxycarbonyl base-1; 2; 4-triazole-3-base, 5-ethoxycarbonyl-1; 2,4-triazole-3-base, pyrido thiazol-2-yl, 6-methylamino pyrido thiazol-2-yl, pyridine-imidazole-2-base, benzothiazole-2-base, pyrimidine-4-base, pyrimidine-2-base, NSC 158269 formyl radical, a chlorobenzylamine formyl radical, carboxylic ethamine formyl radical, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base, pyridazine-3-base, 6-methyl pyridazine-3-base, 6-chlorine pyridazine-3-base, quinoline-2-base, isoquinolyl-1.

X is selected from singly-bound, C1-6 alkyl, oxygen, sulphur, nitrogen.

X more preferably is a singly-bound, C1-4 alkyl, oxygen, sulphur, nitrogen.

X is singly-bound more preferably, C1-3 alkyl, oxygen, sulphur, nitrogen.

X spy is preferably singly-bound, C1-2 alkyl, oxygen, sulphur, nitrogen.

X most preferably is singly-bound, oxygen, sulphur, nitrogen.

Y is selected from C1-6 alkyl, sulphur, nitrogen.

Y more preferably is the C1-4 alkyl, nitrogen, sulphur.

Y is the C1-3 alkyl more preferably, nitrogen.

Y spy is preferably the C1-3 alkyl.

Y most preferably is the C1-2 alkyl.

In the I formula, R1 is a hydrogen, and X is oxygen, and Y is CH ₂The time, R2 is not thiazol-2-yl, pyridine-2-base, 4-(3, the 4-dichlorophenyl) thiazol-2-yl, 4-(4-methoxycarbonyl phenyl) thiazol-2-yl.

In the II formula, R1 is a hydrogen, and X is oxygen, and Y is CH ₂The time, R2 is not pyridine-2-base, 3-pyridone-2-base, 3-sulphonate oxygen yl pyridines-2-base, 3-glucose oxygen glycosides, 5-pyridone-2-base, 5-sulphonate oxygen yl pyridines-2-base.

In order to prepare the described compound of general formula I of the present invention or II, according to the structure of general formula I or II, it is divided into three parts, A (U 25560 part), B (cross structure that has aldehyde radical and carboxyl) and C (amino-contained group).Preparing method of the present invention is divided into two types; One type is synthetic according to the order of ABC; Be about to U 25560 1 and the cross structure compound 2 that has aldehyde radical under proper condition condensation obtain intermediate compound 3, the promotor that its condensation reaction is used comprises that amine such as piperidines, tetrahydrochysene pyrrole iron etc., the carboxyl that utilizes carboxyl or introducing in the compound 3 then with contain 4 reactions of amine groups compound and obtain compound of Formula I 5; This reaction can be passed through the direct amidation of dewatering agent; Like DCC, also can make carboxyl change acyl chlorides into earlier, again with amine H ₂N-R2 reacts amidation; 5 further are reduced and obtain general formula I I compound 6, can adopt common two key method for hydrogenation such as catalytic hydrogenation.

Another kind of is synthetic according to the order of CBA, promptly earlier with compound H ₂2 reactions obtain midbody compound 7 to N-R2 with the cross structure compound that has carboxyl, and this reaction can be passed through the direct amidation of dewatering agent, like DCC, also can make carboxyl change acyl chlorides into earlier, again with amine H ₂N-R2 reacts amidation; To have then aldehyde radical or the compound 7 of introducing aldehyde radical obtain compound of Formula I 5 with U 25560 1 condensation under proper condition, the promotor that its condensation reaction is used comprises that amine such as piperidines, tetrahydrochysene pyrrole iron etc.5 further are reduced and obtain general formula I I compound 6, can adopt common two key method for hydrogenation such as catalytic hydrogenation.

The reaction scheme that synthetic The compounds of this invention is more optimized is being raw material to L m-nitrobenzaldehyde 8, and wherein L is a leavings group, like the chlorine atom.This aldehyde at first obtains midbody 9 with U 25560 1 condensation, can select for use piperidines or tetrahydrochysene pyrrole to iron and be condensation accelerator.Ethyl malonate 10 obtains 11 with midbody 9 reactions under alkaline environment then, and further hydrolysis obtains introducing the midbody 12 of carboxyl.This carboxylic acid 12 and H ₂Dehydration generates acid amides 13 between N-R2.And further the two keys of hydro-reduction obtain compound 14.

Synthetic another reaction scheme of more optimizing of The compounds of this invention also is being raw material to L m-nitrobenzaldehyde 8, and wherein L is a leavings group, like the chlorine atom.This aldehyde at first obtains midbody 9 with U 25560 1 condensation, can select for use piperidines or tetrahydrochysene pyrrole to iron and be condensation accelerator.Midbody 9 and HXCH under alkaline environment then ₂The COOEt reaction obtains midbody 16, and wherein X is O, NH, S.Midbody 16 further hydrolysis obtain introducing the midbody 17 of carboxyl.This carboxylic acid 17 and H ₂Dehydration generates acid amides 18 between N-R2.And further the two keys of hydro-reduction obtain compound 19.

In addition, starting raw material and midbody in the above-mentioned reaction obtain easily, and each step reaction can be according to the document of having reported or can is easy to the ordinary method in the organic synthesis synthesize to those skilled in the art.General formula I and the said compound of general formula I I can solvolyte or the form of non-solvent compound exist, utilize different solvents to carry out crystallization and possibly obtain different solvolytes.General formula I comprises different acid salt with the said pharmacy acceptable salt of general formula I I, like following mineral acid or organic acid acid salt: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid; Methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid; Tartrate, fumaric acid, Hydrocerol A, lactic acid.The said pharmacy acceptable salt of general formula I also comprises Different Alkali metal-salt (lithium, sodium, sylvite), alkaline earth salt (calcium; Magnesium salts) and ammonium salt and the salt of physiologically acceptable cationic organic bases can be provided, like methylamine, n n dimetylaniline; Trimethylamine 99, piperidines, the salt of morpholine and three (2-hydroxyethyl) amine.All these salt within the scope of the present invention all can adopt the ordinary method preparation.In the preparation process of described general formula I and general formula I I compound and solvolyte and its salt, polycrystalline or eutectic possibly appear in different crystallization conditions.

The invention still further relates to the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be through the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, process to be suitable for any formulation of human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.

The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration; Route of administration can be enteron aisle or non-enteron aisle, like oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.

Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.

The compounds of this invention can be processed ordinary preparation, also process is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.

For The compounds of this invention is processed tablet, the various vehicle well known in the art that can be widely used comprises thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, TKK 021, vinyl resin, carbomer, Vinylpyrrolidone polymer, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Sodium Croscarmellose, sodium starch glycolate, sodium hydrogencarbonate and Citric Acid, polyoxyethylene sorbitol fatty ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.

Can also tablet further be processed coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.

For capsule is processed in the administration unit, can the effective constituent The compounds of this invention be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also can the effective constituent The compounds of this invention be processed particle or micropill with thinner, tamanori, disintegrating agent earlier, place hard capsule or soft capsule again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.

For The compounds of this invention is processed injection, can water, ethanol, Virahol, Ucar 35 or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be Prist, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.

In addition, like needs, also can in pharmaceutical prepn, add tinting material, sanitas, spices, correctives or other additive.

For reaching the medication purpose, enhancing treatment effect, medicine of the present invention or pharmaceutical composition can be used any known medication administration.

The dosage of The compounds of this invention pharmaceutical composition according to prevent or treat the character and the severity of disease, the individual instances of patient or animal, route of administration and formulation etc. can have large-scale variation.In general, the appropriate dose scope of the every day of The compounds of this invention is the 0.001-150mg/Kg body weight, is preferably the 0.01-100mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.

Compound of the present invention or compsn can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.

The compounds of this invention is the dual acvator of GK and PPAR or its precursor; Can discharge through regulating Regular Insulin; Tissue is to the susceptibility and the glycogen metabolism multiple action mechanism lowering blood glucose of Regular Insulin; Can be used for preventing and treat 1 type or 2 types especially diabetes B and relevant complication, or other disease relevant with GK and PPAR.

Embodiment

Below will combine embodiment that invention is described further, but not limit the scope of the invention.

