CN1968946B

CN1968946B - benzimidazolone carboxylic acid derivatives

Info

Publication number: CN1968946B
Application number: CN2005800197343A
Authority: CN
Inventors: 安藤幸司; 井口聪; 村濑德晃; 村田好德; 沼田丰治; 曾根大纪; 内田力; 上木达生
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 2004-06-15
Filing date: 2005-06-01
Publication date: 2011-12-21
Anticipated expiration: 2025-06-01
Also published as: JP2006001845A; JP4129445B2; TNSN06414A1; CN1968946A; ZA200610054B; NZ551341A

Abstract

This invention relates to compounds of the formula (I): wherein R<1>, R<2>, R<3>, A and m are each as described herein or a pharmaceutically acceptable salt or solvate thereof, and compositions containing such compounds and the use of such compounds in the treatment of a condition mediated by 5-HT4 receptor activity such as, but not limited to, gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system disease, Alzheimer's disease, cognitive disorder, emesis, migraine, neurological disease, pain, cardiovascular disorders such as cardiac failure and heart arrhythmia, diabetes and apnea syndrome.

Description

Benzimidazolone carboxylic acid derivatives

Technical field

The present invention relates to benzimidazolone carboxylic acid derivatives.These compounds have selectivity 5-HT ₄Receptor agonist activity.The invention still further relates to the pharmaceutical composition that comprises said derivative, be used for the treatment of by 5-HT ₄Receptor active, especially 5-HT ₄The treatment of diseases method and the purposes of receptor agonist activity mediation.

Background technology

Generally speaking, found 5-HT ₄Receptor stimulant can be used for treating diversified disease, as gastroesophageal reflux disease disease, gastrointestinal illness, gastric motility disorder, non-ucler dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, maldigestion, esophagitis, gastroesophageal disorder, feel sick, central nervous system disease, alzheimer's disease, cognitive disorder, vomiting, migraine, neurological disorder, pain, cardiovascular disorder, heart failure, irregular pulse, diabetes and apnea syndrome (see TiPs, 1992,13,141; People such as Ford A.P.D.W., Med.Res.Rev., 1993,13,633; People such as Gullikson G.W., Drug Dev.Res., 1992,26,405; People such as Richard M.Eglen, TiPS, 1995,16,391; People such as Bockaert J., CNS Drugs, 1,6; People such as Romanelli M.N., ArzheimForsch./Drug Res., 1993,43,913; People such as Kaumann A., Naunyn-Schmiedeberg ' s.1991,344,150; And people such as Romanelli M.N., Arzheim Forsch./Drug Res., 1993,43,913).

WO 94/00449 discloses as 5-HT ₄Agonist or antagonist and/or 5-HT ₃The benzimidazolone compound of antagonist.Especially, the compound represented with following formula as an example 10 is disclosed:

Compd A

Need be provided as the novel 5-HT of good drug candidates at present ₄Agonist.Especially, preferred compound should with 5-HT ₄The potent combination of acceptor shows affinity hardly to other acceptors simultaneously, and shows the functional activity as agonist.They should absorb fully from gi tract, stable and have a favourable pharmacokinetic property in metabolism.When the acceptor of target central nervous system, then they should freely pass hemato encephalic barrier, and when the acceptor in the targeting peripheral neural system optionally, then they should not pass hemato encephalic barrier.They answer nontoxic and proof almost is free from side effects.Moreover the ideal drug candidates should exist with physical form stable, that non--water-absorbent reaches preparation easily.

Summary of the invention

In the present invention, find that (1) is rather encircled with piperidines/pyrrolidine ring displacement quinoline and improved 5-HT ₄The affinity of acceptor, and/or (2) import carboxy moiety and reduced affinity to P162a, makes to prevent that QT from prolonging.

Therefore, find unexpectedly that now The compounds of this invention is compared to prior art, has stronger selectivity 5-HT ₄The P162a affinity of agonist activity and/or raising, and therefore can be used for treatment by 5-HT ₄The disease condition of active mediation, as gastroesophageal reflux disease, gastrointestinal illness, gastric motility disorder, non-ucler dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, maldigestion, esophagitis, gastroesophageal disorder, feel sick, central nervous system disease, alzheimer's disease, cognitive disorder, vomiting, migraine, neurological disorder, pain, cardiovascular disorder, heart failure, irregular pulse, diabetes and apnea syndrome (especially causing) because of the opioid administration.

The invention provides the compound of following formula (I):

Or its pharmacy acceptable salt or solvate, wherein

A is the alkylidene group with 1 to 4 carbon atom, this alkylidene group is not substituted or is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 4 and replaces, and wherein any 2 non-halogenic substituents can form optional at least one heteroatomic 3-, the 4-that is selected from N, O and S, 5-or the 6-unit ring of containing with the carbon atom that their connect;

R ¹Be sec.-propyl or cyclopentyl;

R ²Be hydrogen atom, halogen atom or hydroxyl;

R ³Be carboxyl, tetrazyl, 5-oxo-1,2,4-

Diazole-3-base or 5-oxo-1,2,4-thiadiazoles-3-base; And

M is integer 1 or 2.

One embodiment of the invention provide aforesaid formula (I) compound or its pharmacy acceptable salt or solvate, wherein:

A is the alkylidene group with 1 to 4 carbon atom, this alkylidene group is not substituted or is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 4 and replaces, and wherein any 2 non-halogenic substituents can form the optional heteroatomic 6-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect;

R ¹Be sec.-propyl or cyclopentyl;

R ²Be hydrogen atom, halogen atom or hydroxyl;

R ³Be carboxyl, tetrazyl, 5-oxo-1,2,4-

Diazole-3-base or 5-oxo-1,2,4-thiadiazoles-3-base; And

M is integer 1 or 2.

A is the alkylidene group with 1 to 4 carbon atom, this alkylidene group is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 4 and replaces, and wherein any 2 non-halogenic substituents can form the optional heteroatomic 5-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect;

R ¹Be sec.-propyl or cyclopentyl;

R ²Be hydrogen atom, halogen atom or hydroxyl;

R ³Be carboxyl, tetrazyl, 5-oxo-1,2,4- Diazole-3-base or 5-oxo-1,2,4-thiadiazoles-3-base; And

M is integer 1 or 2.

Provide aforesaid formula (I) compound or its pharmacy acceptable salt or solvate in one embodiment of the invention, wherein:

A is the alkylidene group with 1 to 4 carbon atom, this alkylidene group is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 4 and replaces, and wherein any 2 non-halogenic substituents can form optional heteroatomic 3 to the 4-unit's rings that at least one is selected from N, O and S that contain with the carbon atom that their connect;

R ¹Be sec.-propyl or cyclopentyl;

R ²Be hydrogen atom, halogen atom or hydroxyl;

R ³Be carboxyl, tetrazyl, 5-oxo-1,2,4-

Diazole-3-base or 5-oxo-1,2,4-thiadiazoles-3-base; And

M is integer 1 or 2.

And, the invention provides formula (I) compound or its pharmacy acceptable salt or solvate (each is as described herein) is used for the treatment of by 5-HT in manufacturing ₄Receptor active, especially 5-HT ₄Purposes in the medicine of the disease condition of agonist activity mediation.

Preferably, the present invention also provides formula (I) compound or its pharmacy acceptable salt or solvate (each is as described herein) to be used for the treatment of in manufacturing and is selected from gastroesophageal reflux disease, gastrointestinal illness, gastric motility disorder, non-ucler dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, maldigestion, esophagitis, gastroesophageal disorder, feel sick, central nervous system disease, alzheimer's disease, cognitive disorder, vomiting, migraine, neurological disorder, pain, cardiovascular disorder, in heart failure, irregular pulse, purposes in the medicine of the disease of diabetes and apnea syndrome.

And, the invention provides pharmaceutical composition, it comprises formula (I) compound or its pharmacy acceptable salt or solvate (each is as described herein), and the pharmaceutically acceptable carrier that is used for this compound.

Moreover, the invention provides in a kind of treatment mammalian subject by 5-HT ₄The method of the disease condition of receptor active mediation, this method comprises each formula as described herein (I) compound or its pharmacy acceptable salt or the solvate of the Mammals of this treatment of needs being treated significant quantity.

By 5-HT ₄The example of the disease condition of receptor active mediation includes, but is not limited to gastroesophageal reflux disease, gastrointestinal illness, gastric motility disorder, non-ucler dyspepsia, functional dyspepsia, irritable bowel syndrome (IBS), constipation, maldigestion, esophagitis, gastroesophageal disorder, feel sick, central nervous system disease, alzheimer's disease, cognitive disorder, vomiting, migraine, neurological disorder, pain, cardiovascular disorder, in heart failure, irregular pulse, diabetes and apnea syndrome.

And, the invention provides the compound of formula (XI):

Or its salt, wherein:

R ²Be hydrogen atom, hydroxyl or halogen atom;

R ⁶Be hydrogen atom or amino-protecting group;

Y is the alkoxyl group with 1 to 4 carbon atom, dialkyl amido, imidazolyl, phthaloyl imino, succinimido or the alkylsulfonyl with 2 to 8 carbon atoms; And m is 1 or 2.

And, the invention provides the compound of formula (IXa):

Or its salt, wherein:

A is the alkylidene group with 1 to 4 carbon atom, this alkylidene group is not substituted or is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 4 and replaces, and wherein any 2 non-halogenic substituents can form optional heteroatomic 3 to the 6-unit's rings that at least one is selected from N, O and S that contain with the carbon atom that their connect;

R ²Be hydrogen atom, hydroxyl or halogen atom;

R ³Be hydroxyl or carboxyl-protecting group;

R ⁶Be hydrogen atom or amino-protecting group; And

M is 1 or 2.

Compound of the present invention can show lower toxicity, good absorption, distribution, good solubility, lower protein bound affinity, lower drug-drug interactions and good metabolic stability.

Embodiment

In compound of the present invention:

When A is that it can be the straight chain base, and example includes, but is not limited to methylene radical, ethylidene, trimethylene and tetramethylene when having the alkylidene group of 1 to 4 carbon atom.Preferred methylene radical and ethylidene in these, and most preferably the person is an ethylidene.

When the substituting group of A is that it can be the straight or branched base, and example includes, but is not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl and the tertiary butyl when having the alkyl of 1 to 4 carbon atom.Preferred person is the alkyl with 1 to 3 carbon atom in these; More preferably the person is methyl, ethyl, propyl group and sec.-propyl; And most preferably the person is methyl and ethyl.

When the substituting group of Y is when having the alkoxyl group of 1 to 4 carbon atom, the Sauerstoffatom that this representative is replaced by described alkyl, and example includes, but is not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert.-butoxy.In these, preferred person is the alkyl with 1 to 2 carbon atom; And more preferably the person is a methoxyl group.

When the substituting group of Y is when having the dialkyl amido of 2 to 8 carbon atoms, the amino that this representative is replaced by two described alkyl, and example includes, but is not limited to dimethylamino, N-methyl-N-ethylamino, diethylin, dipropyl amino, diisopropylaminoethyl, dibutylamino, two isobutyl amino and N, N-two (1-methyl-propyl) amino.In these, preferred person is the dialkyl amido with 2 to 4 carbon atoms; More preferably the person is dimethylamino, N-methyl-N-ethylamino and diethylin.

When the substituting group of A is hydroxyl with 1 to 4 carbon atom-alkyl, it can be the straight or branched base, and example includes, but is not limited to methylol, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxyl-1-methylethyl, 4-hydroxyl butyl, 3-hydroxyl butyl, 2-hydroxyl butyl, 3-hydroxy-2-methyl propyl group and 3-hydroxyl-1-methyl-propyl.In these, preferred person is the hydroxyl-alkyl with 1 to 3 carbon atom; More preferably the person is methylol, 2-hydroxyethyl and 2-hydroxypropyl, and most preferably the person is methylol and 2-hydroxyethyl.

When the substituting group of A is alkoxyl group with 2 to 6 carbon atoms-alkyl, it can be the straight or branched base, and example includes, but is not limited to methoxymethyl, ethoxyl methyl, 2-methoxy ethyl, 2-ethoxyethyl group, 1-methoxy ethyl, 3-methoxy-propyl, 3-ethoxycarbonyl propyl, 2-methoxy-propyl, 2-methoxyl group-1-methylethyl, 4-methoxyl group butyl, 4-oxyethyl group butyl, 3-methoxyl group butyl, 2-methoxyl group butyl, 3-methoxyl group-2-methyl-propyl and 3-methoxyl group-1-methyl-propyl.In these, preferred person is the alkyl oxy-alkyl with 2 to 4 carbon atoms; More preferably the person is methoxymethyl, 2-methoxy ethyl and 3-methoxy-propyl; And most preferably the person is 2-methoxy ethyl and 3-methoxy-propyl.

When any 2 non--halogenic substituents can form optional at least one N of being selected from that contains with the carbon atom that they connected, heteroatomic 3 of O and S, 4,5 or 6-when ring unit, this ring can be cycloalkyl or heterocyclic radical, and example comprises cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, the methyl cyclopropyl, the ethyl cyclopropyl, the methyl cyclobutyl, methylcyclopentyl, methylcyclohexyl, the ethyl cyclohexyl, the hydroxyl cyclopropyl, the hydroxyl cyclobutyl, the hydroxycyclopent base, hydroxy-cyclohexyl, the methoxyl group cyclopropyl, the methoxyl group cyclobutyl, the methoxyl group cyclopentyl, the methoxyl group cyclohexyl, tetrahydrofuran base and THP trtrahydropyranyl, be preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyl group cyclohexyl and THP trtrahydropyranyl, and most preferably be cyclobutyl, cyclopentyl, cyclohexyl and THP trtrahydropyranyl.

Work as R ⁶During for amino-protecting group, its representative can be by with chemical process such as hydrogenolysis, hydrolysis, electrolysis or photodissociation and the cracked protecting group, and should amino-protecting group be described in (the John Wiley ﹠amp by people such as T.W.Greene; Sons, 1999) in editor's the organic synthesis protecting group (Protective Groups in Organic Synthesis), and example includes, but is not limited to benzyl, C ₂H ₅O (C=O)-, CH ₃(C=O)-, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzyl oxygen base carbonyl and tert-butoxycarbonyl.In these groups, preferred person is a tert-butoxycarbonyl.

Work as R ⁴During for carboxyl-protecting group, its representative can be by with chemical process such as hydrogenolysis, hydrolysis, electrolysis or photodissociation and the cracked protecting group, and this carboxyl-protecting group is described in (the John Wiley ﹠amp by people such as T.W.Greene; Sons; 1999) in Bian Ji the organic synthesis protecting group (Protective Groups in Organic Synthesis); and example includes, but is not limited to methoxyl group, oxyethyl group, tert.-butoxy, methoxymethoxy, 2; 2; 2-three chloroethoxies, benzyl oxygen base, phenylbenzene methoxy base, TMS oxygen base, tertiary butyl dimethylsilyl oxygen base and allyloxy; in these groups, preferred person is tert.-butoxy, methoxy or ethoxy.

Work as R ¹And the substituting group of A is when represent halogen atom, and these can be fluorine, chlorine, bromine or iodine atom, and in these, preferably the person is the fluorine or chlorine atom.

Term used herein " treatment " is meant healing, alleviates and prophylactic treatment, comprises reverse, alleviates, prevents the suitable obstacle of this term or one or more symptoms of disease condition or obstacle or disease condition, or suppress its progress.

Article used herein " one " be meant the odd number of referent and plural form the two, except as otherwise noted.

The The compounds of this invention of preferred classes is those compounds or its pharmacy acceptable salt or the solvate of each formula as described herein (I), wherein:

(A) R ¹Be sec.-propyl;

(B) R ²Be hydrogen atom, fluorine atom or hydroxyl;

(C) R ²Be hydrogen atom;

(D) R ³Be carboxyl or tetrazyl;

(E) R ³Be carboxyl;

(F) A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is not substituted or is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 2 and replaces, and wherein any 2 non-halogenic substituents can form the optional heteroatomic 6-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect;

(G) A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group by 2 be independently selected from by halogen atom, have 1 to 4 carbon atom alkyl, have the hydroxyl-alkyl of 1 to 4 carbon atom and have replacing of group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms together with substituting group (promptly being substituted in the substituting group on the same carbon atom), wherein non-halogen can form the optional heteroatomic 6-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect together with substituting group;

(H) A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2 and replaces, and wherein any 2 these substituting groups can form the optional heteroatomic 5-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect;

(I) A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by the alkyl with 1 to 4 carbon atom, has the hydroxyl-alkyl of 1 to 4 carbon atom and have replacing together with substituting group of group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2, wherein should can form the optional heteroatomic 5-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect together with substituting group;

(J) A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2 and replaces, and wherein this substituting group can form optional heteroatomic 3 to the 4-unit's rings that at least one is selected from N, O and S that contain with the carbon atom that their connect;

(K) A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by the alkyl with 1 to 4 carbon atom, has the hydroxyl-alkyl of 1 to 4 carbon atom and have replacing together with substituting group of group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2, wherein should can form optional heteroatomic 3 to the 4-unit's rings that at least one is selected from N, O and S that contain with the carbon atom that their connect together with substituting group;

(L) A is

(M) A is

(N) A is

(O) A is

(P) A is

(Q) m is an integer 2.

The particularly preferred compound of the present invention is compound or its pharmacy acceptable salt or the solvate of formula (I), wherein

(R) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl or tetrazyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is not substituted or is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 2 and replaces, and wherein any 2 non-halogenic substituents can form the optional heteroatomic 6-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect; And m is an integer 2;

(S) R ¹Be sec.-propyl; R ²Be hydrogen atom; R ³Be carboxyl or tetrazyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group by 2 be independently selected from by halogen atom, have 1 to 4 carbon atom alkyl, have the hydroxyl-alkyl of 1 to 4 carbon atom and have replacing of group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms together with substituting group, wherein should can form the optional heteroatomic 6-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect together with substituting group; And m is an integer 2;

(T) R ¹Be sec.-propyl; R ²Be hydrogen atom; R ³Be carboxyl or tetrazyl; A is

And m is an integer 2;

(U) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is not substituted or is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 2 and replaces, and wherein any 2 non-halogens can form the optional heteroatomic 6-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect together with substituting group; And m is an integer 2;

(V) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl; A is And m is an integer 2;

(W) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl or tetrazyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2 and replaces, and wherein any 2 these substituting groups can form the optional heteroatomic 5-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect; And m is an integer 2;

(X) R ¹Be sec.-propyl; R ²Be hydrogen atom; R ³Be carboxyl or tetrazyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from alkyl with 1 to 4 carbon atom, has the hydroxyl-alkyl of 1 to 4 carbon atom and have replacing together with substituting group of group that alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2, wherein should can form the optional heteroatomic 5-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect together with substituting group; And m is an integer 2;

(Y) R ¹Be sec.-propyl; R ³Be hydrogen atom; R ³Be carboxyl or tetrazyl; A is And m is an integer 2;

(Z) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2 and replaces, and wherein any 2 these substituting groups can form the optional heteroatomic 5-unit ring that at least one is selected from N, O and S that contains with the carbon atom that their connect; And m is an integer 2;

(AA) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl; A is And m is an integer 2;

(AB) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl or tetrazyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2 and replaces, and wherein this substituting group can form optional heteroatomic 3 to the 4-unit's rings that at least one is selected from N, O and S that contain with the carbon atom that their connect; And m is an integer 2;

(AC) R ¹Be sec.-propyl; R ²Be hydrogen atom; R ³Be carboxyl or tetrazyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by the alkyl with 1 to 4 carbon atom, has the hydroxyl-alkyl of 1 to 4 carbon atom and have replacing together with substituting group of group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2, wherein should can form optional heteroatomic 3 to the 4-unit's rings that at least one is selected from N, O and S that contain with the carbon atom that their connect together with substituting group; And m is an integer 2;

(AD) R ¹Be sec.-propyl; R ²Be hydrogen atom; R ³Be carboxyl or tetrazyl; A is

And m is an integer 2;

(AE) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl; A is the alkylidene group with 1 to 2 carbon atom, this alkylidene group is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 2 and replaces, and wherein any 2 non--halogenic substituents can form optional heteroatomic 3 to the 4-unit's rings that at least one is selected from N, O and S that contain with the carbon atom that their connect; And m is an integer 2;

(AF) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl; A is And m is an integer 2;

(AG) R ¹Be sec.-propyl; R ²Be hydrogen atom, fluorine atom or hydroxyl; R ³Be carboxyl; A is

And m is an integer 2;

(AH) R ¹Be sec.-propyl; R ²Be hydrogen atom; R ³Be carboxyl or tetrazyl; A is And m is an integer 2.

One embodiment of the invention provide the compound that is selected from the group of being made up of following compound:

4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid;

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } hexahydrobenzoic acid;

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } Cyclopentane carboxylic acid;

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } cyclopropane-carboxylic acid;

1-{[4-hydroxyl-4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } hexahydrobenzoic acid;

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } cyclobutane-carboxylic acid; And

Its pharmacy acceptable salt or solvate.

One embodiment of the invention provide by the compound that is selected from the group of being made up of following compound:

And pharmacy acceptable salt and solvate.

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } cyclobutane-carboxylic acid;

And pharmacy acceptable salt and solvate.

The pharmacy acceptable salt of formula (I) compound comprises its acid salt and alkali salt (comprising disalt).

The acid salt that is suitable for is formed by the acid that forms non-toxic salt.Example comprises acetate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, borate, camsilate, Citrate trianion, ethanedisulphonate, esilate, formate, fumarate, glucoheptose salt, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/muriate, hydrobromate/bromide, hydriodate/iodide, isethionate, lactic acid salt, malate, maleate, malonate, mesylate, Methylsulfate, naphthoate (naphthylate), the 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, oxalate, palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, glucarate, stearate, succinate, tartrate and trifluoroacetate.

The alkali salt that is suitable for is formed by the alkali that forms non-toxic salt.Example comprises aluminium salt, arginic acid salt, dibenzyl ethylenediamine salt, calcium salt, choline salt, diethyl amine salt, glycol amine salt, glycinate, lysine salt, magnesium salts, meglumine salt, ethanolamine salt, sylvite, sodium salt, tromethane salt and zinc salt.

About being suitable for the comment of salt, see " drug salt handbook: character, selection and purposes (Handbook of Pharmaceutical Salts:Properties, Selection; and Use) " (Wiley-VCH of Stahl and Wermuth, Weinheim, Germany, 2002).The pharmacy acceptable salt of formula (I) compound can be by mixing formula (I) compound and preparation easily with the solution of required suitable acid or alkali as required.Salt can precipitate from solution and collect by filtering, and maybe can reclaim by evaporating solvent.Degree of ionization in the salt can be changed to almost unionization from complete ionization.

