CN101208010A

CN101208010A - Beta-lactamylalkanoic acids for treating premenstrual disorders

Info

Publication number: CN101208010A
Application number: CNA2006800177912A
Authority: CN
Inventors: G·科佩尔; M·米勒
Original assignee: Azevan Pharmaceuticals Inc
Current assignee: Azevan Pharmaceuticals Inc
Priority date: 2005-03-22
Filing date: 2006-03-21
Publication date: 2008-06-25

Abstract

Beta-lactamyl alkanoic acids are described. Methods for treating various premenstrual disorders using or more beta-lactamyl alkanoic acids are also described.

Description

β-Nei acylamino-the alkanoic acid that is used for the treatment of the preceding illness of menstruation

The cross reference of related application

Ask sequence number 60/664 in the interim patent of the U.S. of the application's requirement according to 35 U.S.C. § 119 (e) protection submission on March 22nd, 2005; the U.S. Provisional Patent Application sequence number 60/700 that on July 19th, 239 and 2005 submitted to; 673 rights and interests, the content of these patent disclosures all is combined in herein by reference.

Technical field

The 2-that the present invention relates to replace (azetidine-2-ketone-1-yl) alkanoic acid and derivative thereof.The invention still further relates to the method for the preceding illness of treatment menstruation.Particularly, the present invention relates to β-Nei acylamino-vasopressin antagonists purposes in the illness before the treatment menstruation.

Technical background

Arginine vasopressin (AVP) is for resulting from hypothalamic neurohypophysis neuropeptide, and participated in the many biological processes in the circulatory system, peripheral neverous system (PNS) and the central nervous system (CNS).Particularly, AVP in brain as neurotransmitter.Identify vasopressins receptor subtype important on several pharmacology, comprised vasopressins V _1a, V _1bAnd V ₂The pain tolerance that these vasopressins acceptors relate to multiple spirit, psychology and behavior disease state (comprising depression, anxiety, the disturbance of emotion and stress reaction) and non-opium is mediated.The vasopressins acceptor also relates to many metabolic processes and comprises water metabolism homoiostasis, renal function, cardiovascular function mediation and mammiferous body heat regulation.

Structural modification to vasopressins provides many vasopressin agonists (referring to Sawyer, Pharmacol.Reviews, 13:255 (1961)).In addition, the vasopressins peptide antagonists of several effective as selective is disclosed (referring to Lazslo etc., Pharmacological Reviews, 43:73-108 (1991); Mah and Hofbauer, Drugsof the Future, 12:1055-1070 (1987); Manning and Sawyer, Trends inNeuroscience, 7:8-9 (1984)).In addition, the non-peptidyl vasopressin antagonists of new structure type is disclosed (referring to Yamamura etc., Science, 275:572-574 (1991); Serradiel-Le Gal etc., Journal of Clinical Investigation, 92:224-231 (1993); Serradiel-Le Gal etc., Biochemical Pharmacology, 47 (4): 633-641 (1994)).Finally, the 2-of the replacement of known common structure type (azetidine-2-ketone-1-yl) acetic acid esters and acetamide are as the synthetic intermediate (referring to United States Patent (USP) 4,751,299) of preparation beta-Lactam antibiotic.

Summary of the invention

Introduced the method for the preceding illness of treatment menstruation in the literary composition.In an illustrative embodiment, illness is primary dysmenorrhea (PD) before the described menstruation.In another illustrative embodiment, illness is a dysmenorrhoea anxiety (PMDD) before the menstruation before the described menstruation.Method described in the literary composition comprise need illness before the relief of menstrual (as PD, PMDD and/or with follow these menstruations before the relevant illness of dysfunction) the step of one or more β of female patient-Nei acylamino-vasopressin antagonists (comprising β described in the literary composition-Nei acylamino-alkanoic acid).

