CN101258145A

CN101258145A - Stereoisomeric pyridyl and pyridonyl compounds and methods for the treatment of gastrointestinal and central nervous system disorders

Info

Publication number: CN101258145A
Application number: CNA2006800322117A
Authority: CN
Inventors: P·德鲁兹加拉
Original assignee: ARYx Therapeutics Inc
Current assignee: ARYx Therapeutics Inc
Priority date: 2005-07-05
Filing date: 2006-07-05
Publication date: 2008-09-03
Also published as: CA2612893A1; WO2007005951A2; WO2007005951A3; JP2009500419A; MX2007016373A; EP1907376A2

Abstract

The subject invention provides stereoisomeric compounds of formulae (Xa) and (Xb); wherein the variables are as defined herein, and compositions for the safe and effective treatment of various gastrointestinal disorders including, but not limited to, gastroparesis, gastroesophageal reflux and related conditions. The compounds of the subject invention are also useful in treating a variety of conditions involving the central nervous system.

Description

The method of stereoisomerism pyridyl and pyriconyl compound and treatment stomach and intestine and central nervous system disease

Background of invention

Cisapride is the compound that a class is known as benzamide derivatives, and its parent compound is a metoclopramide.United States Patent (USP) 4,962,115 and 5,057,525 (Van Daele etc., this patent is attached to herein by quoting in full) disclose N-(the 3-hydroxy-4-piperidinyl base) benzamide of cisapride.Van Daele discloses these compounds, its pharmaceutically acceptable acid addition salt and stereochemistry heterogeneous forms stimulating gastrointestinal system dynamic thereof.

As a class medicine, these benzamide derivatives have some outstanding pharmacological actions.The outstanding pharmacologically active of benzamide derivatives is because its influence to the neuron system of neurotransmitter thrombotonin adjusting.For many years, the pharmacology of the effect of thrombotonin and benzamide derivatives is extensively discussed in various illnesss.Therefore, research concentrates on generation and the stores location and the position of serotonin receptor in human body of thrombotonin, so that determine the relation of these positions and various disease states or illness.

About this point, find that thrombotonin produces and the main position of storage is the enterochromaffin cell of gastrointestinal mucosa.Also find for example to pass through to stimulate intestinal smooth muscle when diarrhoea, quicken the intestines transportation and reduce soak time, thrombotonin also has strong hormesis to intestinal motive force.This hormesis also is accompanied by nausea and vomiting.

Because regulate the thrombotonin neuron system in the gi tract, many benzamide derivatives are effective antiemetic, are generally used for being controlled at the vomiting in cancer chemotherapy or the radiotherapy process, particularly when using high emetogenic compound (for example cis-platinum).Almost yes in this effect because this compound can be blocked specific function position (so-called 5HT ₃-acceptor is commonly referred to thrombotonin M-acceptor in scientific literature) thrombotonin (5HT) effect produce.Because impaired enterochromaffin cell discharges thrombotonin from gi tract, chemotherapy and the method for putting can cause the evil nausea and vomiting.The neurotransmitter thrombotonin that discharges stimulates the serotonin receptor in the chemoreceptor trigger region in the postrema district of importing vagus nerve fiber (therefore causing vomiting reflex) and brain into.Still the anatomy position of this effect of unresolved benzamide derivatives and this effect are maincenter (central nervous system) or peripheral nervous system or its combination (Barnes etc., J.Pharm.Pharmacol.40:586-588,1988).Owing to can regulate thrombotonin to 5HT ₃The activity of acceptor, therefore the same with other benzamide derivatives, cisapride can be regarded effective antiemetic as.

Second outstanding activity that act as the gastrointestinal smooth muscle of increase of benzamide derivatives from oesophagus to nearly body centre end small intestine, therefore quicken the conveying of oesophagus and small intestine and promote stomach emptying and raising lower esophageal sphincter meat tonus (Decktor etc., Eur.J.Pharmacol.147:313-316,1988).Though benzamide derivatives itself is not a cholinergic agonist, can be by malicious deep alkali receptor blocking agent (for example coromegine or influence the tetraodotoxin type neurone conduction depressant drug of sodium channel) above-mentioned unstriated muscle effect of blocking-up.Similarly blocking-up activity has been reported the contraction of thrombotonin in small intestine.Generally believe that the main unstriated muscle effect of benzamide derivatives is because to the 5HT that is called on the relay cell of neuroplexus between the myenteron that is arranged in the intestines wall ₄The agonism of the novel serotonin receptor of one class of acceptor.Activate these acceptors and strengthen subsequently from being positioned at the terminal vagusstoff that discharges of parasympathetic nerve around the smooth muscle fibers, the reality that engages of its acceptor on vagusstoff and the level and smooth sarolemma has triggered Muscle contraction just.

Various 5HT acceptors (are comprised 5HT ₄Acceptor) discussion can be for example referring to United States Patent (USP) 6,331, and 401 and 6,632,827, this patent is attached to herein by quoting in full.

Cisapride is mainly used in treatment gastroesophageal reflux disease (GERD).This disease is characterised in that the anti-oesophagus that flow to of gastric content.In the pathogeny of gastroesophageal reflux disease, one of most important factor is for causing that owing to lower esophageal sphincter depletion pressure stops reduction.Can be low owing to rest pressure (basal pressure), sphincter dilatation or uncompensated increase intragastric pressure, cause lower esophageal sphincter depletion.Other pathological factors of this disease are for the stomach emptying of delaying time, because wriggling weakens the corrosive property that the oesophagus that causes is removed deficiency and can be damaged the anti-stream material of mucous membrane of esophagus.Think that cisapride strengthens anti-refluxly stopping and improving the oesophagus clearance rate by increasing lower esophageal sphincter pressure and strengthening peristaltic contraction.

Because cisapride is as the activity of short motion medicine, it also can be used for treating maldigestion, gastroparesis, constipation, postoperative ileus and intestinal pseudo obstruction.Indigestion is characterised in that main gastrointestinal dysfunction symptom or weakens as digestion power or function that the complication of other diseases (for example ecphyaditis, gall-bladder obstacle or malnutrition) causes.Gastroparesis is for because stomach motion unit is unusual or the stomach paralysis that causes as the complication of various diseases (for example diabetes, the sclerosis of gradual system, apocleisis nervosa or myotony malnutrition).The constipation illness is characterised in that because the defecation that various illnesss (for example lacking myenteron meat tonus or intestines spasticity) cause is rare or difficult.The intestinal obstruction of postoperative ileus for causing owing to postoperative destruction muscular tone.The intestinal pseudo obstruction illness is characterised in that constipation, angina and vomiting, but the sign that does not have health to block.

Emphasis is considered drug toxicity when the treatment humans and animals.Give drug-induced toxic side effect and comprise various illnesss, extremely dead from low-grade fever.Have only when the benefit of treatment plan surpasses the risk that treatment may bring and to prove that this pharmacological agent is rational.If the doctor needs each factor of equilibrated that the qualitative and quantitative influence of medicine to be used and the consequence that does not provide medicine to bring to individuality are provided.Other factors of considering comprise any known side effect of patient's body condition, disease stage and development history thereof and concomitant drugs.

Medicine is eliminated normally the Metabolic activity of medicine and medicine excretory result in the body subsequently.Metabolic activity can occur in the vascularity and/or in CC or organ.Liver is the main position of drug metabolism.Metabolic process can be categorized as synthetic and non-building-up reactions.In non-building-up reactions, any combination by oxidation, reduction, hydrolysis or said process changes medicine with chemical process.These methods are referred to as the I elementary reaction.

In II elementary reaction (be also referred to as building-up reactions or put together), parent drug or its intermediate meta-bolites combine with the endogenous substrate, obtain addition or conjugation product.The meta-bolites that forms in building-up reactions is generally more polarity and biological inactive.The result is that these meta-bolitess are easier to be drained by kidney (in urine) or liver (in bile).Building-up reactions comprises that glucuronic acidization, amino acid are puted together, acetylize, sulfo group is puted together and methylate.

More than the cisapride of 90% dosage by the oxidisability N-dealkylation on the piperidines nitrogen or by the aromatic hydroxy metabolism on 4-fluorophenoxy or the benzamide ring.

Find that the administration of human cisapride causes severe side effect, comprise CNS disease, systolic pressure improve, with other drug interaction, diarrhoea and abdominal cramps.In addition, also have report to show that intravenously gives cisapride and do not experience other side effects (Stacher etc. [1987] the Digestive Diseases and Sciences (digestive ailment and science) 32 (11): 1223-1230) that occurs behind the orally give cisapride.Think that these side effects cause by appearing at the meta-bolites that compound oxidation dealkylation in the Cytochrome P450 detoxification system or aromatic hydroxy cause.Cisapride also carries out various undesirable medicine/drug interactions, and this also is the metabolic result of cytochrome p450 system.

Between year December in July, 1993 to 1999, (PROPULSID, Janssen Pharmaceutica Products L.P.) follow at least 341 serious heart disorders to the report cisapride.These heart disorders comprise quivering in ventricular tachycardia, chamber, torsades de pointes ventricular tachycardia (torsades de pointes) and QT prolong.Reported that 80 (80) examples are dead.The result of these side effects is that product is recalled from the open market of the U.S., still, can obtain this medicine by the program that is confined to study.

Because to the influence of heart (prolonging QTc interval, tachycardia, torsades de pointes ventricular tachycardia) with because the disadvantageous drug interaction that liver cell pigment P-450 metabolism causes, limited to and had the 5HT that stomach and intestine (GI) are urged locomotor activity ₄The security of receptor stimulant.The short motion medicine of this type of GI that lacks these tendencies comprises in GERD and the stomach emptying disease it being very valuable in some treatment fields.Some cisapride derivative sees and is set forth in United States Patent (USP) 6,552,046 and WO01/093849 (being attached to herein) by quoting in full, but need have more other compounds of advantageous property.

Have now found that a kind of structure of esterification of cisapride and/or some steric isomer of sense analogue have unique and particularly advantageous performance.

Summary of the invention

The invention provides and be used for safety and the formula Xa of stereoisomerism, sense and/or the analog of the cisapride of effectively treating various gastrointestinal illnesss (including, but not limited to gastroparesis, gastroesophageal reflux and associated conditions) and compound and the composition of Xb.The compounds of this invention also is used for the treatment of the various illnesss that relate to central nervous system.

The compounds of this invention comprises compound and the pharmacy acceptable salt thereof of formula Xa and/or Xb:

Formula Xa

Formula Xb

Wherein

Key on 3 and 4 is cis each other;

L is-(C ₁-C ₆Alkyl)-(on the one hand, be-(C ₃-C ₅Alkyl)-) ,-(C ₁-C ₆Alkyl)-C (O)-or-C (O)-(C ₁-C ₆Alkyl)-, wherein each alkyl is optional independently is halogen, C by 1 or 2 ₁-C ₄The group of alkoxyl group or OH replaces and wherein a carbon atom in the moieties of L can be by-N (R ₉)-replace; Or

L is-(C ₁-C ₄Alkyl)-NR ₉-(C ₁-C ₄Alkyl)-,-(C ₁-C ₄Alkyl)-C (O) NR ₉-,-(C ₁-C ₄Alkyl)-,-(C ₁-C ₄Alkyl)-NR ₉C (O)-or-C (O) NR ₉-(C ₁-C ₄Alkyl)-;

R ₁Be halogen;

R ₂Be amino, NH (C ₁-C ₄Alkyl) or N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl);

R ₃Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH;

R ₄Be H or C ₁-C ₄Alkyl, and be methyl at one aspect preferred; With

R ₅For-O-C ₁-C ₆-alkyl ,-O-C ₃-C ₈Cycloalkyl ,-O-Heterocyclylalkyl, Heterocyclylalkyl, aryl ,-the O-aryl ,-N (R ₉)-(C ₀-C ₆Alkyl)-C (O)-aryl ,-N (R ₉)-C ₀-C ₆Alkyl-aryl ,-the O-heteroaryl ,-N (R ₉)-C ₁-C ₆(O)-heteroaryl or-N (R ₉)-C ₀-C ₆Alkyl-heteroaryl, wherein each cyclic group is not substituted or is replaced by following group in one or more commutable positions: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, hydroxyl, hydroxyl-C ₁-C ₄-alkyl, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) R ₁₁,-O-(C ₀-C ₆Alkyl)-C (O) R ₁₁, methyl sulphonyl, C ₀-C ₆-sulphonamide, NO ₂,-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀Wherein

R ₉Independently be H or C when occurring at every turn ₁-C ₄Alkyl;

R ₁₀Independently be H, optional when occurring by a C who is selected from the group replacement of 5 or 6 yuan of monocyclic heterocycles alkyl rings and OH at every turn ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂,-C (O) NH (C ₁-C ₄Alkyl) ,-C (O) N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) or optional by C ₁-C ₄The piperidyl that alkyl replaces;

R ₁₁Be C ₁-C ₆Alkyl or OH; Or

R ₁₁Be NH ₂,-NH (C ₁-C ₆Alkyl) or-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl); Or

R ₁₁For choosing wantonly by 1 or 2 independently is the C that following group replaces ₁-C ₆Alkoxyl group: C ₁-C ₄Alkoxyl group, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl), Heterocyclylalkyl, OH ,-(C ₀-C ₆Alkyl)-C (O) N (R ₉)-Heterocyclylalkyl ,-the O-Heterocyclylalkyl ,-C ₁-C ₆(O) N (R ₉)-heteroaryl or heteroaryl, wherein

Described Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃,

Described heteroaryl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃Or

R ₁₁For Heterocyclylalkyl or-the O-Heterocyclylalkyl, wherein said Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃With

R ₂₀For-H, C ₁-C ₆Alkoxyl group (preferred C ₁-C ₄Alkoxyl group, more preferably methoxyl group) or OH.

The present invention also comprises the compound that comprises at least a formula Xa and Xb and the composition of at least a pharmaceutically acceptable vehicle, adjuvant, carrier or solvent.

The compound of formula Xa and Xb is used for the treatment of or prevents gastroesophageal reflux disease and remarkable the reduction to follow the side effect that gives cisapride.These side effects raise including, but not limited to diarrhoea, abdominal cramps and blood pressure and heart rate.

In addition, compound of the present invention and composition are used for the treatment of vomiting and other illnesss, including, but not limited to maldigestion, gastroparesis, constipation, postoperative ileus and intestinal pseudo obstruction.Additional benefits is followed the side effect that gives cisapride for also reducing in these methods of treatment.

Advantageously, The compounds of this invention is 5HT ₄Therefore the part of acceptor, can be used for treating the illness by this receptor mediation.These acceptors are positioned at a plurality of zones of central nervous system, and the adjusting of these acceptors can be used for the adjusting that realizes that CNS is required.