The form that form that compound of the present invention can non-solvent closes and solvent close exists.Use term " solvate " to describe the molecular complex that comprises compound of the present invention and one or more pharmaceutically acceptable solvent molecules (for example, ethanol) in this article.When this solvent is water, use term " hydrate ".

Pharmaceutically acceptable solvate of the present invention comprises hydrate and but recrystallisation solvent isotropic substance wherein replaces, for example D ₂O, d ₆-acetone, d ₆The solvate of-DMSO.

Being included in the scope of the invention is for example inclusion compound of complex compound, and medicine-main body inclusion complex wherein, contrasts in above-mentioned solvate, and medicine and main body exist with stoichiometry or non-stoichiometric amount.What also comprised is the title complex that comprises the medicine of two kinds or more kinds of organic and/or inorganic componentss that exist with stoichiometry or non-stoichiometric amount.The gained complex compound is Ionized, partial ionization or nonionicization.About the summary of this class complex compound, referring to J Pharm Sci, 64 (8), 1269-1288 (in August, 1975).

Below all mention formula (I) compound and pharmaceutically acceptable derivates comprises solvate and the complex compound of mentioning its salt, solvate and complex compound and salt thereof.

Term " compound of the present invention " except as otherwise noted, otherwise be meant polymorphic form, prodrug and the isomer thereof (comprising optically-active, geometry and tautomer isomer) of formula (I) compound of preamble definition, hereinafter definition, and formula (I) compound of isotropic substance sign.

" prodrug " of so-called formula (I) compound also within the scope of the invention.Therefore some derivative that has formula very little or that do not have pharmacologically active (I) compound itself for example, passes through hydrolytic rupture when giving to health or on the health time, can changing into the compound with active formula (I) that want.This derivative is called " prodrug ".Can be about the further information that prodrug uses at " Pro-drugs as Novel Delivery Systems; the 14th; ACS SymposiumSeries (T.Higuchi and W Stella) and " Bioreversible Carriers in DrugDesign "; Pergamon Press; find in 1987 (E B Roche edits, AmericanPharmaceutical Association).

According to prodrug of the present invention can (for example) by with known to those skilled in the art as for example H Bundgaard be described in " Design of Prodrugs " (Elsevier, 1985) some part that is called as " prodrug moiety " of describing in replaces the suitable functionality that is present in formula (I) compound and produces.

Example according to prodrugs more of the present invention comprises:

(i) the compound of formula (I) comprise carboxylic functionality (under situation COOH), its ester, for example, with C ₁-C ₈Alkyl displacement hydrogen;

(ii) the compound of formula (I) comprise the carbinol-functional degree (under situation OH), its ether, for example, with C ₁-C ₆Alkanoyloxymethyl displacement hydrogen; With

(iii) the compound in formula (I) comprises uncle or secondary amino group functionality (NH ₂Or-NHR, wherein under the situation of R ≠ H), its acid amides, for example, with C ₁-C ₁₀Alkyloyl is replaced one or two hydrogen.

Further example according to the displacement group of the example of previous example and other prodrug type can find in the above referred-to references.

At last, some compound of formula (I) itself can be used as the prodrug of other compound of formula (I).

Formula (I) compound that comprises one or more unsymmetrical carbons can exist two kinds or more kinds of steric isomer.Comprise under the situation of thiazolinyl or alkenylene at formula (I) compound, how much cis/trans (or Z/E) isomer are possible.Comprise at compound under the situation of ketone for example or oximido or aromatics part, tautomerism (' tautomerism ') can take place.The simplification compound can manifest the isomery that surpasses a type according to this.

Being included in the scope of the invention is all steric isomers, geometrical isomer and the tautomeric form of formula (I) compound, comprises compound and its one or more mixture of showing the isomery that surpasses a type.What also comprised is acid salt or alkali salt, and wherein counter ion are optically active, for example, D-lactate or L-Methionin, or racemic, for example, DL-tartrate or DL-arginine.

The cis/trans isomer can oneself knows by those skilled in the art routine techniques, for example, chromatography is separated with fractionation crystallization.

Preparation/isolating the routine techniques that is used for single enantiomer comprises synthetic or use (for example) chiral hplc (HPLC) resolution of racemic thing (or racemoid of salt or derivative) from the chirality of the suitable pure precursor of optically-active.

Perhaps, racemoid (or racemize precursor) can with suitable activity of optically active compounds (for example, alcohol) or, comprise in the situation of acidity or alkali part at formula (I) compound, with acid or for example tartrate or the reaction of 1-phenyl-ethyl amine of alkali.The gained mixture of diastereomers can separate and one or two of diastereomer can change into corresponding pure enantiomer by method well-known to those having ordinary skill in the art by chromatography and/or fractionation crystallization.

Chipal compounds of the present invention (with its chiral precurser) can use chromatography, HPLC typically, on asymmetric resin, use the moving phase of forming by hydrocarbon (typically heptane or hexane), comprise from 0 to 50% Virahol, typically from 2% to 20%, and from 0 to 5% alkylamine, 0.1% diethylamine obtains with the enrichment enantiomeric form typically.Concentrated elutant provides the mixture of enrichment.

The stereoisomerism aggregation can oneself knows by those skilled in the art routine techniques separate-referring to, for example, " stereochemistry of organic compound (Stereochemistry ofOrganic Compounds) " (Wei Si, New York, 1994) of E L Eliel.

The present invention includes the isotope-labeled compound of all pharmaceutically acceptable formula (I) compounds, wherein one or more atoms are had the same atoms ordinal number, but atomic mass or total mass number and common atomic mass or the different atomic substitutions of finding of total mass number of occurring in nature.

Be fit to be included in the isotropic substance that isotopic example in the The compounds of this invention comprises hydrogen, for example ²H and ³H; The isotropic substance of carbon, for example ¹¹C, ¹³C and ¹⁴C; The isotropic substance of chlorine, for example ³⁶Cl; The isotropic substance of fluorine, for example ¹⁸F; The isotropic substance of iodine, for example ¹²³I and ¹²⁵I; The isotropic substance of nitrogen, for example ¹³N and ¹⁵N; The isotropic substance of oxygen, for example ¹⁵O, ¹⁷O and ¹⁸O; The isotropic substance of phosphorus, for example ³²P; And the isotropic substance of sulphur, for example ³⁵S.

Some isotope-labeled formula (I) compound, for example combine radioisotopic those, can be used for medicine and/or the research of substrate tissue distribution.The radio isotope tritium, just, ³H, and carbon-14, just, ¹⁴C is in view of the ready-made method of their easy combination and detection and be specially adapted to this purpose.

By heavier isotropic substance deuterium for example, just, ²H replaces, and some the treatment advantage that is caused by greater metabolic stability more can be provided, and for example in vivo the transformation period increases or reduce dosage demand and therefore, can be preferred in some cases.

With the isotropic substance of emission positron, for example ¹¹C, ¹⁸F, ¹⁵O and ¹³N replaces, applicable to positron emission tomography (PET) research of checking substrate acceptor occupancy.

Isotope-labeled formula (I) compound usually can oneself knows by those skilled in the art routine techniques or be similar in the similar method of method described in appended embodiment and the preparation, use the isotope-labeled reagent that is fit to replace the nonisotopically labelled reagent that adopts the front and make.

The compound of all formulas (I) all can be by the program described in the universal method shown below or by the ad hoc approach described in embodiment part and the preparation part, or improves one's methods by its routine and to prepare.Except that wherein used any novel intermediates, any one or more of these methods of being used for preparation formula (I) compound also contained in the present invention.

General synthetic

The compounds of this invention can be by preparing the whole bag of tricks that this compounds is known, and the method as shown in A to G as follows is prepared.

Following method A and B have illustrated the preparation of formula (I) compound.Method C to G has illustrated the preparation of various intermediates.

Unless otherwise indicated, the R in the following method ¹, R ², R ³, m and A all as defined above.Hereinafter used term " protecting group " means hydroxyl, carboxyl or amino-protecting group, its be selected from protecting group in the organic synthesis of editing by people such as T.W.Greene ( ProtectiveGroups in Organic Synthesis) (John Wiley ﹠amp; Sons, 1999) typical hydroxyl, carboxyl or the amino-protecting group described in.Below general synthetic in all raw materials be commercially available or by conventional process acquisition known to those skilled in the art, as European Journal ofMedicinal Chemistry, 12 (1), 87-91; 1977, and it is for reference to incorporate its disclosure into this paper.

Method A

The preparation of this method formula (I) compound.

In reaction scheme A, R ^3aBe R as defined above ³Or formula-C (=O)-R ⁴Base, wherein R ⁴Be carboxyl-protecting group.

Term used herein " carboxyl-protecting group " means and can pass through chemical process cracked protecting group, and as hydrogenolysis, hydrolysis, electrolysis or photodissociation, and this carboxy protective based method is described in people such as T.W.Greene (John Wiley; Sons, 1999) protecting group in the organic synthesis of publishing ( Protective Groups in Organic Synthesis) in.Habitual carboxyl-protecting group includes, but is not limited to methoxyl group, oxyethyl group, tert.-butoxy, methoxymethoxy, 2; 2,2-three chloroethoxies, benzyl oxygen base, phenylbenzene methoxy base, TMS oxygen base, tertiary butyl dimethylsilyl oxygen base and allyloxy.In these groups, preferred tertiary butoxy, methoxy or ethoxy.

Steps A 1

In this step, formula of the present invention (I) compound of expectation prepares the compound carbonylation of formula (II) by the compound with formula (III).The compound of formula (II) is for being purchased.The compound of formula (III) can be according to following listed method C preparation.

Reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least in a way).The example of suitable solvents includes, but is not limited to halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride, aromatic hydrocarbon such as benzene, toluene and oil of mirbane; Ethers such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) and two

Alkane; And acid amides such as N, dinethylformamide and N,N-dimethylacetamide.Preferred methylene dichloride in these solvents.

Character to used carbonylation agent is not particularly limited equally, and normally used any carbonylation agent can equally be used for herein in such reaction.The example of this carbonylation agent includes, but is not limited to imdazole derivatives such as N, N '-carbonyl dimidazoles (CDI); Chloro-formic ester such as chlorine potassium acid three chloromethyl esters and chloroformic acid 4-nitro phenyl ester; Urea and triphosgene.Preferred person is a chloroformic acid 4-nitro phenyl ester in these.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is unimportant to the present invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, be to about 120 ℃ temperature, to carry out this reaction easily at about-78 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are general with enough to about 24 hours time.

If R ^3aFor formula-C (=O)-R ⁴Base carries out protective reaction and will obtain carboxyl.This reaction is specified in the protecting group (Protective Groups inOrganic Synthesis) of people's such as T.W.Greene organic synthesis, 369-453, and in (1999), it is for reference that the disclosure is incorporated this paper into.Below enumerate and relate to the general reaction of protecting the tertiary butyl.

Protective reaction carries out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least in a way).The example of suitable solvents includes, but is not limited to halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1, and 2-ethylene dichloride, and aromatic hydrocarbon such as benzene, toluene and oil of mirbane.Preferred person is halogenated hydrocarbon in these solvents.

Protective reaction carries out in the presence of acid.Character to used acid has no particular limits equally, and normally used any acid can equally be used for herein in such reaction.This sour example includes, but is not limited to: sour example hydrochloric acid, acetate, right-toluenesulphonic acids or trifluoroacetic acid.Preferred person is a trifluoroacetic acid in these.

Protective reaction can carry out in the presence of free radical scavenger, the character of used free radical scavenger is not particularly limited equally, and habitual free radical scavenger can be used for herein with being equal in such reaction.The example of this free radical scavenger includes, but is not limited to: HBr, dimethyl sulfoxide (DMSO) or (CH ₃CH ₂) ₃SiH.Preferred person is (CH in these ₃CH ₂) ₃SiH.

Protective reaction can carry out in wide temperature range, and accurate temperature of reaction is unimportant to the present invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be easily at about 0 ℃ to about 100 ℃, more preferably to about 50 ℃ temperature, carry out this reaction at about 0 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes to about 24 hours, more preferably from about 1 hour extremely about 24 hours time generally will be enough.

Method R

Present method illustrates the another kind of preparation method of required formula (I) compound.

Reaction scheme R

In reaction scheme B, R ^3aAs above definition, R ⁵Be amino-protecting group, A ^aAs A defined above or have the alkylidene group of 1 to 3 carbon atom, this alkylidene group is not substituted or is independently selected from by halogen atom, the alkyl with 1 to 4 carbon atom, the substituting group that has the hydroxyl-alkyl of 1 to 4 carbon atom and have a group that the alkoxyl group-alkyl of 2 to 6 carbon atoms forms by 1 to 4 and replaces, wherein can choose wantonly with carbon atom and form 3 to 6 yuan of rings for these substituent 2, and X is halogen atom such as iodine atom, chlorine atom or bromine atoms.

Term used herein " amino-protecting group " means and can pass through chemical process cracked protecting group, and as hydrogenolysis, hydrolysis, electrolysis or photodissociation, and this amino protecting group is described in people such as T.W.Greene (John Wiley ﹠amp; Sons, 1999) in the protecting group (Protective Groups in Organic Synthesis) in the organic synthesis of publishing.Habitual amino-protecting group includes, but is not limited to benzyl, C ₂H ₅O (C=O)-, CH ₃(C=O)-, tertiary butyl dimethylsilyl, tert-butyl diphenyl silylation, benzyl oxygen base carbonyl and tert-butoxycarbonyl.Preferred person is a tert-butoxycarbonyl in these bases.

Step B1

In this step, the compound of the compound of formula V by making formula (IV) (its can by for example with method preparation like formula (II) compound formula (I) compounds described in the method A) go the protection preparation.This goes guard method to be described among the people such as T.W.Greene [protecting group in the organic synthesis (Protective Groups in Organic Synthesis), 494-653, (1999)], and it is for reference that the disclosure is incorporated this paper into.Below enumerate and relate to the typical method of protecting tert-butoxycarbonyl.

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least in a way).The example of suitable solvents includes, but is not limited to halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1, and the 2-ethylene dichloride, and alcohol is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols.Preferred person is an alcohol in these solvents.

This is reflected under the excessive acid existence and carries out.Character to used acid has no particular limits equally, and habitual any acid can equally be used for herein in such reaction.This sour example includes, but is not limited to: sour example hydrochloric acid or trifluoroacetic acid.Preferred person is a hydrochloric acid in these.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is unimportant to the present invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 100 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors extensively change, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are common with enough to about 24 hours time.

Step B2

In this step, formula (I) compound of expectation is by making formula V compound and formula (VI) the compound coupling (B2-a) for preparing described in step B1, or the compound by making formula V and the compound reductive amination (B2-b) of formula (VII) prepare.

(B2-a) with the coupling of formula V compound:

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least in a way).The example of suitable solvents includes, but is not limited to halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Ethers such as ether, Di Iso Propyl Ether, tetrahydrofuran (THF) and two

Alkane; Amine such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methyl piperidine, N-crassitude, pyridine, 4-pyrrolidyl pyridine, N, accelerine and N, N-Diethyl Aniline; And acid amides such as N, dinethylformamide and N,N-dimethylacetamide.Preferred person is N in these, dinethylformamide or N-crassitude.

Be reflected under the alkali existence and carry out.Character to used alkali is not particularly limited equally, and habitual any alkali can equally be used for herein in such reaction.The example of this alkali includes, but is not limited to: amine such as N-methylmorpholine, triethylamine, tripropyl amine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methyl piperidine, pyridine, 4-pyrrolidyl pyridine, picoline, 4-(N, the N-dimethylamino) pyridine, 2,6-two (tertiary butyl)-4-picoline, quinoline, N, accelerine, N, N-Diethyl Aniline, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO) and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU); Alkalimetal hydride such as lithium hydride, sodium hydride and potassium hydride KH; Reach alkali metal alkoxide such as sodium methylate, sodium ethylate, potassium tert.-butoxide.Preferred person is a diisopropylethylamine in these.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is unimportant to the present invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 120 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are common with enough to about 48 hours time.

(B2-b) reductive amination:

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least in a way).The example of suitable solvents includes, but is not limited to halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Ethers such as diethyl ether, Di Iso Propyl Ether, glycol dimethyl ether, tetrahydrofuran (THF) and two Alkane; Alcohol is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols; Acetate and water.Preferred person is halogenated hydrocarbon in these solvents.

Be reflected to go back under the original reagent existence and carry out.Used character of going back original reagent is not particularly limited equally, and habitual any original reagent of going back can equally be used for herein in such reaction.This example of going back original reagent includes, but is not limited to: sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride.Preferred person is a sodium triacetoxy borohydride in these.React required amount of going back original reagent and also can change widely, especially the character of temperature of reaction and raw materials used and solvent according to many factors.Yet, carry out as long as be reflected under the preferred condition, going back original reagent usually will be enough with the stoichiometric ratio of raw material 1 to 3.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is unimportant to the present invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 60 ℃ temperature, to carry out this reaction easily at about-20 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are common with enough to about 24 hours time.

If R ^3aFor formula-C (=O)-R ⁴Base then carries out protective reaction and will obtain carboxyl.This reaction can be carried out under the same terms described in the steps A 1 of method A.

Method C

The preparation of this method formula (III) compound.

Reaction scheme C

In reaction scheme C, X, A, A ^a, R ^3aAnd R ⁶All as above definition.Therefore, work as R ^3aFor-C (=O)-R ⁴The time, above-mentioned formula (IX) compound is as follows.

Step C1

In this step, the compound of formula (IX) by making formula (VIII) the compound and the compound coupling of formula (VI) or by compound the compound reductive amination of formula (VIII) is prepared with formula (VII).The compound of formula (VIII) can or be purchased according to following listed method F and G preparation.

Step C2

In this step, the compound of formula (III) prepares by making formula (IX) compound for preparing described in step C1 go to protect.This reaction can be carried out under condition identical described in the step B1 of method B.

Method D

The preparation of this method formula (IIIa) compound.

Reaction scheme D

In reaction scheme D, R ^3a, R ⁴, R ⁶And each aforesaid definition of Y, and R ⁷For silylation such as tertiary butyl dimethylsilyl, tert-butyl diphenyl silylation, triethyl silyl or TMS, be preferably TMS; R ⁸And R ⁹The independent alkyl of representing halogen atom, having 1 to 4 carbon atom, have the hydroxyl-alkyl of 1 to 4 carbon atom and have the alkoxyl group-alkyl of 2 to 6 carbon atoms, wherein R ⁸And R ⁹Can choose connected carbon atom wantonly and form 3 to 6-unit's rings together; A ^bBe A as defined above, the methylene radical of condition for not comprising methylene radical and being substituted.

Step D1

In this step, the compound of formula (XI) by making formula (VIII) compound and compound condensation in the presence of paraformaldehyde of formula (X) prepare.The compound of formula (VIII) can or be purchased according to method F and G preparation.

If Y is not an alkoxyl group, then reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least in a way).The example of suitable solvents includes, but is not limited to: halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; And alcohol is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols.Preferred person is methylene dichloride or ethanol in these.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is not critical to the invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 120 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors extensively change, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are general with enough to about 48 hours time.

Step D2

In this step, the compound of formula (IIIa) by making formula (XI) compound and the compound of formula (XII) prepare through Mannich reaction.

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Ether such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) and two

Alkane; Nitrile such as acetonitrile and benzonitrile; And acid amides such as N, dinethylformamide, N,N-dimethylacetamide and hexamethyl phosphoric triamide.In these solvents, preferred person is a methylene dichloride.

This is reflected under the Lewis acid existence and carries out.Used lewis acidic character is not particularly limited equally, and normally used any Lewis acid can equally be used for herein in the type reaction.This lewis acidic example includes, but is not limited to: BF ₃, AlCl ₃, FeCl ₃, MgCl ₂, AgCl, Fe (NO ₃) ₃, CF ₃SO ₃Si (CH ₃) ₃, Yb (CF ₃SO ₃) ₃And SnCl ₄In these, preferred person is Yb (CF ₃SO ₃) ₃, MgCl ₂Or CF ₃SO ₃Si (CH ₃) ₃

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is not critical to the invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 100 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are general with enough to about 24 hours time.

Method E

This method formula (III) compound (R wherein ²For hydrogen atom and A are A ^b) preparation.

Reaction scheme E

In reaction scheme E, A ^a, A ^bAnd R ^3aEach is as above definition, and each R and R ' are the alkyl with 1 to 4 carbon atom, are preferably methyl, or aralkyl such as benzyl or styroyl, are preferably benzyl.

Step e 1

In this step, the compound of formula (XIV) prepares by the cyano reduction that makes formula (XIII) compound (being purchased).

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: ethers such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) and two

Alkane; Aromatic hydrocarbon such as benzene, toluene and oil of mirbane; And alcohol is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols.Preferred person is a methyl alcohol in these.

This is reflected to go back under the original reagent existence and carries out.Used character of going back original reagent is not particularly limited equally, and habitual any original reagent of going back can equally be used for herein in such reaction.This example of going back original reagent includes, but is not limited to: metal borohydride such as sodium borohydride and sodium cyanoborohydride; The combination of hydrogen and catalyzer such as palladium-charcoal, platinum and Raney nickel; And hydride compound such as lithium aluminium hydride and diisobutylaluminium hydride.In these, preferred person is a Raney nickel.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is unimportant to the present invention.Temperature of reaction preferably can be along with factors such as the character of solvent and raw materials and is decided.Yet, usually, be to about 100 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are common with enough to about 24 hours time.

Step e 2

In this step, the compound of formula (XVI) prepares by formula (XV) compound that can discuss outsourcing and formula (XIV) compound are reacted.

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: water and alcohol are as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols.Preferred person is water and alcoholic acid mixture in these.

This is reflected under the alkali existence and carries out.Character to used alkali is not particularly limited equally, and habitual any alkali can equally be used for herein in such reaction.The example of this alkali includes, but is not limited to: alkali metal hydroxide such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkali metal alkoxide such as sodium methylate, sodium ethylate, potassium tert.-butoxide and alkaline carbonate are as Quilonum Retard, yellow soda ash and salt of wormwood.Preferred person is a salt of wormwood in these.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is not critical to the invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 120 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are common with enough to about 24 hours time.

Step e 3

In this step, the compound of formula (XVII) changes into cyano group by the carbonyl that makes formula (XVI) compound and prepares in the presence of ptoluene-sulfonyl methyl isocyanide.

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: ethers such as diethyl ether, Di Iso Propyl Ether, ethylene glycol dimethyl ether, tetrahydrofuran (THF) and two Alkane; And alcohol is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols.Preferred person is ethylene glycol dimethyl ether and alcoholic acid mixture in these.