In the illustrative embodiment of described method, give one or more following formula: compounds of patient and pharmaceutically acceptable salt thereof in the text:

Wherein

A is carboxylic acid, ester or acid amides;

B is carboxylic acid or its ester or its amide derivatives; Perhaps B is alcohol or mercaptan, or derivatives thereof;

R ¹Be hydrogen or C ₁-C ₆Alkyl;

R ²For hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, halogen, haloalkyl, cyano group, formoxyl, alkyl-carbonyl or be selected from-CO ₂R ⁸,-CONR ⁸R ⁸' and-NR ⁸(COR ⁹) substituting group; R wherein ⁸And R ⁸' be selected from hydrogen, alkyl, cycloalkyl, the optional aryl that replaces independently of one another or choose the aryl alkyl that replaces wantonly; Or R ⁸And R ⁸' connected nitrogen-atoms forms heterocyclic group together; And R wherein ⁹Be selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, the optional aryl that replaces, the optional aryl alkyl that replaces, the optional heteroaryl that replaces, optional heteroaryl alkyl and the R that replaces ⁸R ⁸' N-(C ₁-C ₄Alkyl);

R ³Be optional amino, carbamoyl (amido), acyl amino formoxyl (acylamido) or the urea groups that replaces; Or R ³Be the nitrogenous heterocyclic group that connects by nitrogen-atoms; With

R ⁴Be alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, alkyl-carbonyl, the optional aryl that replaces, the optional aryl alkyl that replaces, the optional aryl halide substituted alkyl that replaces, the optional alkoxy aryl alkyl that replaces, the optional aryl alkenyl that replaces, the optional aryl haloalkenyl group that replaces or the optional aromatic yl polysulfide yl that replaces.

In another illustrative embodiment of described method, give one or more formulas of patient (I) compound and pharmaceutically acceptable salt thereof in the text:

Wherein

A and A ' are selected from-CO independently of one another ₂H or its ester or its amide derivatives;

N is selected from 0 to about 3 integer;

R ¹Be hydrogen or C ₁-C ₆Alkyl;

R ²For hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl, alkylthio group, halogen, haloalkyl, cyano group, formoxyl, alkyl-carbonyl or be selected from-CO ₂R ⁸,-CONR ⁸R ⁸' and-NR ⁸(COR ⁹) substituting group; R wherein ⁸And R ⁸' be selected from hydrogen, alkyl, cycloalkyl, the optional aryl that replaces independently of one another or choose the aryl alkyl that replaces wantonly; Or R ⁸And R ⁸' connected nitrogen-atoms forms heterocycle together; And R wherein ⁹Be selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, the optional aryl that replaces, the optional aryl alkyl that replaces, the optional heteroaryl that replaces, optional heteroaryl alkyl and the R that replaces ⁸R ⁸' N-(C ₁-C ₄Alkyl);

R ³Be optional amino, carbamoyl, acyl amino formoxyl or the urea groups that replaces; Or R ³Be the nitrogenous heterocyclic group that connects by nitrogen-atoms; With

In another illustrative embodiment of described method, give one or more formulas of patient (II) compound and pharmaceutically acceptable salt thereof in the text:

Wherein

A is-CO ₂H, or its ester or its amide derivatives;

Q is an oxygen; Or Q is sulphur or disulfide bond, or its oxidized derivatives;

N is the integer of 1-3;

R ¹, R ², R ³And R ⁴Define suc as formula I; With

R ⁵" be selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, the optional aryl alkyl that replaces, the optional heterocyclic radical that replaces or the optional heterocyclic radical alkyl that replaces and the optional aminoalkyl that replaces.

The accompanying drawing summary

Fig. 1 shows that the two preparation lot numbers of embodiment 225 are to people's vasopressins V _1aThe binding affinity of acceptor.

Fig. 2 shows the antagonism that inositol-3-phosphate of arginine vasopressin-induce is produced by the compound of embodiment 225.

Fig. 3 shows the increase of arginine vasopressin in the compounds block rat blood pressure of embodiment 225-induce.

Detailed Description Of The Invention

In formula (I) or (II) in the embodiment of compound, A is-CO₂R ⁵ R wherein⁵Be selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optional aryl alkyl, heterocyclic radical, the heterocyclic radical (C that replaces₁-C ₄Alkyl) and R⁶R ⁷N-(C ₂-C ₄Alkyl). In formula (I) or (II) in another embodiment of compound, A is mono-substituted carbamoyl, dibasic carbamoyl or the optional nitrogen heterocycle carbamoyl that replaces.