Advantageously, the invention provides the Stereoisomeric compounds that comprises ester moiety, described ester moiety does not weaken the ability that these compounds provide the treatment benefit, but make easier in serum and/or the degraded of kytoplasm esterase, thereby avoid the relevant Cytochrome P450 medicine detoxification system of the side effect that causes with cisapride and reduce the incidence of this adverse events.

The present invention also provides various methods of treatment, and described method comprises treats the formula Xa of significant quantity and the compound of Xb to the individuality of needs treatment gastroesophageal reflux disease, maldigestion, gastroparesis, constipation, postoperative ileus and intestinal pseudo obstruction and associated conditions.

Advantageously, treatment compound of the present invention is stable when storage, and compares with other drug, and safer drug metabolism is provided, and therefore, uses The compounds of this invention side effect and toxic incidence lower.

On the other hand, the present invention relates to the degradation production (preferred metabolism degradation production) that when esterase acts on treatment compound of the present invention, forms.As described herein, these degradation productions can be used for the clearance rate of monitor treatment compound from the patient.

More on the one hand, the invention provides the method for synthesizing treatment Stereoisomeric compounds of the present invention and being used to prepare the intermediate of described compound.

Embodiment

On the other hand, the invention provides the compound of formula Xa and Xb, wherein

R ₅For-O-C₁-C ₆-alkyl ,-O-C₃-C ₈Cycloalkyl ,-O-Heterocyclylalkyl, Heterocyclylalkyl, wherein Heterocyclylalkyl is selected from piperidines base, piperazine base, pyrroles's alkyl, azabicyclic-octyl group (being in certain embodiments azabicyclic [2.2.2] octyl group, azabicyclic [3.2.1] octyl group), azabicyclic-nonyl, azabicyclic-last of the ten Heavenly stems base, indolinyl, morpholine base, thio-morpholinyl, S, S-dioxo thio-morpholinyl, imidazoles alkyl ,-the O-aryl ,-N (R₉)-C (O)-aryl or-N (R₉)-C ₀-C ₆Alkyl-aryl, wherein each cyclic group is not substituted or is replaced by following group in one or more positions that replace: C₁-C ₆Alkyl, C₁-C ₆Alkoxyl, halogen, C₁-C ₆Alkyl halide base, C₁-C ₆Halogenated alkoxy, hydroxyl, hydroxyl-C₁-C ₄Alkyl, amino ,-NH (C₁-C ₆Alkyl) ,-N (C₁-C ₆Alkyl) (C₁-C ₆Alkyl) ,-C (O) R₁₁Or NO₂ Wherein

R ₉Independently be H or C when occurring at every turn₁-C ₄Alkyl; With

R ₁₁Be C₁-C ₆Alkyl, OH, or

R ₁₁For optional independently be the C that following group replaces by 1 or 2₁-C ₆Alkoxyl: C₁-C ₄Alkoxyl, amino ,-NH (C₁-C ₆Alkyl) ,-N (C₁-C ₆Alkyl) (C₁-C ₆Alkyl) ,-C (O) N (R₉)-Heterocyclylalkyl, Heterocyclylalkyl or assorted aryl, wherein

Described Heterocyclylalkyl is selected from pyrroles's alkyl, piperidines base, piperazine base, morpholine base, azabicyclic-octyl group (being in certain embodiments azabicyclic [2.2.2] octyl group, azabicyclic [3.2.1] octyl group), azabicyclic-nonyl and azabicyclic-last of the ten Heavenly stems base, and wherein said Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3₁-C ₆Alkyl, C₁-C ₆Alkoxyl, hydroxyl, hydroxyl C₁-C ₆Alkyl, C₁-C ₆Alkoxy carbonyl ,-CO₂H、CF ₃Or OCF₃，

Described assorted aryl is selected from pyridine radicals, pyrimidine radicals, quinoline base, isoquinolin base and indyl, and wherein said assorted aryl is optional independently to be that following group replaces: halogen, C by 1,2 or 3₁-C ₆Alkyl, C₁-C ₆Alkoxyl, hydroxyl, hydroxyl C₁-C ₆Alkyl, C₁-C ₆Alkoxy carbonyl ,-CO₂H、CF ₃Or OCF₃ Or

R ₁₁For-the O-Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from piperidines base, pyrroles's alkyl, imidazoles alkyl, morpholine base, azabicyclic-octyl group (being in certain embodiments azabicyclic [2.2.2] octyl group, azabicyclic [3.2.1] octyl group), azabicyclic-nonyl, azabicyclic-last of the ten Heavenly stems base and tetrahydrofuran base, and wherein each Heterocyclylalkyl is optional independently is that following group replaces: halogen, C by 1,2 or 3₁-C ₆Alkyl, C₁-C ₆Alkoxyl, hydroxyl, hydroxyl C₁-C ₆Alkyl, C₁-C ₆Alkoxy carbonyl ,-CO₂H、CF ₃Or OCF₃。

On the other hand, the invention provides the compound of formula Xa and Xb, wherein R₁Be chlorine.

Again on the one hand, the invention provides the compound of formula Xa and Xb, wherein R₂Be ammonia Base.

More on the one hand, the invention provides the compound of formula Xa and Xb, wherein R₃Be first Base.

On the other hand, the invention provides the compound of formula Xa and Xb, wherein R₄Be H Or methyl.

More on the one hand, the invention provides the compound of formula Xa and Xb, wherein R₁Be chlorine; R₂Be amino; R₃Be methyl; R₄Be H or methyl.

Again on the one hand, the invention provides the compound of formula Xa and Xb, wherein R₁Be chlorine; R₂Be amino; R₃Be methyl; R₄Be H, L is-(C₄-C ₆Alkyl)-C (O)-.

On the other hand, the invention provides the compound of formula Xa and Xb, wherein with two Or a plurality of aforesaid aspect combination (two or more previouslydescribed aspects are Combined).

On the other hand, the invention provides the compound of formula XIa and XIb, be such formula Xa and the compound of Xb, wherein R₂₀Be OCH₃, L is-(CH₂) ₅-C(O)-，

Formula XIa

Formula XIb.

More again on the one hand, the invention provides the compound of formula XIa and XIb, wherein R₁Be chlorine; R₂Be amino; R₃Be methyl; R₄Be H or methyl.

More on the one hand, the invention provides the compound of formula XIa and XIb, wherein R₅For-O-Heterocyclylalkyl, wherein said Heterocyclylalkyl are selected from azabicyclic-octyl group (in some embodiment In be 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl), azabicyclic-nonyl, azabicyclic-last of the ten Heavenly stems base, wherein the nitrogen of azepine is optional is replaced by methyl or ethyl; R₄For H or methyl.

Again more on the one hand, the invention provides the compound of formula XIa and XIb, wherein R₅For-the O-Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from piperidines base, piperazine base or pyrroles's alkyl, and it is not substituted separately or is independently replaced for following group 1 or 2 position: C₁-C ₄Alkyl, C₁-C ₄Alkoxyl, halogen, C₁-C ₄The alkyl halide base (is being CF on the one hand₃)、C ₁-C ₄Halogenated alkoxy (is being OCF on the one hand₃), hydroxyl, hydroxyl C₁-C ₄Alkyl, amino ,-NH (C₁-C ₄Alkyl) ,-N (C₁-C ₄Alkyl) (C₁-C ₄Alkyl) ,-(C₁-C ₆Alkyl)-C (O) R₁₁Or NO₂；R ₄Be H or methyl.

Again on the one hand, the invention provides the compound of formula XIa and XIb, wherein R₅For-the O-Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from indolinyl, morpholine base, thio-morpholinyl, S, S-dioxo thio-morpholinyl and imidazoles alkyl, it is not substituted separately or is independently replaced for following group 1 or 2 position: C₁-C ₄Alkyl, C₁-C ₄Alkoxyl, halogen, C₁-C ₄The alkyl halide base (is being CF on the one hand₃)、C ₁-C ₄Halogenated alkoxy (is being OCF on the one hand₃), hydroxyl, hydroxyl C₁-C ₄Alkyl, amino ,-NH (C₁-C ₄Alkyl) ,-N (C₁-C ₄Alkyl) (C₁-C ₄Alkyl) ,-(C₀-C ₆Alkyl)-C (O) R₁₁Or NO₂；R ₄Be H or methyl.

Again on the one hand, the invention provides the compound of formula XIa and XIb, wherein R₅Be-O-phenyl, N (R₉)-(C ₀-C ₆Alkyl)-C (O)-phenyl or-N (R₉)-C ₀-C ₄Alkyl-phenyl, wherein phenyl independently is that following group replaces: C by 1 or 2₁-C ₄Alkyl, C₁-C ₄Alkoxyl, halogen, C₁-C ₄The alkyl halide base (is being CF on the one hand₃)、C ₁-C ₄Halogenated alkoxy (is being OCF on the one hand₃), hydroxyl, hydroxyl C₁-C ₄Alkyl, amino ,-NH (C₁-C ₄Alkyl) ,-N (C₁-C ₄Alkyl) (C₁-C ₄Alkyl) ,-(C₀-C ₆Alkyl)-C (O) R₁₁Or NO₂；R ₄And R₉Independent is H Or methyl.

On the other hand, the invention provides the compound of formula XIa and XIb, wherein R₄For H.

Again on the one hand, the invention provides the compound of formula XIa and XIb, wherein R₁₁For optional independently be the C that following group replaces by 1 or 2₁-C ₆Alkoxyl: C₁-C ₄Alkoxyl, amino ,-NH (C₁-C ₆Alkyl) ,-N (C₁-C ₆Alkyl) (C₁-C ₆Alkyl) ,-(C₀-C ₆Alkyl)-C (O) N (R₉)-Heterocyclylalkyl or Heterocyclylalkyl, wherein said Heterocyclylalkyl are selected from pyrroles's alkyl, piperidines base, piperazine base and morpholine base, and wherein said Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3₁-C ₆Alkyl, C₁-C ₆Alkoxyl, hydroxyl, hydroxyl C₁-C ₆Alkyl, C₁-C ₆Alkoxy carbonyl ,-CO₂H、CF ₃Or OCF₃。

On the other hand, the invention provides the compound of formula XIa and XIb, wherein with two Or a plurality of aforesaid aspect combinations.

On the other hand, the invention provides the compound of formula XIIa and XIIb, namely have the formula Xa of following formula structure and the compound of Xb:

Formula XIIa

Formula XIIb

R wherein₁₅Be H, C₁-C ₆Alkyl, C₁-C ₆Alkoxyl, halogen, C₁-C ₆The alkyl halide base (is being CF on the one hand₃)、C ₁-C ₆Halogenated alkoxy (is being OCF on the one hand₃), hydroxyl, hydroxyl C₁-C ₄Alkyl, amino ,-NH (C₁-C ₆Alkyl) ,-N (C₁-C ₆Alkyl) (C₁-C ₆Alkyl), methyl sulphonyl, C₀-C ₆-sulfonamide or NO₂，R ₁₆For H or-O-(C₀-C ₆Alkyl)-C (O) R₁₁ On the other hand, R₁₅Be H.

Aspect another, the invention provides the compound of formula XIIa and XIIb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be OH.

Again more on the one hand, the invention provides the compound of formula XIIa and XIIb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁For choosing wantonly by 1 or 2 independently is the C that following group replaces ₁-C ₆Alkoxyl group: C ₁-C ₄Alkoxyl group, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) N (R ₉)-Heterocyclylalkyl or Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from azabicyclic-octyl group (being 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl in certain embodiments), azabicyclic-nonyl, azabicyclic-decyl (wherein the nitrogen of azepine is optional is replaced by methyl or ethyl), pyrrolidyl, piperidyl, piperazinyl and morpholinyl, and wherein said Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃, R ₄And R ₉Independent is H or methyl.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁₅Be H, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

Aspect another again, the invention provides the compound of formula XIIa and XIIb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁For choosing wantonly by 1 or 2 independently is the C that following group replaces ₁-C ₆Alkoxyl group: C ₁-C ₄Alkoxyl group, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) or heteroaryl, wherein said heteroaryl is selected from pyridyl, pyrimidyl, quinolyl, isoquinolyl and indyl, and wherein said heteroaryl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃, R ₄And R ₉Independent is H or methyl.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁₅Be H, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

Aspect another, the invention provides the compound of formula XIIa and XIIb, wherein R ₄And R ₉In at least one is H.

On the other hand, the invention provides the compound of formula XIIa and XIIb, wherein with two or more aforesaid aspect combinations.

On the other hand, the invention provides the compound of formula XIIIa and XIIIb, promptly have the formula XIIa of following formula structure and the compound of XIIb:

Formula XIIIa

Formula XIIIb

R wherein ₁₅Be H, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, C ₁-C ₆Haloalkyl (is CF on the one hand ₃), C ₁-C ₆Halogenated alkoxy (is OCF on the one hand ₃), hydroxyl, hydroxyl C ₁-C ₄Alkyl, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl), methyl sulphonyl, C ₀-C ₆-sulphonamide, NO ₂, R ₁₆For H or-O-(C ₀-C ₆Alkyl)-C (O) R ₁₁On the other hand, R ₁₅Be H.

Aspect another, the invention provides the compound of formula XIIIa and XIIIb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be OH, C ₁-C ₄Alkoxyl group (is C on the other hand ₁-C ₃Alkoxyl group) or C ₁-C ₂Alkoxy-C ₁-C ₃Alkoxyl group-.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

Aspect another again, the invention provides the compound of formula XIIIa and XIIIb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl), azabicyclic-octyl group (being 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl in certain embodiments), azabicyclic-nonyl, azabicyclic-decyl, wherein the nitrogen of azepine is optional is replaced by methyl or ethyl; R ₄For H or methyl, pyrrolidyl, piperidyl, morpholinyl, pyridyl or-(C ₀-C ₆Alkyl)-C (O) NH-pyridin-4-yl.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

More on the one hand, the invention provides the compound of formula XIIIa and XIIIb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: amino ,-NH (C ₁-C ₆Alkyl) or-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl).On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

Aspect another, the invention provides the compound of formula XIIIa and XIIIb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: pyrrolidyl, piperidyl, morpholinyl, pyridyl or-(C ₀-C ₆Alkyl)-C (O) NH-pyridin-4-yl.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

More on the one hand, the invention provides the compound of formula XIIIa and XIIIb, wherein R ₄And R ₉In at least one is H.

On the other hand, the invention provides the compound of formula XIIIa and XIIIb, wherein with two or more aforesaid aspect combinations.