This is reflected under the alkali existence and carries out.Character to used alkali is not particularly limited equally, and habitual any alkali can equally be used for herein in such reaction.The example of this alkali includes, but is not limited to: alkali metal alkoxide such as sodium methylate, sodium ethylate and potassium tert.-butoxide.Preferred person is a potassium tert.-butoxide in these.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is not critical to the invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 100 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are common with enough to about 24 hours time.

Step e 4

In this step, the compound of formula (IIIb) prepares by the cyano reduction that makes formula (XVII) compound.This reaction can carried out under the same terms described in the step e 1 of method E.

Method F

This method formula (VIII) compound (R wherein ²Be halogen atom) preparation.

Reaction scheme F

In reaction scheme F, R ^2aBe halogen atom; R ⁶Define as above, and R ¹⁰Be amino protecting group, be preferably benzoyl.

Step F 1

In this step, the compound of formula (XIX) changes into epoxy group(ing) by the carbonyl that makes formula (XVIII) compound and prepares.

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: acid amides such as methane amide, N, dinethylformamide, N,N-dimethylacetamide and hexamethylphosphorictriamide; Sulfoxide such as dimethyl sulfoxide (DMSO) or tetramethylene sulfone.Preferred person is a dimethyl sulfoxide (DMSO) in these solvents.

This is reflected under the alkali existence and carries out.Character to used alkali is not particularly limited equally, and habitual any alkali can equally be used for herein in such reaction.The example of this alkali includes, but is not limited to: alkali metal alkoxide such as sodium methylate, sodium ethylate and potassium tert.-butoxide; And alkaline carbonate, as Quilonum Retard, yellow soda ash and salt of wormwood.Preferred person is a potassium tert.-butoxide in these.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is not critical to the invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be easily at about 0 ℃ to about 100 ℃, more preferably to about 50 ℃ temperature, carry out this reaction at about 10 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes to about 24 hours, more preferably from about 60 minutes extremely about 12 hours time usually will be enough.

Step F 2

In this step, the compound of formula (XX) reacts by the compound that makes hydrogen halide and formula (XIX) and prepares.

Alkane; Acid amides such as methane amide, N, dinethylformamide, N,N-dimethylacetamide and hexamethylphosphorictriamide.Preferred person is a tetrahydrofuran (THF) in these solvents.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is not critical to the invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be easily at about 0 ℃ to about 100 ℃, more preferably from about 10 ℃ are carried out this reaction to about 50 ℃ temperature.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes to about 24 hours, more preferably from about 60 minutes extremely about 12 hours time usually will be enough.

Step F 3

In this step, compound and sodiumazide (F3-a) reaction of formula (XXI) by making formula (XX) then makes the also original preparation of azido-(F3-b).

(F3-a) and reaction of sodium azide

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Ethers such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) and two Alkane; Acid amides such as methane amide, N, dinethylformamide, N,N-dimethylacetamide and hexamethylphosphorictriamide; And sulfoxide such as dimethyl sulfoxide (DMSO) and tetramethylene sulfone.Preferred person is N in these solvents, dinethylformamide.

Add before the sodiumazide,, hydroxyl is changed into leavings group, as methyl sulphonyl, trifluoromethyl sulfonyl and 4-aminomethyl phenyl alkylsulfonyl by adding reagent such as trifluoromethanesulfonyl chloride, methane sulfonyl chloride and toluene sulfonyl chloride.In these reagent, preferred person is a methane sulfonyl chloride.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is not critical to the invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 120 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are general with enough to about 24 hours time.

(F3-h) reduction:

This reaction can be carried out under the identical condition described in the step e 1 of method E.

Step F 4

In this step, the compound of formula (VIIIa) passes through amino protecting group R ⁶Import in the primary amino (F4-a), and make the amino protecting group R of secondary amino group ¹⁰Optionally go protection (F4-b) to prepare.

(F4-a) importing of amino protecting group:

This reaction is by people such as T.W.Greene, and [protecting group of organic synthesis (ProtectiveGroups in Organic Synthesis), 494-653, (1999)] are described in detail, and it is for reference that the disclosure is incorporated this paper into.Below enumerate the type reaction that relates to the blocking group tert-butoxycarbonyl.

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: water, ethers such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) and two

Alkane; And sulfoxide such as dimethyl sulfoxide (DMSO) and tetramethylene sulfone.Preferred person is a tetrahydrofuran (THF) in these solvents.

This reaction is generally carried out in the presence of reagent.Character to agents useful for same is not particularly limited equally, and habitual any reagent can equally be used for herein in such reaction.The example of this reagent includes, but is not limited to: dimethyl dicarbonate butyl ester and 1-(tert-butoxycarbonyl) benzotriazole.In these, preferred person is the dimethyl dicarbonate butyl ester.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is unimportant to the present invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be easily at about 0 ℃ to about 120 ℃, more preferably from about 20 ℃ are carried out this reaction to about 80 ℃ temperature.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes to about 24 hours, more preferably from about 60 minutes extremely about 12 hours time usually will be enough.

(F4-b) go protection

This method is by people such as T.W.Greene, and the protecting group of organic synthesis (describe in detail for ProtectiveGroups in Organic Synthesis, 494-653, and it is for reference that the disclosure is incorporated this paper into by (1999).The combination that below is set forth in hydrogen and catalyzer such as palladium-charcoal or platinum exists down, relates to the typical method of benzoyl protecting group.

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: halogenated hydrocarbon, as methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Alcohol is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols; Reach ethers such as diethyl ether, Di Iso Propyl Ether, tetrahydrofuran (THF) and two Alkane.Preferred person is a methyl alcohol in these solvents.

This reaction can be carried out in wide temperature range, and accurate temperature of reaction is unimportant to the present invention.Preferred temperature of reaction can be decided along with factor such as the character of solvent and raw material.Yet, usually, be to about 120 ℃ temperature, to carry out this reaction easily at about 0 ℃.React required time also along with many factors change widely, especially the character of temperature of reaction and raw materials used and solvent.Yet, carry out as long as be reflected under the top listed optimum condition, about 5 minutes are common with enough to about 24 hours time.

Method G

This method illustrates wherein R ²Preparation for formula (VIII) compound of hydroxyl.

Reaction scheme G

In response diagram G, R ⁶And R ¹⁰Each is as above definition.

Step G1

In this step, carbonyl and the TMS prussiate of formula (XXII) compound by making formula (XVIII) compound (being purchased) reacts and prepares.

This reaction is carried out in the presence of solvent usually and preferably.To the not special restriction of character of the solvent that uses, as long as reaction or the reagent that relates to is not had negative effect and its solubilized reagent (at least to a certain degree).The example of suitable solvents includes, but is not limited to: aromatic hydrocarbon such as benzene, toluene and oil of mirbane; Halogenated hydrocarbon such as methylene dichloride, chloroform, tetracol phenixin and 1, the 2-ethylene dichloride; Ethers such as diethyl ether, Di Iso Propyl Ether, ethylene glycol dimethyl ether, tetrahydrofuran (THF) and two Alkane; Nitrile such as acetonitrile and benzonitrile; And alcohol is as methyl alcohol, ethanol, propyl alcohol, 2-propyl alcohol and butanols.Preferred person is a toluene in these.

This is reflected under the reagent existence and carries out.Character to agents useful for same is not particularly limited equally, and habitual any reagent can equally be used for herein in such reaction.The example of this reagent includes, but is not limited to: Lewis acid such as BF ₃, AlCl ₃, FeCl ₃, AgCl, ZnI ₂, Fe (NO ₃) ₃, CF ₃SO ₃Si (CH ₃) ₃, Yb (CF ₃SO ₃) ₃And SnCl ₄Alkali such as CaO; Ether such as 18-crown ether-6; Acid is as Amberlite XAD-4 resin.Preferred person is ZnI in these ₂

Step G2

In this step, the compound of formula (XXIII) changes into amino by the cyano group with formula (XXII) compound, then makes amino-protecting group R ¹⁰Go to protect and prepare.This reaction can carried out under the same terms described in method E step e 1 and method F step F 4.

Step G3

In this step, the protection of the amino of compound through type (XXIII) compound of formula (VIIIb) and go to protect and prepare.This reaction can carried out under the same terms described in method F step F 4.

Intermediate among formula (I) compound and the above-mentioned preparation method can separate and purifying as distillation, recrystallize or chromatography purification through habitual program.

Be intended for use the The compounds of this invention of pharmaceutical use can crystallization or amorphous products give.They can for example precipitation, crystallization, lyophilize, spraying drying or evaporation drying obtain as solid plug, powder or form of film with for example by this method.Microwave or radiation frequency drying can be used for this purpose.

They can give individually or with one or more other compound combinations of the present invention or with one or more other medicines (or its any combination) combination.Usually, they will give with the form with one or more pharmaceutically acceptable carriers or vehicle bonded preparation.Term " carrier " or " vehicle " use in this article in order to describe The compounds of this invention any composition in addition.The selection of vehicle will depend on that to a great extent for example special mode of administration of multiple factor, vehicle are to solubleness and the influence of stability and the character of formulation.

Being suitable for the pharmaceutical composition of sending of The compounds of this invention and their preparation method is to show and as can be known to those skilled in the art.Said composition and their preparation method can be found in (for example) Remington ' s Pharmaceutical Sciences, the 19th version (Mack publishing company, 1995).

Oral administration

Compound of the present invention can give orally.Give to comprise orally and swallow, make compound enter gi tract, maybe can adopt to give, can directly enter in the blood flow from mouth by this approach compound through cheek or hypogloeeis.

The preparation that is suitable for orally give comprises for example tablet of solid preparation, comprise particle, liquid or powder capsule, lozenge (comprising liquid-filling), chew ingot, many-as and to receive-particle, gelifying agent, solid solution, liposome, membrane agent (comprising mucosal adhesive), avette dose of (ovule), sprays and liquid preparation.

Liquid preparation comprises for example suspension, solution, syrup and elixir.Said preparation can be used as the weighting agent use in soft or the hard capsule and typically comprises carrier, for example, and water, ethanol, polyoxyethylene glycol, propylene glycol, methylcellulose gum or suitable oil and one or more emulsifying agents and/or suspension agent.Liquid preparation also can pass through solid reconstruct (for example, from little cartridge bag) preparation.

Compound of the present invention also can dissolve fast, rapidly disintegrating dosage form for example is described in by Liang and Chen Expert Opinion in Therapeutic Patents, 11(6), those among the 981-986 (2001) are used.

For Tabules, to decide on dosage, medicine can account for about 1 weight % of formulation to about 80 weight %, and the about 5 weight % that more typically account for formulation are to about 60 weight %.Except that medicine, tablet comprises disintegrating agent usually.Examples of disintegrants comprises hydroxypropylcellulose, starch, pregelatinized Starch and the sodiun alginate that primojel, Xylo-Mucine, calcium carboxymethylcellulose, croscarmellose sodium, Crospovidone, polyvinylpyrrolidone, methylcellulose gum, Microcrystalline Cellulose, low alkyl group replace.Usually, disintegrating agent will account for about 1 weight % of formulation to about 25 weight %, preferably account for about 5 weight % to about 20 weight %.

Tackiness agent is commonly used to give the adhesion quality of tablet formulation.Suitably tackiness agent comprises Microcrystalline Cellulose, gelatin, sugar, polyoxyethylene glycol, natural and synthetical glue, polyvinylpyrrolidone, pregelatinized Starch, hydroxypropylcellulose and Vltra tears.Tablet also can comprise thinner, for example lactose (monohydrate, spraying drying monohydrate, anhydrous or the like), N.F,USP MANNITOL, Xylitol, glucose, sucrose, Sorbitol Powder, Microcrystalline Cellulose, starch and dicalcium phosphate dihydrate.

Tablet also can randomly comprise tensio-active agent, for example for example silicon-dioxide and talcum of lauryl sulfate sodium and Polysorbate 80 and glidant.When existing, tensio-active agent can account for about 0.2 weight % of tablet to about 5 weight %, and glidant can account for about 0.2 weight % of tablet to about 1 weight %.

Tablet also comprises lubricant for example Magnesium Stearate, calcium stearate, Zinic stearas, FUMARIC ACID TECH GRADE sodium stearyl ester usually, and the mixture of Magnesium Stearate and lauryl sulfate sodium.About 0.25 weight % that lubricant accounts for tablet usually is to about 10 weight %, preferably from about 0.5 weight % to about 3 weight %.

Other possible composition comprises antioxidant, tinting material, seasonings, sanitas and taste-sequestering agent.

Typical tablet comprises about at the most 80% medicine, and about 10 weight % are to about 90 weight % tackiness agents, and about 0 weight % is to about 85 weight % thinners, and about 2 weight % arrive about 10 weight % lubricants to about 10 weight % disintegrating agents and about 0.25 weight %.

The tablet adulterant can directly compress or form tablet by the cylinder compression.The part of tablet adulterant or adulterant or can be before film-making by wet type-, dry type-or fusing-granulation, fusing is condensed or extrude.Last preparation can comprise one or more layers and can be coated or not coated; Itself in addition can incapsulate.

The preparation of tablet is discussed at " the 1st of Pharmaceutical Dosage Forms:Tablets. ", Marcel Dekker, New York, 1980 (SIBN 0-8247-6918-X) by H.Lieberman and L.Lachman

The solid preparation of orally give can be mixed with promptly release and/or transfer and to release.Transfer release formulation comprise delays-, continue-, pulse-, control-, target and sequencing release.

The preparation of releasing for the suitable accent of the object of the invention is described in United States Patent (USP) the 6th, 106, in No. 864.Other the suitable release tech for example details of high-energy dispersion and infiltration and coating particle is found in people's such as Verma Pharmaceutical Technology On-line, 25 (2), 1-14 (2001).Use chewing gum to realize that sustained release is described among the WO 00/35298.

Administered parenterally

Compound of the present invention also can directly give to blood flow, to intramuscular, or to the internal.Be used for the proper method that parenteral gives comprise in intravenously, intra-arterial, intraperitoneal, the sheath, in the ventricle, in the urethra, in the breastbone, encephalic, intramuscular and subcutaneous.The appropriate device that parenteral gives comprises pin (comprising micropin) syringe, needleless injector and infusion techniques.

Parenteral formulation typically is the aqueous solution, it can comprise for example salt of vehicle, carbohydrate and buffer reagent (preferred about 3 to about 9 pH), but, use for some, they can more suitably be mixed with aseptic non-aqueous solution or merge the dried forms that uses with for example aseptic apirogen water of suitable vehicle.

The preparation of parenteral formulation under aseptic condition for example, by lyophilize, can use standard drug technology well-known to those having ordinary skill in the art to finish easily.

The solubleness that is used in formula (I) compound in the preparation of parenteral solution can be by using suitable compounding process, and for example incorporating solubleness-rising agent into increases.

Be used for preparation that parenteral gives can be mixed with promptly release and/or transfer and release.Transfer release formulation comprise delays-, continue-, pulse-, control-, target and sequencing release.Therefore compound of the present invention can be mixed with solid, semisolid or the thixotropic fluid that is used for the implantation depot forms administration released with the accent that active compound is provided.The example of said preparation comprises the stent and the PGLA microballoon of medicine coating.

Topical

Compound of the present invention also can be administered to skin or mucous membrane partly, just, and by skin or transdermal administration.The exemplary formulations that is used for this purpose comprises gelifying agent, hydrogel adhesive, washing lotion, solution, creme, ointment, face powder, dressing, foam, membrane agent, transdermal patches, wafer, implant, sponge, fiber, bandage and microemulsion.Also can use liposome.Typical carrier comprises alcohol, water, mineral oil, whiteruss, white vaseline, glycerine, polyoxyethylene glycol and propylene glycol.Can mix penetration enhancers-referring to, for example, the JPharm Sci of Finnin and Morgan, 88(10), 955-958 (in October, 1999).

The device of other topical administration comprises by electroporation, iontophoresis, ultrasonic introductory technique (phonophoresis), ultrasonic importing (sonophoresis) and micropin or needleless (Powderject for example ^TM, Bioject ^TMDeng) injected delivery.

The preparation of topical administration can be mixed with promptly release and/or transfer and to release.Transfer release formulation comprise delays-, continue-, pulse-, control-, target and sequencing release.

Suction/intranasal administration

But compound of the present invention also gives or gives by suction in the nose, typically with the form of dry powder (or separately, with mixture, for example, with the dried adulterant form of lactose, or with blended composition particle, for example, with phosphatide, for example phosphatidylcholine mixes) from Diskus or with aerosol spray from pressurizing vessel, pump, atomizer, spraying gun (preferably making electricity consumption hydraulic pneumatic formula (electrohydrodynamics) produce the spraying gun of mist), or atomizer administration use or do not use suitable propelling agent, for example 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3, the 3-heptafluoro-propane.In order to use in the nose, powder can comprise bioadhesive agents, for example, removes acetyl chitin or cyclodextrin.

Pressurizing vessel, pump, atomizer, spraying gun or atomizer comprise the solution or the suspension of The compounds of this invention, it comprises for example ethanol, aqueous ethanolic solution or is suitable for the dispersion of activeconstituents, dissolvingization or prolongs the substituting agent that discharges, propelling agent and option list surface-active agent as solvent, for example sorbitan trioleate, oleic acid, or lactic acid oligomer.

Before being used in dry powder or suspension preparation, the pharmaceutical product micro mist changed into to be adapted to pass through sucking the size (typically being less than 5 microns) send.This can pass through any suitable breaking method, for example spiral spray is milled, fluidised-bed spray is milled, form receive particle treatment with supercritical fluid, high pressure homogenizing or spraying drying and realize.

Capsule (utilize (for example) gelatin or Vltra tears make), bubble eye and the cartridge case that is used for sucker or insufflator can be mixed with and comprise compound of the present invention, suitable powder matrix lactose or starch and the usefulness correction agent powdered mixture of l-leucine, N.F,USP MANNITOL or Magnesium Stearate for example for example.Lactose can be the form of anhydrous or monohydrate, is preferably the latter.Other appropriate excipients comprises dextran, glucose, maltose, Sorbitol Powder, Xylitol, fructose, sucrose and trehalose.

Being fit to be used in the each driving of pharmaceutical solutions in the spraying gun that uses the electrohydrodynamics device to produce mist can comprise about 1 microgram and can change to about 100 microlitres from about 1 microlitre to about 20 milligrams The compounds of this invention and driving volume.Typical formulation can comprise compound, propylene glycol, aqua sterilisa, ethanol and the sodium-chlor of formula (I).Can comprise glycerine and polyoxyethylene glycol in order to the replace solvents that replaces propylene glycol.

Suitable correctives, for example menthol and left menthol or sweeting agent, for example asccharin or soluble saccharin, can add to this to be intended for use to suck/preparation of the present invention that gives in the nose in.Be used to suck/preparation of intranasal administration for example can use (DL-lactic acid-oxyacetic acid) altogether (PGLA) be mixed with promptly release and/or transfer and release.Transfer release formulation comprise delays-, continue-, pulse-, control-, target and sequencing release.

If Foradil Aerolizer formoterol fumarate and aerosol, then measure unit is by the valve decision of conveying and metering amount.Unit of the present invention is usually through arranging to contain about 1 dosing or " air blowing dosage (puff) " to about 100 microgram formula (I) compounds.Total every day, dosage was generally between about 50 micrograms are to about 20 milligrams, and it can single dose or with whole day (often) dosed administration of separating repeatedly.

Rectum/intravaginal administration

Compound of the present invention can give by rectum or vagina, for example, and with the form of suppository, vaginal suppository or enema.Theobroma oil is traditional suppository base, but as suitably can use various substitutes.

The preparation that is used for rectum/vagina administration can be mixed with promptly release and/or transfer and to release.Transfer release formulation comprise delays-, continue-, pulse-, control-, target and sequencing release.

Eyes/ear administration

Compound of the present invention also can directly be administered to eyes or ear, typically in wait to open, pH-regulates, micronization suspension in the sterile saline or the dropping liquid form of solution.Other preparation that suitable E ﹠ E gives comprise ointment, biology can decompose (for example absorbability gel sponge, collagen) and abiotic the decomposition (for example siloxanes) implant, wafer, eyeglass and particle or little bag system, for example vesica agent (niosomes) or liposome.Polymkeric substance is cross linked polyacrylate, polyvinyl alcohol, hyaluronic acid, cellulosic polymer for example, for example, and Vltra tears, Natvosol or methylcellulose gum, or assorted polysaccharide polymkeric substance, for example, gelan glue, can with sanitas, for example benzalkonium chloride is blended together.Said preparation also can be sent by iontophoresis.

The preparation that is used for the administration of eye/ear can be mixed with promptly release and/or transfer and to release.Transfer release formulation comprise delays-, continue-, pulse-, control-, target and sequencing release.

Other technology

Compound of the present invention can with the soluble large molecule entity, for example cyclodextrin and its suitable derivatives or contain the combination of polymers of polyoxyethylene glycol, so as to improve when in any above-mentioned mode of administration, using they solubleness, dissolution rate, cover taste masking road, bioavailability and/or stability.

The drug-cyclodextrin complex compound for example, is found and can be used in most formulation and administration path usually.Clathrate complex and non-clathrate complex both can use.As with the substituting of the direct complexing of medicine, can use cyclodextrin as supplementary additive, just as carrier, thinner or solubilizing agent.The most normal be used in these purposes be α-, β-and γ-Huan Hujing, its example can be found among international patent application no WO 91/11172, WO 94/02518 and the WO 98/55148.

The kit of parts (kit)

Want to give the combination of active compound as possible, for example, in order to treat the purpose of the specified disease or the patient's condition, within the scope of the invention be, two kinds or more kinds of pharmaceutical composition, at least wherein a kind of comprising, can be combined into the form that is suitable for the kit that composition gives altogether easily according to compound of the present invention.

Therefore kit of the present invention comprises two kinds or more kinds of separated drug composition, and at least wherein a kind of comprises according to formula of the present invention (I) compound and be used for keeping dividually the device of said composition, for example container, the bottle that separates, or separate the paper tinsel bag.The example of such kit is the blister of being familiar with that is used for package troche, capsule or the like.

Kit of the present invention is suitable for giving different dosage form especially, and for example oral and parenteral is used for giving the composition that this separates with different spacing of doses, or is used for progressively increasing the composition that (titrating) is separated from each other.For helping conformability, kit typically comprises the explanation of administration and can provide so-called memory supplementary unit.

Dosage

For administration to human patients, The compounds of this invention every day total dose generally between about 0.05 milligram to about 100 milligrams, certainly decide according to mode of administration, preferably between about 0.1 milligram to about 50 milligrams, and more preferably between about 0.5 milligram to about 20 milligrams.For example, total dose every day that oral administration may need is between about 1 milligram to about 20 milligrams, but intravenous dosages may only need be about 0.5 milligram to about 10 milligrams.Every day, total dose can single dose or the dosed administration that separates.