Should be understood that, when occurring in described in the text each embodiment of heterocyclic radical, all select independently at every turn. In illustrative one side, heterocyclic radical is independently selected from tetrahydrofuran base, morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperazine base or quininuclidinyl; Wherein said morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperazine base or quininuclidinyl are optional by C at N₁-C ₄Alkyl or the optional aryl (C that replaces₁-C ₄Alkyl) replaces.

It is to be further understood that and work as R⁶And R⁷All select independently of one another when occurring in described in the text each embodiment at every turn. Another illustrative aspect, R⁶Be independently selected from hydrogen or alkyl; R⁷Be independently selected from alkyl, cycloalkyl, the optional aryl that replaces or the optional aryl alkyl that replaces when occurring at every turn. Another illustrative aspect, R⁶And R⁷Connected nitrogen-atoms forms the optional heterocycle that replaces together, such as pyrrolidinyl, piperidyl, morpholinyl, piperazinyl and homopiperazine base; Wherein said piperazinyl or homopiperazine base are also optional by R at N¹³Replace; R wherein¹³Independently be selected from hydrogen, alkyl, cycloalkyl, alkoxy carbonyl, the optional aryloxycarbonyl that replaces, the optional aryl alkyl that replaces and the optional aroyl that replaces when occurring at every turn.

In another embodiment, described formula (I) compound is diester, acid-ester or diacid, comprises its pharmaceutically acceptable salt, and wherein A and A ' select independently of one another. In another embodiment, described formula (I) compound is ester-acid amide, wherein among A and the A ' one be ester, and another is acid amides. In another embodiment, described formula (I) compound is diamides, and wherein A and A ' are selected from mono-substituted carbamoyl, dibasic carbamoyl and the optional nitrogen heterocycle carbamoyl that replaces independently of one another.

In a kind of variant of formula (I) compound; A and/or A ' are the carbamoyl of independent mono-substituted formula C (O) NHX-that selects, and wherein X is selected from alkyl, cycloalkyl, alkoxyalkyl, the optional aryl that replaces, optional aryl alkyl, heterocyclic radical, the heterocyclic radical-(C that replaces₁-C ₄Alkyl), R⁶R ⁷N-and R⁶R ⁷N-(C ₂-C ₄Alkyl), wherein each heterocyclic radical is selected independently.

In another variant, A and/or A ' are independent dibasic formula C (O) NR that selects¹⁴The carbamoyl of X-, wherein R¹⁴Be selected from hydroxyl, alkyl, alkoxy carbonyl and benzyl; And X is selected from alkyl, cycloalkyl, alkoxyalkyl, the optional aryl that replaces, optional aryl alkyl, heterocyclic radical, the heterocyclic radical-(C that replaces₁-C ₄Alkyl), R⁶R ⁷N-and R⁶R ⁷N-(C ₂-C ₄Alkyl), wherein each heterocyclic radical is selected independently.

In another variant, A and/or A ' are the nitrogenous heterocyclic acid amides of the independent optional replacement of passing through the nitrogen-atoms connection of selecting. Exemplary nitrogen heterocyclic ring includes but not limited to optional pyrrolidinyl, piperidyl, piperazinyl, homopiperazine base, triazolidinyl, triazine radical,  oxazolidinyl, different  oxazolidinyl, thiazolidinyl, the isothiazole alkyl, 1 that replaces, 2- piperazine base, 1,3- piperazine base, morpholinyl,  two oxazolidinyls and thiadiazoles alkyl. These optional substituting groups comprise such as defined radicals R in the literary composition¹⁰、R ¹²、R ⁶R ⁷N-and R⁶R ⁷N-(C ₁-C ₄Alkyl). In one embodiment, A and/or A ' are independently selected from optional pyrrolidone-base, piperidone base, 2-(pyrrolidin-1-yl methyl) pyrrolidin-1-yl or 1,2,3, the 4-tetrahydroisoquinoline that replaces-2-base, and connect by nitrogen.