On the other hand, the invention provides the compound of formula XIVa and XIVb, promptly have the formula Xa of following formula structure and the compound of Xb:

Formula XIVa

Formula XIVb

R wherein ₁₅Be H, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, C ₁-C ₆Haloalkyl (is CF on the one hand ₃), C ₁-C ₆Halogenated alkoxy (is OCF on the one hand ₃), hydroxyl, hydroxyl C ₁-C ₄Alkyl, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl), methyl sulphonyl, C ₀-C ₆-sulphonamide or NO ₂, R ₁₆For H or-O-(C ₀-C ₆Alkyl)-C (O) R ₁₁On the other hand, R ₁₅Be H.

More on the one hand, the invention provides the compound of formula XIVa and XIVb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be OH, C ₁-C ₄Alkoxyl group (is C on the other hand ₁-C ₃Alkoxyl group) or C ₁-C ₂Alkoxy-C ₁-C ₃Alkoxyl group-.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.More on the one hand, R ₄And R ₉In at least one is H.

Aspect another again, the invention provides the compound of formula XIVa and XIVb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl), azabicyclic-octyl group (being 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl in certain embodiments), azabicyclic-nonyl, azabicyclic-decyl, wherein the nitrogen of azepine is optional is replaced by methyl or ethyl; R ₄For H or methyl, pyrrolidyl, piperidyl, morpholinyl, pyridyl or-(C ₀-C ₆Alkyl)-C (O) NH-pyridin-4-yl.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

More on the one hand, the invention provides the compound of formula XIVa and XIVb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: amino ,-NH (C ₁-C ₆Alkyl) or-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl).On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

Aspect another, the invention provides the compound of formula XIVa and XIVb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: pyrrolidyl, piperidyl, morpholinyl, pyridyl or-(C ₀-C ₆Alkyl)-C (O) NH-pyridin-4-yl.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

More on the one hand, the invention provides the compound of formula XIVa and XIVb, wherein R ₄And R ₉In at least one is H.

On the other hand, the invention provides the compound of formula XIVa and XIVb, wherein with two or more aforesaid aspect combinations.

On the other hand, the invention provides the compound of formula XVa and XVb, promptly have the formula Xa of following formula structure and the compound of Xb:

Formula XVa

Formula XVb

Wherein n is 1 or 2.

More on the one hand, the invention provides the compound of formula XVa and XVb, wherein R ₄Be H or methyl, R ₁₁Be OH, C ₁-C ₄Alkoxyl group (is C on the other hand ₁-C ₃Alkoxyl group) or C ₁-C ₂Alkoxy-C ₁-C ₃Alkoxyl group-.On the other hand, R ₄And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.More on the one hand, R ₄And R ₉In at least one is H.

Aspect another again, the invention provides the compound of formula XVa and XVb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl), azabicyclic-octyl group (being 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl in certain embodiments), azabicyclic-nonyl, azabicyclic-decyl, wherein the nitrogen of azepine is optional is replaced by methyl or ethyl; R ₄For H or methyl, pyrrolidyl, piperidyl, morpholinyl, pyridyl or-C (O) NH-pyridin-4-yl.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

More on the one hand, the invention provides the compound of formula XVa and XVb, wherein R ₄And R ₉Independent is H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: amino ,-NH (C ₁-C ₆Alkyl) or-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl).On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

Aspect another, the invention provides the compound of formula XVa and XVb, wherein R ₄Be H or methyl, R ₁₁Be the C that is replaced by following group ₁-C ₄Alkoxyl group: azabicyclic-octyl group (being 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl in certain embodiments), azabicyclic-nonyl, azabicyclic-decyl, wherein the nitrogen of azepine is optional is replaced by methyl or ethyl; R ₄For H or methyl, pyrrolidyl, piperidyl, morpholinyl, pyridyl or-(C ₀-C ₆Alkyl)-C (O) NH-pyridin-4-yl.On the other hand, R ₄, R ₉And R ₁₁As preceding definition, R ₁Be chlorine, R ₂Be amino, R ₃Be methyl.

On the other hand, the invention provides the compound of formula XVa and XVb, wherein with two or more aforesaid aspect combinations.

On the other hand, the invention provides among formula Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or the XVb each compound, wherein R ₁And R ₂As followsly on pyridine ring and pyridone ring, locate:

On the other hand, the invention provides among formula Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or the XVb each compound, wherein the key 3 of center piperidine ring has " S " configuration, and key 4 has " R " configuration.

More on the one hand, the invention provides among formula Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or the XVb each compound, wherein R ₁And R ₂As followsly on pyridine ring and pyridone ring, locate:

And the key 3 of center piperidine ring has " S " configuration, and key 4 has " R " configuration.

On the other hand, the invention provides among formula Xa, Xb, XIa, XIb, XIIa, XIIb, XIIIa, XIIIb, XIVa, XIVb, XVa or the XVb each compound, wherein key 3 has " R " configuration, and key 4 has " S " configuration.

And the key 3 of center piperidine ring has " R " configuration, and key 4 has " S " configuration.

More on the one hand, the invention provides the compound of formula Xa and Xb, wherein:

R ₁Be chlorine; R ₂Be amino; R ₃(for Xb) is methyl; R ₄Be H, and R ₁And R ₂On pyridine ring and pyridone ring, have following location:

With

L is-(C ₃-C ₅Alkyl)-, one of them carbon atom can be by-N (R ₉)-or-(C ₂-C ₆Alkyl)-C (O)-replacement.Aspect another, R ₁, R ₂And R ₃(for the R of pyridyl ring ₃) as preceding definition with on pyridine ring and pyridone ring, locate R as previously mentioned ₄As preceding definition, R ₅For-the O-Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from azabicyclic-octyl group (being 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl in certain embodiments), azabicyclic-nonyl, azabicyclic-decyl (wherein the nitrogen of azepine is optional is replaced by methyl or ethyl), piperidyl, piperazinyl and pyrrolidyl, and wherein piperidyl, piperazinyl and pyrrolidyl are not substituted or are independently replaced for following group 1 or 2 position: C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, halogen, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, hydroxyl, hydroxyl C ₁-C ₄Alkyl, amino ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) R ₁₁Or NO ₂, wherein

R ₁₁For choosing wantonly by 1 or 2 independently is the C that following group replaces ₁-C ₆Alkoxyl group: C ₁-C ₄Alkoxyl group, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) N (R ₉)-Heterocyclylalkyl or Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from azabicyclic-octyl group (being 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl in certain embodiments), azabicyclic-nonyl, azabicyclic-decyl, and wherein the nitrogen of azepine is optional is replaced by methyl or ethyl; R ₄Be H or methyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl, wherein said Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃

R ₁Be chlorine; R ₂Be amino; R ₃(for Xb) is methyl; R ₄Be H, and R ₁, R ₂And R ₃On pyridine ring and pyridone ring, have following location:

With

L is-(C ₃-C ₅Alkyl)-, one of them carbon atom can be by-N (R ₉)-or-(C ₂-C ₆Alkyl)-C (O)-replacement.Aspect another, R ₁, R ₂And R ₃As preceding definition with on pyridine ring and pyridone ring, locate R as previously mentioned ₄As preceding definition, R ₅For being selected from following Heterocyclylalkyl: azabicyclic-octyl group (being 1-azabicyclic [2.2.2] oct-3-yl or 8-azabicyclic [3.2.1] oct-3-yl in certain embodiments), azabicyclic-nonyl, azabicyclic-decyl, wherein the nitrogen of azepine is optional is replaced by methyl or ethyl.

Again more on the one hand, the invention provides the compound of formula Xa and Xb, wherein

With

L is-(C ₃-C ₅Alkyl)-, one of them carbon atom can be by-N (R ₉)-or-(C ₂-C ₆Alkyl)-C (O)-replacement.Aspect another, R ₁, R ₂And R ₃As preceding definition with on pyridine ring and pyridone ring, locate R as previously mentioned ₄As preceding definition, R ₅For-N (R ₉)-C ₀-C ₄Alkyl-aryl or-N (R ₉)-(C ₀-C ₆Alkyl)-and C (O)-aryl, wherein said aryl is not substituted or is replaced by following group in one or more commutable positions: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, hydroxyl, hydroxyalkyl, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) R ₁₁Or NO ₂More on the one hand, described aryl is quilt-(C ₀-C ₆Alkyl)-C (O) R ₁₁Replace and choose wantonly and independently be selected from the phenyl that following group replaces: C by 1 or 2 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, CF ₃, OCF ₃, hydroxyl, hydroxyalkyl, amino ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) or NO ₂, wherein

R ₁₁For choosing wantonly by 1 or 2 independently is the C that following group replaces ₁-C ₆Alkoxyl group: C ₁-C ₄Alkoxyl group, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) N (R ₉)-Heterocyclylalkyl or Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from pyrrolidyl, piperidyl, piperazinyl and morpholinyl, and wherein said Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃One preferred aspect, group-(C ₀-C ₆Alkyl)-C (O) R ₁₁Link to each other with 4 of phenyl ring.

More on the one hand, shown in the key 3 of center piperidine ring and 4 be positioned such that:

One preferred aspect, shown in the key 3 of center piperidine ring and 4 be positioned such that:

The compounds of this invention comprises compound (promptly having the formula Xa of following formula structure and/or the compound of Xb) or its pharmacy acceptable salt of formula XX-a or XX-b:

XX-a, or

Wherein

R ₁Be halogen;

R ₂Be amino or single or two (C ₁-C ₄Alkyl) amino;

R ₃Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH;

R ₄Be H or C ₁-C ₄Alkyl;

R ₅For independently being the phenyl or naphthyl that following group replaces: C by 1 or 2 separately ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH ,-O-C ₂-C ₄Alkyloyl, halogen, halo C ₁-C ₄Alkyl, halo C ₁-C ₄Alkoxyl group ,-CO ₂R ₁₀,-(C ₁-C ₄Alkyl)-CO ₂R ₁₀

R ₉Be H or C ₁-C ₄Alkyl;

R ₁₀Independently be H, optional when occurring by a C who is selected from the group replacement of 5 or 6 yuan of monocyclic heterocycles alkyl rings and OH at every turn ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂,-C (O) NH (C ₁-C ₄Alkyl) ,-C (O) N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) or optional by C ₁-C ₄The piperidyl that alkyl replaces; With

R ₂₀Be C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group.

Aspect another, the invention provides the compound of formula (XX-2a) or formula (XX-2b), promptly have the compound of the formula (XX-a) or the formula (XX-b) of following formula structure:

Formula XX-2a or

Formula XX-2b

Wherein

R ₁₇Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH ,-O-C ₂-C ₄Alkyloyl, halogen, halo C ₁-C ₄Alkyl, halo C ₁-C ₄Alkoxyl group ,-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀With

R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH ,-O-C ₂-C ₄Alkyloyl, halogen, halo C ₁-C ₄Alkyl (CF for example ₃), halo C ₁-C ₄Alkoxyl group (OCF for example ₃) ,-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein the cis each other of the key on 3 and 4 of piperidines basic rings.

More on the one hand, shown in key 3 and 4 be positioned such that:

One preferred aspect, shown in key 3 and 4 be positioned such that:

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-NR ₉-(C ₁-C ₂Alkyl)-; R ₁₇Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxy or halogen; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH or-O-C ₂-C ₄Alkyloyl.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Again more on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-NR ₉-(C ₁-C ₂Alkyl)-; R ₁₇Be halogen, halo C ₁-C ₄Alkyl or halo C ₁-C ₄Alkoxyl group; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

On the other hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-NR ₉-(C ₁-C ₂Alkyl)-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Aspect another, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-NR ₉-(C ₁-C ₂Alkyl)-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be O-C ₂-C ₄Alkyloyl, halogen, halo C ₁-C ₄Alkyl or halo C ₁-C ₄Alkoxyl group.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-NR ₉-(C ₁-C ₂Alkyl)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Again more on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁C ₂Alkyl)-NR ₉-(C ₁-C ₂Alkyl)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl (for example methyl), C ₁-C ₄Alkoxyl group (for example methoxyl group) or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-NR ₉-(C ₁-C ₂Alkyl)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Aspect another, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein

L is-(C ₁-C ₃Alkyl)-NR ₉-(C ₁-C ₃Alkyl)-;

R ₁₀Be H, optional by a C who is selected from the group replacement of 5 or 6 yuan of monocyclic heterocycles alkyl rings and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces;

R ₁₇For OH ,-O-C ₂-C ₄Alkyloyl ,-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀With

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein

L is-(C ₁-C ₃Alkyl)-NR ₉-(C ₁-C ₃Alkyl)-;

R ₁₀For H, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₃Alkyl)-NR ₉-(C ₁-C ₃Alkyl)-; R ₁₀Be H; R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be H.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₃Alkyl)-NR ₉-(C ₁-C ₃Alkyl)-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be H, methyl, methoxyl group, OH, F or Cl.

Aspect another again, the invention provides the compound of formula (XX-3a) or formula (XX-3b), the compound that promptly has the formula (XX-2a) or the formula (XX-2b) of following formula structure:

XX-3a, or

XX-3b。

Again more on the one hand, the invention provides the compound of formula (XX-3a) or formula (XX-3b), wherein R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₉Be H or methyl; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₂The piperidyl that alkyl replaces.

On the other hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein

L is-(C ₂-C ₄Alkyl)-;

R ₁₇For OH ,-O-C ₂-C ₄Alkyloyl ,-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₇Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxy or halogen; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH or-O-C ₂-C ₄Alkyloyl.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Again more on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₇Be halogen, halo C ₁-C ₄Alkyl or halo C ₁-C ₄Alkoxyl group; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

On the other hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Aspect another, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be O-C ₂-C ₄Alkyloyl, halogen, halo C ₁-C ₄Alkyl or halo C ₁-C ₄Alkoxyl group.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Again more on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl (for example methyl), C ₁-C ₄Alkoxyl group (for example methoxyl group) or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

L is-(C ₂-C ₄Alkyl)-;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

L is-(C ₂-C ₄Alkyl)-;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₀Be H; R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be H.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₂-C ₄Alkyl)-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be H, methyl, methoxyl group, OH, F or Cl.

L is-(C ₁-C ₃Alkyl)-C (O) NR ₉-;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-; R ₁₇Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxy or halogen; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH or-O-C ₂-C ₄Alkyloyl.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Again more on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-; R ₁₇Be halogen, halo C ₁-C ₄Alkyl or halo C ₁-C ₄Alkoxyl group; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

On the other hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Aspect another, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be O-C ₂-C ₄Alkyloyl, halogen, halo C ₁-C ₄Alkyl or halo C ₁-C ₄Alkoxyl group.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl (for example methyl), C ₁-C ₄Alkoxyl group (for example methoxyl group) or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₂Alkyl)-C (O) NR ₉-; R ₁₀Be H; R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be H.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₃Alkyl)-C (O) NR ₉-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be H, methyl, methoxyl group, OH, F or Cl.