These dosage be based on body weight about 65 kilograms to about 70 kilograms average mankind.The doctor can determine body weight to drop on this extraneous curee such as baby and older's dosage easily.

Conjoint therapy

As mentioned above, The compounds of this invention presents 5-HT ₄Agonist activity.5-HT of the present invention ₄Applicable and at least a other pharmacologically active agents of agonist or compound coupling are especially in the treatment gastroesophageal reflux disease.For example, 5-HT ₄Agonist, the formula of especially above-mentioned definition (I) compound or its pharmacy acceptable salt or solvate can be selected from following pharmacologically active agents associating with one or more, administration simultaneously, in regular turn or dividually:

(i) histamine H ₂Receptor antagonist, for example Ranitidine HCL, lafutidine, nizatidine, cimitidine, famotidine and roxatidine;

(ii) proton pump inhibitor, for example omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, Yi Nala azoles (ilaprazole) and lansoprazole;

(iii) sour pump antagonist, for example contract draw thunder account for (soraprazan), all thunders of class account for (revaprazan) (YH-1885), AZD-0865, CS-526, AU-2064 and YJA 20379-8;

(iv) oral antiacid mixture, for example Maalox , Aludrox

And Gaviscon

(v) mucous membrane protection base, for example zinc L-carnosine, Yi Kabeite sodium, rebamipide, teprenone, cetraxate, sucralfate, a chlorine woods (chloropylline)-copper and plaunotol;

(vi) GABA _BAgonist, for example baclofen and AZD-3355;

(vii) for example clonidine, Mei Tuomeiding, lofexidine, moxonidine, tizanidine, guanfacine, guanabenz, talipexole and dexmedetomidine of α 2 agonists;

(viii) for example theophylline, aminophylline and doxofylline of xantheine derivative;

(ix) calcium channel blocker, for example Aranidipine, Lacidipine (62, method sieve Horizon (falodipine), Azelnidipine, clinidipine, lomerizine, diltiazem

, Procorum, efonidipine, nisoldipine, peace Flordipine, lercanidipine, bevantolol, nicardipine, Isrodipine, benidipine, verapamil, nitrendipine, barnidipine, Propafenone, Manidipine, Bepridil, nifedipine, nilvadipine, nimodipine and fasudil;

(x) benzodiazepine

Agonist, for example diazepam, Zaleplone, azoles pyrrole dawn, haloxazolam, clonazepam, prazepam, quazepam, flutazolam, triazolam, lormetazepam, midazolam, tofisopam, clobazam, flunitrazepam and flutoprazepam;

(xi) for example prostaglandin(PG), Misoprostol, day general of prostaglandin analogue for Buddhist nun (treprostinil), Yi Suopu days alcohol (esoprostenol), latanoprost, ciloprost, Beraprost, enprostil, Ibudilast and ozagrel;

(xii) histamine H ₃Agonist is R-Alpha-Methyl histamine and BP-294 for example;

(xiii) anti-stomach agent for example anti--tert-Amyloxycarbonyltetragastrin vaccine, itriglumide and Z-360;

(xiv) 5-HT ₃Antagonist is dolasetron, Palonosetron, Lotronex, azasetron, ranimustine, mirtazapine, granisetron, tropisetron, E-3620, ondansetron and indisetron for example;

(xv) for example imipramine, amitriptyline, clomipramine, amoxapine and Tymelvt of tricyclic antidepressants;

(xvi) for example good crust spray of gaba agonist fourth, topiramate, Xi Luoxi dissolve, clonazepam, progabide, brotizolam, Zopiclone, Pregabalin and according to Zopiclone (eszopiclone);

(xvii) for example morphine, heroine, hydromorphone, oxymorphone, levorphanol, left promise coffee alkane, methadone, Pethidine, fentanyl, Cocaine, morphine monomethyl ether, paracodin, oxycodone, hydrocodone, Propoxyphene, Nalmefene, nalorphine, naloxone, TREXUPONT, buprenorphine, butorphanol, nalbuphine and pentazocine of opioid analgesic agent;

(xviii) for example Sostatin, AN-238 and PTR-3173 of somatostatin analogue;

(xix) Cl channel activator Lu Bipusi ketone (lubiprostone) for example;

(xx) selectivity serotonin reuptake inhibitor for example Sertraline, escitalopram, fluoxetine, nefazodone, fluvoxamine, citalopram, Midalcipran, paroxetine, Venlafaxine, U-26225A, sibutramine, duloxetine, Venlafaxine (desvenlafaxine) and dapoxetine fall;

(xxi) for example Wyovin and tropine of anticholinergic;

(xxii) cathartic Trifyba for example

, Fybogel

, Konsyl

, Isogel , Regulan

, Celevac

And Normacol

(xxiii) fiber product Metamucil for example

(xxiv) spasmolytic mebeverine for example;

(xxv) for example metoclopramide, domperidone and levosulpiride of dopamine antagonist;

(xxvi) cholinergic agent prostigmin(e) for example;

(xxvii) for example bright, itopride and the E2020 of lycoremine, metrifonate, Li Fansi of AChE inhibitor;

(xxviii) tachykinin (NK) antagonist, especially NK-3, NK-2 and NK-1 antagonist, for example nepadutant, Sha Leidutan, Talnetant;

(α R, 9R)-7-[3, two (trifluoromethyl) benzyls of 5-]-8,9,10,11-tetrahydrochysene-9-methyl-5-(4-aminomethyl phenyl)-7H-[1,4] diazocine [2,1-g] [1,7] naphthyridines-6-13-diketone (TAK-637) also, 5-[[(2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group-3-(4-fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone (MK-869), lanepitant, Dapitant and

3-[[2-methoxyl group-5-(trifluoromethoxy) phenyl] methylamino]-2-phenyl-piperidines (2S, 3S).

Estimate bioactive method:

5-HT by following program determination The compounds of this invention ₄Receptor binding affinity.

Human 5-HT ₄In conjunction with (1)

Prepare human 5-HT _{4 (d)}The HEK293 cell of transfection and make it in inner (in-house) growth.With the cell suspension collected in having replenished proteinase inhibitor mixed solution (Boehringer, dilution in 1: 1000) (pH 7.4 for 50mM HEPES, 4 ℃), and use the hand-held Polytron PT 1200 be arranged under the full power to break instrument homogenizing on ice 30 seconds.Homogenate is 40,000xg and 4 ℃ centrifugal 30 minutes down.Then granular sludge is resuspended among the 50mMHEPES (7.4,4 ℃ of pH) and once centrifugal more in the same manner.With final granular sludge resuspending in the 50mM of proper volume HEPES (pH 7.4 is at 25 ℃), homogenizing, five equilibrium sample and be stored under-80 ℃ up to use.Use BCA protein analysis test kit (PIERCE) and ARVOsx plate reading machine (Wallac) to make the film fraction of five equilibrium sample carry out determination of protein concentration.

For in conjunction with the experiment for, at room temperature with 25 microlitres [ ³H]-GR113808 (Amersham), final 0.2nM) and the film homogenate of 150 microlitres and test compound that WGA-SPA pearl (Amersham) aaerosol solution (10 micrograms of protein and 1 milligram of SPA pearl/hole) is cultivated 25 microlitres 60 minutes.Under ultimate density, measure non-specific binding by 1 μ M GR113808 (Tocris).Cultivate by centrifugal termination the under 1000rpm.

The radioactivity of receptors bind is by quantizing with MicroBeta plate counter (Wallac) counting.

All compounds of embodiment all demonstrate 5HT ₄Receptor affinity.

Human 5-HT ₄In conjunction with (2)

Prepare human 5-HT _{4 (d)}The HEK293 cell of transfection and make it in growth inside.With the cell suspension collected in having replenished proteinase inhibitor mixed solution (Boehringer, dilution in 1: 1000) (pH 7.4 for 50mM Tris damping fluid, 4 ℃) in, and use the hand-held Polytron PT 1200 be arranged under the full power to break instrument homogenizing on ice 30 seconds.Homogenate was 40,000 * g and 4 ℃ centrifugal 10 minutes down.Then granular sludge is resuspended in the 50mM Tris damping fluid (7.4,4 ℃ of pH) and once centrifugal more in the same manner.With final granular sludge resuspending in containing 10mM MgCl ₂The 50mM Tris damping fluid (7.4,25 ℃ of pH) of proper volume in, homogenizing, five equilibrium sample and be stored under-80 ℃ up to use.Use BCA protein analysis test kit (PIERCE) and ARVOsx plate reading machine (Wallac) that the film fraction of five equilibrium sample is carried out determination of protein concentration.

For in conjunction with the experiment for, at room temperature with 50 microlitres [ ³H] test compound 60 minutes of 5-HT (Amersham, final 8.0nM) and 400 microlitre film homogenate (300 microlitres protein/pipe) cultivation, 50 microlitres.Under ultimate density, measure non-specific binding by 50 μ M GR113808 (Tocris).Use the BRANDEL collector, filter by fast vacuum on the glass fibers filter paper that soaks with 0.2%PEI and stop all cultivations, then with 50mM Tris damping fluid (7.4,25 ℃ of pH) washing three times.Use liquid scintillation counting, utilize Packard LS counter to quantize the radioactivity of receptors bind.

All compounds of embodiment all demonstrate 5HT ₄Receptor affinity.

Human 5-HT _{4 (d}) cAMP of agonist in the HEK293 cell of transfection-bring out raises

Set up human 5-HT in inside _{4 (d)}The HEK293 cell of transfection.This cell is at 37 ℃ and 5%CO ₂In the DMEM that is supplemented with 10%FCS, 20mM HEPES (pH 7.4), 200 mcg/ml hygromycin B (Gibco), 100 units per ml penicillin and 100 mcg/ml Streptomycin sulphates, grow down.Cell grows to 60-80% and converges.In the day before yesterday with compound treatment, the FCS of dialysis (Gibco) is normal to be replaced, and cell cultures is spent the night.Compound prepares in 96-orifice plate (12.5 microlitres/hole).With PBS/1mM EDTA collecting cell, centrifugal and wash with PBS.When analyzing beginning, with the cell granular sludge with 1.6 * 10 ⁵The concentration of cells/ml, resuspending and at room temperature left standstill 15 minutes in the DMEM that is supplemented with 20mM HEPES, 10 μ M Pargylines (Sigma) and 1mM3-isobutyl--1-methyl xanthine (Sigma).Reaction is by cell being added in the plate (12.5 microlitres/hole) and initial.After at room temperature cultivating 15 minutes, add 1%Triton X-100 termination reaction (25 microlitres/hole), and plate was at room temperature left standstill 30 minutes.The cAMP based on fluorescence (Schering) that carries out even time resolution according to the operation instructions of manufacturer detects.Use ARVO _SXMultiple sign counter (Wallac) measure HTRF (excite 320nm, emission 665nm/620nm, time of lag 50 μ s, window times 400 μ s).Based on the proportion grading data of the fluorescence intensity of each hole under 620nm and 665nm, it is quantitative then to use the cAMP typical curve to carry out cAMP.The enhancing that will be produced by the cAMP that each compound elicits is standardized into the cAMP amount that is produced by 1000nM serotonin (Sigma).

All compounds of embodiment all show 5HT ₄Receptor agonist activity.

Human P162a combination

Prepare the HEK293S cell of human HERG transfection and make it in growth inside.In 50mM Tris-HCl (7.4,4 ℃ of pH), and use the hand-held Polytron PT 1200 that is arranged under the full power to break instrument the cell suspension collected homogenizing on ice 20 seconds.Homogenate was 48,000 * g and 4 ℃ centrifugal 20 minutes down.Then make granular sludge resuspending, homogenizing and once centrifugal more in the same manner.With 50mMTris-HCl, 10mM KCl, the 1mM MgCl of final granular sludge resuspending in proper volume ₂In (7.4,4 ℃ of pH), homogenizing, five equilibrium sample and be stored under-80 ℃ up to use.Use BCA protein analysis test kit (PIERCE) and ARVOsx plate reading machine (Wallac) to make the film fraction of five equilibrium sample carry out determination of protein concentration.

In the 96-orifice plate of cumulative volume 200 microlitres, carry out binding analysis.At room temperature with 20 microlitres [ ³H]-P162a (Amersham, final 5nM) and 160 microlitre film homogenate (25 micrograms of protein) cultivate the test compound 60 minutes of 20 microlitres.Under ultimate density, measure non-specific binding with 10 μ M P162as.Use the Skatron cell harvestor with 50mMTris-HCl, 10mM KCl, 1mM MgCl ₂(pH 7.4 is at 4 ℃) stop cultivating by filtering with fast vacuum on the GF/B Betaplate strainer of 0.5% pre-soaking.The strainer drying places sample sack and fills scintillation solution Betaplate Scint.With WallacBetaplate rolling counters forward and strainer bonded radioactivity.

The Caco-2 perviousness

According to Shiyin Yee, Pharmaceutical Research, the method described in 763 (1997) is measured the Caco-2 perviousness.

Make the Caco-2 cell go up growth 14 days in filter support (Falcon HTS porous insertion system).Remove substratum from top and substrate outside compartment the two, and under 37 ℃ in the shaking table water-bath, with 50 cycles per minute, cultivate individual layer in advance with 0.3 milliliter of top damping fluid and 1.0 milliliters of substrate outside damping fluids of heating in advance.The top damping fluid is by Han Keshi equilibrated salts solution (Hanks Balanced Salt Solution), 25mM D-Glucose monohydrate, 20mMMES biological buffer, 1.25mM CaCl ₂And 0.5mM MgCl ₂(pH 6.5) are formed.Substrate outside damping fluid is by Han Keshi equilibrated salts solution, 25mM D-Glucose monohydrate, 20mM HEPES biological buffer, 1.25mM CaCl ₂And 0.5mM MgCl ₂(pH 7.4) are formed.The pre-cultivation when finishing, the damping fluid of removing substratum and will containing test compound solution (10 μ M) makes an addition in the compartment of top.In the time of 1 hour, inset is moved on in the hole that contains fresh substrate outside damping fluid.Drug level in the damping fluid is analyzed with LC/MS and is measured.

Flow rate (F, quality/time) is calculated by the slope of the accumulation performance of matrix on the receiver-side, and apparent permeability coefficient (P _App) be to calculate by following equation.

P _app(cm/sec)＝(F*VD)/(SA*MD)

Wherein SA is the surface-area (0.3cm of transmission ²), VD is donor volume (0.3 milliliter), MD is the medicine total amount on the donor side when t=0.The mean value that all insert for data represented 2 times.The individual layer degree of integration is transmitted by Lucifer Yellow and measures.

The transformation period of human liver microsome (HLM)

Under 37 ℃ on the 96-deep-well plates, to contain 3.3mM MgCl ₂And 100mM potassium phosphate buffer (Ph 7.4) the culture experiment compound (1 μ M) of 0.78 mg/ml HLM (HL101).Reaction mixture is divided into two groups, non--P450 and P450 group.NADPH only makes an addition in the reaction mixture of P450 group.Collect the five equilibrium sample that P450 organizes sample at 0,10,30 and 60 minute time point, wherein 0 minute time point is meant that NADPH makes an addition to the time in the P450 group reaction mixture.When-10 and 65 minutes time points, collect the five equilibrium sample of non--P450 group.The five equilibrium sample of collecting is with target acetonitrile solution extraction in containing.Sedimentary protein is with centrifugal (2000rpm, 15 minutes) rotation sedimentation.With the compound concentration in the LC/MS/MS systematic survey supernatant liquor.

By the natural logarithm of compound/interior target peak area ratio was mapped to the time, obtain elimination half life values.The slope of best-fit line by point produces metabolic speed (k).This can use following equation to change into elimination half life values.

The transformation period=ln 2/k

Embodiment

In the present invention of following non-limiting example illustrated, wherein except as otherwise noted, otherwise all reagent are all commercially available, all operations all at room temperature or under the envrionment temperature carries out, that is to say, between about 18-25 ℃, rotatory evaporator is used in the evaporation of solvent, carries out with about 60 ℃ at the most bath temperature under reduced pressure; By tlc (tlc) monitoring reaction, and only provide the reaction times for illustrating; The fusing point that provides (m.p.) not calibrated (polymorphic may obtain different fusing points); The structure and the purity of at least a all separating compounds of affirmation by following technology: tlc (Merck silica gel 60 F ₂₅₄The TLC plate of precoating or Merck NH ₂F _254SThe HPTLC plate of precoating), mass spectroscopy, nucleus magnetic resonance (NMR), infrared absorption spectrum (IR) or trace analysis.Only provide yield for purposes of illustration.Hurried column chromatography is used Merck silica gel 60 (230-400 mesh ASTM) or Fuji Silysia Chromatorex DU3050 (amino-type, 30-50 micron) carries out.Harmonic analysis mass-spectrometric data (EI) obtains with Integrity (Waters) mass spectrograph or Automass 120 (JEOL) mass spectrograph.Harmonic analysis mass-spectrometric data (ESI) obtains with ZMD2 (Waters) mass spectrograph or Quattro II (Micromass) mass spectrograph.The NMR data are under 270MHz (JEOL JNM-LA 270 photometers) or 300MHz (JEOL JNM-LA300), use deuterated chloroform (99.8%D) and dimethyl sulfoxide (DMSO) (99.9%D) as solvent (except as otherwise noted), with respect to as interior target tetramethylsilane (TMS), measure with per 1,000,000 umbers (ppm); Used routine is abbreviated as: s=is unimodal, d=doublet, t=triplet, q=quartet, m=multiplet, br.=broad peak etc.IR spectrum is measured with Shimazu infrared spectrometer (IR-470).Specific rotation is used JASCO DIP-370 digital polarimeter, and (Japan Spectroscopic Co. Ltd.) measures.Chemical symbol has its implication commonly used; B.p. (boiling point); M.p. (fusing point); L (liter), ml (milliliter), g (gram), mg (milligram), mol (mole), mmol (mmole), eq (equivalent).Powder x-ray diffraction (PXRD) pattern uses the Rigaku RINT-TTR powder x-ray diffraction instrument that is equipped with automatic sampling interchanger, 2 θ-θ protractor, beam divergence breach, secondary single-shot look device and scintillometer to measure.Be used for analyzing by powder filling is prepared sample on aluminum sample loader.Sample rotates by 60.00rpm, and at room temperature with Cu-K α radiation with 4 ° of/minute scannings.

Embodiment 1:

4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid

Step 1.4-cyano group tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester

At 0 ℃ and N ₂In, the DMF (100 milliliters) of dropping cyano-containing tert.-butyl acetate (25.0 grams, 0.177 mole) in DMF (200 milliliters) stirred suspension that contains NaH (17.7 grams, 0.443 mole).Make mixture be warming up to envrionment temperature and stirred 1 hour.Then, two (2-bromotrifluoromethane) ethers (49.3 grams, 0.177 mole) are made an addition in the mixture, and make the gained mixture stir 24h down at 90 ℃.After being cooled to 0 ℃, mixture is with water (100 milliliters) quencher.Volatile component is removed in evaporation, and residue is with the mixture precipitation of EtOAc-toluene (1: 2,500 milliliters) and water (500 milliliters).Organic phase is with water (500 milliliters) washing three times, with Na ₂SO ₄Drying, after filtration and the evaporation.Solid obtains 19.0 gram (57%) white crystals title compounds with hexane wash and vacuum drying.

¹H-NMR(CDCl ₃)δ：3.96(2H，dt，J＝3.9Hz，12.3Hz)，3.73(2H，dt，J＝2.6Hz，12.3Hz)，2.20-1.94(4H，m)，1.52(9H，s)。

Step 2.4-(amino methyl) tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester

Contain 4-cyano group tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester (18.95 grams, 0.0897 mole, methyl alcohol (200 milliliters) mixture hydrogenation at room temperature (3atm) 12h of step 1) and Raney nickel (1.00 gram).Then, mixture is filtered through Celite pad, and vacuum concentrated filtrate, 16.01 gram (83%) yellow syrupy shape title compounds obtained.

¹H-NMR (CDCl ₃) δ: 3.86 (2H, dt, J=4.1Hz, 11.4Hz), 3.48 (2H, dt, J=2.5Hz, 11.5Hz), 2.75 (2H, s), 2.03 (2H, br d, J=10.7Hz), 1.55-1.35 (13H, m comprise 9H, s, 1.49ppm).

Step 3.4-[(4-oxo-piperidine-1-yl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester

In containing 4-(amino methyl) tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester (8.00 grams, 0.0372 mole, step 2) and K ₂CO ₃The EtOH-H of (0.51 gram, 0.0372 mole) ₂Drip in O (2: 1,240 milliliters) the backflow mixture and contain 1-ethyl-1-methyl-4-oxo-piperidine

Iodide (12.0 grams, 0.0445 mole, organic chemistry periodical (J.Org.Chem.) 1995, 60, EtOH-H 4324-4330) ₂O (2: 1,150 milliliters), and make the gained mixture stir 1h down at uniform temp (backflow).After being cooled to room temperature, solvent removed in vacuo.Pour residue into saturated NaHCO ₃In the aqueous solution (200 milliliters), and with CH ₂Cl ₂(200 milliliters three times) extraction mixture.Extraction liquid is through Na ₂SO ₄Dry and concentrated.Residue carries out chromatography with hexane/ethyl acetate (3: 1 to 2: 1) wash-out on silicagel column, obtain 10.77 gram (98%) colourless syrup shape title compounds.

MS(ESI)m/z：298(M+H) ⁺。

¹H NMR (CDCl ₃) δ 3.84 (2H, br d, J=11.4Hz), 3.50 (2H, dt, J=2.0Hz, 11.7Hz), 2.85 (4H, t, J=5.9Hz), 2.61 (2H, s), 2.39 (4H, t, J=6.1Hz), 2.05 (2H, d, J=11.5Hz), 1.75-1.45 (11H, m comprise 9H, s, 1.49ppm).

Step 4.4-[(4-cyano group piperidines-1-yl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester

Under 0 ℃ in containing 4-[(4-oxo-piperidine-1-yl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester (8.77 the gram; 0.0295 mole; 1 of step 3); add ptoluene-sulfonyl methyl isocyanide (11.51 grams in 2-glycol dimethyl ether (250 milliliters) stirred solution; 0.0590 mole), EtOH is (3.96 milliliters; 0.0678 mole) and t-BuOK (11.58 grams, 0.1032 mole).Make the gained mixture stir 16h down at 50 ℃.After the cooling, pour reaction mixture into saturated NaHCO ₃In the aqueous solution (200 milliliters), and mixture is with CH ₂Cl ₂(200 milliliters * 3 times) extraction.Extraction liquid is through Na ₂SO ₄Dry and concentrated.Residue carries out chromatography with hexane/ethyl acetate (2: 1) wash-out on silicagel column, obtain 5.76 gram (63%) yellow syrupy shape title compounds.