Determining instrument: NMR spectrum is with Vaariaan Mercury 300 type NMRs.Mass spectrum is with ZAD-2F and VG300 mass spectrograph.

Embodiment 1: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-methyl-isoxazole-3-yl) ethanamide

4-chloro-3-nitrobenzaldehyde

(14g 100mmol) puts in the dense sulphur (150mL), and (8.5g 100mmol) joins in the above-mentioned reaction solution in batches, and control reaction temperature is no more than 40 ℃, finishes, and removes ice-water bath, reacts 24h under the room temperature with SODIUMNITRATE under the ice-water bath with 4-chloro-benzaldehyde.Reaction is poured into reaction solution among the trash ice 400g after finishing, and gets the Off-white solid product, and filtration drying gets white solid 16.4g. ¹H?NMR(CDCl ₃，300MHz)δppm：10.05(s，1H，CH)，8.37(s，1H，ArH)，8.04(d，1H，ArH)，7.76(d，1H，ArH)；MS(FAB)：185(M+1)

(Z)-and 5-(4-chloro-3-nitrophenyl methylene radical) thiazolidine-2, the 4-diketone

Will between the nitro 4-chloro-benzaldehyde (6.2g, 33mmol) and U 25560 (3.9g, 33mmol); Put into respectively in the toluene (30mL), stir adding piperidines (3mL) and Glacial acetic acid min. 99.5 (10mL) down, heating reflux reaction 4h; Leave standstill to room temperature, filter, filter cake washes with acetonitrile (5mL).Drying gets light yellow solid (6.7g, 71.3%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:12.79 (s, 1H, NH), 8.31 (s, 1H, CH), 7.92 (d, 1H, ArH), 7.86 (s, 1H, ArH), 7.84 (d, 1H, ArH); MS (FAB): 284 (M+1)

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) ethyl malonate

(1g 25mmol) puts among the DMSO (50mL), stirs to add ethyl malonate (5.8g down with NaH; 37.5mmol), be warming up to 100 ℃ of stirring reaction 1h, be cooled to room temperature and add 5-(4-chloro-3-oil of mirbane) thiazolidine-2; 4-diketone (7g; 25mmol), behind the reaction 40min, be heated to 100 ℃ of reaction 1h under the room temperature.After reaction finishes with the reaction solution impouring to saturated NH ₄Among the Cl (400mL), there is a large amount of light yellow solid depositions to produce.Filter, filter cake water (100mL) flushing, drying gets yellow solid (4.3g, 42.2%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:12.79 (s, 1H, NH), 8.35 (s, 1H, CH), 7.94 (d, 1H, ArH), 7.93 (s, 1H, ArH), 7.67 (d, 1H, ArH), 5.48 (s, 1H, CH), 4.44 (q, 4H, 2CH ₂), 1.17 (t, 6H, 2CH ₃); MS (FAB): 409 (M+1)

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetate

(4g 1mmol) puts in 20% the hydrochloric acid soln (80mL) heating reflux reaction 12h with (Z)-2-(4-((2, the 4-U 25560) methyl)-2-oil of mirbane) ethyl malonate.Be cooled to room temperature, filter, filter cake water (20mL) flushing.Filter cake is put in the water (30mL), used NaHCO under stirring ₃Saturated solution is regulated about pH value to 8, filters.Filtrating is regulated about pH value to 5 with concentrated hydrochloric acid, filters, and drying, recrystallizing methanol obtains white crystal (1.12g, 36.4%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:12.75 (s, 1H, OH), 12.65 (s, 1H, NH), 8.30 (s, 1H, CH), 7.87 (d, 1H, ArH), 7.83 (s, 1H, ArH), 7.69 (d, 1H, ArH), 4.04 (s, 2H ,-CH ₂-); MS (ESI): 307 (M-1)

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-methyl-isoxazole-3-yl) ethanamide

Under the ice bath with 3-amino-5-methyl-isoxazole (98mg, 1mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (191mg; 1mmol), (129mg 1mmol) puts into respectively among the exsiccant DMF (15mL) diisopropylethylamine; (308mg 1mmol) joins in the reaction solution in batches with (4-((2, the 4-U 25560) methyl) 2-oil of mirbane) acetate behind the reaction 5min; Ice bath removes ice bath, stirring reaction 10h under the room temperature after stirring 1h.Reaction solution is evaporated to 5mL, in impouring to the water (30mL), leaves standstill under the vigorous stirring, filter, filter cake water (10mL) flushing, drying.Post separates (CH ₂Cl ₂: MeOH=1: 1), recrystallizing methanol gets pale yellow crystals (112mg, 34.0%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:12.78 (s, 1H, NH), 11.23 (s, 1H, NH), 8.31 (s, 1H, CH), 8.21 (s, 1H, ArH), 7.92 (d, 1H, ArH), 7.70 (d, 1H, ArH), 6.51 (s, 1H, CH), 4.18 (s, 2H, CH ₂), 2.34 (s, 3H, CH ₃); HRMS (FAB): C ₁₆H ₁₃N ₄O ₆S (M+1), measured value: 389.05550 (M+1), calculated value: 389.05558 (M+1)

Embodiment 2: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(thiazol-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is thiazolamine for (100mg, 1mmol).Silicagel column separates, and gets pearl crystal (44mg, 11.3%) after the recrystallizing methanol: ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.65 (s, 1H, NH), 9.57 (s, 1H, NH), 8.32 (s, 1H, CH), 7.89 (d, 1H, J=6.9Hz, ArH), 7.85 (s, 1H, ArH), 7.81 (d, 1H, ArH), 7.71 (d, 1H, ArH), 7.65 (d, 1H, ArH), 4.04 (s, 2H, CH ₂); HRMS (FAB): C ₁₅H ₁₁N ₄O ₅S ₂(M+1), measured value: 391.0170 (M+1), calculated value: 391.0157 (M+1)

Embodiment 3: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(4-methylthiazol-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is 2-amino-4-methylthiazol for (114mg, 1mmol).Silicagel column separates, and recrystallizing methanol gets light yellow solid (73mg, 18.1%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:12.77 (s, 1H, NH), 10.72 (s, 1H, NH), 8.30 (s, 1H, CH), 7.81 (s, 1H, ArH), 7.80 (d, 1H, ArH), 7.65 (d, 1H, ArH), 6.22 (s, 1H, ArH), 4.22 (s, 2H, CH ₂), 2.23 (s, 3H, CH ₃); HRMS (FAB): C ₁₆H ₁₃N ₄O ₅S ₂(M+1), measured value: 405.0333 (M+1), calculated value: 405.03273 (M+1)

Embodiment 4: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(pyridine-2-yl) ethanamide

Operation is synthetic with embodiment's 1.Difference be the 2-EL-970 charging capacity for (94mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains yellow crystals (117mg, 30.5%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:10.94 (s, 1H, NH), 8.67 (s, 1H, NH), 8.22 (s, 1H; CH), 8.20 (s, 1H, ArH), 7.82 (d, 1H, ArH), 7.1-7.6 (m, 1H; ArH), 7.60 (d, 1H, ArH), 7.15 (d, 1H, ArH), 7.09 (d; 1H, ArH), 6.72-6.74 (m, 1H, ArH), 4.40 (s, 2H, CH ₂); HRMS (FAB): C ₁₇H ₁₃N ₄O ₅S (M+1), measured value: 385.0606 (M+1), calculated value: 385.06066 (M+1)

Embodiment 5: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-picoline-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is 2-amino-3-picoline for (108mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), ethyl alcohol recrystallization obtains brown crystal (105mg, 26.4%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:11.01 (s, 1H, NH), 9.31 (s, 1H, NH), 8.29 (s, 1H, CH), 8.20 (s; 1H, ArH), 7.97 (d, 1H, ArH), 7.87 (d, 1H, ArH), 7.79 (s, 1H; ArH), 7.69 (d, 1H, ArH), 7.64 (d, 1H, ArH), 4.51 (s, 2H, CH ₂), 2.54 (s, 3H, CH ₃); HRMS (FAB): C ₁₈H ₁₅N ₄O ₅S (M+1), measured value: 399.0766 (M+1), calculated value: 399.07631 (M+1)