Aspect another again, the invention provides the compound of formula (XX-4a) or formula (XX-4b), the compound that promptly has the formula (XX-2a) or the formula (XX-2b) of following formula structure:

XX-4a, or

XX-4b。

Again more on the one hand, the invention provides the compound of formula (XX-4a) or formula (XX-4b), wherein R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₉Be H or methyl; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₂The piperidyl that alkyl replaces.

Aspect another again, the invention provides the compound of formula (XX-5a) or formula (XX-5b), the compound that promptly has the formula (XX-2a) or the formula (XX-2b) of following formula structure:

XX-5a or

XX-5b。

Again more on the one hand, the invention provides the compound of formula (XX-5a) or formula (XX-5b), wherein R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₉Be H or methyl; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₂The piperidyl that alkyl replaces.

L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-; R ₁₇Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxy or halogen; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH or-O-C ₂-C ₄Alkyloyl.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Again more on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-; R ₁₇Be halogen, halo C ₁-C ₄Alkyl or halo C ₁-C ₄Alkoxyl group; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

On the other hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be H, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Aspect another, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O); R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be O-C ₂-C ₄Alkyloyl, halogen, halo C ₁-C ₄Alkyl or halo C ₁-C ₄Alkoxyl group.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

Again more on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl (for example methyl), C ₁-C ₄Alkoxyl group (for example methoxyl group) or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₃The piperidyl that alkyl replaces; R ₁₇For-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group or OH.Preferred R ₁₇Or R ₁₈In a 4-position at phenyl.

L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-;

R ₁₈Be H; With

R ₂₀Be methoxy or ethoxy (preferred methoxyl group on the one hand).

Aspect another again, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-; R ₁₀Be H; R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₁₈Be H.

More on the one hand, the invention provides the compound of formula (XX-2a) or formula (XX-2b), wherein L is-(C ₁-C ₄Alkyl)-NR ₉C (O)-; R ₁₇For OH or-O-C ₂-C ₄Alkyloyl; R ₁₈Be H, methyl, methoxyl group, OH, F or Cl.

Aspect another again, the invention provides the compound of formula (XX-6a) or formula (XX-6b), the compound that promptly has the formula (XX-2a) or the formula (XX-2b) of following formula structure:

XX-6a, or

XX-6b。

Again more on the one hand, the invention provides the compound of formula (XX-6a) or formula (XX-6b), wherein R ₁₇For-CO ₂R ₁₀Or-(C ₁-C ₄Alkyl)-CO ₂R ₁₀R ₉Be H or methyl; R ₁₀Be H, optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl, quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₂The piperidyl that alkyl replaces.

Aspect another, the invention provides the compound of formula (XX-6a) or formula (XX-6b), wherein R ₁₇For-CO ₂R ₁₀, R ₁₀Be H or optional by a C who is selected from the group replacement of morpholinyl, pyrrolidyl and OH ₁-C ₄Alkyl.

More on the one hand, the invention provides the compound of formula (XX-6a) or formula (XX-6b), wherein R ₁₇For-CO ₂R ₁₀, R ₁₀For quinuclidinyl ,-C (O) NH ₂Or it is optional by C ₁-C ₂The piperidyl that alkyl replaces.

On the other hand, the invention provides the compound of formula (XX-6a) or formula (XX-6b), wherein R ₁₇For-CO ₂R ₁₀, R ₁₀For H or by C ₁-C ₂The piperidyl that alkyl replaces.

The present invention also provides the method for treatment vomiting, maldigestion, gastroparesis, constipation, intestinal pseudo obstruction, gastroesophageal reflux or postoperative ileus, and described method comprises the formula Xa that needs the patient treatment of this treatment significant quantity and the compound or its salt of Xb.

The invention provides with cisapride and compare serum and/or the more responsive compound of kytoplasm esterase degraded, therefore avoid following the metabolic side effect of Cytochrome P450.

Advantageously, treatment compound of the present invention is stable when storage, but shorter in the physiological environment half-life, therefore, uses The compounds of this invention side effect and toxicity incidence lower.

A preferred aspect of the present invention provides the treatment Stereoisomeric compounds that is used for the treatment of gastroesophageal reflux disease and comprises ester group, and described compound is responsive to the esterase degraded, thereby decomposes described compound and promote it from effectively being removed by the individuality for the treatment of.One preferred aspect, described treatment Stereoisomeric compounds is by the metabolism of I stage medicine detoxification system.

Other aspects of the present invention relate to when the degradation production that treatment compound of the present invention produces under the effect of esterase (preferred metabolism degradation production, promptly meta-bolites is generally the acid of parent ester).In urine or blood plasma, exist these degradation productions to can be used for the clearance rate of monitor therapy compound from the patient.

Is particularly advantageous by esterase degraded The compounds of this invention for drug metabolism, and this is because these enzymes distribute ubiquitously, and its activity depends on that the degree of age, sex or morbid state is different with the metabolism of oxidisability liver drug.

The present invention also provides the method for treatment various diseases (for example gastroesophageal reflux disease), and described method comprises the stereoisomerism structure and/or the sense analogue of at least a cisapride of the individual treatment significant quantity that needs treatment.One concrete aspect, the invention provides the pharmaceutical composition of the compound of the stereoisomerism structure of cisapride and/or sense analogue and these esterifications.

The present invention also provides treatment vomiting and these other illnesss (including, but not limited to maldigestion, gastroparesis, constipation and intestinal pseudo obstruction) significantly to reduce material and the method for following the side effect that gives cisapride simultaneously.

A preferred aspect of the present invention provides the treatment Stereoisomeric compounds that is used for the treatment of gastroesophageal reflux, maldigestion, gastroparesis, constipation, postoperative ileus and intestinal pseudo obstruction and comprises ester group, and described compound decomposes under the effect of esterase and promotes it from effectively being removed by the individuality for the treatment of.

The present invention also provides the method for synthetic uniqueness of the present invention and favourable compound.More particularly, the present invention has instructed the preparation and the purification process of this Stereoisomeric compounds.The method of adding these ester moieties and preparation and purifying steric isomer is for well known to a person skilled in the art, and uses guidance provided herein easily to carry out.

Preferred compound

One preferred aspect, the invention provides the isolating steric isomer of the Compound I that comprises three chiral centres.

6-(4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid rubane-3-base ester Ia

6-(4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid rubane-3-base ester Ib

Compound I a and Ib

Two in the chiral centre are present among cisapride and the norcisapride, and are cis-configuration in active medicines:

Therefore, for example the norcisapride of pharmaceutical active is the racemic mixture of two kinds of cis enantiomers:

(-) cisapride (+) Norcisapride

On the one hand, The present invention be more particularly directed to the configuration of the 3rd chiral centre in the 3-hydroxyl rubane part of the structure of cisapride and/or sense analogue.This group is being converted into this paper and is being called ± eliminates during the acidic metabolite of Compound I Ia and IIb:

6-(4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid IIa

6-(4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid IIb

Compound I Ia and IIb

Preferred Compound I a of the present invention and Ib steric isomer by R or S 3-hydroxyl rubane and (+)-or structure/sense analogue of (-)-norcisapride combine preparation, it is characterized in that pyridyl or pyriconyl partly replace the phenyl moiety of norcisapride, obtain compound III a, IIIb, IVa, IVb, Va, Vb, VIa and VIb.

6-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester IIIa

6-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester IIIb

(-) of compound III a and IIIb:Ia and Ib (R)-compound

6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester IVa

6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester IVb

Compound IV a and IVb:(+) (R)-compound

6-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester Va

6-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester Vb

Compound Va and Vb:(-) (S)-compound

6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester VIa

6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester VIb

Compound VI a and VIb:(+) (S)-compound

One preferred aspect, the present invention relates to the stereoisomerism isolated compound and comprise described compound compositions.The isolating stereoisomeric forms in any ratio of The compounds of this invention does not contain another kind (being that stereoisomerism is excessive) substantially.In other words, " R " form of compound does not contain the serpentine formula of compound substantially, therefore, for serpentine formula stereoisomerism excessive.On the contrary, the serpentine formula of compound does not contain " R " form of compound substantially, therefore, for " R " form stereoisomerism excessive.In one aspect of the invention, it is excessive that isolating Stereoisomeric compounds is at least about 80% stereoisomerism.One preferred aspect, it is excessive that described compound is at least about 90% stereoisomerism.One preferred aspect, it is excessive that described compound is at least about 95% stereoisomerism.One also preferred aspect, it is excessive that described compound is at least about 97.5% stereoisomerism.One most preferred aspect, it is excessive that described compound is at least about 99% stereoisomerism.Equally, " (+) " of compound and " (-) " form also are that stereoisomerism is excessive.

As described herein, various steric isomers have specific beyond thought performance, can advantageously be applicable to one group of situation that treatment is specific.Therefore, for example in the quinuclidinyl ester moiety, comprise (compound of 3 ' R)-isomer (being compound III a, IIIb, IVa and IVb) can pass through the esterase tachymetabolism in human plasma, and comprise 3-hydroxyl rubane (compound of 3 ' S)-isomer (being compound Va, Vb, VIa and VIb) metabolism slowly many.

Therefore, for example work as preferred acting duration in short-term, for example produce gastric motility, when for example pulse suffers from the patient of acute gastroparesis or acute gastroesophageal reflux, can use (3 ' R)-isomer of Compound I a and Ib at the acute attack moderate stimulation.The esterase tachymetabolism is that another advantage of substantially not too active meta-bolites (being Compound I Ia or IIb) is that the possibility and the toxicity of drug-drug interactions is very low.Therefore, use these action times short (R)-isomer can be advantageously used for and for example be used for the treatment of PN and because the iv formulation in its incomplete adult's of CYP450 phylogeny the gastroesophageal reflux that name can not metabolic drug.In these newborn infants, more favourable by the medicine of non-CYP450 system (for example esterase) tachymetabolism.On the other hand, Compound I (3 ' S)-isomer is preferably used in the chronic disease of same disease, for example diabetic subject or cancer patients's gastroparesis or need to use among the chronic gastroesophageal reflux patient of nurse in 24 hours under the mitigation state.

Except metabolism result's difference, these independent isomer are to 5-HT ₄Acceptor also has different binding affinities, and is therefore active different, thereby has different therepic use.

The conclusion of these Considerations is: when 3 and 4 each other during cis, (for example Compound I is 4 kinds of mixture of isomers a) to each compound, is made up of 2 pairs of enantiomers.The first pair of enantiomer for (+) (R)-Compound I a and (-) (S)-Compound I a (being respectively compound IV a and Va), the second pair of enantiomer for (-) (R)-Compound I and (+) (S)-Compound I (being respectively compound III a and VIa).Each enantiomer centering, each independent enantiomer has the hydrolysis rate of different esterases and to 5-HT ₄The avidity performance of acceptor.These different performances make it have not interchangeable independent favourable therepic use, and promptly the therepic use of each isomer is specific, and is not suitable for racemic mixture.Avidity difference and metabolic rate difference to acceptor can not be predicted, also can not scrutinize these performances when the test racemic mixture.

Definition

Term used herein " alkyl " comprises those alkyl that specify number carbon atom.Alkyl can be straight or branched.The example of " alkyl " have methyl, ethyl, propyl group, sec.-propyl, butyl, different-, secondary-and tert-butyl, amyl group, hexyl, heptyl, 3-ethyl-butyl etc.If do not specify carbonatoms, then should " alkyl " part have 1-6 carbon atom.

The alkyl of the described number carbon atom that term " alkoxyl group " expression links to each other with parent molecular moiety by oxygen.The example of alkoxyl group has methoxyl group, oxyethyl group, propoxy-and isopropoxy.

" aryl " is meant the aromatic carbocyclic with optional monocycle (for example phenyl) that condenses or link to each other with other aromatic hydrocarbon rings or non-aromatic hydrocarbon ring." aryl " comprise wherein at least one ring for aromatic ring (for example 1,2,3,4-tetralyl, naphthyl), wherein each ring optional by following specified group list-, two-or three-a plurality of condensed rings of replacing, and many rings of uncondensed (for example biphenyl or dinaphthalene).Preferred aryl groups of the present invention is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydro naphthyl, fluorenyl, tetralin base or 6,7,8,9-tetrahydrochysene-5H-benzo [a] cycloheptenyl.More preferably phenyl, xenyl and naphthyl.Phenyl most preferably.Aryl is not substituted or is replaced by various groups in one or more commutable positions according to the rules herein.For example this aryl can be chosen wantonly by following group and replace: C for example ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C ₁-C ₆) alkylamino, two (C ₁-C ₆) alkylamino, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, amino (C ₁-C ₆) alkyl, list (C ₁-C ₆) alkylamino (C ₁-C ₆) alkyl or two (C ₁-C ₆) alkylamino (C ₁-C ₆) alkyl.

Term " halogenated alkoxy " is meant by at least one halogen atom and replaces and the optional alkoxyl group that is also replaced by at least one other halogen atom that wherein each halogen independently is F, Cl, Br or I.Preferred halogen is F or Cl.Preferred halogenated alkoxy comprises 1-6 carbon atom, more preferably 1-4 carbon atom, also more preferably 1-2 carbon atom." halogenated alkoxy " comprises perhalogeno alkoxyl group, for example OCF ₃Or OCF ₂CF ₃

Term " heteroaryl " is meant and comprises the heteroatomic aromatic ring system that at least one is selected from nitrogen, oxygen and sulphur.Described hetero-aromatic ring can be condensed or links to each other with one or more hetero-aromatic rings, aromatics or non-aromatic hydrocarbon ring or heterocycloalkyl ring.The example of heteroaryl has pyridyl, pyrimidyl, quinolyl, benzothienyl, indyl, indolinyl, pyridazinyl, pyrazinyl, pseudoindoyl, isoquinolyl, quinazolyl, quinoxalinyl, 2, the 3-phthalazinyl, imidazolyl isoxazolyl, pyrazolyl oxazolyl, thiazolyl, the indolizine base, indazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, furyl, thienyl, pyrryl oxadiazole base, thiadiazolyl group, benzo [1,4] oxazinyl, triazolyl, tetrazyl, isothiazolyl, 1, the 5-phthalazinyl, the isochroman base, chromanyl, tetrahydro isoquinolyl, iso-dihydro-indole-group, different benzo tetrahydrofuran base, different benzo tetrahydro-thienyl, isobenzo-thienyl benzoxazolyl, the pyridopyridine base, the benzo tetrahydrofuran base, the benzo tetrahydro-thienyl, purine radicals, benzo dioxane pentadienyl, triazinyl, pteridyl, benzothiazolyl, imidazopyridyl, the Imidazothiazole base, dihydrobenzo Yi oxazinyl, Ben Bing Yi oxazinyl benzoxazinyl, dihydrobenzo isothiazine base, benzopyranyl, the benzo thiapyran base, the chromone base, the chroman ketone group, pyridyl-N-oxide compound, tetrahydric quinoline group, the dihydroquinoline base, the dihydroquinoline ketone group, the dihydro-isoquinoline ketone group, the melilotine base, the dihydro isocoumarinyl, the isoindoline ketone group, benzodioxan base benzoxazolinone base, pyrryl N-oxide compound, pyrimidyl N-oxide compound, pyridazinyl N-oxide compound, pyrazinyl N-oxide compound, quinolyl N-oxide compound, indyl N-oxide compound, indolinyl N-oxide compound, isoquinolyl N-oxide compound, quinazolyl N-oxide compound, quinoxalinyl N-oxide compound, 2,3-phthalazinyl N-oxide compound, imidazolyl N-oxide compound isoxazolyl N-oxide compound oxazolyl N-oxide compound, thiazolyl N-oxide compound, indolizine base N-oxide compound, indazolyl N-oxide compound, benzothiazolyl N-oxide compound, benzimidazolyl-N-oxide compound, pyrryl N-oxide compound oxadiazole base N-oxide compound, thiadiazolyl group N-oxide compound, triazolyl N-oxide compound, tetrazyl N-oxide compound, benzo thiapyran base S-oxide compound, benzo thiapyran base S, the S-dioxide.Preferred heteroaryl comprises pyridyl, pyrimidyl, quinolyl, indyl, pyrryl, furyl, thienyl and imidazolyl.Preferred heteroaryl comprises pyridyl, pyrryl and indyl.Heteroaryl is not substituted or is replaced by various groups in one or more commutable positions according to the rules herein.For example this heteroaryl can be chosen wantonly by following group and replace: C for example ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C ₁-C ₆) alkylamino, two (C ₁-C ₆) alkylamino, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, amino (C ₁-C ₆) alkyl, list (C ₁-C ₆) alkylamino (C ₁-C ₆) alkyl or two (C ₁-C ₆) alkylamino (C ₁-C ₆) alkyl.