In another variant, A and/or A ' are the acid amides of the piperidyl of the independent optional replacement of passing through the nitrogen-atoms connection of selecting. Exemplary optional substituting group comprises that hydroxyl, alkyl, cycloalkyl, alkoxyl, alkoxy carbonyl, hydroxy alkoxy alkyl comprise (hydroxyl (C₂-C ₄Alkoxyl))-(C₂-C ₄Alkyl), R⁶R ⁷N-、R ⁶R ⁷The N-alkyl comprises R⁶R ⁷N-(C ₁-C ₄Alkyl), diphenyl methyl, the optional aryl that replaces, the optional aryl (C that replaces₁-C ₄Alkyl) and piperidines-1-base (C₁-C ₄Alkyl). In one embodiment, A and/or A ' be independent select at 4 piperidyls that replace and connect by nitrogen-atoms.

In another variant, A and/or A ' are the acid amides of the piperazinyl of the independent optional replacement of passing through the nitrogen-atoms connection of selecting. Exemplary optional substituting group comprises that hydroxyl, alkyl, cycloalkyl, alkoxyl, alkoxy carbonyl, hydroxy alkoxy alkyl comprise (hydroxyl (C₂-C ₄Alkoxyl))-(C₂-C ₄Alkyl), R⁶R ⁷N-、R ⁶R ⁷The N-alkyl comprises R⁶R ⁷N-(C ₁-C ₄Alkyl), diphenyl methyl, the optional aryl that replaces, the optional aryl (C that replaces₁-C ₄Alkyl) and piperidines-1-base (C₁-C ₄Alkyl). In one embodiment, A and/or A ' be independent select at 4 piperazinyls that replace and connect by nitrogen-atoms.

In another variant, A and/or A ' are the acid amides of the homopiperazine base of the independent optional replacement of passing through the nitrogen-atoms connection of selecting. Exemplary optional substituting group comprises that hydroxyl, alkyl, cycloalkyl, alkoxyl, alkoxy carbonyl, hydroxy alkoxy alkyl comprise (hydroxyl (C₂-C ₄Alkoxyl))-(C₂-C ₄Alkyl), R⁶R ⁷N-、R ⁶R ⁷The N-alkyl comprises R⁶R ⁷N-(C ₁-C ₄Alkyl), diphenyl methyl, the optional aryl that replaces, the optional aryl (C that replaces₁-C ₄Alkyl) and piperidines-1-base (C₁-C ₄Alkyl). In one embodiment, A and/or A ' be independent select at 4 homopiperazine bases that replace and connect by nitrogen-atoms. In another embodiment, A and/or A ' be independent select at 4 by alkyl, aryl, aryl (C₁-C ₄Alkyl) the homopiperazine base that replaces and connect by nitrogen-atoms.

In another embodiment of formula (I) compound, A ' is mono-substituted carbamoyl, dibasic carbamoyl or the optional nitrogen heterocycle carbamoyl that replaces. In another embodiment of formula (I) compound, A ' is-CO₂R ⁵'; R wherein⁵' be selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, choose the aryl alkyl, heterocyclic radical, the heterocyclic radical (C that replace wantonly₁-C ₄Alkyl) and R⁶R ⁷N-(C ₂-C ₄Alkyl); Wherein heterocyclic radical is independently selected from tetrahydrofuran base, morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperazine base or quininuclidinyl at every turn when occurring; Wherein said morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, homopiperazine base or quininuclidinyl are chosen wantonly on N by C₁-C ₄Alkyl or the optional aryl (C that replaces₁-C ₄Alkyl) replaces. In a variant, R⁵' comprise R for choosing the heterocyclic radical alkyl or the optional aminoalkyl that replaces that replace wantonly⁶R ⁷N-(C ₂-C ₄Alkyl).

In another embodiment, the A in described formula (II) compound is selected from mono-substituted carbamoyl, dibasic carbamoyl and the optional nitrogen heterocycle carbamoyl that replaces.

In a variant, A is the mono-substituted carbamoyl of formula C (O) NHX-, and wherein X is selected from alkyl, cycloalkyl, alkoxyalkyl, the optional aryl that replaces, optional aryl alkyl, heterocyclic radical, the heterocyclic radical-(C that replaces₁-C ₄Alkyl), R⁶R ⁷N-and R⁶R ⁷N-(C ₂-C ₄Alkyl), wherein each heterocyclic radical is selected independently.