Embodiment 6: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-chloropyridine-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is 2-amino-5-chloropyridine for (128mg, 1mmol).Silicagel column separates (CH ₂C1 ₂: MeOH=100: 1), ethyl alcohol recrystallization obtains pearl crystal (145mg, 34.7%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:12.71 (s, 1H, NH), 11.02 (s, 1H, NH), 8.38 (s, 1H, CH), 8.29 (s; 1H, ArH), 8.21 (s, 1H, ArH), 7.98 (d, 1H, ArH), 7.79 (d, 1H; ArH), 7.69 (d, 1H, JArH), 7.67 (d, 1H, ArH), 4.25 (s, 2H, NH ₂); HRMS (FAB): C ₁₇H ₁₂ClN ₄O ₅S (M+1), measured value: 419.0221 (M+1), calculated value: 419.02169 (M+1)

Embodiment 7: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-isopropyl formate pyridine-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is 6-amino-nicotinic acid isopropyl ester for (180mg, 1mmol).Silicagel column separates (CH ₂C1 ₂: MeOH=100: 1), the Virahol recrystallization obtains white crystal (117mg, 24.9%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.70 (s, 1H, NH), 9.86 (s, 1H, NH), 8.98 (s, 1H, ArH), 8.75 (s, 1H; CH), 8.40 (s, 1H, ArH), 8.34 (d, 1H, ArH), 8.30 (d, 1H, ArH), 7.97 (d; 1H, ArH), 7.75 (d, 1H, ArH), 4.94 (q, 1H, CH), 4.19 (s, 2H, CH ₂), 1.35 (d, 6H, 2CH ₃); HRMS (FAB): C ₂₁H ₁₉N ₄O ₇S (M+1), measured value: 471.0977 (M+1), calculated value: 471.09744 (M+1)

Embodiment 8: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-ethyl formate pyridine-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is 6-amino-nicotinic acid ethyl ester for (166mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), ethyl alcohol recrystallization obtains white crystal (92mg, 20.2%): ¹HNMR (Acetone-d ₆, 300MHz) δ ppm:10.95 (s, 1H, NH), 8.80 (s, 1H, NH), 8.55 (s, 1H, ArH), 8.17 (s; 1H, CH), 8.07 (s, 1H, ArH), 7.87 (d, 1H, ArH), 7.72 (d, 1H; ArH), 7.63 (d, 1H, ArH), 7.53 (d, 1H, ArH), 4.22 (q, 2H, CH ₂), 1.29 (t, 3H, CH ₃); MS (FAB): 457 (M+1)

Embodiment 9: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-methyl-formiate pyridine-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is 6-amino-nicotinic acid methyl esters for (152mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), ethyl alcohol recrystallization obtains white crystal (159mg, 40.0%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.65 (s, 1H, NH), 9.25 (s, 1H, NH), 8.88 (s, 1H, ArH), 8.73 (s; 1H, CH), 8.39 (s, 1H, ArH), 8.32 (d, 1H, ArH), 8.239 (d, 1H; ArH), 7.89 (d, 1H, ArH), 7.80 (d, 1H, ArH), 4.19 (s, 2H, CH ₂), 3.85 (s, 3H, CH ₃); HRMS (FAB): C ₁₉H ₁₅N ₄O ₇S (M+1), actual value: 443.0673 (M+1), calculated value: 443.06614 (M+1)

Embodiment 10: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(pyrimidine-2-base) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is the 2-aminopyrimidine for (95mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains white crystal (49mg, 12.7%): ¹H NMR (CDCl ₃-d ₁, 300MHz) δ ppm:12.91 (s, 1H, NH), 9.62 (s, 1H, NH), 9.51 (d, 2H, ArH), 9.44 (s, 1H, CH), 8.63 (s, 1H, ArH), 8.22 (d, 1H, ArH), 8.11 (d, 1H, ArH), 7.64 (t, 1H, ArH), 4.23 (s, 2H, CH ₂); MS (FAB): 386 (M+1)

Embodiment 11: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(benzothiazole-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is the 2-aminobenzothiazole for (150mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains white crystal (130mg, 29.5%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.63 (s, 1H, NH), 11.33 (s, 1H, NH), 9.31 (s, 1H, CH), 8.22 (s, 1H; ArH), 7.96 (d, 1H, ArH), 7.82 (d, 1H, ArH), 7.78 (d, 1H, ArH), 7.27 (d; 1H, ArH), 7.12 (m, 1H, ArH), 6.95 (m, 1H, ArH), 4.22 (s, 2H, CH ₂); MS (FAB): 411 (M+1)

Embodiment 12: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(quinoline-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is the 2-quinolylamine for (144mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains white crystal (207mg, 47.7%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:12.74 (s, 1H, NH), 11.17 (s, 1H, NH), 8.21 (s, 1H, CH), 8.16 (s, 1H; ArH), 7.89 (m, 1H, ArH), 7.84 (d, 1H, ArH), 7.79 (d, 1H, ArH), 7.73 (d; 1H, ArH), 7.65 (d, 1H, ArH), 7.48 (m, 1H, ArH), 4.31 (s, 2H, CH ₂); MS (FAB): 435 (M+1)

Embodiment 13: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-ethyl formate thiazol-2-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is 2-amino-5-ethyl formate thiazole for (172mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains grey crystal (161mg, 34.8%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.37 (s, 1H, NH), 9.00 (s, 1H, NH), 8.33 (s, 1H, CH), 7.85 (s, 1H, ArH), 7.88 (d, 1H, ArH), 7.81 (d, 1H, ArH), 6.48 (s, 1H, ArH), 4.17 (q, 2H, CH ₂), 3.32 (s, 2H, CH ₂), 1.22 (t, 3H, CH ₃); MS (FAB): 463 (M+1)

Embodiment 14: (E)-and 2-(2-(2-(4-((Z)-(2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetamido) thiazole-5-yl)-2-(methoxy imino) ETHYLE ACETATE

Operation is synthetic with embodiment's 1.The charging capacity that difference is 2-(thiazolamine)-2-methoxy imino ETHYLE ACETATE for (229mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains yellow crystals (196.7mg, 39.7%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.82 (s, 1H, NH), 8.32 (s, 1H, NH), 8.12 (s, 1H, CH), 7.91 (s, 1H, ArH), 7.78 (d, 1H, ArH), 7.54 (s, 1H, ArH), 7.51 (s, 1H, ArH), 4.30 (q, 2H, CH ₂), 4.19 (s, 2H, CH ₂), 4.02 (s, 3H, CH ₃), 1.28 (t, 3H, CH ₃); MS (FAB): 520 (M+1)

Embodiment 15: (E)-and 2-(2-(2-(4-((Z)-(2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetamido) thiazole-5-yl)-2-(2-fluoro ethoxy imido grpup) ETHYLE ACETATE

Operation is synthetic with embodiment's 1.The charging capacity that difference is 2-(thiazolamine)-2-(2-fluoro ethoxy imido grpup) ETHYLE ACETATE for (261mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains white crystal (262.8mg, 47.7%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.77 (s, 1H, NH), 8.33 (s, 1H, NH), 8.21 (s, 1H, CH), 7.90 (s, 1H, ArH), 7.79 (d, 1H, ArH), 7.64 (s, 1H, ArH), 7.57 (s, 1H, ArH), 4.64 (t, 2H, CH ₂), 4.31-4.44 (m, 4H, CH ₂), 4.27 (s, 2H, CH ₂), 1.28 (t, 3H, CH ₃); MS (FAB): 552 (M+1)

Embodiment 16: (Z)-and 2-(2-amino-4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(methylamine formyl radical) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is the N-methyl urea for (150mg, 2mmol).The silicagel column separation (ETHYLE ACETATE: sherwood oil=4: 1), obtain white powder (37.1mg, 10.2%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.76 (s, 1H, NH), 12.15 (t, 1H, NH), 9.31 (s, 1H, NH), 8.31 (s, 1H, CH), 7.93 (s, 1H, ArH), 7.69 (d, 1H, ArH), 7.65 (d, 1H, ArH), 2.55 (s, 2H, CH ₂), 1.15 (s, 3H, CH ₃); MS (FAB): 367 (M+1)

Embodiment 17: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(1-imido grpup ethyl) ethanamide