Term " Heterocyclylalkyl " is meant and comprises heteroatomic ring or the member ring systems that at least one is preferably selected from nitrogen, oxygen and sulphur that wherein said heteroatoms is in non-aromatic ring.Described heterocycloalkyl ring is optional to link to each other for condensed or with other heterocycloalkyl rings and/or non-aromatic hydrocarbon ring and/or phenyl ring.Preferred Heterocyclylalkyl has 3-7 atom.Preferred Heterocyclylalkyl has 5 or 6 atoms.The example of Heterocyclylalkyl has azabicyclic [2.2.2] octyl group (also being " quinuclidinyl " or quinuclidine derivatives in all cases), azabicyclic [3.2.1] octyl group, morpholinyl, thio-morpholinyl, thio-morpholinyl S-oxide compound, thio-morpholinyl S, the S-dioxide, piperazinyl, high piperazinyl, pyrrolidyl, pyrrolinyl, THP trtrahydropyranyl, piperidyl, tetrahydrofuran base, tetrahydro-thienyl, homopiperidinyl, high morpholinyl, high-sulfur is for morpholinyl, high-sulfur is for morpholinyl S, S-dioxide oxazoline ketone group, the pyrazoline base, the pyrrolin base, the dihydro pyrazinyl, the dihydropyridine base, the dihydro-pyrimidin base, the dihydrofuran base, dihydro pyranyl, tetrahydro-thienyl S-oxide compound, tetrahydro-thienyl S, S-dioxide and high-sulfur are for morpholinyl S-oxide compound.Preferred Heterocyclylalkyl comprises azabicyclic [2.2.2] octyl group, azabicyclic [3.2.1] octyl group, piperidyl, piperazinyl, pyrrolidyl, thio-morpholinyl, S, S-dioxo thio-morpholinyl, morpholinyl and imidazolidyl.More preferably azabicyclic [2.2.2] octyl group, azabicyclic [3.2.1] octyl group, piperidyl, piperazinyl, pyrrolidyl, imidazolidyl and morpholinyl.Heterocyclic radical is not substituted or is replaced by various groups in one or more commutable positions according to the rules herein.For example this heterocyclic radical can be chosen wantonly by following group and replace: C for example ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, hydroxyl, cyano group, nitro, amino, list (C ₁-C ₆) alkylamino, two (C ₁-C ₆) alkylamino, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, amino (C ₁-C ₆) alkyl, list (C ₁-C ₆) alkylamino (C ₁-C ₆) alkyl, two (C ₁-C ₆) alkylamino (C ₁-C ₆) alkyl or=O.

Term " pharmacy acceptable salt " or " its pharmacy acceptable salt " are meant the salt by pharmaceutically acceptable non-toxicity acid or alkali (comprising inorganic bronsted lowry acids and bases bronsted lowry and organic bronsted lowry acids and bases bronsted lowry) preparation.Because The compounds of this invention is an alkalescence, therefore can be by pharmaceutically acceptable non-toxicity acid preparation salt.The suitable pharmaceutically acceptable acid addition salt of The compounds of this invention comprises acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pounces on the additive salt of acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Preferred acid addition salt is muriate and vitriol.Aspect most preferred, the structure of cisapride and/or sense analogue give with the form of free alkali or list or dihydrochloride.

Term used herein " treatment " comprises the prevention described compound of administration or comprises the pharmaceutical composition (" prevention ") and the treatment therapy of described compound, with the disease or the illness that reduce or elimination this paper mentions.The prevention administration is meant preventing disease and can be used for treating the patient that may have or suffer from one or more disease risks that this paper mentions.Therefore, term used herein " treatment " or derivatives thereof comprises when prophylactically giving activeconstituents of the present invention or give this activeconstituents after the morbid state outbreak, partially or completely suppresses described morbid state." prevention " is meant that giving one or more activeconstituentss to Mammals avoids any disease as herein described and other diseases with the protection Mammals.

Term " treatment significant quantity " is meant the required amount of result of treatment that obtains, for example: 1) be enough to alleviate the amount, 2 of reflux disease) be enough to alleviate the amount or 3 of nausea and vomiting) be enough to alleviate the amount of the illness that causes by the gastroenteritic power function obstacle.The structure and/or the sense analogue of the cisapride of treatment significant quantity comprise above-mentioned dosage and administration frequency timetable.

" Mammals " can for example be mouse, rat, pig, horse, rabbit, sheep, ox, cat, dog or people.One preferred aspect, Mammals is behaved.

Term " individuality " is defined as the one Mammals that gives The compounds of this invention.Mammals can for example be mouse, rat, pig, horse, rabbit, sheep, ox, cat, dog or people.One preferred aspect, individuality is the people.

Term " cisapride of esterification " is meant the structure with cisapride and/or the treatment compound of the present invention of sense analogue, it comprises hydrolyzable group (being generally ester), not weakening these compounds provides the ability of treatment benefit, but make these compounds more responsive, and reduce the interaction of cytochrome P-450 medicine detoxification system and cisapride compound lytic enzyme (particularly serum and/or kytoplasm esterase) degraded.The metabolism of the esterase-mediation of the cisapride compound of esterification reduces effect and the reduction or eliminate side effect that cisapride cause of cytochrome P-450 medicine detoxification system in the cisapride metabolism.

Term used herein " analog " is meant the compound that has the common structural performance with parent compound.For example the analog of cisapride can have one or more structural performances jointly with parent cisapride compound, for example the aromatic ring of Qu Daiing links to each other with piperidine ring by acid amides connection base, but other aspect differences structurally for example comprise or lack one or more other chemical parts.Another example is the phenyl ring that replaces cisapride with pyridine ring or pyridone ring.

Term used herein " sense analogue " is meant the compound that has the common functional properties with parent compound.The common structure feature of the sense analogue of cisapride and cisapride seldom (if any) for example, but realized similar function, for example all as 5-HT ₄Agonist)

Term " side effect " is for example suffered from diarrhoea including, but not limited to various gastrointestinal illnesss, abdominal cramps, and abdominal discomfort, tired, headache, systolic pressure raises, dead, ventricular tachycardia, quiver in the chamber, the torsades de pointes ventricular tachycardia, QT prolongs, heart rate quickens, neuropathy and CNS disease and cisapride and the other drug that gives simultaneously are (such as, but be not limited to digoxin, diazepam, ethanol, coumarin acetic acid, Cimitidine Type A/AB, thunder Buddhist nun ladder fourth, paracetamol and Proprasylyte) interaction.

Term used herein " gastroesophageal reflux disease " is meant anti-incidence and the symptom that flow to the illness that oesophagus causes of stomach inclusion.

Term used herein " causes antiemetic effect " and " antiemetic treatment " is meant and alleviates or prevent spontaneous or follow the nausea and vomiting symptom of emetogenic cancer chemotherapy or radiotherapy-induced.

Term used herein " illness that treatment gastroenteritic power function obstacle causes " is meant and treats symptom and the illness of following this disease (including, but not limited to gastroesophageal reflux disease, maldigestion, gastroparesis, constipation, postoperative ileus and intestinal pseudo obstruction).

Term used herein " short motion " is meant and promotes wriggling, therefore promotes to move through gi tract.

Term used herein " maldigestion " is meant that illness is characterised in that weakening can cause main gastrointestinal dysfunction symptom or because the digestion power or the function of the complication that other diseases (for example ecphyaditis, gall-bladder obstacle or malnutrition) causes.

Term used herein " gastroparesis " is meant because the stomach paralysis that stomach motion unit is unusual or the complication of various diseases (for example diabetes, the sclerosis of gradual system, apocleisis nervosa or myotony malnutrition) causes.

Term used herein " constipation " is meant that illness is characterised in that the defecation that is caused by the illness that for example lacks myenteron meat tonus or intestines spasticity is rare or difficult.

Term used herein " postoperative ileus " is meant because postoperative destroys the intestinal obstruction that muscular tone causes.

Term used herein " intestinal pseudo obstruction " is meant that illness is characterised in that constipation, angina and vomiting, but the sign that does not have health to block.

The preparation of compound

The chemosynthesis of the various analogues of cisapride can be adopted disclosed european patent application 0 on April 13 nineteen eighty-three, 076,530A2, United States Patent (USP) 4,962,115 and 5,057,525 and the described method of Drug Development Res.8:225-232 (1986) of Van Daele etc. carry out, the disclosed content of each document is attached to herein by quoting in full.This synthetic can followingly the improvement for example introduced ester group and when an opportunity arises with the part that contains pyridyl of optional replacement in synthetic

Or contain the part of pyriconyl

The phenyl moiety that replaces the replacement of natural cisapride

The exemplary nonrestrictive synthesis flow of the cisapride analogue of some esterification of the present invention is provided in WO01/093849.

Further specify the present invention by following examples, but should not be construed as scope of the present invention or spirit is confined to described concrete grammar.Those skilled in the art recognize that and to change raw material and can use other step to prepare the described compound that the present invention includes of following examples.Those skilled in the art also recognize and can utilize different solvents or reagent to realize some above-mentioned conversion.In some cases, the active function groups that can need protection is realized above conversion.Usually group and connection and to remove the required condition of this blocking group be conspicuous for the organic synthesis those skilled in the art need protection.When using blocking group, can need deprotection steps.The suitable blocking group of protection and deprotection and method (for example Protecting Groups in Organic Synthesis (blocking group in the organic synthesis) described blocking group and the method for T.Greene) are known in this field and understand.

Unless otherwise indicated, otherwise all reagent and solvent are the standard industry level, and need not to be further purified and can directly use.The suitable atmosphere of realization response (for example air, nitrogen, hydrogen, argon gas etc.) it will be apparent to those skilled in the art that.

6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester dihydrochloride for structurally and/or on the sense with 5-HT ₄The small molecules that the receptor stimulant cisapride is correlated with is designed for low and/or elimination QT prolongation and CYP450-dependence metabolism in the relevant density loss of the treatment of expection.

Embodiment 1

Preparation 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester dihydrochloride (being also referred to as the N-7505 dihydrochloride)

The N-7505 dihydrochloride comprises three chiral centres and can enantiomer and the chemosynthesis of diastereisomericallypure pure product form.Can for example estimate the chiral purity of main raw material, to guarantee N-7505 dihydrochloride and the diastereisomericallypure pure degree that contains other compounds of the present invention of one or more chiral centres by chirality HPLC or chirality GC method.

A following explanation 6-(exemplary synthetic method of (3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester dihydrochloride (N-7505 dihydrochloride).Racemize 6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide can be used as the synthetic raw material.The effective chemical method for splitting can be used for preparing enantiomeric pure 6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide.Can estimate the chiral purity of enantiomeric pure 6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide by chirality HPLC method, to guarantee that chiral purity is more than or equal to for example 98% enantiomer excessive (e.e.) quality.Enantiomeric pure 6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide can react under alkaline condition with 6-bromocaproic acid ethyl ester subsequently, prepares corresponding alkylating ethyl ester.Transesterification reaction between the ethyl ester and (R)-(-)-3-hydroxyl rubane (measure be preferably greater than or equal 98%e.e by chirality GC) is used to prepare the N-7505 dihydrochloride.End product is with the dihydrochloride isolated in form.

Step 1: resolution of racemic 6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide

(-)-dibenzoyl-L-tartrate ((-)-DBT, about 1 weight part) is dissolved in the ethanol, filters, remove remaining particle.Individually racemize 6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide (about 0.8 weight part) is dissolved in the mixture of second alcohol and water subsequent filtration.Filtrate is heated to about 75 ℃, adds (-)-DBT solution subsequently., after 30 minutes mixture was slowly cooled off several hours to about 5 ℃ in stir about under this temperature, product salt is collected in vacuum filtration, uses EtOH/H ₂The washing of O mixture.Be heated to about 79 ℃, slowly cool to about 5 ℃ subsequently as previously mentioned, use EtOH/H ₂O recrystallization wet cake.On vacuum filter, collect product, use EtOH/H ₂The O washing obtains wet cake.

Wet cake is suspended in water, use 7% (W/W) NaOH aqueous solution with pH regulator to about 12.With resulting suspension stir about 3 hours under room temperature, vacuum filtration subsequently, washing solid matter, vacuum-drying.Handle again with (-)-DBT with after product, form salt by above-mentioned identical universal method.Subsequently as mentioned above with the isolating salt of NaOH aqueous solution neutralization.Product is separated on strainer, dry as previously mentioned, obtain (+)-6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide alkali (about 0.25 weight part).It is about 100% (+)-6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide that chirality HPLC analyzes e.e.Specific rotation is about+5 ° of (methyl alcohol; 25 ℃ and 589nm), turn out to be the positive isomer of 6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide.