In another variant, A is formula C (O) NR¹⁴Dibasic carbamoyl of X-, wherein R¹⁴Be selected from hydroxyl, alkyl, alkoxy carbonyl and benzyl; And X is selected from alkyl, cycloalkyl, alkoxyalkyl, the optional aryl that replaces, optional aryl alkyl, heterocyclic radical, the heterocyclic radical-(C that replaces₁-C ₄Alkyl), R⁶R ⁷N-and R⁶R ⁷N-(C ₂-C ₄Alkyl), wherein each heterocyclic radical is selected independently.

In another variant, A is the nitrogenous heterocyclic acid amides by the optional replacement of nitrogen-atoms connection. Exemplary nitrogen heterocyclic ring includes but not limited to optional pyrrolidinyl, piperidyl, piperazinyl, homopiperazine base, triazolidinyl, triazine radical,  oxazolidinyl, different  oxazolidinyl, thiazolidinyl, the isothiazole alkyl, 1 that replaces, 2- piperazine base, 1,3- piperazine base, morpholinyl,  two oxazolidinyls and thiadiazoles alkyl. These optional substituting groups comprise such as defined radicals R in the literary composition¹⁰、R ¹²、R ⁶R ⁷N-and R⁶R ⁷N-(C ₁-C ₄Alkyl). In one embodiment, A is pyrrolidone-base, piperidone base, 2-(pyrrolidin-1-yl methyl) pyrrolidin-1-yl or 1,2,3,4-tetrahydroisoquinoline-2-base, and each described group is optionally substituted and connects by nitrogen-atoms.

In another variant, A is the acid amides by the piperidyl of the optional replacement of nitrogen-atoms connection. Exemplary optional substituting group comprises that hydroxyl, alkyl, cycloalkyl, alkoxyl, alkoxy carbonyl, hydroxy alkoxy alkyl comprise (hydroxyl (C₂-C ₄Alkoxyl))-(C₂-C ₄Alkyl), R⁶R ⁷N-、R ⁶R ⁷The N-alkyl comprises R⁶R ⁷N-(C ₁-C ₄Alkyl), diphenyl methyl, the optional aryl that replaces, the optional aryl (C that replaces₁-C ₄Alkyl) and piperidin-1-yl (C₁-C ₄Alkyl). In one embodiment, A is the piperidyl that replaces and connect by nitrogen-atoms at 4.

In another variant, A is the acid amides by the piperazinyl of the optional replacement of nitrogen-atoms connection. Exemplary optional substituting group comprises that hydroxyl, alkyl, cycloalkyl, alkoxyl, alkoxy carbonyl, hydroxy alkoxy alkyl comprise (hydroxyl (C₂-C ₄Alkoxyl))-(C₂-C ₄Alkyl), R⁶R ⁷N-、R ⁶R ⁷The N-alkyl comprises R⁶R ⁷N-(C ₁-C ₄Alkyl), diphenyl methyl, the optional aryl that replaces, the optional aryl (C that replaces₁-C ₄Alkyl) and piperidin-1-yl (C₁-C ₄Alkyl). In one embodiment, A is the piperazinyl that replaces and connect by nitrogen-atoms at 4.

In another variant, A is the acid amides by the homopiperazine base of the optional replacement of nitrogen-atoms connection. Exemplary optional substituting group comprises that hydroxyl, alkyl, cycloalkyl, alkoxyl, alkoxy carbonyl, hydroxy alkoxy alkyl comprise (hydroxyl (C₂-C ₄Alkoxyl))-(C₂-C ₄Alkyl), R⁶R ⁷N-、R ⁶R ⁷The N-alkyl comprises R⁶R ⁷N-(C ₁-C ₄Alkyl), diphenyl methyl, the optional aryl that replaces, the optional aryl (C that replaces₁-C ₄Alkyl) and piperidin-1-yl (C₁-C ₄Alkyl). In one embodiment, A is the homopiperazine base that replaces and connect by nitrogen-atoms at 4. In another embodiment, A is by alkyl, aryl, aryl (C at 4₁-C ₄Alkyl) the homopiperazine base that replaces and connect by nitrogen-atoms.