(188mg drips sat.NaHCO in aqueous solution 2mmol) (20mL) to B amidine hydrochloric acid salt ₃(aq.) be alkalescence to pH, dichloromethane extraction, dry removal of solvent under reduced pressure obtains the oily matter (76mg) of ethanamidine.Carrying out (Z)-2-(4-((2,4-dioxy thiazolone-5-methylene radical) methyl)-2-oil of mirbane)-N-(1-ethyl imino-) ethanamide according to the compound method of embodiment 1 synthesizes.The silicagel column separation (ETHYLE ACETATE: sherwood oil=4: 1), obtain white solid (27.1mg, 7.7%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:11.35 (s, 1H, NH), 8.72 (s, 1H, NH), 8.30 (s, 1H, CH), 7.82 (s, 1H, ArH), 7.79 (d, 1H, ArH), 7.75 (s, 1H, ArH), 2.55 (s, 2H, CH ₂), 1.22 (s, 3H, CH ₃); MS (FAB): 349 (M+1)

Embodiment 18: (Z)-and 2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(1H-tetrazolium-5-yl) ethanamide

Operation is synthetic with embodiment's 1.The charging capacity that difference is the 2-amino tetrazole for (127.5mg, 1.5mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains gray solid (133.9mg, 35.7%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.37 (s, 1H, NH), 11.26 (s, 1H, NH), 8.84 (s, 1H, NH), 8.31 (s, 1H, CH), 7.84 (s, 1H, ArH), 7.85 (d, 1H, ArH), 7.65 (d, 1H, ArH), 4.29 (s, 2H, CH ₂); MS (FAB): 376 (M+1)

Embodiment 19: (Z)-3-(2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetamido)-1H-1,2,4 ,-triazole-5-methyl-formiate

Operation is synthetic with embodiment's 1.Difference is 3-amino-1H-1,2,4, the charging capacity of-triazole-5-methyl-formiate be (142mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains light yellow look crystal (144.7mg, 33.5%): ¹H NMR (DMSO-d ₆, 300MHz) δ ppm:13.47 (s, 1H, NH), 12.39 (s, 1H, NH), 9.85 (s, 1H, NH), 8.66 (s, 1H, CH), 8.42 (s, 1H, ArH), 8.24 (d, 1H, ArH), 7.89 (d, 1H, ArH), 4.29 (s, 2H, CH ₂), 3.96 (s, 3H, CH ₃); MS (FAB): 434 (M+1)

Embodiment 20: (Z)-3-(2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetamido)-1H-1,2,4 ,-triazole-5-ethyl formate

Operation is synthetic with embodiment's 1.Difference is at 3-amino-1H-1,2,4, the charging capacity of-triazole-5-ethyl formate be (158mg, 1mmol).Silicagel column separates (CH ₂Cl ₂: MeOH=100: 1), recrystallizing methanol obtains yellow crystals (176.2mg, 39.5%): ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:13.51 (s, 1H, NH), 12.38 (s, 1H, NH), 9.83 (s, 1H, NH), 8.52 (s, 1H, CH), 8.30 (s, 1H, ArH), 8.21 (d, 1H, ArH), 7.68 (d, 1H, ArH), 4.29 (q, 2H, CH ₂), 4.01 (s, 2H, CH ₂), 3.96 (t, 3H, CH ₃); MS (FAB): 447 (M+1).

Embodiment 21. (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenylsulfenyl) acetate

With 5-(4-chloro-3-nitro tolylene) thiazolidine-2, (284mg 1mmol) puts among the ethanol 50mL 4-ketone, and (144mg, 1.2mmol), the NaOH drips of solution with 5mL10% adds reaction system, heating reflux reaction 1h again to add the 2-ethyl thioglycolate under stirring.Stop heating, be cooled to room temperature, have small amount of solid to separate out, filter, filter cake washes with ethanol 3mL, merging filtrate, and concentrating under reduced pressure obtains a little raffinate, ETHYLE ACETATE 100mL extraction, organic phase anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains the yellow solid 154.6mg of (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenylsulfenyl) ETHYLE ACETATE, productive rate 42.0%.Do not make purifying, directly drop into step reaction down.

(73.6mg 0.2mmol) puts among the THF 10mL, stirs to add Lithium Hydroxide MonoHydrate (24mg down with (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenylsulfenyl) ETHYLE ACETATE; 1mmol) with water 2mL in, heating reflux reaction 3h, stop the heating, removal of solvent under reduced pressure; There is yellow solid to produce in the raffinate, filters, filter cake water 2mL flushing; Drying gets solid matter 25.2mg, productive rate 37.1%. ¹H?NMR(DMSO-d ₆，300MHz)δppm：12.85(s，1H，OH)，10.85(s，1H，NH)，8.43(s，1H，CH)，7.88(d，1H，ArH)，7.73(s，1H，ArH)，7.70(d，1H，ArH)，4.09(s，2H，CH)。MS(ESI)：339(M-1)

Embodiment 22. (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenylsulfenyl)-N-(pyridine-2-yl)-ethanamide

With the 2-EL-970 (18.8mg, 0.2mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI; 38.2mg, 0.2mmol), diisopropylethylamine (DIEA; 25.8mg, 0.2mmol) put into respectively among the exsiccant DMF solution 10mL, (4-((2 with (Z)-2-under stirring; 4-U 25560-5-subunit) methyl)-and the 2-nitrophenylsulfenyl) (68.0mg 0.2mmol) joins in the reaction solution acetate in batches, stirring reaction 16h under the room temperature.With the reaction solution concentrating under reduced pressure, raffinate water 10mL soaks, and obtains light yellow solid, filters drying.The post separation obtains buff powder 29.2mg, productive rate 35.1%. ¹HNMR(DMSO-d ₆，300MHz)δppm：10.88(s，1H，NH)，8.53(s，1H，NH)，8.42(s，1H，ArH)，8.35(s，1H，CH)，8.02(d，1H，ArH)，7.76-7.88(m，3H，ArH)，7.66(d，1H，ArH)，7.60(m，1H，ArH)，7.14(m，1H，ArH)，4.19(s，2H，CH)MS(FAB)：417(M+1)

Embodiment 23. (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitro-phenoxy) acetate

With 5-(4-chloro-3-nitro tolylene) thiazolidine-2, (284mg 1mmol) puts among the ethanol 50mL 4-ketone, and (110mg, 1.2mmol), the NaOH drips of solution with 5mL10% adds reaction system, heating reflux reaction 1h again to add the 2-hydroxy methyl acetate under stirring.Concentrating under reduced pressure obtains a little raffinate, ETHYLE ACETATE 50mL extraction, organic phase anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains the yellow solid 94.2mg of (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitro-phenoxy) ETHYLE ACETATE, productive rate 27.8%.MS (FAB): 339 (M+1) do not make purifying and directly drop into step reaction down.

(67.6mg 0.2mmol) puts among the THF 10mL, stirs to add Lithium Hydroxide MonoHydrate (24mg down with (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitro-phenoxy) ETHYLE ACETATE; 1mmol) with water 2mL in, heating reflux reaction 3h, stop the heating, removal of solvent under reduced pressure; There is yellow solid to produce in the raffinate, filters, filter cake water 2mL flushing; Drying gets solid matter 37.7mg, productive rate 58.2%. ¹HNMR(DMSO-d ₆，300MHz)δppm：12.74(s，1H，OH)，10.89(s，1H，NH)，8.91(s，1H，CH)，8.31(s，1H，ArH)，7.86(d，1H，ArH)，7.70(d，1H，ArH)，4.20(s，2H，CH)MS(ESI)：323(M-1)

Embodiment 24. (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenylsulfenyl)-N-(pyridine-2-yl)-ethanamide

With the 2-EL-970 (18.8mg, 0.2mmol), EDCI (38.2mg; 0.2mmol), (25.8mg 0.2mmol) puts into respectively among the exsiccant DMF solution 10mL DIEA; (4-((2 with (Z)-2-under stirring; 4-U 25560-5-subunit) methyl)-and the 2-nitro-phenoxy) (62.8mg 0.2mmol) joins in the reaction solution acetate in batches, stirring reaction 16h under the room temperature.With the reaction solution concentrating under reduced pressure, raffinate water 10mL soaks, and obtains yellow solid, filters drying.The post separation obtains buff powder 21.5mg, productive rate 26.8%. ¹HNMR(DMSO-d ₆，300MHz)δppm：12.77(s，1H，NH)，11.26(s，1H，NH)，8.84(s，1H，CH)，8.31(s，1H，ArH)，7.91-8.27(m，3H，ArH)，7.71(d，1H，ArH)，7.01(m，1H，ArH)，6.90(m，1H，ArH)，4.23(s，2H，CH)MS(ESI)：402(M+1)