Step 2: with the coupling of 6-bromocaproic acid ethyl ester

(+)-6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide (about 1 weight part), salt of wormwood (about 0.48 weight part) and potassiumiodide (about 0.063 weight part) are suspended in the anhydrous USP ethanol.Under room temperature, 6-bromocaproic acid ethyl ester (about 0.76 weight part) is slowly added in this suspension.Mixture heating up is refluxed, finish until reaction.Be cooled to room temperature subsequently, reaction mixture is filtered,, filtrate decompression is concentrated into half volume approximately to remove for example inoganic solids.Stir fast down, by crude product slowly being added to precipitated product in the cold water (about 13 weight parts).The vacuum filtration throw out, washing as previously mentioned by being dissolved in the dehydrated alcohol, slowly adds to cold water subsequently subsequently, and redeposition is more than twice.Resulting wet cake washs with normal heptane, subsequently resuspending in ethyl acetate and normal heptane (1: 9, v/v) in, stir about 1 hour, subsequent filtration, vacuum-drying obtains the product of 0.73 weight part coupling.

Step 3: with the rubane coupling of (R)-3-hydroxyl and form dihydrochloride

With the ester products (1 weight part) of step 2 and (R)-3-hydroxyl rubane (about 1.12 weight parts) is suspended in the toluene, slowly adds ethanolato-titanium (IV) (about 0.5 weight part) subsequently in the suspension of this stirring.Under nitrogen gas stream, mixture heating up to about 91 ℃, is removed ethanol to flask applying portion vacuum with azeotropic by water distilling apparatus subsequently.Add other toluene according to circumstances, to keep the minimum solvent volume in the flask.Think after about 33 hours to react and finish.

Mixture is cooled to about room temperature, water extraction 5 times.With the organic layer concentrating under reduced pressure, subsequently resulting resistates is dissolved in again among the EtOH/iPrOH (about 1: 1 v/v), filter by 0.45 micron membranes strainer subsequently, to remove any particle.Concentrated hydrochloric acid is slowly added in the filtrate of stirring, with the 6-that is settled out required product dihydrochloride form ((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester.Resulting suspension was stirred several hours under room temperature, and vacuum filtration is collected, and uses EtOH/iPrOH (1: 1; V/v) rinsing obtains 0.53 weight part crude product salt.

With crude product 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester dihydrochloride resuspending in ethanol, reflux, subsequently at about 1 hour internal cooling to room temperature.Product is collected in vacuum filtration, uses the ethanol rinsing, subsequently dry air.The solid resuspending in ethanol, is warmed to about 55 ℃, obtains clear soln, add warm Virahol subsequently, allow product precipitate by slowly cooling to room temperature.Resulting suspension was stirred several hours, and vacuum filtration subsequently is with for example isopropyl alcohol.With product vacuum-drying, started under the room temperature vacuum-drying several hours, subsequently in about 55 ℃ of following vacuum-dryings, until reaching constant weight.

Embodiment 2

Preparation 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester

Step 1: synthetic 4-(dibenzyl amino)-3-methoxyl group piperidines-1-ethyl formate (1):

In the DMF solution of racemize 4-amino-3-methoxyl group piperidines-1-ethyl formate (1 molar part), add bromotoluene (about 2.2 molar part), salt of wormwood (about 2.4 molar part) and potassiumiodide (about 0.2 molar part) respectively.Reaction is heated to about 80 ℃.After about 6 hours, water (about 12 parts by volume) is diluting reaction slowly, uses for example ethyl acetate extraction subsequently.Organic layer salt water washing is with after anhydrous Na ₂SO ₄Dry.Subsequent filtration, concentrated solvent obtains yellowish-orange buttery 1 (1 molar part).

Step 2. is synthesized N, N-dibenzyl-3-methoxyl group piperidines-4-amine (2):

The aqueous isopropanol that adds NaOH (about 10 molar part) in 1 the solution stirs mixture and reflux subsequently.Behind about 5 hours of about 3-, reaction is cooled to room temperature, removes alcoholic solvent by rotary evaporation subsequently.The dilute with water mixture is used ethyl acetate extraction subsequently.Organic layer salt water washing is with after anhydrous Na ₂SO ₄Dry.Subsequent filtration, concentrated solvent obtains crude product oily matter, through SiO ₂Purifying (CH ₂Cl ₂: MeOH: NH ₄OH, (pact) 15: 1: 0.01), obtain 2.

Step 3. synthetic (3S, 4R)-N, N-dibenzyl-3-methoxyl group piperidines-4-amine (3):

(-)-dibenzoyl-L-tartrate (about 1.2 weight parts) is dissolved in the ethanol, slowly adds to the solution of 2 (about 1 weight parts) subsequently.With the solution mild heat, be cooled to room temperature subsequently, with the crystal salt product.Salt is filtered, use EtOH/H ₂The O washing suspends in water subsequently, by adding the NaOH aqueous solution (7%wt/wt) alkalization, reaches about 12 until pH.With suspension vigorous stirring under room temperature, with the solid filtering, washing, vacuum-drying obtains cis-isomer 3.

Step 4. synthesize 6-((3S, 4R)-4-(dibenzyl amino)-3-methoxyl group piperidines-1-yl) ethyl hexanoate (4):

In the DMF solution of 3 (1 molar part), add bromocaproic acid ethyl ester (about 1.2 molar part), salt of wormwood (about 1.4 molar part) and potassiumiodide (about 0.2 molar part) respectively.Reaction is heated to 80 ℃ subsequently.After about 8 hours, water (about 12 parts by volume) is diluting reaction slowly, uses ethyl acetate extraction subsequently.Organic layer salt water washing is with after anhydrous Na ₂SO ₄Dry.Subsequent filtration, concentrated solvent obtains crude product.Through SiO ₂Purifying obtains alkylating product 4.

Step 5. synthesize 6-((3S, 4R)-4-(dibenzyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester (5):

Purity titanium tetraethoxide is added to 4 (1 molar part) and (R)-(-)-mixture of 3-hydroxyl rubane (1 molar part) in toluene.Reaction mixture is equipped with the dean-stark device, extremely about 90 ℃ of postheating, applying portion vacuum (adding other toluene as required, to keep required solvent levels) subsequently.Subsequently mixture is cooled to room temperature, uses the ethyl acetate diluting reaction, subsequently water is added to resulting mixture.Organic layer is separated, and the salt water washing is through anhydrous Na ₂SO ₄Drying is filtered, and concentrates.Through SiO ₂Purifying obtains being rich in 5 of enantiomer.

Step 6. synthesize 6-((3S, 4R)-4-amino-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester (6):

The EtOH solution of 5 (1 molar part) is added in the reaction flask that fills palladium carbon (about 0.2 molar part).With the mixture evacuate air, use H subsequently subsequently ₂Atmosphere places under the hydrogenolysis condition.After reaction is finished,, wash with EtOH subsequently with celite Celite pad filtering palladium.By the rotary evaporation concentrated filtrate, obtain 6.

Step 7. synthesize 6-((3S, 4R)-4-(6-amino-4-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester (7):

Under about 0 ℃, in the THF solution of for example Vinyl chloroformate (1 molar part), add (optional replacement) nicotinic acid (1 molar part) in batches.Mixture is warmed to room temperature (rt) lasts about 1 hour, be cooled to about 0 ℃ subsequently, drip the solution of compound 6 (1 molar part) subsequently.Subsequently reaction is warmed to room temperature.After reaction is finished, by adding saturated NaHCO ₃EA (ethyl acetate) extraction is used in solution quencher reaction subsequently.With organic layer salt water washing, through anhydrous Na ₂SO ₄Drying is filtered, and concentrates, and obtains required product 76-((3S, 4R)-4-(6-amino-4-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester.

Embodiment 3

Optionally synthetic 6-(method of (3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester dihydrochloride (N-7505 dihydrochloride):

Under acidic conditions, in the presence of acetate, 1-benzyl piepridine-4-ketone (1) and Hydrogen bromide reaction produce N-benzyl-3-bromine piperidin-4-one-(2).Handle 2 with sodium methylate and methanol solution, obtain 1-benzyl-4,4-dimethoxy piperidines-3-alcohol (3).[exist beta-amino that the reaction of Favorskii-type can not take place.] use the hydride base hydroxyl that methylates, subsequently DMF (dimethyl formamide) as solvent in the presence of, with the methyl iodide processing, obtain compound 4.

In the presence of heat, use 1% sulphuric acid hydrolysis acetal subsequently, obtain piperidines 5, can for example use sodium cyanoborohydride and ammonium acetate in methyl alcohol, to carry out reductive amination subsequently, obtain 1-benzyl-3-methoxyl group piperidines-4-amine (6).In this step, can carry out the chiral separation technology to 6.Can followingly finish, for example use (-)-DBT or tartaric other variants, in the presence of suitable solvent, obtain proprietary asymmetric pure compound 7.In the presence of the THF solvent, can use the Boc acid anhydrides to finish the Boc radical protection of primary amine in 7, make 8.In the presence of the hydrogen atmosphere that alkylation step is set, use the Pd/C hydrogenolysis in methyl alcohol to carry out debenzylating reaction.In the presence of the alkali of gentleness and DMF, handle the own nitrile of 6-bromine, produce compound 10.In the presence of diluted acid, use (R)-3-hydroxyl rubane that nitrile is converted into ester, produce 11.Use TFA to remove the Boc group subsequently, obtain free amine, in the presence of coupler (for example Vinyl chloroformate), can carry out coupled reaction, obtain the N-7505 dihydrochloride of enantiomeric pure material form with required nicotinic acid.

Perhaps can in the presence of the alkali of gentleness, use 6-bromocaproic acid ethyl ester alkylated compound 9.Remove the Boc group subsequently, obtain compound 14.Use (R)-hydroxyl rubane and purity titanium tetraethoxide in toluene solvant, to carry out 14 transesterify of titanium mediation, produce 156-((3S, 4R)-4-amino-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester.In the presence of coupler (for example Vinyl chloroformate), free amine 15 can with required nicotinic acid (under the situation of this embodiment, be 6-amino-5-chloro-2-methoxyl group nicotinic acid) carry out coupled reaction, obtain 16, i.e. the N-7505 dihydrochloride of enantiomeric pure material form.The ester of Carlsburg esterase hydrolyzed S-configuration, therefore remaining untouched stays the ester of R configuration.Therefore also can obtain 18 with the non-enantiomer mixture of Carlsburg esterase treatment 17 is 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) basic ester dihydrochloride of caproic acid (R)-rubane-3-.

Embodiment 4

(+) and (-)-6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide or (+) and (-)-6-amino-5-chloro-N-(3-methoxyl group piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-methane amide can split enantiomer by using usual manner, thereby by its racemic mixture preparation, the fractionation mode is for example according to United States Patent (USP) 6,147,093, J.Jacques, A.Collet and S.H.Wilen (Wiley-Interscience, New York, NY) the described method of Tetrahedron (1977) 33:2725 of " Enantiomer, Racemates and Resolutions (enantiomer; racemic modification and fractionation) " or S.H.Wilen etc. splits into the acid of different optically-actives.

Use preparative column chromatography evaporating solvent subsequently, can easily make 4 kinds of isomer of above-mentioned each compound that is lower than milligram quantities.This method is used to prepare the purpose of small amount of sample to be used to analyze and characterize.This method is the conventional standard isolation methods of using that is used to separate and characterize meta-bolites in assay laboratory.

Below describe and use (+)-6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide, the exemplary synthetic route of compound IV b, compound VI b and (+)-Compound I Ib as raw material.Compound III b, compound Vb are identical with the route of (-)-Compound I Ib, and difference is to use (-)-6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide as raw material.

Embodiment 5

Preparation (+)-Compound I Ib ethyl ester

KI and K with (+)-6-amino-5-chloro-2-methoxyl group-N-(3-methoxyl group piperidin-4-yl) niacinamide and 6-bromocaproic acid ethyl ester (each 1 equivalent), catalytic amount ₂CO ₃The molar mixture that waits of (2 equivalent) heated several hours down or finishes until the reaction of TLC analysis revealed in about 60 ℃ in DMF (dimethyl formamide).After being cooled to room temperature, add entry, mixture extracts with EtOAc subsequently.The organic extract that merges is water, 10% the LiCl aqueous solution and salt water washing successively, with after Na ₂SO ₄Dry.Concentrate, obtain (+)-Compound I Ib ethyl ester.

Preparation (+)-Compound I Ib

With crude product (+)-Compound I Ib ethyl ester (1 equivalent) of above preparation, the mixture of KOH (2M, 5 equivalents) in MeOH (methyl alcohol) and THF (tetrahydrofuran (THF), enough dissolving) under room temperature stir about 1-2 hour.Vacuum is removed MeOH and THF, subsequently the dilute with water resistates.Wash with organic solvent (for example EtOAc).Use HCl that water layer is acidified to pH and be about 5.With the throw out filtering, drying obtains (+)-Compound I Ib.

Preparation compound IV b and compound VI b

With (+)-Compound I Ib (1 equivalent), (R)-(-)-3-hydroxyl rubane hydrochloride (1 equivalent), EDAC (1-ethyl-3-(3-dimethyl propyl)-carbodiimide, 1 equivalent) and the mixture of DMAP (4-dimethylaminopyridine, 1 equivalent) in DMF in about 50 ℃ of following heated overnight.Behind cooling and the dilute with water,, obtain compound IV b by chromatography or crystallization purifying mixture.Equally, use (S)-(+)-3-hydroxyl rubane, make compound VI b.

Basically according to the following compound of method for preparing.Use ChemDraw Ultra the 8.03rd and/or 9.0 editions (deriving from Cambridgesoft Corporation or ACD Nameprosoftware, the 6.0th edition) name compound.

Basically according to the following compound of method for preparing.Use ChemDraw Ultra the 8.03rd and/or 9.0 editions (deriving from Cambridgesoft Corp.) name compound.

Preparation, administration and purposes

What give that the medicine-feeding rate of disclosed compound and route and this area used is similar, and is well known by persons skilled in the art (for example referring to Physicians ' Desk Reference, the 54th edition, Medical Economics Company, Montvale, NJ, 2000).

When treatment acute or chronic disease and/or illness as herein described, the prevention of the structure of cisapride and/or sense analogue or therapeutic dose become with the seriousness and the administration route of illness to be treated.Dosage and possible administration frequency also become according to age, body weight and the reaction of individual patient.Usually for illness as herein described, total per daily dose scope of the structure of cisapride and/or sense analogue is the about 200mg of about 1mg-, is single dose or divided dose.Preferred per daily dose scope should be the about 100mg of about 5mg-, is single dose or divided dose, and most preferably the per daily dose scope should be the about 75mg of about 5mg-, is single dose or divided dose.Administration was 1-4 time in preferred one day., use during begin treatment than low dosage during the patient in treatment, the about 10mg of probably about 5mg-according to patient's comprehensive response, increases to subsequently and is up to more than about 50mg.For patient and the kidney or the weak patient of liver function of children and over-65s, also to recommend to bring into use low dosage, this dosage is decided according to the response and the blood levels of individuality.In some cases, also can use these scopes dosage in addition, this point it will be apparent to those skilled in the art that.In addition, it should be noted that clinicist or treatment doctor be in conjunction with the response of individual patient, how and when know interrupt, adjustment or stopped treatment.