In another variant, A is the acid amides by the heterocycle of nitrogen-atoms connection, and wherein said heterocycle is replaced by heterocyclic radical, heterocyclic radical alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aryl alkyl.

In another embodiment, formula (I) or (II) in A be the acid amides of the optional benzyl that replaces, the optional 1-naphthyl methyl that replaces or the optional 2-naphthyl methyl amine that replaces. Optional substituting group includes but not limited to 2,3-dichloro, 2,5-dichloro, 2,5-dimethoxy, 2-trifluoromethyl, 2-fluoro-3-trifluoromethyl, 2-fluoro-5-trifluoromethyl, 2-methyl, 2-methoxyl group, 3,4-dichloro, 3,5-two (trifluoromethyl), 3,5-dichloro, 3,5-dimethyl, 3,5-difluoro, 3,5-dimethoxy, 3-bromine, 3-trifluoromethyl, 3-chloro-4-fluorine, 3-chlorine, 3-fluoro-5-trifluoromethyl, 3-fluorine, 3-methyl, 3-nitro, 3-trifluoromethoxy, 3-methoxyl group, 3-phenyl, 4-trifluoromethyl, 4-chloro-3-trifluoromethyl, 4-fluoro-3-trifluoromethyl, 4-methyl etc.

In another embodiment, formula (I) or (II) in A be the acid amides of the optional benzyl that replaces-N-methyl amine. In another embodiment, formula (I) or (II) in A be the acid amides of the optional benzyl that replaces-N-butylamine (comprising normal-butyl and the tert-butyl group). In another embodiment, formula (I) or (II) in A be the acid amides of the optional benzyl that replaces-N-benzyl amine. Optional substituting group includes but not limited to 2,3-dichloro, 3,5-dichloro, 3-bromine, 3-trifluoromethyl, 3-chlorine, 3-methyl etc.

In another embodiment, formula (I) or (II) in A be the acid amides of optional 1-phenyl ethyl amine, 2-phenyl ethyl amine, 2-phenyl propyl amine or the 1-phenylbenzyl amine that replaces. In another embodiment, formula (I) or (II) in A be the acid amides of the optional 1-phenyl ethyl amine that replaces, 2-phenyl ethyl amine, 2-phenyl propyl amine, 1-phenylbenzyl amine-N-methyl amine. In another embodiment, formula (I) or (II) in A be the acid amides of the optional 2-phenyl that replaces-Beta-alanine or derivatives thereof, 1-Super Odrinex etc. Optional substituting group includes but not limited to 3-trifluoromethoxy, 3-methoxyl group, 3,5-dimethoxy, 2-methyl etc.

In another embodiment, formula (I) or (II) in A be the acid amides of optional 1-phenycyclopropyl amine, 1-benzyl ring amylamine or the 1-benzyl ring hexyl amine that replaces. Optional substituting group includes but not limited to 3-fluorine, 4-methoxyl group, 4-methyl, 4-chlorine, 2-fluorine etc.

In another embodiment, formula (I) or (II) in A be the acid amides of the optional hetervaromatic methyl amine that replaces, described heteroaryl includes but not limited to 2-furyl, 2-thienyl, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals etc. Optional substituting group includes but not limited to 5-methyl, 3-chlorine, 2-methyl etc.

In another embodiment, formula (I) or (II) in A be the acid amides of the aryl bicyclic of fractional saturation, include but not limited to optional 1-, 2-, 4-and 5-indanyl amine, 1-and the 2-tetralyl amine that replaces, indolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl etc.

In another embodiment, formula (I) or (II) in A be the piperidines that replaces or the acid amides of piperazine. Substituting group on piperidines or the piperazine comprises heterocyclic radical, heterocyclic radical alkyl, the optional aryl that replaces and the optional aryl alkyl that replaces. Exemplary piperidines and piperazine comprise following formula:

In another embodiment, the A ' in the formula (I) is the acid amides of the heterocycle of the replacement that connects by nitrogen-atoms.Substituting group comprises alkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical, heterocyclic radical alkyl, aryl and aryl alkyl.In an embodiment variant, the A ' in the formula (I) is the acid amides by the heterocycle that is replaced by alkyl, cycloalkyl, cycloalkyl-alkyl, heterocyclic radical or heterocyclic radical alkyl of nitrogen-atoms connection.