Embodiment 25. (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-oil of mirbane amido)-N-(pyridine-2-yl)-ethanamide

With 5-(4-chloro-3-nitro tolylene) thiazolidine-2, (284mg 1mmol) puts among the ethanol 50mL 4-ketone, and (124mg, 1.2mmol), the NaOH drips of solution with 5mL10% adds reaction system, heating reflux reaction 1h again to add 2-glycine methyl esters under stirring.Stop heating, be cooled to room temperature, have small amount of solid to separate out, filter, filter cake washes with ethanol 3mL, merging filtrate, and concentrating under reduced pressure obtains a little raffinate, ETHYLE ACETATE 50mL extraction, organic phase anhydrous sodium sulfate drying.Removal of solvent under reduced pressure obtains the light yellow solid 88.5mg of (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-oil of mirbane amido) ETHYLE ACETATE, productive rate 25.2%.MS (FAB): 352 (M+1) do not make purifying and directly drop into step reaction down.

(70.2mg 0.2mmol) puts among the THF 10mL, stirs to add Lithium Hydroxide MonoHydrate (24mg down with (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-oil of mirbane amido) ETHYLE ACETATE; 1mmol) with water 2mL in, heating reflux reaction 3h, stop the heating, removal of solvent under reduced pressure; There is yellow solid to produce in the raffinate, filters, filter cake water 2mL flushing; Drying gets solid matter 53.9mg, productive rate 83.2%.Do not make purifying, directly drop into step reaction down.MS(ESI)：323(M-1)

With the 2-EL-970 (18.8mg, 0.2mmol), EDCI (38.2mg; 0.2mmol), (25.8mg 0.2mmol) puts into respectively among the exsiccant DMF solution 10mL DIEA; (4-((2 with (Z)-2-under stirring; 4-U 25560-5-subunit) methyl)-and 2-oil of mirbane amido) (62.8mg 0.2mmol) joins in the reaction solution acetate in batches, stirring reaction 16h under the room temperature.With the reaction solution concentrating under reduced pressure, raffinate water 10mL soaks, and obtains yellow solid, filters drying.The post separation obtains buff powder 27.7mg, productive rate 34.6%. ¹HNMR(DMSO-d ₆，300MHz)δppm：12.07(s，1H，NH)，10.83(s，1H，NH)，8.89(s，1H，CH)，8.47(s，1H，ArH)，7.89-8.22(m，4H，ArH，NH)，7.59(m，1H，ArH)，7.34(m，1H，ArH)，7.12(d，1H，ArH)，4.43(s，2H，CH)。MS(ESI)：401(M+1)

Embodiment 26. (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-aminocarbonyl phenyl)-N-(5-isopropyl formate pyridine-2-yl) ethanamide

(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-(470mg 1mmol) puts among the mixing solutions 15mL of dioxane and methyl alcohol (5: 1) N-(5-isopropyl formate pyridine-2-yl) ethanamide with (Z)-2-; The palladium carbon 95mg of adding 10%, normal pressure hydrogenation reduction reaction 5h removes by filter palladium carbon; Filter residue is with methyl alcohol 5mL flushing, and concentrating under reduced pressure behind the merging filtrate obtains the tawny solid residue; Recrystallizing methanol gets pale yellow crystals 375mg, productive rate 85.2%: ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.53 (s, 1H, NH), 10.17 (s, 1H, NH), 8.75 (s, 1H, ArH), 8.31 (s, 1H, CH), 7.85-8.12 (m, 3H, ArH), 7.33 (d, 1H, ArH), 7.11 (s, 1H, ArH), 5.73 (bs, 2H, NH ₂), 4.76 (m, 1H, CH), 3.82 (s, 2H, CH ₂), 1.73 (d, 6H, 2CH ₃); MS:441 (M+1)

Embodiment 27. (Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-aminocarbonyl phenyl)-N-(5-picoline-2-yl) ethanamide

(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-(398mg 1mmol) puts among the mixing solutions 15mL of dioxane and methyl alcohol (5: 1) N-(5-picoline-2-yl) ethanamide with (Z)-2-; The palladium carbon 80mg of adding 10%, normal pressure hydrogenation reduction reaction 5h removes by filter palladium carbon; Filter residue is with methyl alcohol 5mL flushing, and concentrating under reduced pressure behind the merging filtrate obtains the brown solid residue; Recrystallizing methanol gets yellow crystals 212mg, productive rate 57.6%: ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:11.73 (s, 1H, NH), 10.17 (s, 1H, NH), 8.75 (s, 1H, CH), 8.55 (s, 1H, ArH), 7.99-8.32 (m, 3H, ArH), 7.64 (d, 1H, ArH), 7.25 (s, 1H, ArH), 5.37 (bs, 2H, NH ₂), 3.62 (s, 2H, CH ₂), 2.34 (s, 3H, CH ₃); MS (FAB): 369 (M=1)

Embodiment 28.2-(2-amido-4-((2,4-U 25560-5-yl) methyl) phenyl)-N-(5-picoline-2-yl) ethanamide

(4-((2,4-U 25560-5-subunit) methyl)-2-oil of mirbane)-(404mg 1mmol) puts among the mixing solutions 15mL of dioxane and methyl alcohol (5: 1) N-(4-methylthiazol) ethanamide with (Z)-2-; The palladium carbon 85mg of adding 10% sets the reaction flask internal pressure for 40psi hydro-reduction reaction 8h, removes by filter palladium carbon; Filter residue washes with methyl alcohol 5mL, concentrating under reduced pressure behind the merging filtrate, and raffinate soaks with 5mL methyl alcohol; The refrigerator freeze overnight has light yellow solid to produce, and filters; Recrystallizing methanol gets yellow crystals 83mg, productive rate 22.1%: ¹HNMR (MeOH-d ₄, 300MHz) δ ppm:9.07 (s, 1H, NH), 8.53 (s, 1H, NH), 7.37-7.59 (m, 3H, ArH), 7.04 (d, 1H, ArH), 5.62 (bs, 2H, NH ₂), 4.04 (t, 1H, CH), 3.62 (s, 2H, CH ₂), 2.88-3.24 (m, 2H, CH ₂), 2.25 (s, 3H, CH ₃); MS (FAB): 377 (M+1)

Embodiment 29.2-(2-amido-4-((2,4-U 25560-5-yl) methyl) phenyl)-N-(the different third oxygen formyl radical pyridine-2-yl of 5-) ethanamide

(4-((2,4-U 25560-5-subunit) methyl)-2-oil of mirbane)-(470mg 1mmol) puts among the mixing solutions 15mL of dioxane and methyl alcohol (5: 1) ethanamide N-(the different third oxygen formyl radical pyridine-2-yl of 5-) with (Z)-2-; The palladium carbon 95mg of adding 10% sets the reaction flask internal pressure for 40psi hydro-reduction reaction 8h, removes by filter palladium carbon; Filter residue washes with methyl alcohol 5mL, concentrating under reduced pressure behind the merging filtrate, and raffinate soaks with 5mL methyl alcohol; The refrigerator freeze overnight has pale solid to produce, and filters; Recrystallizing methanol gets white crystal 37mg, productive rate 8.4%: ¹HNMR (MeOH-d ₄, 300MHz) δ ppm:9.93 (s, 1H, NH), 9.41 (s, 1H, NH), 8.88 (s, 1H, ArH), 8.14-8.45 (m, 3H, ArH), 7.57 (s, 1H, ArH), 7.01 (d, 1H, ArH), 5.22 (bs, 2H, NH ₂), 4.93 (t, 1H, CH), 4.55 (t, 1H, CH), 4.17 (s, 2H, CH ₂), 3.34-3.74 (m, 2H, CH ₂), 1.66 (d, 6H, 2CH ₃); MS (FAB): 443 (M+1)