Can prepare pharmaceutically available composition according to known method preparation The compounds of this invention.Adopt as well known to those skilled in the art and multiple source that be easy to get to describe various preparations in detail.For example Remington ' s Pharmaceutical the Science of E.W.Martin has described the preparation that can use in conjunction with the present invention.Usually the preparation present composition makes the bioactive compounds of significant quantity and suitable carriers make up, to promote effectively to give described composition.

Composition of the present invention comprises various compositions, for example suspensoid, solution and elixir; Aerosol; Or under the situation of oral solid formulation (for example pulvis, capsule and tablet); comprise various carriers; for example starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc. are compared the preferred oral solid preparation with oral liquid.Preferred oral solid formulation is a capsule.Most preferred oral solid formulation is a tablet.In solid dosage, the preferred amount of activeconstituents (being the structure and/or the sense analogue of cisapride) is about 5mg, 10mg and 25mg.

In addition, acceptable carrier can be solid or liquid.The preparation of solid form comprises pulvis, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials that can be used as thinner, correctives, solubilizing agent, lubricant, suspension agent, tackiness agent, tablet disintegrant or encapsulating material.

Disclosed pharmaceutical composition can be subdivided into the unitary dose that comprises an amount of activeconstituents.Unit dosage can be packaged preparation, for example parcel tablet, capsule and the pulvis in paper or plastic containers or in bottle or ampoule.Unitary dose also can be the liquid-based preparation or prepares with in solid food to be mixed, Chewing gum or the lozenge.

Handle outside the above common formulation, The compounds of this invention can give also that (for example United States Patent (USP) 3,845 by controllable release mode and/or transmitting device, 770,3,916,899,3,536,809,3,598,123 and 4,008,719 is described), the disclosed content of each patent is attached to herein by quoting in full.

Can use any suitable administration route, the structure and/or the sense analogue of the cisapride of effective dose is provided for the patient.For example can use oral, rectum, parenteral (subcutaneous, intramuscularly, vein), through form administrations such as skins.Formulation comprises tablet, lozenge, dispersion agent, suspensoid, solution, capsule, patch etc.

An aspect of of the present present invention provides a kind of treatment Mammals gastroesophageal reflux disease, significantly reduce the method for following the side effect that gives cisapride simultaneously, described method comprises structure and/or sense analogue or its pharmacy acceptable salt of the cisapride that needs the human therapy of this treatment significant quantity.A preferred aspect is for treating people's gastroesophageal reflux disease.

Another aspect of the present invention provides a kind of composition that is used for the treatment of the people who suffers from gastroesophageal reflux disease, and described composition comprises structure and/or sense analogue or its pharmacy acceptable salt of the cisapride for the treatment of significant quantity.

One side more of the present invention provides a kind of Mammals antiemetic effect that causes, significantly reduce the method for following the side effect that gives cisapride simultaneously, described method comprises structure and/or sense analogue or its pharmacy acceptable salt of the cisapride that needs the Mammals of this antiemetic treatment treatment significant quantity.Preferred mammal is behaved.

On the other hand, the present invention includes and be used for the treatment of the mammiferous antiemetic composition that needs antiemetic treatment, described composition comprises structure and/or sense analogue or its pharmacy acceptable salt of the cisapride for the treatment of significant quantity.

Other aspects of the present invention comprise a kind of method for the treatment of the illness that Mammals digestive tract power dysfunction causes, described method comprises structure and/or sense analogue or its pharmacy acceptable salt of the cisapride of the Mammals treatment significant quantity that needs this gastroenteritic power function treating dysfunction.The illness that the gastroenteritic power function obstacle causes is including, but not limited to maldigestion, gastroparesis, constipation, postoperative ileus and intestinal pseudo obstruction.Preferred mammal is behaved.

Find that cisapride enters central nervous system and and 5HT ₄Receptors bind, this shows that cisapride can have maincenter-mediation.Cisapride is 5HT ₄The effective part of acceptor, and these acceptors are positioned at a plurality of zones of central nervous system.Regulate serotoninergic system and have multiple behavior effect.Therefore, The compounds of this invention can be used for treatment: 1) cognitive disorder, including, but not limited to Alzheimer ' s disease; 2) behavior disorder is including, but not limited to schizophrenia, manic, obsession with to the work use obstacle of material of spirit; 3) emotional handicap is including, but not limited to depression and anxiety; With 4) control autonomic function obstacle, including, but not limited to spontaneous hypertension and somnopathy.

Therefore, the present invention also provides the method for the cognition of treatment Mammals, behavior, mood or spontaneous function control obstacle, and described method comprises structure and/or sense analogue or its pharmacy acceptable salt of the cisapride for the treatment of significant quantity.Preferred mammal is behaved.

Be understood that, each embodiment as herein described and aspect are only presented for purposes of illustration, in view of the present invention, those skilled in the art should be able to propose various changes or variation, and these should be included in the application's the spirit and scope and be included in the scope of subsidiary claim.In addition, all patents, patent application, provisional application and publication that this paper mentions or quotes are attached to herein by quoting in full, quote degree not can with this specification sheets clearly instruct inconsistent.

The present invention and preparation and use mode of the present invention and method are described so far, and all clear and concise and accurate terms make that the technician can prepare and use in the field involved in the present invention.It should be understood that above each the preferred aspect of the present invention of having described, under the situation of the spirit or scope that do not break away from claims of the present invention, can change.The material of the present invention that will point out and explicitly call for protection the present invention relates to especially, following claim is summed up this specification sheets.

Claims

1. a compound and pharmacy acceptable salt thereof with following formula structure:

Formula Xa

Formula Xb

Wherein

Key on 3 and 4 is cis each other;

L is-(C ₁-C ₆Alkyl)-,-(C ₁-C ₆Alkyl)-C (O)-or-C (O)-(C ₁-C ₆Alkyl)-, wherein each alkyl is optional independently is halogen, C by 1 or 2 ₁-C ₄The group of alkoxyl group or OH replaces, and wherein a carbon atom in the moieties of L can be by-N (R ₉)-replace; Or

R ₁Be halogen;

R ₃Be H or C ₁-C ₄Alkyl;

R ₄Be H or methyl; With

R ₉Independently be H or C when occurring at every turn ₁-C ₄Alkyl;

R ₁₁Be C ₁-C ₆Alkyl or OH; Or

R ₁₁For choosing wantonly by 1 or 2 independently is the C that following group replaces ₁-C ₆Alkoxyl group: C ₁-C ₄Alkoxyl group, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) N (R ₉)-Heterocyclylalkyl ,-the O-Heterocyclylalkyl ,-C ₁-C ₆(O) N (R ₉)-heteroaryl or heteroaryl, wherein

R ₁₁For-the O-Heterocyclylalkyl, wherein said Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃With

2. the compound of claim 1, wherein R ₁Be chlorine.

3. the compound of claim 1, wherein R ₂Be amino.

4. the compound of claim 1, wherein R ₃Be methyl.

5. the compound of claim 1, wherein R ₄Be H.

6. the compound of claim 1, wherein

R ₁Be chlorine; R ₂Be amino; R ₃Be methyl; R ₄Be H, and R ₁And R ₂On pyridine ring or pyridone ring, have following location:

7. the compound of claim 6, wherein L is-(C ₃-C ₅Alkyl)-, one of them carbon atom can be by-N (R ₉)-or-(C ₂-C ₆Alkyl)-C (O)-replacement.

8. the compound of claim 7, wherein

R ₅For-the O-Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from azabicyclic-octyl group, azabicyclic-nonyl, azabicyclic-decyl, piperidyl, piperazinyl and pyrrolidyl, the nitrogen of azepine is optional in wherein said azabicyclic-octyl group, azabicyclic-nonyl, the azabicyclic-decyl is replaced by methyl or ethyl, and wherein said piperidyl, piperazinyl and pyrrolidyl are not substituted or are independently replaced for following group 1 or 2 position: C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, halogen, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, hydroxyl, hydroxyl C ₁-C ₄Alkyl, amino ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) R ₁₁Or NO ₂, wherein

R ₁₁For choosing wantonly by 1 or 2 independently is the C that following group replaces ₁-C ₆Alkoxyl group: C ₁-C ₄Alkoxyl group, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) N (R ₉)-Heterocyclylalkyl or Heterocyclylalkyl, wherein said Heterocyclylalkyl is selected from pyrrolidyl, piperidyl, piperazinyl and morpholinyl, and wherein said Heterocyclylalkyl is optional independently to be that following group replaces: halogen, C by 1,2 or 3 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, hydroxyl, hydroxyl C ₁-C ₆Alkyl, C ₁-C ₆Alkoxy carbonyl ,-CO ₂H, CF ₃Or OCF ₃

9. the compound of claim 7, wherein

R ₅For being selected from the Heterocyclylalkyl of 1-azabicyclic [2.2.2] oct-3-yl and 8-azabicyclic [3.2.1] oct-3-yl, wherein the nitrogen in 8-azabicyclic [3.2.1] oct-3-yl is optional is replaced by methyl or ethyl.

10. the compound of claim 7, wherein

R ₅For-N (R ₉)-C ₀-C ₄Alkyl-aryl or-N (R ₉)-C (O)-aryl, wherein said aryl are not substituted or are replaced by following group in one or more commutable positions: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, hydroxyl, hydroxyalkyl, amino ,-NH (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyl) ,-(C ₀-C ₆Alkyl)-C (O) R ₁₁Or NO ₂

11. the compound of claim 10, wherein

Described aryl is quilt-(C ₀-C ₆Alkyl)-C (O) R ₁₁Replace and choose wantonly and independently be selected from the phenyl that following group replaces: C by 1 or 2 ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, CF ₃, OCF ₃, hydroxyl, hydroxyalkyl, amino ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) or NO ₂And

12. the compound of claim 11, wherein group-(C ₀-C ₆Alkyl)-C (O) R ₁₁Link to each other with 4 of phenyl ring.

13. the compound of claim 1 or its pharmacy acceptable salt, described compound is:

1) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid;

2) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid;

3) 6-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid;

4) 6-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid;

5) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester;

6) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester;

7) 6-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester;

8) 6-((3R, 4S)-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester;

9) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester;

10) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester;

11) 6-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester;

12) 6-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester;

13) 6-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester;

14) 6-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester;

15) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester;

16) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (S)-rubane-3-base ester;

17) 6-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester;

18) 6-((3R, 4S)-4-(6-amino-5-fluoro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester;

19) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester;

20) 6-((3S, 4R)-4-(6-amino-5-fluoro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester;

21) 6-((3S, 4R)-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester);

22) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester);

23) 6-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester);

24) 6-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (8-methyl-8-azabicyclo [3.2.1] oct-3-yl ester);

25) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid;

26) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid;

27) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid;

28) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid;

29) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) methyl benzoate;

30) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) methyl benzoate;

31) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) methyl benzoate;

32) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) methyl benzoate;

33) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) ethyl benzoate;

34) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) ethyl benzoate;

35) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) ethyl benzoate;

36) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) ethyl benzoate;

37) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) isopropyl benzoate;

38) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) isopropyl benzoate;

39) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) isopropyl benzoate;

40) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) isopropyl benzoate;

41) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-methoxyl group ethyl ester);

42) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-methoxyl group ethyl ester);

43) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-methoxyl group ethyl ester);

44) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-methoxyl group ethyl ester);

45) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(tetramethyleneimine-1-yl) ethyl ester;

46) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(tetramethyleneimine-1-yl) ethyl ester;

47) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(tetramethyleneimine-1-yl) ethyl ester;

48) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(tetramethyleneimine-1-yl) ethyl ester;

49) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1-methyl piperidine-4-base ester);

50) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1-methyl piperidine-4-base ester);

51) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1-methyl piperidine-4-base ester);

52) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1-methyl piperidine-4-base ester);

53) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(pyridine-2-yl) ethyl ester;

54) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(pyridine-2-yl) ethyl ester;

55) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(pyridine-2-yl) ethyl ester;

56) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(pyridine-2-yl) ethyl ester;

57) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(dimethylamino) ethyl ester;

58) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(dimethylamino) ethyl ester;

59) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(dimethylamino) ethyl ester;

60) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(dimethylamino) ethyl ester;

61) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1-methyl piperidine-3-base ester);

62) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1-methyl piperidine-3-base ester);

63) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1-methyl piperidine-3-base ester);

64) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1-methyl piperidine-3-base ester);

65) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-morpholino ethyl ester);

66) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-morpholino ethyl ester);

67) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-morpholino ethyl ester);

68) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-morpholino ethyl ester);

69) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1,4-lupetidine-4-base ester);

70) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1,4-lupetidine-4-base ester);

71) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1,4-lupetidine-4-base ester);

72) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (1,4-lupetidine-4-base ester);

73) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid;

74) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid;

75) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid;

76) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid;

77) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-oxo-2-(piperidin-4-yl amino) ethyl ester);

78) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-oxo-2-(piperidin-4-yl amino) ethyl ester);

79) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-oxo-2-(piperidin-4-yl amino) ethyl ester);

80) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-oxo-2-(piperidin-4-yl amino) ethyl ester);

81) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid;

82) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid;

83) 1-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid;

84) 1-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid;

85) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-methyl-formiate;

86) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-methyl-formiate;

87) 1-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-methyl-formiate;

88) 1-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-methyl-formiate;

89) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidine-4-ethyl formate;

90) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidine-4-ethyl formate;

91) 1-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidine-4-ethyl formate;

92) 1-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidine-4-ethyl formate;

93) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid (2-methoxyl group ethyl ester);

94) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid (2-methoxyl group ethyl ester);

95) 1-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid (2-methoxyl group ethyl ester);

96) 1-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid (2-methoxyl group ethyl ester);

97) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid;

98) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid;

99) 4-(((2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid;

100) 4-(((2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid;

101) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) methyl benzoate;

102) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) methyl benzoate;

103) 4-(((2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) methyl benzoate;

104) 4-(((2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) methyl benzoate;

105) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) methyl benzoate;

106) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) methyl benzoate;

107) 4-((2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) methyl benzoate;

108) 4-((2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) methyl benzoate;

109) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) isopropyl benzoate;

110) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) isopropyl benzoate;

111) 4-((2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) isopropyl benzoate;

112) 4-((2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) isopropyl benzoate;

113) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) ethyl benzoate dihydrochloride;

114) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) ethyl benzoate dihydrochloride;