MS(ESI)m/z：309(M+H ⁺)。

¹H-NMR (CDCl ₃) δ: 3.81 (2H, dt, J=3.1Hz, 11.0Hz), 3.48 (2H, dt, J=2.1Hz, 11.7Hz), 2.76-2.64 (2H, m), 2.64-2.52 (1H, m), (4H, m comprise 2H to 2.50-2.35, s, 2.46ppm), 1.98 (2H, br d, J=11.9Hz), and 1.92-1.70 (4H, m), 1.65-1.40 (11H, m comprises 9H, s, 1.47ppm).

Step 5.4-{[4-(amino methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester

Make and contain 4-[(4-cyano group piperidines-1-yl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester (5.76 grams, 0.0187 mole, methyl alcohol (100 milliliters) mixture hydrogenation at room temperature (3atm) 12h of step 4) and Raney nickel (3.00 gram).Then, mixture is filtered and vacuum concentrated filtrate through Celite pad, obtain 5.72 gram (98%) yellow syrupy shape title compounds.

MS(ESI)m/z：313(M+H ⁺)。

¹H-NMR (CDCl ₃) δ: 3.80 (2H, dt, J=3.1Hz, 11.5Hz), 3.49 (2H, dt, J=2.1Hz, 12.2Hz), 2.80 (2H, br d, J=11.5Hz), (4H, m comprise 2H to 2.58-2.40, s, 2.43ppm), 2.15 (2H, br t, J=7.3Hz), 1.98 (2H, br d, J=13.7Hz), (16H, m comprise 9H to 1.70-1.40, s, 1.47ppm), 1.30-1.10 (2H, m).

Step 6.4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester

Make to contain right-chloroformate nitrophenyl ester (4.14 gram, 0.0205 mole), 1-sec.-propyl-1, and 3-dihydro-2H-benzimidazolyl-2 radicals-ketone (3.62 grams, 0.0205 mole, pharmaceutical chemistry periodical (J.Med.Chem.) 1999,42,2870-2880) and Et ₃The CH of N (7.81 milliliters, 0.0560 mole) ₂Cl ₂(100 milliliters) mixture at room temperature stirs 4h.Then, add 4-{[4-(amino methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester (5.72 grams, 0.0187 mole, step 5), and make the gained mixture at room temperature stir 24h.Reaction mixture is with saturated NaHCO ₃The aqueous solution (300 milliliters) dilution is with CH ₂Cl ₂(300 milliliters) extraction three times.The extraction liquid that merges is with Na ₂SO ₄Dry and concentrated.Residue carries out chromatography with hexane/ethyl acetate (1: 1) wash-out on the NH-silicagel column, obtain 9.83 gram (100%) yellow syrupy shape title compounds.

MS(ESI)m/z：515(M+H) ⁺。

¹H NMR (CDCl ₃) δ 8.90 (1H, t, J=4.9Hz), 8.31-8.21 (1H, m), 7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.80 (2H, dt, J=3.1Hz, 11.5Hz), 3.49 (2H, dt, J=1.7Hz, 11.4Hz), 3.28 (2H, t, J=6.4Hz), 2.81 (2H, brd, J=10.4Hz), 2.44 (2H, s), 2.16 (2H, t, J=10.4Hz), 1.98 (2H, d, J=12.4Hz), 1.81-1.20 (22H, m, comprise 6H, d, J=7.1Hz, 1.56ppm and 9H, s, 1.47ppm).

Step 7.4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid

Under 0 ℃ in containing 4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid tert-butyl ester (3.67 grams, 7.13 mmole, add dense HCl (40 milliliters) in the THF of step 6) (80 milliliters) stirred solution, and make the gained mixture at room temperature stir 20h.Enriched mixture is except that desolvating and pouring residue into saturated NaHCO ₃In the aqueous solution.Mixture is with CH ₂Cl ₂Extract three times, organic layer is with Na ₂SO ₄Dry.Remove the acquisition residue that desolvates, make it on silicagel column with MeOH/CH ₂Cl ₂(1: 10) wash-out carries out chromatography, obtains 3.01 gram (92%) title compounds.Make product from the THF recrystallize, obtain white crystals shape title compound (0.893 gram).

MS(ESI)m/z：459(M+H) ⁺。

¹H NMR (CDCl ₃) δ 8.99 (1H, t, J=5.6Hz), 8.30-8.15 (1H, m), 7.25-7.105 (3H, m), and 4.80-4.60 (1H, m), 3.95-3.70 (4H, m), 3.34 (2H, t, J=6.3Hz), 3.14 (2H, br d, J=12.0Hz), (4H, m comprise 2H to 2.65-2.45, s, 2.59ppm), 1.92 (4H, t, J=13.8Hz), 1.85-1.40 (11H, m comprises 6H, d, and J=6.9Hz, 1.57ppm).

m.p.：176℃。

IR(KBr)v：3281，2947，1720，1688，1611，1595，1547，1481，1447，1375，1200，1159，1136，1105，760cm ^-1。

C ₂₄H ₃₄N ₄O ₅Calculated value: C, 62.86; H, 7.47; N, 12.22.Measured value: C, 62.77; H, 7.42; N, 12.16.

Synthetic 4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } another path of tetrahydrochysene-2H-pyrans-4-carboxylic acid is described below.

Step 8.{[1-(ethoxyl methyl) piperidin-4-yl] methyl } t-butyl carbamate

In ethanol (19 milliliters) stirred solution that contains (piperidin-4-yl methyl) t-butyl carbamate (7.0 grams, 33 mmoles), add paraformaldehyde (1.2 grams, 39 mmoles) and salt of wormwood (5.4 grams, 39 mmoles) at ambient temperature.Make mixture stir 4h at ambient temperature.Mixture is after filtration and with ethanol (50 milliliters) washing leaching cake.Volatile component is removed in evaporation, obtains white powder title compound 8.9 grams (quantitatively).

¹H-NMR(CDCl ₃)δ：4.60(1H，brs)，4.07(2H，s)，3.49(2H，q，J＝7.1Hz)，3.08-2.83(4H，m)，2.50-2.36(2H，m)，1.75-1.60(2H，m)，?1.44(9H，s)，1.52-1.35(1H，m)，1.19(3H，t，J＝7.1Hz)，1.31-1.12(2H，m)。

Step 9.[methoxyl group (tetrahydrochysene-4H-pyrans-4-subunit) methoxyl group] (trimethylammonium) silane

Reach down in the nitrogen at 0 ℃, in tetrahydrofuran (THF) (4 milliliters) stirred solution that contains diisopropylamine (1.6 grams, 0.016 mole), drip n-Butyl Lithium (1.59M in the hexane, 9.2 milliliters, 0.014 mole), and stirred 20 minutes.Then, make reaction mixture be cooled to-40 ℃, add and to contain (2.0 milliliters of tetrahydrochysene-2H-pyrans-4-carboxylate methyl ester (1.9 grams, 0.013 mole) and TMS chlorine, 0.015 tetrahydrofuran (THF) (1 milliliter) mole), and make the gained mixture in 3h, be warming up to room temperature gradually.Volatile component is removed in evaporation, and residue filters through the Celite pad with hexane wash.Vacuum-drying filtrate, the glassy yellow oily title compound of acquisition 2.9 grams (quantitatively).

¹H-NMR(CDCl ₃)δ：3.64-3.59(4H，m)，3.52(3H，s)，2.24(2H，t，J＝5.2Hz)，2.15(2H，t，J＝5.3Hz)，0.22(9H，s)。

Step 10.4-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylicesters

(4 restrain in containing { [1-(ethoxyl methyl) piperidin-4-yl] methyl } t-butyl carbamate under 0 ℃, 14 mmoles, step 8) and [methoxyl group (tetrahydrochysene-4H-pyrans-4-subunit) methoxyl group] (trimethylammonium) silane (2.9 grams, 13 mmoles, drip (0.24 milliliter of TMS trifluoromethayl sulfonic acid ester in the methylene dichloride of step 9) (30 milliliters) stirred solution, 1.3 mmole), and make the gained mixture at room temperature stir 12h.Reaction mixture is with saturated sodium bicarbonate aqueous solution (150 milliliters) quencher, and with methylene dichloride (30 milliliters * 2) extraction, and the organic layer that merges is with dried over sodium sulfate.Remove the acquisition residue that desolvates, make this resistates on silicagel column, carry out chromatography, obtain 6.3 gram (64%) clear, colorless oily title compounds with ethyl acetate/hexane (1: 1) wash-out.

MS(ESI)m/z：371(M+H) ⁺。

¹H-NMR(CDCl ₃)δ：4.57(1H，br?s)，3.84-3.78(2H，m)，3.70(3H，s)，3.49-3.41(2H，m)，2.99-2.95(2H，m)，2.73-2.68(2H，m)，2.47(2H，s)，2.19-2.11(2H，m)，2.06-2.01(2H，m)，1.61-1.51(5H，m)，1.44(9H，s)，1.24-1.11(2H，m)。

Step 11.4-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylic acid

At room temperature in containing the 4-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylate methyl ester (6.47 grams, 17.5 mmole adds the 5N NaOH aqueous solution (10 milliliters) (heat release) in the MeOH of step 10) (32 milliliters) solution.Make gained solution stir 7h down, then in ice-cooled bath, be cooled to 5-10 ℃ at 60 ℃.In this solution, add 5N HCl (10 milliliters), and concentrated gained solution (the pH value is about 6).In residue, add 2-propyl alcohol (80 milliliters).Concentrate this solution.In residue, add 2-propyl alcohol (80 milliliters) and concentrated once again.Residue dilutes with EtOH (80 milliliters), and makes mixture at room temperature stir 2h.Make it to remove by filter NaCl through Celite pad (5.0 gram).Celite pad is with EtOH (20 milliliters) washing and concentrate the filtrate that merges.Add CH in the residue ₃CN (40 milliliters) and concentrated.Find to form white depositions in the process of this program.In residue, add CH ₃CN (40 milliliters), and make gained suspension at room temperature stir 2h.This mixture after filtration and the gained solid with CH ₃CN (10 milliliters) washing, then drying under reduced pressure obtains 4.1 gram (65%) white powder title compounds.

¹H?NMR(300MHz，CDCl ₃)δ4.66(1H，m)，3.93-3.82(3H，m)，3.15-2.99(4H，m)，2.58(2H，s)，2.58-2.45(2H，m)，1.98-1.76(4H，m)，1.55-1.35(6H，m)，1.44(9H，s)。

mp?129℃。

Step 12.4-{[4-(amino methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid 4-toluene sulfonic acide ester

At N ₂In 300 milliliters of 3-neck round-bottomed flasks, add down the 4-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] tetrahydrochysene-2H-pyrans-4-carboxylic acid (10 grams, 28 mmoles, step 11), and at room temperature pour into and contain p-TsOH H ₂IPA (150 milliliters) solution of O (16 grams, 84 mmoles).The gained mixture reaches N down at 60 ℃ ₂In stir 7h, and slowly drip Et when broadcasting crystal seed in the 2h inherence ₃N (8.6 milliliters, 62 mmoles).Add Et ₃Can form white depositions in the N process.The gained white suspension stirs 3h down at 60 ℃, stirs 5h and at room temperature stirs 10h down at 50 ℃.Suspension after filtration and the gained solid with IPA (100 milliliters) washing, at 50 ℃ of dry 5h down, obtain 10.5 gram (87%) white powder title compounds.

¹H-NMR(D ₂O)δ7.54(2H，d，J＝7.4Hz)，7.22(2H，J＝7.4Hz)，3.80-3.65(2H，m)，3.55-3.40(4H，m)，3.20-2.75(6H，m)，2.24(3H，s)，?1.90-1.80(6H，m)，1.55-1.35(4H，m)。

mp?247℃。

Step 13.4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid

Contain 1-sec.-propyl-1, the CH of 3-dihydro-2H-benzimidazolyl-2 radicals-ketone (1.0 grams, 5.7 mmoles) and chloroformic acid 4-nitro phenyl ester (1.14 grams, 5.7 mmoles) ₂Cl ₂(20 milliliters) mixture at room temperature reaches N ₂The middle stirring 5 minutes.In this mixture, slowly add Et ₃N (1.7 milliliters, 12.5 mmoles), and at room temperature the mixture that produces is made an addition to contain 4-{[4-(amino methyl) piperidines-1-yl] methyl tetrahydrochysene-2H-pyrans-4-carboxylic acid 4-toluene sulfonic acide ester (2.4 grams, 5.7 mmoles, the CH of step 12) ₂Cl ₂In (15 milliliters) mixture.The gained mixture at room temperature stirs 2h.Mixture is with the 0.5N HCl aqueous solution (100 milliliters) washing, and organic layer is with saturated NaHCO ₃The aqueous solution (75 milliliters) washing then concentrates organic layer.Residue dilutes with EtOAc (75 milliliters), and is concentrated into about 15 milliliters.After product is broadcast crystalline substance, this mixture was at room temperature stirred 30 minutes.In the process of this program, form solid and filter this mixture.The gained solid 50 ℃ of following vacuum-dryings, obtains 1.9 gram (73%) white solid state title compounds with EtOAc (10 milliliters) washing.

Step 14.4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid benzene sulfonate

At room temperature in containing 4-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } tetrahydrochysene-2H-pyrans-4-carboxylic acid (750 milligrams, the CH of step 13) ₃Add the CH that contains Phenylsulfonic acid monohydrate (288 milligrams) in CN (5 milliliters) suspension ₃CN (5 milliliters) solution.The gained mixture at room temperature stirred 2 days, and through concentrating.The residue drying obtains 909 milligrams of (90%) solid-state title compounds.

¹H-NMR (CD ₃OD) δ 9.10 (1H, t, J=5.7Hz), 8.11 (1H, dt, J=8.0,0.8Hz), 7.88-7.76 (2H, m), 7.46-7.36 (3H, m), 7.32 (1H, dt, J=8.0,0.8Hz), 7.22 (1H, td, J=7.8,1.4Hz), 7.13 (1H, td, J=7.8,1.4Hz), 4.70 (1H, sextet, J=6.9Hz), 3.85-3.55 (5H, m), 3.50-3.38 (4H, m), 3.23-3.05 (2H, m), 2.15-1.90 (5H, m), 1.78-1.58 (5H, m), 1,55 (6H, d, J=6.9Hz).

mp?223℃。

C ₃₀H ₄₀N ₄O ₈The calculated value of S: C, 58.42; H, 6.54; N, 9.08.Measured value: C, 58.50; H, 6.51; N, 9.11.

PXRD(2θ(+/-0.1)：5.3，12.6，21.4，21.9)。

Embodiment 2:

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } hexahydrobenzoic acid

Step 1.4-cyanocyclohexanoic alkane carboxylic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 1, use pentamethylene bromide to prepare title compound.

¹H-NMR(CDCl ₃)δ：2.07(2H，d，J＝13.0Hz)，1.85-1.57(7H，m)，1.50(9H，s)，1.35-1.15(1H，m)。

Step 2.1-(amino methyl) the hexahydrobenzoic acid tert-butyl ester

Prepare title compound with being similar to the method shown in embodiment 1 step 2.

MS(ESI)m/z：214(M+H) ⁺。

¹H-NMR (CDCl ₃) δ: 2.69 (2H, s), 2.02 (2H, d, J=13.2Hz), 1.65-1.05 (19H, m comprise 9H, s, 1.47ppm).

Step 3.1-[(4-oxo-piperidine-1-yl) methyl] the hexahydrobenzoic acid tert-butyl ester

Prepare title compound with being similar to the method shown in embodiment 1 step 3.

MS(ESI)m/z：296(M+H)+。

¹H-NMR (CDCl ₃) δ: 2.84 (4H, t, J=6.1Hz) 2.57 (2H, s), 2.38 (4H, t, J=6.1Hz), 2.04 (2H, d, J=12.2Hz), 1.65-1.15 (17H, m comprise 9H, s, 1.47ppm).

Step 4.1-[(4-cyano group piperidines-1-yl) methyl] the hexahydrobenzoic acid tert-butyl ester

Prepare title compound with being similar to the method shown in embodiment 1 step 4.

MS(ESI)m/z：307(M+H) ⁺。

¹H-NMR (CDCl ₃) δ: 2.53-2.66 (2H, m), 2.53-2.48 (1H, m), 2.48-2.30 (4H, m comprise 2H, s, 2.41ppm), 1.97 (2H, d, J=12.5Hz), 1.92-1.70 (4H, m), 1.65-1.10 (19H, m comprise 9H, s, 1.45ppm).

Step 5.1-{[4-(amino methyl) piperidines-1-yl] methyl } the hexahydrobenzoic acid tert-butyl ester

Prepare title compound with being similar to the method shown in embodiment 1 step 5.

MS(ESI)m/z：311(M+H) ⁺。

¹H-NMR (CDCl ₃) δ: 2.81 (2H, d, J=11.37Hz), 2.55 (2H, d, J=5.8Hz), 2.39 (2H, s), 2.11 (2H, t, J=11.0Hz), 2.03-1.85 (5H, m), 1.65-1.10 (21H, m comprise 9H, s, 1.45ppm).

Step 6.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } the hexahydrobenzoic acid tert-butyl ester

Prepare title compound with being similar to the method shown in embodiment 1 step 6.

MS(ESI)m/z：513(M+H) ⁺。

¹H NMR (CDCl ₃) δ 8.89 (1H, t, J=5.3Hz), 8.33-8.20 (1H, m), 7.23-7.10 (3H, m), and 4.80-4.60 (1H, m), 3.27 (2H, t, J=6.3Hz), 2.82 (2H, d, J=11.5Hz), 2.39 (2H, s), 2.12 (2H, t, J=11.4Hz), 1.97 (2H, d, J=13.2Hz), (28H, m comprise 6H to 1.73-1.10, d, J=6.9Hz, 1.56ppm and 9H, s, 1.45ppm).

Step 7.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } hexahydrobenzoic acid

Prepare title compound with being similar to the method shown in embodiment 1 step 7.

MS(ESI)m/z：457(M+H) ⁺。

¹H NMR (CDCl ₃) δ 8.98 (1H, t, J=5.8Hz), 8.28-8.18 (1H, m), 7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.34 (2H, t, J=6.3Hz), 3.11 (2H, d, J=11.9Hz), 2.61 (2H, s), 2.48 (2H, t, J=12.2Hz), 2.05-1.20 (21H, m, comprise 6H, d, J=6.9Hz, 1.57ppm).

m.p.：151℃。

IR(KBr)v：3291，2930，1732，1690，1545，1481，1373，1298，1202，1134，762cm ^-1。

C ₂₅H ₃₆N ₄O ₄Calculated value: C, 65.76; H, 7.95; N, 12.27.Measured value: C, 65.41; H, 8.18; N, 12.18.

Embodiment 3

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } Cyclopentane carboxylic acid

Step 1.1-(iodomethyl) cyclopentane carboxylic acid methyl

At N ₂In and maintain under-10 ℃, in containing HN (iPr) ₂Add n-BuLi (1.58M in the hexane, 5.43 milliliters, 8.58 mmoles) in THF (5 milliliters) stirred solution of (1.31 milliliters, 9.36 mmoles), and make mixture stir 1h down at-10 ℃.Then, in this mixture, dripping THF (3 milliliters) solution that contains cyclopentane carboxylic acid methyl (1.00 grams, 7.80 mmoles) under 0 ℃, and making mixture stir 2h down at 0 ℃.At last, in this mixture, adding CH under 0 ℃ ₂I ₂(0.628 milliliter, 7.80 mmoles), and make the gained mixture at room temperature stir 16h.Reaction mixture is with saturated NH ₄The Cl aqueous solution (50 milliliters) quencher is with Et ₂O (75 milliliters) extracts secondary, and the organic layer that merges washs with salt solution (75 milliliters).Organic layer is with Na ₂SO ₄Drying, after filtration and concentrate.Remove the acquisition residue that desolvates, make it that (1: 20-1: 10) wash-out carries out chromatography, obtains 1.085 gram (52%) colorless oil title compounds with the EtOAc/ hexane on silicagel column.

¹H-NMR(CDCl ₃)δ3.73(3H，s)，3.42(2H，s)，2.30-2.15(2H，m)，1.80-1.55(6H，m)。

Step 2.1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] cyclopentane carboxylic acid methyl

Contain 1-(iodomethyl) cyclopentane carboxylic acid methyl (5.52 grams, 0.0206 mole, step 1), (piperidin-4-yl methyl) t-butyl carbamate (8.83 grams, 0.0412 mole) and iPr ₂N-Methyl pyrrolidone (70 milliliters) mixture of NEt (10.76 milliliters, 0.0618 mole) stirs 24h down at 120 ℃.After the cooling, reaction mixture is with saturated NaHCO ₃The aqueous solution (200 milliliters) dilution, with AcOEt (200 milliliters) extraction three times, and the organic layer that merges is with water (200 milliliters) and salt solution (200 milliliters) washing.Organic layer is with Na ₂SO ₄Drying, after filtration and concentrate.Remove the acquisition residue that desolvates, make it on silica gel, to carry out chromatography, obtain 4.91 gram (67%) yellow syrupy shape title compounds with EtOAc/ hexane (1: 1) wash-out.

MS(ESI)m/z：355(M+H) ⁺。

¹H-NMR(CDCl ₃)δ4.58(1H，br?s)，3.66(3H，s)，2.97(2H，t，J＝6.3Hz)，2.77(2H，br?d，J＝11.5Hz)，2.55(2H，s)，1.70-1.50(9H，m)，1.44(9H，s)，1.25-1.08(2H，m)。

Step 3.1-{[4-(amino methyl) piperidines-1-yl] methyl } cyclopentane carboxylic acid methyl

Make and contain the 1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] CH of cyclopentane carboxylic acid methyl (1.16 gram, 3.27 mmoles, step 2) ₂Cl ₂(25 milliliters) and trifluoroacetic acid (5 milliliters) solution at room temperature stirs 1.5h.Reaction mixture warp again concentrates, and with saturated NaHCO ₃The aqueous solution (100 milliliters) alkalization is with CHCl ₃(100 milliliters) extraction five times.The extraction liquid drying that merges and concentrated obtains 0.831 gram (100%) yellow syrup title compound.