Embodiment 30.2-(2-amido-4-((2,4-U 25560-5-yl) methyl) phenyl)-N-(pyridine-2-yl) ethanamide

(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-(384mg 1mmol) puts among the mixing solutions 15mL of dioxane and methyl alcohol (5: 1) N-(pyridine-2-yl) ethanamide with (Z)-2-; The palladium carbon 80mg of adding 10% sets the reaction flask internal pressure for 40psi hydro-reduction reaction 8h, removes by filter palladium carbon; Filter residue washes with methyl alcohol 5mL, concentrating under reduced pressure behind the merging filtrate, and raffinate soaks with 5mL methyl alcohol; The refrigerator freeze overnight has brown solid to produce, and filters; Recrystallizing methanol gets isabelline crystal 95mg, productive rate 26.7%: ¹HNMR (MeOH-d ₄, 300MHz) δ ppm:9.31 (s, 1H, NH), 8.79 (s, 1H, NH), 8.33 (s, 1H, ArH), 7.62-7.90 (m, 4H, ArH), 7.24 (d, 1H, ArH), 6.55 (d, 1H, ArH), 6.09 (bs, 2H, NH ₂), 4.90 (t, 1H, CH), 4.82 (s, 2H, CH ₂), 4.27-4.52 (m, 2H, CH ₂); MS (FAB): 357 (M+1)

Embodiment 31.2-(2-amido-4-((2,4-U 25560-5-yl) methyl) phenyl)-N-(5 methyl-isoxazoles-3-yl) ethanamide

(4-((2,4-U 25560-5-subunit) methyl)-2-oil of mirbane)-(388mg 1mmol) puts among the mixing solutions 15mL of dioxane and methyl alcohol (5: 1) N-(5-methyl-isoxazole-3-yl) ethanamide with (Z)-2-; The palladium carbon 80mg of adding 10% sets the reaction flask internal pressure for 40psi hydro-reduction reaction 8h, removes by filter palladium carbon; Filter residue washes with methyl alcohol 5mL, concentrating under reduced pressure behind the merging filtrate, and raffinate soaks with 5mL methyl alcohol; The refrigerator freeze overnight has light yellow solid to produce, and filters; Recrystallizing methanol gets yellow crystals 42mg, productive rate 11.7%: ¹HNMR (MeOH-d ₄, 300MHz) δ ppm:8.60 (s, 1H, NH), 8.01 (s, 1H, NH), 7.89 (s, 1H, ArH), 7.75 (d, 1H, ArH), 7.58 (d, 1H, ArH), 7.37 (s, 1H, ArH), 5.56 (bs, 2H, NH ₂), 4.72 (t, 1H, CH), 4.31 (s, 2H, CH ₂), 3.42-3.56 (m, 2H, CH ₂), 2.48 (s, 3H, CH ₃); MS (FAB): 361 (M+1)

Embodiment 32. (Z)-6-(4-((2,4-U 25560-5-subunit) methyl)-benzoylamino) isopropyl nicotinate

With 6-amino-nicotinic acid isopropyl ester (180mg, 1mmol) with (Z)-(249mg 1mmol) puts into respectively among the exsiccant methylene dichloride 20mL Benzoyl chloride 99min. 4-((2,4-U 25560-5-subunit) methyl); Be added dropwise under stirring triethylamine (101mg, 1mmol), stirring reaction 12h under the room temperature; Pressurization removes and desolvates, and raffinate water 10mL soaks, and has solid to separate out; Filtration drying, the post separation (developping agent: ETHYLE ACETATE: sherwood oil=3: 2) obtain light yellow solid 92mg, productive rate 22.4%: ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:12.27 (s, 1H, NH), 9.12 (s, 1H, NH), 8.67 (s, 1H, NH), 8.13-8.55 (m, 5H, ArH), 7.53 (d, 1H, ArH), 7.19 (d, 1H, ArH), 6.83 (s, 1H, ArH), 4.35 (m, 1H, CH), 1.83 (d, 6H, 2CH ₃); MS (FAB): 412 (M+1)

Embodiment 33. (Z)-4-((2,4-U 25560-5-subunit) methyl)-N-(pyridine-2-yl) BM

With the 2-EL-970 (94mg, 1mmol) with (Z)-(249mg 1mmol) puts into respectively among the exsiccant methylene dichloride 20mL Benzoyl chloride 99min. 4-((2,4-U 25560-5-subunit) methyl); Stir be added dropwise to down triethylamine (101mg, 1mmol), stirring reaction 12h under the room temperature, pressurization is except that desolvating; Obtain the brown thick liquid, water 10mL soaks, and has solid to separate out; Filtration drying, the post separation (developping agent: ETHYLE ACETATE: sherwood oil=3: 2) obtain light yellow solid 127mg, productive rate 39.1%: ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:11.15 (s, 1H, NH), 9.50 (s, 1H, NH), 8.50 (s, 1H, NH), 8.25-8.39 (m, 3H, ArH), 7.53-7.69 (m, 4H, ArH), 7.35 (t, 1H, ArH); MS (FAB): 326 (M+1)

Embodiment 34. (Z)-4-((2,4-U 25560-5-subunit) methyl)-N-(5-picoline-2-yl) BM

With 2-amino-5-picoline (108mg, 1mmol) with (Z)-4-((2,4-U 25560-5-subunit) methyl) Benzoyl chloride 99min. (249mg; 1mmol) put into respectively among the exsiccant methylene dichloride 20mL, be added dropwise under stirring triethylamine (101mg, 1mmol); Stirring reaction 12h under the room temperature, pressurization removes and desolvates, and obtains yellow raffinate; Water 10mL soaks, and has solid to separate out, filtration drying; The post separation (developping agent: ETHYLE ACETATE: sherwood oil=3: 2) obtain light yellow solid 105mg, productive rate 31.0%: ¹HNMR (DMSO-d ₆, 300MHz) δ ppm:11.83 (s, 1H, NH), 10.17 (s, 1H, NH), 8.32 (s, 1H, NH), 7.83-8.20 (m, 5H, ArH), 7.59 (d, 1H, ArH), 7.01 (d, 1H, ArH), 2.12 (s, 3H, CH3); MS (FAB): 340 (M+1)

Pharmacological evaluation

Experimental example 1: external activity evaluation:

Activation to gk

1. reaction principle:

2. reaction system is formed:

Comprise 5mmol/l ATP in the reaction system, 0.2U/ml G6PDH, 0.2mmol/l NADP, 5mmol/lMgCl ₂, 1mmol/l DTT, 25mmol/l KCl, 100mmol/l Tris-HCl, different concns glucose, 1%DMSO, different concns test-compound and recombination human source liver GK protein liquid.

3. operating process:

Preparation reaction mixture (ATP, G6PDH, NADP, MgCl ₂, DTT, KCl, glucose Tris-HCl) → add test-compound → addings reorganization GK protein liquid → room temperature measuring 340nm absorbance, and is designated as initial value (0min) → 37 ℃ incubation, every at a distance from 10 minutes 340nm readings once till the 60min → calculation result.

4. method of calculation:

Activate multiple=(OD _t-OD ₀) _{Sample hose}/ (OD _t-OD ₀) _{Reaction tubes}

Annotate: sample hose is to add test-compound in the system, and reaction tubes shines for the reaction pair that does not add test-compound.Activate multiple＞1.5 and be regarded as the positive.

The active result of part embodiment

Activation to px vegetation activated receptor

1. principle:

PPAR γ combines the back to activate with its part, insert in the nucleus, forms heterodimer with another nuclear receptor RXR, can specific recognition dna sequence dna PPRE (PPAR responsive element), and the latter regulates and control the expression of series of genes.Set up the luciferase reporter gene of PPRE regulation and control, make the expression level reaction PPAR activated level of reporter gene.

2. method:

1) PPAR γ is expressed in construction, the plasmid vector of RXR, and PPAR γ, the luciferase reporter gene plasmid vector of the response element PPRE regulation and control of RXR.

2) with the method for liposome transfection (Lipofectamine2000, invitrogen), cotransfection PPAR, RXR, PPRE-luciferase expression plasmid advance mammal cell line 293E cell.