115) 4-((2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) ethyl benzoate dihydrochloride;

116) 4-((2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) ethyl benzoate dihydrochloride;

117) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino formyl radical) phenylformic acid (R)-rubane-3-base ester;

118) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino formyl radical) phenylformic acid (R)-rubane-3-base ester;

119) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino formyl radical) phenylformic acid (R)-rubane-3-base ester;

120) 4-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino formyl radical) phenylformic acid (R)-rubane-3-base ester;

121) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid 2-(tetramethyleneimine-1-yl) ethyl ester;

122) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid (1-methyl piperidine-4-base ester);

123) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid (2-morpholino ethyl ester);

124) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) phenylformic acid;

125) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) phenylformic acid (3-hydroxy propyl ester);

126) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) phenylformic acid (piperidin-4-yl ester);

127) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino formyl radical) phenylformic acid;

128) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethylamino formyl radical) phenylformic acid (piperidin-4-yl ester);

129) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) acetate;

130) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) ethyl acetate;

131) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) acetate (1-methyl piperidine-4-base ester);

132) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) acetate (3-hydroxy propyl ester);

133) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) acetate (rubane-3-base ester);

134) 6-amino-5-chloro-N-((3S, 4R)-1-(2-(4-hydroxy phenyl amino)-2-oxoethyl)-3-methoxyl group piperidin-4-yl)-2-methoxyl group niacinamide;

135) acetate 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenyl ester;

136) 4-(3-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propyl group) phenylformic acid;

137) 4-(3-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propyl group) phenylformic acid (2-morpholino ethyl ester);

138) 4-(3-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propyl group) phenylformic acid 2-(tetramethyleneimine-1-yl) ethyl ester;

139) 4-(3-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propyl group) phenylformic acid (1-methyl piperidine-4-base ester);

140) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-hydroxy methacrylate);

141) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-amino-2-oxo ethyl ester);

142) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(piperazine-1-yl) ethyl ester;

143) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid 2-(tetramethyleneimine-1-yl) ethyl ester;

144) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid (1-methyl piperidine-4-base ester);

145) 4-(((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethyl) (methyl) amino) methyl) phenylformic acid (2-morpholino ethyl ester);

146) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) phenylformic acid;

147) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) phenylformic acid (3-hydroxy propyl ester);

148) 4-((2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino) methyl) phenylformic acid (piperidin-4-yl ester);

149) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino formyl radical) phenylformic acid;

150) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethylamino formyl radical) phenylformic acid (piperidin-4-yl ester);

151) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) acetate;

152) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) ethyl acetate;

153) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) acetate (1-methyl piperidine-4-base ester);

154) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) acetate (3-hydroxy propyl ester);

155) 2-(4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenyl) acetate (rubane-3-base ester);

156) 6-amino-5-chloro-N-((3S, 4R)-1-(2-(4-hydroxy phenyl amino)-2-oxoethyl)-3-methoxyl group piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-methane amide;

157) acetate 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenyl ester;

158) 4-(3-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propyl group) phenylformic acid;

159) 4-(3-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propyl group) phenylformic acid (2-morpholino ethyl ester);

160) 4-(3-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propyl group) phenylformic acid 2-(tetramethyleneimine-1-yl) ethyl ester;

161) 4-(3-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propyl group) phenylformic acid (1-methyl piperidine-4-base ester);

162) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-hydroxy methacrylate);

163) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid (2-amino-2-oxo ethyl ester);

164) 4-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) kharophen) phenylformic acid 2-(piperazine-1-yl) ethyl ester.

14. the compound of claim 1 or its pharmacy acceptable salt, described compound is:

1) 3-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) benzyl propionate;

2) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) isopropyl propionate;

3) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propionic acid 4-(methylsulfonyl) benzyl ester;

4) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propionic acid (tetrahydrochysene-2H-pyrans-2-yl) methyl esters;

5) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) cyclohexyl propionate;

6) 3-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propionic acid peopentyl ester;

7) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propionic acid (4-methoxy benzyl ester);

8) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) propionic acid (pyridin-4-yl methyl esters);

9) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate;

10) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (4-fluoro-methylbenzyl ester);

11) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) jasmal;

12) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (4-methyl benzyl ester);

13) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2-methoxy benzyl ester);

14) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (4-benzyl chloride ester);

15) 2-((3R, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (4-methoxy benzyl ester);

16) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (piperidin-4-yl ester);

17) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2-methoxyl group ethyl ester);

18) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2-hydroxy methacrylate);

19) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2-benzyl chloride ester);

20) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 4-(trifluoromethyl) benzyl ester;

21) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (3-methyl benzyl ester);

22) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (3-benzyl chloride ester);

23) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 2-(trifluoromethyl) benzyl ester;

24) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2-morpholino ethyl ester);

25) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (tetrahydrochysene-2H-pyrans-2-yl) methyl esters;

26) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2-fluoro-methylbenzyl ester);

27) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (3-fluoro-methylbenzyl ester);

28) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (3-methoxy benzyl ester);

29) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 2-(methylsulfonyl) ethyl ester;

30) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) isopropyl acetate;

31) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethyl acetate;

32) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 2-(pyridine-2-yl) ethyl ester;

33) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (pyridine-2-base methyl esters);

34) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (pyridin-3-yl methyl esters);

35) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (piperidines-3-base methyl esters);

36) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) hexalin acetate;

37) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (1-methoxy propyl-2-base ester);

38) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2,3,4-trimethoxy benzyl ester);

39) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2,3-dimethoxy benzyl ester);

40) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 1-(4-fluorophenyl) ethyl ester;

41) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 3-(4-fluorophenoxy) propyl ester;

42) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (3-fluoro-4-methyl benzyl ester);

43) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (4-fluoro-3-methyl benzyl ester);

44) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (2-fluoro-6-methyl benzyl ester);

45) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (tetrahydrochysene-2H-pyrans-4-base ester);

46) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 2-(2-methoxy ethoxy) ethyl ester;

47) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 2-(2-(2-methoxy ethoxy) oxyethyl group) ethyl ester;

48) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate peopentyl ester;

49) 2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate 2-(piperazine-2-yl) ethyl ester;

50) 2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) acetate (pyridin-4-yl methyl esters);

51) (R)-3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid;

52) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid (R)-methyl esters;

53) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid 4-(methylsulfonyl) benzyl ester;

54) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid (4-fluoro-methylbenzyl ester);

55) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid (S)-4-(methylsulfonyl) benzyl ester;

56) (S)-3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid;

57) 3-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid (S)-methyl esters;

58) 4-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) butyric acid;

59) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (4-fluoro-methylbenzyl ester);

60) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (2-methoxyl group ethyl ester);

61) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid peopentyl ester;

62) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (pyridine-2-base methyl esters);

63) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid 2-(piperazine-1-yl) carbethoxy hydrochloride;

64) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid 2-(dimethylamino) ethyl ester;

65) 6-[(3S, 4R)-4-{[(6-amino-5-chloro-2-methoxypyridine-3-yl) carbonyl] amino }-3-methoxyl group piperidines-1-yl] caproic acid (1-adamantyl methyl esters);

66) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid cyclohexyl;

67) 6-[(3S, 4R)-4-{[(6-amino-5-chloro-2-methoxypyridine-3-yl) carbonyl] amino }-3-methoxyl group piperidines-1-yl] caproic acid (2-adamantane esters);

68) 6-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid dicyclo [2.2.1] heptan-2-base ester;

69) 2-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) oxyethyl group) acetate;

70) 2-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) oxyethyl group) methyl acetate;

71) 2-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) oxyethyl group) hexalin acetate;

72) 2-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) oxyethyl group) hexalin acetate;

73) 2-(2-((3R, 4S)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) oxyethyl group) acetate (piperidin-4-yl ester) hydrochloride;

74) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid;

75) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-methyl-formiate;

76) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidine-4-ethyl formate;

77) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid (2-methoxyl group ethyl ester);

78) 6-amino-5-chloro-N-((3R, 4S)-1-(2-hydroxyethyl)-3-methoxyl group piperidin-4-yl)-2-methoxyl group niacinamide;

79) 6-amino-5-chloro-2-methoxyl group-N-((3R, 4S)-3-methoxyl group piperidin-4-yl) niacinamide;

80) 6-amino-5-chloro-N-((3R, 4S)-1-(3-(4-fluorophenoxy) propyl group)-3-methoxyl group piperidin-4-yl)-2-methoxyl group niacinamide;

81) 3-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) benzyl propionate;

82) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) isopropyl propionate;

83) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propionic acid 4-(methylsulfonyl) benzyl ester;

84) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propionic acid (tetrahydrochysene-2H-pyrans-2-yl) methyl esters;

85) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) cyclohexyl propionate;

86) 3-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propionic acid peopentyl ester;

87) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propionic acid (4-methoxy benzyl ester);

88) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) propionic acid (pyridin-4-yl methyl esters);

89) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate;

90) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (4-fluoro-methylbenzyl ester);

91) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) jasmal;

92) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (4-methyl benzyl ester);

93) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2-methoxy benzyl ester);

94) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (4-benzyl chloride ester);

95) 2-((3R, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (4-methoxy benzyl ester);

96) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (piperidin-4-yl ester);

97) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2-methoxyl group ethyl ester);

98) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2-hydroxy methacrylate);

99) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2-benzyl chloride ester);

100) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 4-(trifluoromethyl) benzyl ester;

101) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (3-methyl benzyl ester);

102) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (3-benzyl chloride ester);

103) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 2-(trifluoromethyl) benzyl ester;

104) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2-morpholino ethyl ester);

105) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (tetrahydrochysene-2H-pyrans-2-yl) methyl esters;

106) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2-fluoro-methylbenzyl ester);

107) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (3-fluoro-methylbenzyl ester);

108) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (3-methoxy benzyl ester);

109) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 2-(methylsulfonyl) ethyl ester;

110) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) isopropyl acetate;

111) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethyl acetate;

112) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 2-(pyridine-2-yl) ethyl ester;

113) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (pyridine-2-base methyl esters);

114) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (pyridin-3-yl methyl esters);

115) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (piperidines-3-base methyl esters);

116) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) hexalin acetate;

117) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (1-methoxy propyl-2-base ester);

118) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2,3,4-trimethoxy benzyl ester);

119) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2,3-dimethoxy benzyl ester);

120) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 1-(4-fluorophenyl) ethyl ester;

121) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 3-(4-fluorophenoxy) propyl ester;

122) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (3-fluoro-4-methyl benzyl ester);

123) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (4-fluoro-3-methyl benzyl ester);

124) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (2-fluoro-6-methyl benzyl ester);

125) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (tetrahydrochysene-2H-pyrans-4-base ester);

126) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 2-(2-methoxy ethoxy) ethyl ester;

127) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 2-(2-(2-methoxy ethoxy) oxyethyl group) ethyl ester;

128) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate peopentyl ester;

129) 2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate 2-(piperazine-2-yl) ethyl ester;

130) 2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) acetate (pyridin-4-yl methyl esters);

131) (R)-3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid;

132) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid (R)-methyl esters;

133) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid 4-(methylsulfonyl) benzyl ester;

134) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid (4-fluoro-methylbenzyl ester);

135) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid (S)-4-(methylsulfonyl) benzyl ester;

136) (S)-3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid;

137) 3-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl)-2 Methylpropionic acid (S)-methyl esters;

138) 4-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) butyric acid;

139) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (4-fluoro-methylbenzyl ester);

140) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (2-methoxyl group ethyl ester);

141) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid peopentyl ester;

142) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (pyridine-2-base methyl esters);

143) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid 2-(piperazine-1-yl) carbethoxy hydrochloride;

144) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid 2-(dimethylamino) ethyl ester;

145) 6-[(3S, 4R)-4-{[(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-yl) carbonyl] amino }-3-methoxyl group piperidines-1-yl] caproic acid (1-adamantyl methyl esters);

146) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid cyclohexyl;

147) 6-[(3S, 4R)-4-{[(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-yl) carbonyl] amino }-3-methoxyl group piperidines-1-yl] caproic acid (2-adamantane esters);

148) 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid dicyclo [2.2.1] heptan-2-base ester;

149) 2-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) oxyethyl group) acetate;

150) 2-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) oxyethyl group) methyl acetate;

151) 2-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) oxyethyl group) hexalin acetate;

152) 2-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) oxyethyl group) hexalin acetate;

153) 2-(2-((3R, 4S)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) oxyethyl group) acetate (piperidin-4-yl ester) hydrochloride;

154) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid;

155) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-methyl-formiate;

156) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidine-4-ethyl formate;

157) 1-(2-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) ethanoyl) piperidines-4-formic acid (2-methoxyl group ethyl ester);

158) 6-amino-5-chloro-N-((3R, 4S)-1-(2-hydroxyethyl)-3-methoxyl group piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-methane amide;

159) 6-amino-5-chloro-N-((3R, 4S)-3-methoxyl group piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-methane amide;

160) 6-amino-5-chloro-N-((3R, 4S)-1-(3-(4-fluorophenoxy) propyl group)-3-methoxyl group piperidin-4-yl)-2-oxo-1,2-dihydropyridine-3-methane amide.

15. the compound of claim 1, described compound is 6-((3S, 4R)-and 4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester or 6-((3S, 4R)-and 4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester.

16. the compound of claim 1, described compound is 6-((3S, 4R)-and 4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester or 6-((3S, 4R)-and 4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) salt of caproic acid (R)-rubane-3-base ester.

17. a composition, described composition comprise compound or its pharmacy acceptable salt and at least a pharmaceutically acceptable carrier, solvent, auxiliary material or the vehicle of claim 1.

18. a method for the treatment of vomiting, maldigestion, gastroparesis, constipation, intestinal pseudo obstruction, gastroesophageal reflux or postoperative ileus, described method comprises the compound or its salt that needs the patient of this treatment claim 1.

19. the method for claim 17, wherein intravenously gives described compound or its salt.

20. composition, described composition comprises at least a and at least a pharmaceutically acceptable carrier in the following material, solvent, auxiliary material or vehicle: 6-((3S, 4R)-and 4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester, 6-((3S, 4R)-4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-and 3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester, 6-((3S, 4R)-and 4-(6-amino-5-chloro-2-methoxyl group nicotinoyl amino)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester dihydrochloride and 6-((3S, 4R)-and 4-(6-amino-5-chloro-2-oxo-1,2-dihydropyridine-3-formamido group)-3-methoxyl group piperidines-1-yl) caproic acid (R)-rubane-3-base ester dihydrochloride.

21. a method for the treatment of vomiting, maldigestion, gastroparesis, constipation, intestinal pseudo obstruction, gastroesophageal reflux or postoperative ileus, described method comprises the compound or its salt that needs the patient of this treatment claim 14.