MS(ESI)m/z：255(M+H)+。

¹H-NMR(CDCl ₃)δ3.66(3H，s)，2.78(2H，d，J＝11.5Hz)，2.62-2.50(4H，m)，2.15-1.98(4H，m)，1.80-1.40(9H，m)，1.30-1.05(2H，m)。

Step 4.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } cyclopentane carboxylic acid methyl

MS(ESI)m/z：457(M+H) ⁺。

¹H NMR (CDCl ₃) δ 8.94 (1H, t, J=5.7Hz), 8.28-8.20 (7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.66 (3H, s), 3.27 (2H, t, J=6.4Hz), 2.84 (2H, d, J=11.6Hz), 2.62 (2H, s), 2.20-2.00 (4H, m), 1.75-1.50 (15H, m comprise 6H, d, J=7.0Hz, 1.56ppm), 1.40-1.20 (2H, m).

Step 5.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } Cyclopentane carboxylic acid

Make and contain 1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } cyclopentane carboxylic acid methyl (1.33 grams, 2.90 mmole, 4 N-HCl of step 4) (6 milliliters) and acetate (6 milliliters) mixture stir 18h under refluxing.After the cooling, reaction mixture is through concentrating and with NaHCO ₃The aqueous solution (100 milliliters) alkalization is with CH ₂Cl ₂(150 milliliters) extraction three times.The extraction liquid that merges is with Na ₂SO ₄Drying, after filtration and concentrate.Residue on silicagel column with MeOH/CH ₂Cl ₂(1: 10) wash-out carries out chromatography, obtains 1.12 gram (85%) white solid state title compounds.Crude compound is from EtOAc * 2 recrystallize, and 50 ℃ of following vacuum-dryings 2 days, obtains 610 milligrams of white crystals title compounds.

MS(ESI)m/z：443(M+H) ⁺。

m.p.：165℃。

IR(KBr)v：3271，2934，1736，1684，1607，1558，1483，1454，1379，1358，1298，1209，1167，1097，758cm ^-1。

¹H NMR (CDCl ₃) δ 9.00 (1H, t, J=5.5Hz), 8.30-8.18 (1H, m), 7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.34 (2H, t, J=11.0Hz), 2.32-2.17 (2H, m), 2.00-1.30 (17H, m comprise 6H, d, and 7.0Hz, 1.57ppm).

C ₂₄H ₃₄N ₄O ₄0.2H ₂The calculated value of O: C, 64.61; H, 7.77; N, 12.56.Measured value: C, 64.34; H, 7.79; N, 12.48.

Synthetic 1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } another path of Cyclopentane carboxylic acid is described below.

Step 6.1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] cyclopentane carboxylic acid methyl

According to program described in embodiment 1 step 10, use [cyclopentylidene (methoxyl group) methoxyl group] (trimethylammonium) silane (synthetic (Synthesis), 1982,1,58-60) replace [methoxyl group (tetrahydrochysene-4H-pyrans-4-subunit) methoxyl group] (trimethylammonium) silane to prepare title compound.

MS(ESI)m/z：355(M+H) ⁺。

¹H-NMR(CDCl ₃)δ4.58(1H，br?s)，3.66(3H，s)，2.97(2H，t，?J＝6.3Hz)，2.77(2H，br?d，J＝11.5Hz)，2.55(2H，s)，2.18-1.95(4H，m)，1.70-1.50(9H，m)，1.44(9H，s)，1.25-1.08(2H，m)。

Step 7.1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] Cyclopentane carboxylic acid

At room temperature in containing the 1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] (2.8 grams, 8.0 mmoles add the 2N NaOH aqueous solution (6 milliliters) (heat release) to cyclopentane carboxylic acid methyl in the MeOH of step 6) (11 milliliters) solution.Gained solution stirs 4h down at 70 ℃, then is cooled to 5-10 ℃ in ice-cooled bath.The Dropwise 5 N HCl aqueous solution (6 milliliters) in this solution.Concentrate gained solution (the pH value is about 6) and in residue, add 2-propyl alcohol (40 milliliters).Concentrate this solution, in residue, add CH ₃CN (40 milliliters).The gained mixture at room temperature stirs 2h, makes it to remove by filter NaCl through Celite pad (5.0 gram).Concentrated filtrate obtains 2.4 gram (quantitatively) white solid state title compounds.

¹H?NMR(300MHz，DMSO-d6)δ6.90-6.75(1H，m)，2.95-2.80(2H，m)，2.79(2H，t，J＝6.4Hz)，2.58(2H，s)，2.25-2.05(2H，m)，2.05-1.85(2H，m)，1.65-1.50(6H，m)，1.50-1.25(3H，m)，1.37(9H，s)，1.20-0.95(2H，m)。

mp?150℃。

Step 8.1-{[4-(amino methyl) piperidines-1-yl] methyl } Cyclopentane carboxylic acid 4-toluene sulfonic acide ester

At room temperature in 100 milliliters of 2-neck round-bottomed flasks, in containing the 1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] (interpolation contains p-TsOH H to Cyclopentane carboxylic acid in the THF of step 7) (25 milliliters) mixture for 5 grams, 14.7 mmoles ₂THF (25 milliliters) solution of O (8.4 grams, 44 mmoles).The gained mixture reaches N down at 70 ℃ ₂Middle stirring 3h, and be cooled to room temperature.In this solution, slowly drip Et ₃N (6 milliliters, 44 mmoles).Add Et ₃Can form white depositions in the N process, and make the gained mixture at room temperature stir 14h.Suspension after filtration and the gained solid with THF (10 milliliters) washing, at 50 ℃ of dry 5h down, obtain 5.9 gram (97%) white solid state title compounds.

¹H-NMR(D ₂O)δ7.51(2H，J＝8.2Hz)，7.19(2H，J＝8.2Hz)，3.38(2H，d，J＝11.0Hz)，3.09(2H，d，J＝2.6Hz)，2.88(2H，t，J＝12.1Hz)，?2.79(2H，t，J＝6.6Hz)，2.21(3H，s)，1.94-1.75(5H，m)，1.61-1.27(9H，m)。

Step 9.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } Cyclopentane carboxylic acid

Make to contain 1-sec.-propyl-1 CH of 3-dihydro-2H-benzimidazolyl-2 radicals-ketone (10 grams, 56.8 mmoles) and chloroformic acid 4-nitro phenyl ester (11.4 grams, 56.8 mmoles) ₂Cl ₂(150 milliliters) mixture at room temperature stirred 5 minutes.In this mixture, slowly add Et ₃N (17.4 milliliters, 125 mmoles), and at room temperature the gained mixture is made an addition to contain 1-{[4-(amino methyl) piperidines-1-yl] methyl Cyclopentane carboxylic acid 4-toluene sulfonic acide ester (23.4 the gram, 56.8 mmoles, the CH of step 8) ₂Cl ₂In (75 milliliters) mixture.Stir after 10 minutes, add Et ₃N (7.9 milliliters, 56.8 mmoles), and make the gained mixture at room temperature stir 2h.Mixture washs with the 1N HCl aqueous solution (100 milliliters).Organic layer concentrates down in 50 ℃, till about 5vol, and is replacing till about 5vol with acetone (50 milliliters * 3) under 80 ℃.In this mixture, adding H under 80 ℃ ₂O (100 milliliters), and the gained mixture concentrates down at 100 ℃.After being cooled to 50 ℃, with 20%N, the N-dimethylaminoethanol aqueous solution (100 milliliters) makes an addition in this mixture, and finds solid.The gained mixture cools off in ice-cold bath, and makes it to stir 18h under this temperature.Mixture after filtration and the gained solid with H ₂O (100 milliliters) washing 50 ℃ of following vacuum dryings, obtains 17.9 gram (71%) white solid state title compounds.

mp.166℃

PXRD(2θ(+/-0.1)：4.4，8.8，13.2，17.6)。

Embodiment 4

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } the cyclopropane carboxylic acid acid hydrochloride

Step 1.1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] the cyclopropane carboxylic acid tert-butyl acrylate

According to the program described in embodiment 3 steps 1, use cyclopropane carboxylic acid tert-butyl acrylate (J.Organomet.Chem., 1983, 252, 267-274) replace cyclopentane carboxylic acid methyl to prepare 1-(iodomethyl) cyclopropane carboxylic acid tert-butyl acrylate (comprising raw material, 3: 2 mixtures).Need not be further purified and be used for next step.

Prepare title compound with being similar to the method shown in embodiment 3 steps 2.

MS(ESI)m/z：369(M+H) ⁺。

¹H?NMR(CDCl ₃)δ4.59(1H，br?s)，2.99(2H，d，J＝5.9Hz)，2.89(2H，br?d，J＝11.5Hz)，2.57(2H，s)，2.00(2H，t，J＝11.7Hz)，1.62(2H，d，J＝12.9Hz)，1.55-1.35(1H，m)，1.44(9H，s)，1.42(9H，s)，1.30-1.15(2H，m)，1.13(2H，dd，J＝3.8Hz，6.6Hz)，0.74(2H，dd，J＝3.5Hz，6.3Hz)。

Step 2.1-{[4-(amino methyl) piperidines-1-yl] methyl } the cyclopropane carboxylic acid tert-butyl acrylate

Method prepares title compound shown in embodiment 3 steps 3 with being similar to.

MS(ESI)m/z：269(M+H) ⁺。

¹H NMR (CDCl ₃) δ 2.96 (2H, br d, J=11.5Hz), 2.60-2.50 (4H, m), 2.00 (2H, t, J=11.4Hz), 1.75-1.35 (14H, m, comprise 2H, br d, J=9.6Hz, 1.66ppm and 9H, s, 1.43ppm), 1.33-1.16 (2H, m), 1.13 (2H, dd, J=4.0Hz, 6.9Hz), 0.74 (2H, dd, J=3.8Hz, 6.6Hz).

Step 3.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } the cyclopropane carboxylic acid tert-butyl acrylate

Method prepares title compound shown in embodiment 3 steps 4 with being similar to.

MS(ESI)m/z：471(M+H) ⁺。

¹H NMR (CDCl ₃) δ 8.91 (1H, br t, J=5.5Hz), 8.32-8.20 (1H, m), 7.25-7.10 (3H, m), 4.80-4.60 (1H, m), 3.30 (2H, t, J=6.4Hz), 2.91 (2H, br d, J=11.6Hz), 2.57 (2H, s), 2.01 (2H, br t, J=9.5Hz), 1.73 (2H, brd, J=12.1Hz), 1.67-1.50 (10H, m, comprise 6H, d, J=7.0Hz, 1.56ppm), 1.43 (9H, s), 1.34-1.20 (2H, m), 1.12 (2H, dd, J=4.0Hz, 7.0Hz), 0.73 (2H, dd, J=3.9Hz, 6.8Hz).

Step 4.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } the cyclopropane carboxylic acid acid hydrochloride

Method prepares title compound shown in embodiment 1 step 7 with being similar to.

MS(ESI)m/z：415(M+H) ⁺。

m.p.：206℃。

IR(KBr)v：2936，2700，1732，1688，1556，1485，1383，1359，1182，1164，758cm ^-1。

¹H NMR (DMSO-d ₆) δ 8.86 (1H, t, J=6.3Hz), 8.07 (1H, dd, J=1.0Hz, 7.8Hz), 7.45 (1H, d, J=7.1Hz), 7.22 (1H, dt, J=1.3Hz, 7.6Hz), 7.15 (1H, dt, J=1.2Hz, 7.7Hz), 4.95-4.60 (1H, m), and 3.70-3.10 (6H, m), 3.10-2.90 (2H, m), 1.86 (3H, m comprises 2H, d, and J=11.2Hz, 1.86ppm), 1.70-1.53 (2H, m), 1.49 (6H, d, J=6.9Hz), 1.35-1.15 (4H, m).

C ₂₂H ₃₀N ₄O ₄HCl0.2H ₂The calculated value of O: C, 58.13; H, 6.96; N, 12.33. measured value: C, 57.93; H, 6.97; N, 12.18.

Embodiment 5

3-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the propionic salt hydrochlorate

Step 1.4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-carboxylic acid tert-butyl ester

At room temperature in containing 1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (J.Med.Chem.1999,42,2870-2880) (3.00 grams, 17.02 mmole) and (7.12 milliliters of triethylamines, 51.06 add 14 milliliters of tetrahydrofuran (THF)s that contain triphosgene (5.15 grams, 17.02 mmoles) in 70 milliliters of tetrahydrofuran (THF) stirred solutions mmole).Make reaction mixture refluxed 19h.Mixture is cooled to room temperature again, adds to contain 4-(amino methyl) piperidines-1-carboxylic acid tert-butyl ester (J.Prugh, L.A.Birchenough and M.S.Egbertson, Synth.Commun., 1992,22,2357-60) 10 milliliters of tetrahydrofuran (THF)s of (3.28 grams, 15.32 mmoles).The reaction mixture 24h that refluxes again.Again through cooling and with 50 milliliters of saturated NaHCO ₃Aqueous solution alkalization, and with 100 milliliters of ethyl acetate extractions three times.The extraction liquid that merges is with the salt water washing, with MgSO ₄Dry and concentrated.Residue obtains 3.99 gram (62%) colorless oil title compounds through hurried chromatography (eluent: hexane/ethyl acetate=5/1 is to 1/2).

¹H-NMR(CDCl ₃)δ：9.04-8.88(1H，m)，8.83-8.20( ¹H，m)，7.26-7.10(3H，m)，4.80-4.60( ¹H，m)，4.28-4.02(2H，m)，3.32(2H，t，J＝6.1Hz)，2.82-2.60(2H，m)，1.94-1.10(5H，m)，1.57(6H，d，J＝7.1Hz)，1.45(9H，s)。

Step 2.3-sec.-propyl-2-oxo-N-(piperidin-4-yl methyl)-2,3-dihydro-1H-benzo miaow formula-1-methane amide

Make and contain 4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) 50 milliliters of piperidines-1-carboxylic acid tert-butyl ester (3.992 gram, 9.58 mmoles) contain the methyl alcohol of 10% hydrochloric acid and the solution of 10 milliliters of concentrated hydrochloric acids at room temperature stirs 18h.Then enriched mixture and with Na ₂CO ₃Aqueous solution alkalization is with CHCl ₃(100 milliliters) extraction three times.The extraction liquid drying that merges and concentrated.Residue is through hurried chromatography (NH-silica gel, eluent: CH ₂Cl ₂/ methyl alcohol=100/1), obtains 2.272 gram (75%) colorless oil title compounds.

MS(ESI)m/z：317(M+H) ⁺。

¹H-NMR(CDCl ₃)δ：8.93( ¹H，br)，8.32-8.22( ¹H，m)，7.24-7.02(3H，m)，4.80-4.61( ¹H，m)，3.31(2H，t，J＝6.0Hz)，3.20-3.05(2H，m)，2.79-2.54(2H，m)，1.84-1.52(3H，m)，1.57(6H，d，J＝6.9Hz)，1.36-1.13(2H，m)。

Step 3.3-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the propionic acid tert-butyl ester

Make and contain 3-sec.-propyl-2-oxo-N-(piperidin-4-yl methyl)-2,3-dihydro-1H-benzoglyoxaline-1-methane amide (0.50 gram, 1.58 mmole, step 2), tert-butyl acrylate is (0.340 milliliter, 2.37 mmole) and THF (20 milliliters) the mixture backflow 18h of iPrNEt (0.275 milliliter, 2.37 mmoles).After the cooling, reaction mixture is with saturated NaHCO ₃The aqueous solution (100 milliliters) dilution is with CH ₂Cl ₂(100 milliliters) extraction three times.The extraction liquid that merges is with Na ₂SO ₄Dry, after filtration and concentrate.Residue on silicagel column with MeOH/CH ₂Cl ₂(wash-out of 1:20 → 1:10), then (1:5 → 1:2) wash-out carries out chromatography, obtains 0.111 gram (16%) colourless syrup shape title compound with the EtOAc/ hexane on NH-silica gel.

MS(ESI)m/z：445(M+H) ⁺。

¹H NMR (CDCl ₃) δ 8.94 (1H, br s), and 8.30-8.20 (1H, m), 7.25-7.11 (3H, m), 7.11-7.00 (1H, m), 4.80-4.62 (1H, m), 3.31 (2H, t, J=6.2Hz), 2.95 (2H, br t, J=11.6Hz), 2.68 (2H, t, J=7.2Hz), 2.43 (2H, t, J=7.7Hz), 2.03 (2H, br t, J=11.4Hz), 1.98-1.82 (1H, m), 1.79 (2H, d, J=12.1Hz), 1.56 (6H, d, J=7.2Hz), and 1.50-1.30 (11H, m comprise 9H, s, 1.44ppm).

Step 4.3-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the propionic salt hydrochlorate

MS(ESI)m/z：389(M+H) ⁺。

IR(KBr)v：2939，2637，1724，1682，1542，1466，1373，1217，1194，953，762cm ^-1。

¹H NMR (DMSO-d ₆) δ 8.86 (1H, t, J=5.9Hz), 8.07 (1H, dd, J=0.8Hz, 7.7Hz), 7.49 (1H, d, J=7.6Hz), 7.22 (1H, dt, J=1.3Hz, 7.6Hz), 7.15 (1H, dt, J=1.0Hz, 7.6Hz), 4.75-4.60 (1H, m), 3.70-3.10 (6H, m), 2.93 (2H, br t, J=11.2Hz), 2.85-2.70 (2H, m), 1.95-1.75 (3H, m comprise 2H, d, and J=11.5Hz, 1.87ppm), 1.65-1.40 (8H, m comprise 6H, d, and J=7.1Hz, 1.49ppm).

C ₂₀H ₂₈N ₄O ₄HCl0.8H ₂The calculated value of O: C, 54.68; H, 7.02; N, 12.75.Measured value: C, 54.67; H, 6.88; N, 12.70.

Embodiment 6

1-{[4-hydroxyl-4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } hexahydrobenzoic acid

Step 1.1-(iodomethyl) hexahydrobenzoic acid methyl esters

Prepare title compound with being similar to the method shown in embodiment 3 steps 1.

¹H?NMR(CDCl ₃)δ3.73(3H，s)，3.32(2H，s)，2.20-2.05(2H，m)，1.70-1.20(8H，m)。

Step 2.1-[(4-{[(tert-butoxycarbonyl) amino] methyl }-4-hydroxy piperidine-1-yl) methyl] the hexahydrobenzoic acid methyl esters

With being similar to the method shown in embodiment 3 steps 2, use [(4-hydroxy piperidine-4-yl) methyl] t-butyl carbamate (Chem.Pharm.Bull., 2002, 50(9) 1187-1194) and 1-(iodomethyl) hexahydrobenzoic acid methyl esters (step 1) of embodiment 6 prepares title compound.

MS(ESI)m/z：385(M+H) ⁺。

¹H NMR (CDCl ₃) δ 4.86 (1H, br s), 3.66 (3H, s), 3.11 (2H, d, J=6.3Hz), 2.55-2.45 (6H, m), 2.03 (2H, br d, J=10.4Hz), 1.70-1.15 (18H, m comprise 9H, s, 1.44ppm).

Step 3.1-{[4-(amino methyl)-4-hydroxy piperidine-1-yl] methyl } the hexahydrobenzoic acid methyl esters

Prepare title compound with being similar to the method shown in embodiment 3 steps 3.

MS(ESI)m/z：285(M+H) ⁺。

¹H?NMR(CDCl ₃)δ3.66(3H，s)，2.61(1H，br?s)，2.57-2.45(5H，m)，2.35-2.11(3H，m)，2.04(2H，br?d，J＝11.5Hz)，1.65-1.45(6H，m)，1.45-1.20(4H，m)。

Step 4.1-{[4-hydroxyl-4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } the hexahydrobenzoic acid methyl esters

Prepare title compound with being similar to the method shown in embodiment 3 steps 4.

MS(ESI)m/z：487(M+H) ⁺。

¹H?NMR(CDCl ₃)δ9.12(1H，t，J＝5.6Hz)，8.30-8.20(1H，m)，7.25-7.10(3H，m)，4.80-4.65(1H，m)，3.66(3H，s)，3.54(2H，d，J＝5.9Hz)，2.60-2.45(6H，m)，2.03(2H，br?d，J＝9.1Hz)，1.75-1.47(12H，m)，1.47-1.15(6H，m)。

Step 5.1-{[4-hydroxyl-4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } hexahydrobenzoic acid

Prepare title compound with being similar to the method shown in embodiment 3 steps 5.

MS(ESI)m/z：473(M+H) ⁺。

m.p.：184℃。

IR(KBr)v：3437，3273，2943，1732，1688，1601，1533，1479，1452，1371，1134，978，762cm ^-1。

¹H NMR (DMSO-d ₆) δ 8.94 (1H, t, J=5.6Hz), 8.09 (1H, d, J=7.7Hz), 7.43 (1H, d, J=7.7Hz), 7.22 (1H, t, J=7.8Hz), 7.14 (1H, t, J=7.4Hz), 4.75-4.58 (1H, m), 4.59 (1H, s), 2.47 (2H, s), 4.00-3.00 (6H, m), 1.86 (2H, d, J=11.4Hz), 1.60-1.10 (18H, m comprises 6H, d, and J=6.9Hz, 1.49ppm).

C ₂₅H ₃₆N ₄O ₅0.5H ₂The calculated value of O: C, 62.35; H, 7.74; N, 11.63.Measured value: C, 62.52; H, 7.70; N, 11.66.

Embodiment 7

1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } cyclobutane-carboxylic acid

Step 1.1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] the cyclobutane-carboxylic acid methyl esters

At ambient temperature, be 1-formyl radical cyclobutane-carboxylic acid methyl esters (2.13 grams, 15 mmoles, Davis, CharlesR. in containing (piperidin-4-yl methyl) t-butyl carbamate (12.8 grams, 60 mmoles); Swenson, Dale C.; Burton, Donald J., J.Org.Chem., 1993,58,6843) tetrahydrofuran (THF) add acetate (8.6 milliliters, 150 mmoles) in stirring the mixture.After 30 minutes, sodium triacetoxy borohydride (12.7 grams, 60 mmoles) is made an addition in the mixture.Then, make mixture heating up to 60 ℃ 2h.

After the cooling, pour reaction mixture into saturated NaHCO ₃In the aqueous solution.Water layer is with dichloromethane extraction three times.The organic phase that merges is with the salt water washing, with MgSO ₄Dry and concentrated.Residue carries out chromatography with hexane/ethyl acetate (1: 1) wash-out on silicagel column, obtain 4.25 gram (83%) white solid state title compounds.

MS(ESI)m/z：341(M+H ⁺)。

¹H-NMR(CDCl ₃)δ：3.69(3H，s)，2.96(2H，t，J＝6.2Hz)，2.75(2H，d，J＝11.4Hz)，2.67(2H，s)，2.37-2.46(2H，m)，1.78-2.05(6H，m)，1.45-1.65(2H，m)，1.43(9H，s)，1.09-1.21(2H，m)。

Step 2.1-{[4-(amino methyl) piperidines-1-yl] methyl } the cyclobutane-carboxylic acid methyl esters

According to program described in embodiment 3 steps 3, from the 1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] (step 1) of embodiment 7 prepares title compound to the cyclobutane-carboxylic acid methyl esters.