3) the 293E cell transfecting was used trysinization after 24 hours, was divided into some parts behind the counting cells; Mix with the substratum that adds sample respectively; In suitable culture plate, cultivated 24 hours, this step must be set up negative control (adding DMSO), positive control (like Rosiglitazone); Each sample is set up parallel-group. and sample concentration can be provided with some gradients as required, and for example 10 ^-9～10 ^-5M.

4) after dosing 24-48 hour, with the abundant lysing cell of cell pyrolysis liquid, collect each porocyte lysate in the culture plate, (Luciferase Assay System Promega), measures the fluorescence reading with chemiluminescence detector immediately to add the luciferase reaction substrate.

3. Compound P PAR screening active ingredients:

With the luciferase reporter gene method of above-mentioned foundation, the PPAR γ of comparative compound activates active.Calculate the relative reactivity of SCREENED COMPOUND: the fluorescent value reading of compound is compared with the fluorescent value reading of positive control rosiglitazone, and the activity of establishing rosiglitazone is 100%, and the activity of other compounds is expressed as relative reactivity, that is:

The relative reactivity of SCREENED COMPOUND=sample reading/positive control reading * 100%

The active result of part embodiment

Claims

1. the thiazolidine diketone derivative shown in general formula I and II comprises its pharmacologically acceptable salt, the precursor of its same biological function or verivate

In the formula

R2 is selected from-C (O) NHR1 ,-C (NH) R1, and-C (S) NHR1 and the hetero-aromatic ring that is connected through ring carbon atom: it contains 5-6 annular atoms, wherein has 1-4 to be selected from nitrogen, the heteroatoms of sulphur or oxygen; Or it contains 9-10 annular atoms, is condensed by aromatic ring that contains 6 annular atomses or hetero-aromatic ring and the hetero-aromatic ring that contains 5-6 annular atoms to form, and 1-5 heteroatoms that is selected from nitrogen, oxygen or sulphur arranged in the ring; At least one nitrogen-atoms is arranged in the ortho position of heterocycle shack carbon atom in the said hetero-aromatic ring; Said aromatic ring or hetero-aromatic ring do not replace for having, single replacement or polysubstituted.Substituting group is selected from R3, and R3 comprises following groups: halogen, amino, C1-6 alkylamino, C1-6 alkyl amido, carboxyl, ester group, 2-(methoxyimino) acetic ester-2-base, 2-(2-fluorine ethoxy imino) acetic ester-2-base, nitro, cyanic acid, methanesulfonamido, C1-6 alkyl, C1-6 alkoxyl group, perfluor replace the substituted C1-6 alkylamino of heteroaryl, R3, the substituted C1-6 alkyl amido of R3, the substituted C1-6 alkoxyl group of R3, the substituted C1-6 alkylthio of R3 that C1-4 alkyl, C1-6 alkylthio, perfluor replacement C1-4 alkyl sulphonyl, the substituted phenyl of R3 or 5-6 unit ring contain 1-5 heteroatoms (nitrogen, oxygen, sulphur).

X is selected from singly-bound, C1-6 alkyl, oxygen, sulphur, nitrogen.

Y is selected from C1-6 alkyl, sulphur, nitrogen.

2. according to the compound of claim 1, it is characterized in that:

R2 more preferably is-C (O) NHCH3 that-C (NH) CH3 and the hetero-aromatic ring that is connected through ring carbon atom: it contains 5-6 annular atoms, wherein has 1-4 to be selected from nitrogen, the heteroatoms of sulphur or oxygen; Or it contains 9-10 annular atoms, is condensed by aromatic ring that contains 6 annular atomses or hetero-aromatic ring and the hetero-aromatic ring that contains 5-6 annular atoms to form, and 1-5 heteroatoms that is selected from nitrogen, oxygen or sulphur arranged in the ring; At least one nitrogen-atoms is arranged in the ortho position of heterocycle shack carbon atom in the said hetero-aromatic ring; Said aromatic ring or hetero-aromatic ring do not replace for having, single replacement or polysubstituted.Substituting group is selected from R3, and R3 comprises following groups: halogen, amino, C1-6 alkylamino, C1-6 alkyl amido, carboxyl, ester group, 2-(methoxyimino) acetic ester-2-base, 2-(2-fluorine ethoxy imino) acetic ester-2-base, cyanic acid, methanesulfonamido, C1-6 alkyl, C1-6 alkoxyl group, trifluoromethyl, C1-6 alkylthio, trifluoromethyl sulfonyl, the substituted phenyl of R3 or 5-6 unit ring contain the substituted C1-6 alkylamino of heteroaryl, R3, the substituted C1-6 alkyl amido of R3, the substituted C1-6 alkoxyl group of R3, the substituted C1-6 alkylthio of R3 of 1-5 heteroatoms (nitrogen, oxygen, sulphur).

X more preferably is a singly-bound, C1-4 alkyl, oxygen, sulphur, nitrogen.

Y more preferably is the C1-4 alkyl, nitrogen, sulphur.

3. according to the compound of claim 2:

R2 more preferably from-C (O) NHCH3 ,-C (NH) CH3, thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base, 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, 5-ethoxycarbonyl thiazol-2-yl, 5-(2-(methoxyimino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-(2-(2-fluorine ethoxy imino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-methyl-isoxazole-3-base, pyridine-2-base, 5-picoline-2-base, 5-carboxyl pyridine-2-base, 5-chloropyridine-2-base, 5-fluorine pyridine-2-base, 5-methoxycarbonyl yl pyridines-2-base, 5-ethoxycarbonyl yl pyridines-2-base, the different third oxygen formyl radical pyridine of 5--2-base, 5-carbamyl yl pyridines-2-base, pyrazole-3-yl, basic, the 3-methyl isophthalic acid of N-methylpyrazole-3-; 2; 4-thiadiazoles-5-base, 3-methoxyl group-1; 2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid; 3; 4-thiadiazoles-2-base, 1H-tetrazolium-5-base, 5-methoxycarbonyl base-1; 2; 4-triazole-3-base, 5-ethoxycarbonyl-1; 2,4-triazole-3-base, pyrido thiazol-2-yl, 6-methylamino pyrido thiazol-2-yl, pyridine-imidazole-2-base, benzothiazole-2-base, pyrimidine-4-base, pyrimidine-2-base, methylamine formyl radical, NSC 158269 formyl radical, a chlorobenzylamine formyl radical, carboxylic ethamine formyl radical, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base, pyridazine-3-base, 6-methyl pyridazine-3-base, 6-chlorine pyridazine-3-base, quinoline-2-base, isoquinolyl-1;

X is singly-bound more preferably, C1-3 alkyl, oxygen, sulphur, nitrogen.

Y is the C1-3 alkyl more preferably, nitrogen.

4. according to the compound of claim 3:

R1 spy is preferably nitro, amino, hydroxyl, methyl.

R2 special preferred from-C (O) NHCH3 ,-C (NH) CH3, thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base, 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, 5-ethoxycarbonyl thiazol-2-yl, 5-(2-(methoxyimino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-(2-(2-fluorine ethoxy imino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-methyl-isoxazole-3-base, pyridine-2-base, 5-picoline-2-base, 5-carboxyl pyridine-2-base, 5-chloropyridine-2-base, 5-fluorine pyridine-2-base, 5-methoxycarbonyl yl pyridines-2-base, 5-ethoxycarbonyl yl pyridines-2-base, the different third oxygen formyl radical pyridine of 5--2-base, 5-carbamyl yl pyridines-2-base, pyrazole-3-yl, basic, the 3-methyl isophthalic acid of N-methylpyrazole-3-; 2; 4-thiadiazoles-5-base, 3-methoxyl group-1; 2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid; 3; 4-thiadiazoles-2-base, 1H-tetrazolium-5-base, 5-methoxycarbonyl base-1; 2; 4-triazole-3-base, 5-ethoxycarbonyl-1; 2,4-triazole-3-base, pyrido thiazol-2-yl, 6-methylamino pyrido thiazol-2-yl, pyridine-imidazole-2-base, benzothiazole-2-base, pyrimidine-4-base, pyrimidine-2-base, methylamine formyl radical, NSC 158269 formyl radical, a chlorobenzylamine formyl radical, carboxylic ethamine formyl radical, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base, pyridazine-3-base, 6-methyl pyridazine-3-base, 6-chlorine pyridazine-3-base, quinoline-2-base, isoquinolyl-1;

X spy is preferably singly-bound, C1-2 alkyl, oxygen, sulphur, nitrogen.