MS(ESI)m/z：241(M+H ⁺)。

¹H-NMR(CDCl ₃)δ：3.67(3H，s)，2.72-2.78(2H，m)，2.66(2H，s)，2.54(2H，d，J＝6.2Hz)，2.34-2.47(2H，m)，1.79-2.04(8H，m)，1.54-1.64(2H，m)，1.05-1.35(3H，m)。

Step 3.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } the cyclobutane-carboxylic acid methyl esters

According to program described in embodiment 1 step 6, by 1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and 1-[(4-{[(tertbutyloxycarbonyl) amino] methyl } piperidines-1-yl) methyl] cyclobutane-carboxylic acid methyl esters (step 2 of embodiment 7) preparation title compound.

¹H-NMR(CDCl ₃)δ：8.92-8.86(1H，m)，8.28-8.24(1H，m)，7.20-7.12(3H，m)，4.75-4.62(1H，m)，3.70(3H，s)，3.27(2H，t，J＝6.4Hz)，2.85-2.72(2H，m)，2.68(2H，s)，2.47-2.35(2H，m)，2.05-1.92(4H，?m)，1.92-1.76(2H，m)，1.71-1.61(2H，m)，1.56(6H，d，J＝7.0Hz)，1.32-1.17(2H，m)。

MS(ESI)m/z：443(M+H ⁺)。

Step 4.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } cyclobutane-carboxylic acid

According to program described in embodiment 3 steps 5, from 1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } (step 3) of embodiment 7 prepares title compound to the cyclobutane-carboxylic acid methyl esters.

IR(KBr)v：3293，2979，2937，2875，1732，1687，1610，1548，1479，1375，1298，1203，1099，761，704cm ^-1。

¹H-NMR(CDCl ₃)δ：9.02-8.95(1H，m)，8.26-8.22(1H，m)，7.22-7.12(3H，m)，4.76-4.62(1H，m)，3.33(2H，t，J＝6.2Hz)，3.10-3.00(2H，m)，2.77(2H，s)，2.58-2.48(2H，m)，2.44-2.24(2H，m)，1.92-1.79(2H，s)，1.99-1.80(5H，m)，1.56(6H，d，J＝7.0Hz)，1.50-1.33(3H，m)。

MS(ESI)m/z：429(M+H ⁺)。

C ₂₃H ₃₂N ₄O ₄Calculated value: C, 64.46; H, 7.53; N, 13.07.Measured value: C, 64.47; H, 7.43; N, 12.93.

Synthetic 1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } another path of cyclobutane-carboxylic acid is described below.

Step 5.1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] cyclobutane carboxylate

According to the program described in embodiment 1 step 10, use [inferior cyclobutyl (oxyethyl group) methoxyl group] (trimethylammonium) silane (Chem.Commun., 1971,136-137) replace [methoxyl group (tetrahydrochysene-4H-pyrans-4-subunit) methoxyl group] (trimethylammonium) silane and prepare title compound.

MS(ESI)m/z：355(M+H) ⁺。

¹H-NMR(CDCl ₃)δ：4.55(1H，br)，4.17(2H，q，J＝7.1Hz)，2.96(2H，t，J＝6.3Hz)，2.76(2H，d，J＝11.4Hz)，2.48-2.33(2H，m)，2.05-1.80(6H，m)，1.43(9H，s)，1.25(3H，q，J＝7.1Hz)，1.40-1.05(7H，m)。

Step 6.1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] cyclobutane-carboxylic acid

Contain the 1-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl] (mixture of step 5), 2N NaOH (18 milliliters) and EtOH (12 milliliters) heats 4h down at 50 ℃ to the cyclobutane carboxylate for 4.2 grams, 11.9 mmoles.Gained solution cools off in ice bath, and adds 2N HCl (about 19 milliliters) till the about 5-6 of the pH of mixture.All with CH ₂Cl ₂/ iPrOH (3: 1,30 milliliters * 3) extraction.Organic layer drying (the Na that merges ₂SO ₄) and filter.Concentrated filtrate obtains 3.8 gram (98%) yellow solid-state title compounds.

¹H?NMR(300MHz，CDCl ₃)δ4.08(1H，m)，3.20-3.10(2H，m)，3.08-2.99(2H，m)，2.91(2H，s)，2.60-2.38(4H，m)，2.35-2.16(2H，m)，2.05-1.76(6H，m)，1.65(1H，m)，1.44(9H，s)。

mp?160℃。

Step 7.1-{[4-(amino methyl) piperidines-1-yl] methyl } cyclobutane-carboxylic acid 4-toluene sulfonic acide ester

At N ₂In 500 milliliters of 3-neck round-bottomed flasks, make to contain the 1-[(4-{[(tert-butoxycarbonyl down) amino] methyl } piperidines-1-yl) methyl] (THF of step 6) (150 milliliters) mixture at room temperature stirred 10 minutes cyclobutane-carboxylic acid for 30 grams, 92 mmoles.At room temperature in this suspension, add and contain p-TsOH H ₂THF (150 milliliters) solution of O (52.4 grams, 276 mmoles).After stirring 10 minutes under this temperature, make gained solution under refluxad heat 3h.After being cooled to room temperature, when broadcasting crystal seed, the 1h inherence adds Et very lentamente ₃N (28.1 milliliters, 202 mmoles).Add Et ₃Form white depositions in the process of N.The gained white suspension at room temperature stirs 6h, after filtration and the solid of gained with THF (100 milliliters * 2) washing, at 50 ℃ of dry 5h down, obtain 35 gram (96%) white powder title compounds.

¹H-NMR(D ₂O)δ7.40(2H，d，J＝7.2Hz)，7.07(2H，d，J＝7.2Hz)，3.28-3.00(4H，m)，2.80-2.57(4H，m)，2.09(3H，s)，2.18-1.97(2H，m)，1.85-1.58(8H，m)，1.36-1.12(2H，m)。

mp：210℃。

Step 8.1-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } cyclobutane-carboxylic acid

Make to contain 1-sec.-propyl-1 CH of 3-dihydro-2H-benzimidazolyl-2 radicals-ketone (486 milligrams, 2.8 mmoles) and chloroformic acid 4-nitro phenyl ester (556 milligrams, 2.8 mmoles) ₂Cl ₂(10 milliliters) mixture at room temperature stirred 5 minutes.In this mixture, slowly add Et ₃N (0.84 milliliter, 6.1 mmoles), and this mixture becomes solution.At room temperature this solution is made an addition to and contains 1-{[4-(amino methyl) piperidines-1-yl] methyl } cyclobutane-carboxylic acid 4-toluene sulfonic acide ester (1.1 grams, 2.8 mmoles, the CH of step 7) ₂Cl ₂In (5 milliliters) mixture.Stir after 10 minutes, add Et ₃N (0.38 milliliter, 2.8 mmoles), and make the gained mixture at room temperature stir 2h.This mixture is with the 0.5N HCl aqueous solution (10 milliliters) and saturated NaHCO ₃The aqueous solution (10 milliliters) washing then concentrates organic layer.At room temperature in residue, add saturated NaHCO ₃The aqueous solution (15 milliliters) and heptane (15 milliliters), and make it under this temperature, to stir 6h.Find solid and filter this mixture.The gained solid is with H ₂O and heptane wash.Obtain the thick material of white solid state (1.0 grams, 82%) after drying.This thick material (4.0 gram) obtains 2.6 gram white solid state title compounds (66%) from toluene (36 milliliters) recrystallize purifying.

mp.173℃。

PXRD(2θ(+/-0.1)：10.8，16.9，18.9，26.5)。

Embodiment 8:

N-({ 1-(2-oxygen base carbonyl-2-methyl-propyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

Step 1.[{1-(2-benzyl oxygen base carbonyl-2-methyl-propyl) piperidin-4-yl } methyl] t-butyl carbamate

At ambient temperature, in containing (piperidin-4-yl methyl) t-butyl carbamate (38.8 grams, 181 mmoles) N, ((25.6 restrain by 3-chlorine pivalyl chloride for 14.2 grams, 124 mmoles to add 3-chlorine PIVALIC ACID CRUDE (25) benzyl ester in dinethylformamide (100 milliliters) stirred solution, 165 mmoles) and benzyl alcohol (19.6 the gram, 181 mmoles) preparation), ethyl diisopropyl amine (64.0 grams, 495 mmoles) and sodium iodide (27.1 grams, 181 mmoles).The gained mixture stirs 14h down at 120 ℃.Volatile component is removed in evaporation, and the gained residue carries out chromatography with hexane/ethyl acetate (1: 1) wash-out on silicagel column, obtains 640 milligrams (1%) faint yellow oily title compound.

MS(ESI)m/z：405(M+H ⁺)。

¹H?NMR(CDCl ₃)δ7.43-7.23(5H，m)，5.10(2H，s)，4.58(1H，brt)，2.95(2H，m)，2.71(2H，m)，2.46(2H，br?s)，2.06(2H，m)，1.57-1.36(3H，m)，1.44(9H，s)，1.12(2H，m)，1.17(6H，s)。

Step 2.N-({ 1-(2-benzyl oxygen base carbonyl-2-methyl-propyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

At room temperature in containing 1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (J.Med.Chem.1999,42,2870-2880) (411 milligrams, 2.33 mmole) and (1.00 milliliters of triethylamines, 7.17 add chloroformic acid 4-nitro phenyl ester (470 milligrams, 2.33 mmoles) during methylene dichloride mmole) (20.0 milliliters) stirs the mixture.The gained mixture at room temperature stirs 2h.In this mixture, add and contain 1-(2-benzyl oxygen base carbonyl-2-methyl-propyl)-4-amino methyl piperidine hydrochlorate { by concentrated [{ 1-(2-benzyl oxygen base carbonyl-2-methyl-propyl) piperidin-4-yl } methyl] t-butyl carbamate ((640 milligrams of step 1) of embodiment 1,1.49 mmole) and contain the mixture preparation of the MeOH (20.0 milliliters) of 10%HCl and methylene dichloride (5.00 milliliters) suspension of triethylamine (1.00 milliliters, 7.17 mmoles).The gained mixture at room temperature stirs 13h and add the 0.5M NaOH aqueous solution in mixture.Mixture is with dichloromethane extraction.Extraction liquid is with the 0.5M NaOH aqueous solution and salt water washing, with MgSO ₄Drying and vacuum concentration.Residue obtains 508 milligrams (63%) faint yellow oily title compound through preparative thin-layer chromatography method (silica gel is with methylene chloride (10: 1) wash-out) purifying.

MS(ESI)m/z：507(M+H ⁺)。

¹H NMR (CDCl ₃) δ 8.89 (1H, br t, J=5.7Hz), 8.26 (1H, m), 7.43-7.05 (8H, m), 5.10 (2H, s), 4.70 (1H, septets, J=7.0Hz), 3.26 (2H, m), 2.75 (2H, m), (2.48 2H, br s), 2.11 (2H, m), 1.61 (2H, m), 1.56 (6H, d, J=7.0Hz), 1.52 (1H, m), 1.26 (2H, m), 1.18 (6H, s).

Step 3.N-({ 1-(2-oxygen base carbonyl-2-methyl-propyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

At room temperature reach to make in the hydrogen and contain N-({ 1-(2-benzyl oxygen base carbonyl-2-methyl-propyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide (step 2 of embodiment 8) (418 milligrams, 0.825 mmole) and 20%Pd (OH) ₂Methyl alcohol (80 milliliters) mixture of/C (58.0 milligrams) stirs 12h.Filtering catalyst on Celite pad, and reduction vaporization filtrate.The gained solid is with hexane-CH ₂Cl ₂Recrystallize obtains 285 milligrams (84%) colourless solid-state title compound.

MS(ESI)m/z：417(M+H) ⁺。

¹H NMR (DMSO-d ₆) δ 8.80 (1H, br t, J=5.8Hz), 8.05 (1H, m), 7.42 (1H, m), 7.20 (1H, m), 7.12 (1H, m), 4.65 (1H, septet, J=7.0Hz), 3.20 (2H, m), 2.85 (2H, m), (2.44 2H, br s), 2.18 (2H, m), 1.61 (2H, m), 1.50 (1H, m), 1.47 (6H, d, J=7.0Hz), 1.20 (2H, m), 1.04 (6H, s).Do not find to be equivalent to the signal of carboxylic acid.

C ₂₂H ₃₂N ₄O ₄0.1H ₂The calculated value of O: C, 63.17; H, 7.76; N, 13.39.Measured value: C, 62.78; H, 7.74; N, 13.11.

Embodiment 9:

N-({ 1-(2-tetrazolium-2-methyl-propyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

Step 1.2-benzyl-alpha, alpha-alpha-dimethyl-2H-tetrazolium-5-acetate, ethyl ester

At ambient temperature in containing α, alpha-alpha-dimethyl tetrazolium-5-acetate, ethyl ester (J.Med.Chem.1996,39,2354-2366) (6.87 grams, 37.3 mmoles) and K ₂CO ₃During stirring the mixture, the acetone (200 milliliters) of (12.3 grams, 89.0 mmoles) adds bromotoluene (4.45 milliliters, 37.4 mmoles).The gained mixture stirs 18h and concentrating under reduced pressure down at 50 ℃.The gained residue carries out chromatography with hexane/ethyl acetate (10: 1) wash-out on silicagel column, obtain 6.14 gram (60%) colorless oil title compounds.

MS(ESI)m/z：275(M+H ⁺)。

¹H?NMR(CDCl ₃)δ7.45-7.23(5H，m)，5.73(2H，s)，4.11(2H，q，J＝7.2Hz)，1.70(6H，s)，1.13(3H，t，J＝7.2Hz)。

Step 2.2-benzyl-alpha, alpha-alpha-dimethyl-2H-tetrazolium-5-acetaldehyde

Under-78 ℃ in containing the 2-benzyl-alpha, alpha-alpha-dimethyl-2H-tetrazolium-5-ethyl acetate acetaldehyde (the step 1) of embodiment 9 (6.14 grams, 22.4 add DIBAL (1.0M in the toluene, 50.0 milliliters, 50.0 mmoles) during methylene dichloride mmole) (100 milliliters) stirs the mixture.The gained mixture stirs 4h down at-78 ℃.In reaction mixture, add DIBAL (1.0M in the toluene, 25.0 milliliters, 25.0 mmoles), and make the gained mixture stir 8h down at-78 ℃.In this mixture, add the 2M HCl aqueous solution (100 milliliters) and saturated NH ₄The Cl aqueous solution (20 milliliters).Separate organic layer, with dried over mgso and concentrating under reduced pressure.The gained residue carries out chromatography with hexane/ethyl acetate (10: 1) wash-out on silicagel column, obtain 3.45 gram (67%) colorless oil title compounds.

MS(ESI)m/z：231(M+H ⁺)。

¹H?NMR(CDCl ₃)δ9.68(1H，s)，7.45-7.23(5H，m)，5.74(2H，s)，1.56(6H，s)。

Step 3.[{1-(2-(2-benzyl tetrazolium)-2-methyl-propyl) piperidin-4-yl } methyl] t-butyl carbamate

In containing the 2-benzyl-alpha, alpha-alpha-dimethyl-2H-tetrazolium-5-acetaldehyde (step 2 of embodiment 9) (1.28 grams, 5.56 mmole) and in tetrahydrofuran (THF) (300 milliliters) stirred solution of (piperidin-4-yl methyl) t-butyl carbamate (2.40 grams, 11.2 mmoles) add NaBH (OAc) ₃(5.90 grams, 27.8 mmoles) and AcOH (1.67 grams, 27.8 mmoles).The gained mixture stirs 9 hours and concentrating under reduced pressure down at 60 ℃.In oil residues that stirs and solid, add saturated NaHCO ₃The aqueous solution and methylene dichloride.Separate organic layer, with dried over mgso and concentrating under reduced pressure.The gained residue carries out chromatography with hexane/ethyl acetate (1: 1) wash-out on silicagel column, obtain 830 milligrams of (35%) colorless oil title compounds.

MS(ESI)m/z：429(M+H) ⁺。

¹H?NMR(CDCl ₃)δ7.43-7.23(5H，m)，5.72(2H，s)，4.50(1H，brt)，2.91(2H，m)，2.58(2H，br?s)，2.49(2H，m)，2.05(2H，m)，1.68-1.14(3H，m)，1.44(9H，s)，1.38(6H，s)，1.00(2H，m)。

Step 4.N-({ 1-(2-(2-benzyl tetrazolium)-2-methyl-propyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

According to program described in embodiment 8 steps 2, from 1-sec.-propyl-1, (step 3) of embodiment 9 prepares title compound to t-butyl carbamate for 3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [{ 1-(2-(2-benzyl tetrazolium)-2-methyl-propyl) piperidin-4-yl } methyl].

MS(ESI)m/z：531(M+H ⁺)。

¹H NMR (CDCl ₃) δ 8.86 (1H, br t, J=5.7Hz), 8.26 (1H, m), 7.43-7.08 (8H, m), 5.72 (2H, s), 4.70 (1H, septet, J=7.0Hz), 3.21 (2H, m), 2.59 (2H, br s), 2.51 (2H, m), 2.07 (2H, m), 1.65-1.32 (3H, m), 1.56 (6H, d, J=7.0Hz), 1.38 (6H, s), 1.10 (2H, m).

Step 5.N-({ 1-(2-methyl-2-tetrazolium propyl group) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

According to program described in embodiment 8 steps 3, from N-({ 1-(2-(2-benzyl tetrazolium)-2-methyl-propyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2, the 3-dihydro-(step 4) of embodiment 9 prepares title compound to 1H-benzoglyoxaline-1-methane amide.

MS(ESI)m/z：441(M+H) ⁺。

¹H NMR (DMSO-d ₆) δ 8.77 (1H, br t, J=5.9Hz), 8.04 (1H, m), 7.40 (1H, m), 7.18 (1H, m), 7.11 (1H, m), 4.63 (1H, septet, J=7.0Hz), 3.15 (2H, m), (2.54 2H, br s), 2.43 (2H, m), 2.10 (2H, m), and 1.60-1.25 (3H, m), 1.45 (6H, d, J=7.0Hz), 1.32 (6H, s), 1.14 (2H, m).Do not find to be equivalent to the signal of tetrazolium.

C ₂₂H ₃₂N ₈O ₄0.95H ₂The calculated value of O: C, 57.74; H, 7.47; N, 24.48.Measured value: C, 58.03; H, 7.43; N, 24.10.

Embodiment 10:

N-({ 1-(2-cyclopentyl-2-tetrazolium ethyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

Step 1. α-cyclopentyl tetrazolium-5-acetate, ethyl ester

At ambient temperature in contain 1-cyano group-1-Cyclopentane carboxylic acid ethyl ester (Bioorg.Med.Chem.Lett.1999,9,369-374) 1 of (6.19 gram, 37.0 mmoles), 4-two

Add in alkane (100 milliliters) stirred solution ⁿBu ₃SnN ₃(12.3 grams, 37.0 mmoles).Gained mixture backflow 15h and concentrating under reduced pressure.Interpolation contains 1 of 4M HCl in the gained residue, and 4-two

Alkane (50 milliliters), and concentrating under reduced pressure.Gained oily matter obtains the crude product of yellow oily title compound with the hexane wash secondary, and it is not further purified and is used for next step.

Step 2.2-benzyl-alpha-cyclopentyl-2H-tetrazolium-5-acetate, ethyl ester

According to program described in the step 1 of embodiment 9, from α-cyclopentyl tetrazolium-5-acetate, (step 1) of embodiment 10 prepares title compound to ethyl ester.

MS(ESI)m/z：301(M+H ⁺)。

¹H?NMR(CDCl ₃)δ7.45-7.23(5H，m)，5.73(2H，s)，4.11(2H，q，J＝7.1Hz)，2.55-2.35(4H，m)，1.88-1.56(4H，m)，1.12(3H，t，J＝7.1Hz)。

Step 3.2-benzyl-alpha-cyclopentyl-2H-tetrazolium-5-acetaldehyde

According to program described in the step 2 of embodiment 9, from 2-benzyl-alpha-cyclopentyl-2H-tetrazolium-5-acetate, ethyl ester (step 2 of embodiment 10) preparation title compound.

MS(ESI)m/z：257(M+H ⁺)。

¹H?NMR(CDCl ₃)δ9.71(1H，s)，7.50-7.30(5H，m)，5.74(2H，s)，2.45-2.18(4H，m)，1.85-1.66(4H，m)。

Step 4.[{1-(2-(2-benzyl tetrazolium)-2-cyclopentyl ethyl) piperidin-4-yl } methyl] t-butyl carbamate

According to program described in the step 3 of embodiment 9, from 2-benzyl-alpha-cyclopentyl-(step 3) of embodiment 10 prepares title compound to 2H-tetrazolium-5-acetaldehyde.

MS(ESI)m/z：455(M+H) ⁺。

¹H?NMR(CDCl ₃)δ7.43-7.23(5H，m)，5.72(2H，s)，4.67(1H，brt)，2.88(2H，m)，2.66(2H，br?s)，2.48(2H，m)，2.24(2H，m)，1.93(2H，m)，1.83(2H，m)，1.78-1.48(4H，m)，1.43(9H，s)，1.37(2H，m)，1.23(1H，m)，0.94(2H，m)。

Step 5.N-(1-(2-benzyl tetrazolium)-2-cyclopentyl ethyl) and piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

According to program described in the step 2 of embodiment 8, from 1-sec.-propyl-1, (step 4) of embodiment 10 prepares title compound to t-butyl carbamate for 3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [{ 1-(2-(2-benzyl tetrazolium)-2-cyclopentyl ethyl) piperidin-4-yl } methyl].

MS(ESI)m/z：557(M+H ⁺)。

¹H NMR (CDCl ₃) δ 8.85 (1H, br t, J=5.5Hz), 8.26 (1H, m), 7.43-7.08 (8H, m), 5.73 (2H, s), 4.70 (1H, septet, J=7.0Hz), 3.19 (2H, m), 2.70 (2H, br s), 2.53 (2H, m), 2.25 (2H, m), and 2.15-1.35 (11H, m), 1.56 (6H, d, J=7.0Hz), 1.07 (2H, m).

Step 6.N-({ 1-(2-cyclopentyl-2-tetrazolium ethyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

According to program described in the step 3 of embodiment 8, from N-({ 1-(2-benzyl tetrazolium)-2-cyclopentyl ethyl } piperidin-4-yl) methyl)-3-sec.-propyl-2-oxo-2, the 3-dihydro-(step 5) of embodiment 10 prepares title compound to 1H-benzoglyoxaline-1-methane amide.

MS(ESI)m/z：467(M+H) ⁺。

¹H NMR (DMSO-d ₆) δ 8.76 (1H, br t, J=5.9Hz), 8.04 (1H, m), 7.40 (1H, m), 7.18 (1H, m), 7.11 (1H, m), 4.64 (1H, septet, J=7.0Hz), 3.14 (2H, m), (2.63 2H, br s), 2.54 (2H, m), 2.08 (2H, m), 2.00 (2H, m), 1.76 (2H, m), 1.68-0.96 (9H, m), 1.46 (6H, d, J=7.0Hz).Do not find to be equivalent to the signal of tetrazolium.

C ₂₄H ₃₄N ₈O ₄1.0H ₂O0.5CH ₂Cl ₂Calculated value: C, 55.83; H, 7.08; N, 21.26.Measured value: C, 55.71; H, 7.48; N, 20.86.

Embodiment 11:

N-({ 1-(2-cyclohexyl-2-tetrazolium ethyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

Step 1. α-cyclohexyl tetrazolium-5-acetate, ethyl ester

According to program described in the step 1 of embodiment 10, from 1-cyano group-1-hexahydrobenzoic acid, ethyl ester (Bioorg.Med.Chem.Left.1999,9,369-374) preparation title compound.

Step 2.2-benzyl-alpha-cyclohexyl-2H-tetrazolium-5-acetate, ethyl ester

According to program described in the step 1 of embodiment 9, from α-cyclohexyl tetrazolium-5-acetate, (step 1) of embodiment 11 prepares title compound to ethyl ester.

MS(ESI)m/z：315(M+H ⁺)。

¹H?NMR(CDCl ₃)δ7.45-7.23(5H，m)，5.75(2H，s)，4.11(2H，q，J＝7.1Hz)，2.36-2.16(4H，m)，1.70-1.44(6H，m)，1.12(3H，t，J＝7.1Hz)。

Step 3.2-benzyl-alpha-cyclohexyl-2H-tetrazolium-5-acetaldehyde

According to program described in the step 2 of embodiment 9, from 2-benzyl-alpha-cyclohexyl-2H-tetrazolium-5-acetate, ethyl ester (step 2 of embodiment 11) preparation title compound.

MS(ESI)m/z：271(M+H ⁺)。

¹H?NMR(CDCl ₃)δ9.55(1H，s)，7.45-7.25(5H，m)，5.75(2H，s)，2.34-2.16(2H，m)，2.14-1.94(2H，m)，1.70-1.32(6H，m)。

Step 4.[{1-(2-(2-benzyl tetrazolium)-2-cyclohexyl ethyl) piperidin-4-yl } methyl] t-butyl carbamate

According to program described in the step 3 of embodiment 9, from 2-benzyl-alpha-cyclohexyl-(step 3) of embodiment 11 prepares title compound to 2H-tetrazolium-5-acetaldehyde.

MS(ESI)m/z：469(M+H) ⁺。

¹H?NMR(CDCl ₃)δ7.43-7.23(5H，m)，5.74(2H，s)，4.55(1H，brt)，2.87(2H，m)，2.62-1.05(17H，m)，2.49(2H，br?s)，1.43(9H，s)，0.93?(2H，m)。

Step 5.N-({ 1-(2-(2-benzyl tetrazolium)-2-cyclohexyl ethyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

According to program described in the step 2 of embodiment 8, from 1-sec.-propyl-1, (step 4) of embodiment 11 prepares title compound to t-butyl carbamate for 3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [{ 1-(2-(2-benzyl tetrazolium)-2-cyclohexyl ethyl) piperidin-4-yl } methyl].

MS(ESI)m/z：571(M+H ⁺)。

¹H NMR (CDCl ₃) δ 8.86 (1H, br t, J=5.7Hz), 8.26 (1H, m), 7.43-7.08 (8H, m), 5.73 (2H, s), 4.70 (1H, septet, J=7.0Hz), 3.18 (2H, m), 2.51 (2H, br s), 2.45-1.15 (17H, m), 1.56 (6H, d, J=7.0Hz), 1.04 (2H, m).

Step 6.N-({ 1-(2-cyclohexyl-2-tetrazolium ethyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

According to program described in the step 3 of embodiment 8, from N-({ 1-(2-(2-benzyl tetrazolium)-2-cyclohexyl ethyl) piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2, the 3-dihydro-(step 5) of embodiment 11 prepares title compound to 1H-benzoglyoxaline-1-methane amide.

MS(ESI)m/z：481(M+H) ⁺。

¹H NMR (DMSO-d ₆) δ 8.76 (1H, br t, J=5.9Hz), 8.04 (1H, m), 7.41 (1H, m), 7.18 (1H, m), 7.12 (1H, m), 4.64 (1H, septet, J=7.0Hz), 3.14 (2H, m), 2.38 (2H, br s), 2.33-2.10 (4H, m), 1.98 (2H, m), 1.65-0.96 (13H, m), 1.46 (6H, d, J=7.0Hz).Do not find to be equivalent to the signal of tetrazolium.

Embodiment 12:

1-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the hexahydrobenzoic acid hydrochloride

Step 1.1-(4-oxo-piperidine-1-yl) the hexahydrobenzoic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 3, use 1-aminocyclohexane carboxylic acid tert-butyl ester people such as (, J.Chem.Soc. .1965,6239,6243) Kenner preparation title compound.

MS(ESI)m/z：282(M+H ⁺)。

¹H-NMR(CDCl ₃)δ：2.92(4H，t，J＝5.9Hz)，2.41(4H，t，J＝6.0Hz)，2.01-1.89(2H，m)，1.76-1.62(4H，m)，1.45(9H，s)，1.53-1.33(4H，m)。

Step 2.1-(4-cyano group piperidines-1-yl) the hexahydrobenzoic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 4, use 1-(4-oxo-piperidine-1-yl) the hexahydrobenzoic acid tert-butyl ester to prepare title compound.

MS(ESI)m/z：293(M+H ⁺)。

¹H-NMR(CDCl ₃)δ：2.94-2.85(2H，m)，2.67-2.56(1H，m)，2.55-2.42(2H，m)，1.96-1.72(6H，m)，1.70-1.23(8H，m)，1.48(9H，s)。

Step 3.1-[4-(amino methyl) piperidines-1-yl] the hexahydrobenzoic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 5, use 1-(4-cyano group piperidines-1-yl) the hexahydrobenzoic acid tert-butyl ester to prepare title compound.

¹H-NMR(CDCl ₃)δ：3.07-3.18(2H，m)，2.55(2H，d，J＝6.4Hz)，2.15-1.94(4H，m)，1.47(9H，s)，1.76-1.19(13H，m)，1.19-1.03(2H，m)。

MS(ESI)m/z：297(M+H ⁺)。

Step 4.1-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the hexahydrobenzoic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 6, use 1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and 1-(4-cyano group piperidines-1-yl) the hexahydrobenzoic acid tert-butyl ester prepares title compound.

¹H-NMR(CDCl3)δ：8.97-8.86(1H，m)，8.29-8.24(1H，m)，7.21-7.11(3H，m)，4.78-4.64(1H，m)，3.29(2H，t，J＝6.2Hz)，3.19-3.09(2H，m)，2.16-2.05(2H，m)，2.04-1.93(2H，m)，1.83-1.73(2H，m)，1.56(6H，d，J＝7.0Hz)，1.46(9H，s)，1.70-1.39(2H，m)，1.38-1.16(7H，m)。

MS(ESI)m/z：499(M+H ⁺)。

Step 5.1-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the hexahydrobenzoic acid hydrochloride

At room temperature in containing 1-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] (400 milligrams of the hexahydrobenzoic acid tert-butyl esters, 0.802 add trifluoroacetic acid (5 milliliters, 65.2 mmoles) in methylene dichloride mmole) (5 milliliters) stirred solution.Behind the 12h, volatile component is removed in decompression.In residue, add and contain two of 4N HCl

Alkane (5.0 milliliters), and stirred 10 minutes.Then, volatile matter is removed in decompression.Residue precipitates in diethyl ether/ethanol, obtains 370 milligrams of colourless powder shape title compounds.

¹H-NMR(DMSO-d ₆)δ：8.94-8.82(1H，m)，7.45(1H，d，J＝7.9Hz)，7.27-7.10(2H，m)，4.73-4.61(1H，m)，3.71-3.19(7H，m)，2.98-2.81(2H，m)，2.38-2.26(2H，m)，1.98-1.53(10H，m)，1.49(6H，d，J＝7.0Hz)，1.38-1.03(2H，m)。

MS(ESI)m/z：443(M+H ⁺)。

C ₂₄H ₃₅N ₄O ₄2H ₂The calculated value of O: C, 55.97; H, 7.63; N, 10.88.Measured value C, 55.61; H, 7.51; N, 10.48.

Embodiment 13:

2-ethyl-2-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } butyric acid

Step 1.2-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl]-the 2 Ethylbutanoic acid methyl esters

With the method shown in the step 1 that is similar to embodiment 7, use 2-ethyl-2-formyl radical methyl-butyrate (Okano, K.; Morimoto, T.; Sekiya, M.Journal of theChemical Society, Chemical Communications, 1985,3,119) the preparation title compound.

¹H-NMR(CDCl ₃)δ：4.62-4.48(1H，br)，3.65(3H，s)，3.01-2.93(2H，m)，2.73-2.65(2H，m)，2.46(2H，s)，2.13-2.02(2H，m)，1.73-1.50(6H，m)，1.44(9H，s)，1.28-1.10(3H，m)，0.76(6H，t，J＝7.5Hz)。

MS(ESI)m/z：357(M+H ⁺)。

Step 2.2-ethyl-2-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } methyl-butyrate

According to program described in the step 2 of embodiment 8, from 1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and 2-[(4-{[(tert-butoxycarbonyl) amino] methyl } piperidines-1-yl) methyl]-(step 1) of embodiment 13 prepares title compound to the 2 Ethylbutanoic acid methyl esters.

¹H-NMR(CDCl ₃)δ：8.92-8.86(1H，m)，8.28-8.23(1H，m)，7.20-7.12(3H，m)，4.77-4.61(1H，m)，3.65(3H，s)，3.27(2H，t，J＝6.4Hz)，2.75-2.66(2H，m)，2.47(2H，s)，2.16-2.05(2H，m)，1.72-1.49(10H，m)，1.38-1.21(5H，m)，0.76(6H，d，J＝7.5Hz)。

MS(ESI)m/z：459(M+H ⁺)。

Step 3.2-ethyl-2-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } butyric acid

According to program described in the step 5 of embodiment 3, from 2-ethyl-2-{[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] methyl } (step 3) of embodiment 13 prepares title compound to methyl-butyrate.

¹H-NMR(CDCl ₃)δ：8.03-8.94(1H，m)，8.27-8.21(1H，m)，7.20-7.12(3H，m)，4.76-4.63(1H，m)，3.34(2H，t，J＝6.2Hz)，3.16-3.05(2H，m)，2.60(2H，s)，2.55-2.38(2H，m)，1.94-1.38(2H，m)，1.80-1.38?(15H，m)，0.88(6H，d，J＝7.5Hz)。

MS(ESI)m/z：445(M+H ⁺)。

C ₂₄H ₃₇N ₄O ₄Cl0.2H ₂The calculated value of O: 59.48; H, 7.78; N, 11.56.Measured value: C, 59.38; H, 7.74; N, 11.29.

Embodiment 14:

1-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the Cyclopentane carboxylic acid hydrochloride

Step 1.1-(4-oxo-piperidine-1-yl) the Cyclopentane carboxylic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 3, use the 1-aminocyclopentanecarboxylic acid tert-butyl ester (WO 9105796) preparation title compound.

MS(ESI)m/z：268(M+H ⁺)。

¹H-NMR(CDCl ₃)δ：2.93(4H，t，J＝5.9Hz)，2.41(4H，t，J＝6.0Hz)，2.39-2.26(2H，m)，1.85-1.54(8H，m)，1.46(9H，s)。

Step 2.1-(4-cyano group piperidines-1-yl) the Cyclopentane carboxylic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 4, use 1-(4-oxo-piperidine-1-yl) the Cyclopentane carboxylic acid tert-butyl ester to prepare title compound.

MS(ESI)m/z：279(M+H ⁺)。

¹H-NMR(CDCl ₃)δ：2.94-2.82(2H，m)，2.67-2.49(3H，m)，2.33-2.21(2H，m)，1.96-1.72(5H，m)，1.70-1.40(6H，m)，1.48(9H，s)。

Step 3.1-[4-(amino methyl) piperidines-1-yl] the Cyclopentane carboxylic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 5, use 1-(4-cyano group piperidines-1-yl) the Cyclopentane carboxylic acid tert-butyl ester to prepare title compound.

¹H-NMR(CDCl ₃)δ：3.07-2.95(2H，m)，2.60-2.52(2H，m)，2.41-1.19(4H，m)，1.76-1.62(4H，m)，1.61-1.40(12H，m)，1.19-1.03(2?H，m)。

MS(ESI)m/z：283(M+H ⁺)。

Step 4.1-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the Cyclopentane carboxylic acid tert-butyl ester

With being similar to the method shown in embodiment 1 step 6, using 1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and 1-[4-(amino methyl) piperidines-1-yl] the Cyclopentane carboxylic acid tert-butyl ester prepares title compound.

¹H-NMR(CDCl ₃)δ：8.96-8.84(1H，m)，8.29-8.22(1H，m)，7.21-7.11(3H，m)，4.77-4.56(1H，m)，3.29(2H，t，J＝6.2Hz)，3.07-2.94(2H，m)，2.37-2.17(4H，m)，1.82-1.63(6H，m)，1.56(6H，d，J＝7.1Hz)，1.46(9H，s)，1.61-1.49(2H，m)，1.38-1.16(3H，m)。

MS(ESI)m/z：485(M+H ⁺)。

Step 5.1-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the Cyclopentane carboxylic acid hydrochloride

With method shown in the step 5 that is similar to embodiment 12, using 1-[4-({ [(3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-yl) carbonyl] amino } methyl) piperidines-1-yl] the Cyclopentane carboxylic acid tert-butyl ester prepares title compound.

¹H-NMR(DMSO-d ₆)δ：8.91-8.82(1H，m)，8.07(1H，d，J＝7.5Hz)，7.45(1H，d，J＝7.7Hz)，7.26-7.09(2H，m)，4.74-4.56(1H，m)，3.60-3.00(6H，m)，2.26-2.10(4H，m)，1.96-1.57(9H，m)，1.49(6H，d，J＝7.0Hz)。

MS(ESI)m/z：429(M+H ⁺)。

C ₂₃H ₃₃N ₄O ₄The calculated value of Cl: C, 59.41; H, 7.15; N, 12.05.Measured value: C, 59.14; H, 7.22; N, 11.82.

Embodiment 15:

N-(1-[(4-oxygen base carbonyl tetrahydrochysene-2H-pyrans-4-yl) methyl]-4-fluorine piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

Step 1. tetrahydropyran-4-base-benzyl carboxylate

Make and contain tetrahydropyran-4-base-carboxylic acid (910 milligrams, 6.99 mmoles) and SOCl ₂The mixture of (5.0 milliliters) stirs 1h down at 60 ℃, and vacuum concentration.In residue, add benzyl alcohol (1.52 grams, 14.1 mmoles) and tetrahydrofuran (THF) (5.0 milliliters) at ambient temperature.Make the gained mixture stir 13h at ambient temperature, and vacuum concentration.Residue obtains 1.08 gram (70%) faint yellow oily title compounds through preparative thin layer chromatography (silica gel is with hexane/ethyl acetate (2: 1) wash-out) purifying.

¹H?NMR(CDCl ₃)δ7.45-7.25(5H，m)，5.13(2H，s)，3.95(2H，m)，3.42(2H，m)，2.59(1H，m)，1.94-1.68(4H，m)。

Step 2.4-iodomethyl tetrahydropyran-4-base-benzyl carboxylate

According to program described in the step 1 of embodiment 3, (step 1) of embodiment 15 prepares title compound from tetrahydropyran-4-base-benzyl carboxylate.

¹H?NMR(CDCl ₃)δ7.45-7.25(5H，m)，5.19(2H，s)，3.80(2H，m)，3.47(2H，m)，3.31(2H，s)，2.18(2H，m)，1.56(2H，m)。

Step 3.N-benzoyl-4-tert-butoxycarbonyl amino methyl-4-fluorine piperidines

Make and contain N-benzoyl-4-amino methyl-4-fluorine piperidines (J.Med.Chem.1999; 42,1648-1660) (3.54 grams, 15.0 mmoles) and tert-Butyl dicarbonate (4.91 grams; 22.5 mixture at room temperature stirs 15h to methyl alcohol mmole) (80 milliliters), and vacuum concentration.The gained residue carries out chromatography with hexane/ethyl acetate (1: 1) wash-out on silicagel column, obtain 4.52 gram (89%) colorless oil title compounds.

MS(ESI)m/z：337(M+H) ⁺。

¹H?NMR(CDCl ₃)δ7.55-7.25(5H，m)，5.16(1H，br?t，J＝6.3Hz)，4.51(1H，m)，3.62(1H，m)，3.55-3.00(4H，m)，2.10-1.25(4H，m)，1.43(9H，s)。

Step 4.4-tert-butoxycarbonyl amino methyl-4-fluorine piperidines

Make and contain N-benzoyl-4-tert-butoxycarbonyl amino methyl-4-fluorine piperidines (step 3) of embodiment 15 (4.42 grams, 13.1 mmoles), NaOH (2.62 grams, 65.5 mmoles), H ₂The mixture backflow 15h of O (9.00 milliliters) and ethanol (90.0 milliliters), and vacuum concentration.In the gained residue, add water and chloroform.Separate organic layer, with dried over mgso and concentrating under reduced pressure.The gained solid is with hexane-CH ₂Cl ₂Recrystallize obtains 1.77 gram (58%) colourless solid-state title compounds.

MS(ESI)m/z：233(M+H) ⁺。

¹H NMR (CDCl ₃) δ 4.93 (1H, m), 3.30 (2H, dd, J=21.5,6.3Hz), 2.91 (4H, m), (4H, m), 1.45 (9H s), finds to be equivalent to amino signal to 1.88-1.34.

Step 5. (1-[(4-benzyl oxygen base carbonyl tetrahydrochysene-2H-pyrans-4-yl) methyl]-4-fluorine piperidin-4-yl } methyl) t-butyl carbamate

According to program described in the step 2 of embodiment 3, from 4-tert-butoxycarbonyl amino methyl-4-fluorine piperidines (step 4) of embodiment 15 and 4-iodomethyl tetrahydropyran-4-base-benzyl carboxylate (step 2 of embodiment 15) preparation title compound.

MS(ESI)m/z：465(M+H) ⁺。

¹H?NMR(CDCl ₃)δ7.45-7.25(5H，m)，5.16(2H，s)，4.78(1H，brt)，3.80(2H，m)，3.46(2H，m)，3.23(2H，dd，J＝21.9，6.3Hz)，2.64-2.32(4H，m)，2.52(2H，s)，2.08(2H，m)，1.90-1.35(6H，m)，1.45(9H，s)。

Step 6.N-(1-[(4-benzyl oxygen base carbonyl tetrahydrochysene-2H-pyrans-4-yl) methyl]-4-fluorine piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

According to program described in the step 6 of embodiment 1, from 1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and ({ 1-[(4-benzyl oxygen base carbonyl tetrahydrochysene-2H-pyrans-4-yl) methyl]-4-fluorine piperidin-4-yl } methyl) (step 5) of embodiment 15 prepares title compound to t-butyl carbamate.

MS(ESI)m/z：567(M+H ⁺)。

¹H NMR (CDCl ₃) δ 9.08 (1H, br t, J=6.0Hz), 8.25 (1H, m), 7.46-7.06 (8H, m), 5.16 (2H, s), 4.71 (1H, septets, J=7.0Hz), 3.80 (2H, m), 3.54 (2H, dd, J=20.9,6.0Hz), 3.46 (2H, m), 2.65-2.36 (4H, m), 2.53 (2H, br s), 2.08 (2H, m), 1.88-1.44 (6H, m), 1.56 (6H, d, J=7.0 Hz).

Step 7.N-(1-[(4-oxygen base carbonyl tetrahydrochysene-2H-pyrans-4-yl) methyl]-4-fluorine piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2,3-dihydro-1H-benzoglyoxaline-1-methane amide

According to program described in the step 3 of embodiment 1, from N-({ 1-[(4-benzyl oxygen base carbonyl tetrahydrochysene-2H-pyrans-4-yl) methyl]-4-fluorine piperidin-4-yl } methyl)-3-sec.-propyl-2-oxo-2, the 3-dihydro-(step 6) of embodiment 15 prepares title compound to 1H-benzoglyoxaline-1-methane amide.

MS(ESI)m/z：477(M+H) ⁺。

¹H NMR (CD ₃OD) δ 7.93 (1H, m), 7.12 (1H, m), 7.02 (1H, m), 6.93 (1H, m), 4.49 (1H, septet, J=7.0Hz), 3.65-3.36 (6H, m), 3.15-2.82 (4H, m), 2.80 (2H, br s), 1.98-1.70 (6H, m), 1.35 (6H, d, J=7.0Hz), 1.34 (2H, m).Do not find to be equivalent to the signal of acid amides and carboxylic acid.

All publications, include, but is not limited among the application to be quoted issue patent, patent application and journal article each to incorporate this paper in full into it for reference.

Though above described the present invention with reference to disclosed embodiment, it only is of the present invention illustrating that those skilled in the art can understand detailed particular experiment easily.Should be appreciated that, can carry out various improvement under the spirit of the present invention not departing from.Therefore, only limit the present invention with following claim.

Claims

1. the compound of following formula,

Or its pharmacy acceptable salt, wherein:

A is the alkylidene group with 1 to 2 carbon atom, and this alkylidene group is selected from the alkyl with 1 to 3 carbon atom by 2 and replaces, and wherein said 2 substituting groups can form optional 3-to the 6-unit ring that contains an O atom with the carbon atom that they connected;

R ¹Be sec.-propyl;

R ²Be hydrogen atom or hydroxyl;

R ³Be carboxyl or tetrazyl; And

M is an integer 2.

2. according to the compound of claim 1, or its pharmacy acceptable salt, wherein

R ²Be hydrogen atom; And

Described 2 substituting groups are together with substituting group.

3. according to the compound of claim 1, or its pharmacy acceptable salt, wherein

R ¹Be sec.-propyl;

R ²Be hydrogen atom;

R ³Be carboxyl or tetrazyl;

A is

And

M is an integer 2.

4. according to the compound of claim 1, this compound is selected from:

Or its pharmacy acceptable salt.

5. pharmaceutical composition, it comprises according to each compound or its pharmacy acceptable salt in the claim 1 to 4, and pharmaceutically acceptable carrier.