Y spy is preferably the C1-3 alkyl.

5. according to the compound of claim 4:

R1 most preferably is nitro, amino, hydroxyl;

R2 most preferably from-C (O) NHCH3 ,-C (NH) CH3, thiazol-2-yl, 4-methylthiazol-2-base, 5-diuril azoles-2-base, 5-fluorine thiazol-2-yl, 5-carboxyl thiazol-2-yl, 4-methoxycarbonyl base thiazol-2-yl, 4-hydroxymethylthiazole-2-base, 4-carboxyl methylene radical thiazol-2-yl, 4-ester group methylene radical thiazol-2-yl, 5-ethoxycarbonyl thiazol-2-yl, 5-(2-(methoxyimino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-(2-(2-fluorine ethoxy imino) ETHYLE ACETATE-2-yl) thiazol-2-yl, 5-methyl-isoxazole-3-base, pyridine-2-base, 5-picoline-2-base, 5-carboxyl pyridine-2-base, 5-chloropyridine-2-base, 5-fluorine pyridine-2-base, 5-methoxycarbonyl yl pyridines-2-base, 5-ethoxycarbonyl yl pyridines-2-base, the different third oxygen formyl radical pyridine of 5--2-base, 5-carbamyl yl pyridines-2-base, pyrazole-3-yl, basic, the 3-methyl isophthalic acid of N-methylpyrazole-3-; 2; 4-thiadiazoles-5-base, 3-methoxyl group-1; 2; 4-thiadiazoles-5-base, 5-methyl isophthalic acid; 3; 4-thiadiazoles-2-base, 1H-tetrazolium-5-base, 5-methoxycarbonyl base-1; 2; 4-triazole-3-base, 5-ethoxycarbonyl-1; 2,4-triazole-3-base, pyrido thiazol-2-yl, 6-methylamino pyrido thiazol-2-yl, pyridine-imidazole-2-base, benzothiazole-2-base, pyrimidine-4-base, pyrimidine-2-base, NSC 158269 formyl radical, a chlorobenzylamine formyl radical, carboxylic ethamine formyl radical, pyrazine-2-base, 5-methylpyrazine-2-base, 5-methylthiopyrazine-2-base, pyridazine-3-base, 6-methyl pyridazine-3-base, 6-chlorine pyridazine-3-base, quinoline-2-base, isoquinolyl-1;

X most preferably is singly-bound, oxygen, sulphur, nitrogen.

Y most preferably is the C1-2 alkyl.

6. according to the compound of claim 1, described compound is selected from:

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(thiazol-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(4-methylthiazol-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(pyridine-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-picoline-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-chloropyridine-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-isopropyl formate pyridine-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-ethyl formate pyridine-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-methyl-formiate pyridine-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(pyrimidine-2-base) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(benzothiazole-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(quinoline-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(5-ethyl formate thiazol-2-yl) ethanamide

(E)-2-(2-(2-(4-((Z)-(2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetamido) thiazole-5-yl)-2-(methoxy imino) ETHYLE ACETATE

(E)-2-(2-(2-(4-((Z)-(2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetamido) thiazole-5-yl)-2-(2-fluoro ethoxy imido grpup) ETHYLE ACETATE

(Z)-2-(2-amino-4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(methylamine formyl radical) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(1-imido grpup ethyl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl)-N-(1H-tetrazolium-5-yl) ethanamide

(Z)-and 3-(2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetamido)-1H-1,2,4 ,-triazole-5-methyl-formiate

(Z)-and 3-(2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenyl) acetamido)-1H-1,2,4 ,-triazole-5-ethyl formate

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-nitrophenylsulfenyl)-N-(pyridine-2-yl)-ethanamide

Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-oil of mirbane amido)-N-(pyridine-2-yl)-ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-aminocarbonyl phenyl)-N-(5-isopropyl formate pyridine-2-yl) ethanamide

(Z)-2-(4-((2,4-U 25560-5-subunit) methyl)-2-aminocarbonyl phenyl)-N-(5-picoline-2-yl) ethanamide

2-(2-amido-4-((2,4-U 25560-5-yl) methyl) phenyl)-N-(5-picoline-2-yl) ethanamide

2-(2-amido-4-((2,4-U 25560-5-yl) methyl) phenyl)-N-(the different third oxygen formyl radical pyridine-2-yl of 5-) ethanamide

2-(2-amido-4-((2,4-U 25560-5-yl) methyl) phenyl)-N-(pyridine-2-yl) ethanamide

2-(2-amido-4-((2,4-U 25560-5-yl) methyl) phenyl)-N-(5 methyl-isoxazoles-3-yl) ethanamide

(Z)-6-(4-((2,4-U 25560-5-subunit) methyl)-benzoylamino) isopropyl nicotinate

(Z)-4-((2,4-U 25560-5-subunit) methyl)-N-(pyridine-2-yl) BM

(Z)-4-((2,4-U 25560-5-subunit) methyl)-N-(5-picoline-2-yl) BM

7. according to the compound of claim 1-6, it is characterized in that described medicinal salt comprises with mineral acid, organic acid, alkalimetal ion, alkaline earth metal ion maybe can provide physiologically acceptable cationic organic bases to combine salt and the ammonium salt that forms.

8. according to the compound of claim 1-6, it is characterized in that described mineral acid is selected from hydrochloric acid, Hydrogen bromide, phosphoric acid or sulfuric acid; Described organic acid is selected from methylsulfonic acid, tosic acid, trifluoroacetic acid, matrimony vine acid, toxilic acid tartrate, fumaric acid, Hydrocerol A or lactic acid; Described alkalimetal ion is selected from lithium ion, sodium ion, potassium ion; Described alkaline earth metal ion comprises calcium ion, mg ion; Describedly can provide physiologically acceptable cationic organic bases to be selected from methylamine, n n dimetylaniline, Trimethylamine 99, piperidines, morpholine or three (2-hydroxyethyl) amine.

9. the method for preparing the said compound of claim 1-7 comprises following method:

10. the method for preparing the said compound of claim 1-7, the reaction scheme of more optimizing are being raw material to L m-nitrobenzaldehyde 8, and wherein L is a leavings group, like the chlorine atom.This aldehyde at first obtains midbody 9 with U 25560 1 condensation, can select for use piperidines or tetrahydrochysene pyrrole to iron and be condensation accelerator.Ethyl malonate 10 obtains 11 with midbody 9 reactions under alkaline environment then, and further hydrolysis obtains introducing the midbody 12 of carboxyl.This carboxylic acid 12 and H ₂Dehydration generates acid amides 13 between N-R2.And further the two keys of hydro-reduction obtain compound 14.

11. synthetic another reaction scheme of more optimizing of The compounds of this invention also is being raw material to L m-nitrobenzaldehyde 8, wherein L is a leavings group, like the chlorine atom.This aldehyde at first obtains midbody 9 with U 25560 1 condensation, can select for use piperidines or tetrahydrochysene pyrrole to iron and be condensation accelerator.Midbody 9 and HXCH under alkaline environment then ₂The COOEt reaction obtains midbody 16, and wherein X is O, NH, S.Midbody 16 further hydrolysis obtain introducing the midbody 17 of carboxyl.This carboxylic acid 17 and H ₂Dehydration generates acid amides 18 between N-R2.And further the two keys of hydro-reduction obtain compound 19.

12. a pharmaceutical composition comprises as carrier commonly used on the described compound of the claim 1-8 of effective constituent or its pharmaceutically useful salt and the pharmacopedics.

13. the salt of the described compound of claim 1-8 or its pharmaceutically acceptable acid or alkali the preparation prevention with or the medicine of treatment and gk and px vegetation activated receptor diseases associated in application.

14. the application according to claim 12 is characterized in that, described and gk and px vegetation activated receptor diseases associated are selected from the chronic complicating diseases and the obesity of mellitus, mellitus.

15. the application according to claim 14 is characterized in that, described mellitus are selected from type 1 diabetes or diabetes B; The chronic complicating diseases of described mellitus is selected from retinopathy, ephrosis, neurosis, ischemic heart disease or arteriosclerosis.