In another embodiment, the A ' in the formula (I) is the acid amides of optional aryl-heterocyclic base amine, aryl alkyl heterocyclic radical amine, heterocyclic radical alkylamine or the heteroaryl alkyl amine that replaces.

Be understood that the above-mentioned exemplary A that includes chiral centre and/or the arbitrary optical voidness enantiomter in A ' example all are included in the compound as herein described; Perhaps, can use racemic form.For example, one or both in the following enantiomter can be included in the compound as herein described: (R)-and 1-(3-methoxyphenyl) ethylamine, (R)-1-(3-trifluoromethyl) ethylamine, (R)-1,2,3,4-tetrahydrochysene-1-naphthylamine, (R)-1-indanyl amine, (R)-α, N-dimethyl benzyl amine, (R)-α-Jia Jibianji amine, (S)-1-(3-methoxyphenyl) ethylamine, (S)-1-(3-trifluoromethyl) ethylamine, (S)-1,2,3,4-tetrahydrochysene-1-naphthylamine, (S)-1-indanyl amine and (S)-α-Jia Jibianji amine etc.

In another embodiment of formula (II) compound, Q is oxygen or sulphur.In another embodiment of formula (II) compound, R " is the optional aryl alkyl that replaces.In another embodiment of formula (II) compound, A is the acid amides of substituted piperidine or piperazine.

In another embodiment of formula (I) compound, n is 1 or 2.In another embodiment of formula (II) compound, n is 1 or 2.In a variant of formula (II) compound, n is 1.

In formula (I) or (II) in another embodiment of compound, R ²For hydrogen, alkyl, alkoxyl, alkylthio group, cyano group, formoxyl, alkyl-carbonyl or be selected from-CO ₂R ⁸With-CONR ⁸R ⁸' substituting group, R wherein ⁸And R ⁸' be selected from hydrogen and alkyl independently of one another.

In formula (I) or (II) in another embodiment of compound, R ¹Be hydrogen.In formula (I) or (II) in another embodiment of compound, R ¹Be methyl.In formula (I) or (II) in another embodiment of compound, R ²Be hydrogen.In formula (I) or (II) in another embodiment of compound, R ²Be methyl.In formula (I) or (II) in another embodiment of compound, R ¹And R ²Be hydrogen.

In formula (I) or (II) in another embodiment of compound, R ³Be formula:

R wherein ¹⁰And R ¹¹Be selected from hydrogen, the optional alkyl that replaces, the optional cycloalkyl that replaces, alkoxy carbonyl, alkyl-carbonyl oxygen base, the optional aryl that replaces, the optional aryl alkyl that replaces, the optional alkoxy aryl that replaces, the optional aromatic yl alkyl carbonyl oxygen base that replaces, diphenyl methoxy base, triphenyl methoxyl group etc. independently of one another; And R ¹²Be selected from hydrogen, alkyl, cycloalkyl, alkoxy carbonyl, the optional aryloxycarbonyl that replaces, the optional aryl alkyl that replaces, the optional aroyl that replaces etc.

In formula (I) or (II) in another embodiment of compound, R ³Be formula:

R wherein ¹⁰, R ¹¹And R ¹²Such as in the literary composition definition.

In formula (I) with (II) in another embodiment of compound, R ³Be formula:

In formula (I) or (II) in another embodiment of compound, R ³Be formula:

R wherein ¹⁰And R ¹¹Such as in the literary composition definition.

In formula (I) or (II) in another embodiment of compound, R ⁴Be formula:

Wherein Y is electron withdraw group such as halogen, and R is that hydrogen or optional substituting group such as halogen, alkyl and alkoxyl comprise the 2-methoxyl group.In a variant, Y is a chlorine.

Be understood that except that when the formula (I) of A=A ' and n=0 and (II) compound be chirality on α-carbon.In an embodiment of formula (I) compound, when n was 1, the spatial chemistry of α-carbon was (S) or (R) or for the epimer mixture.In another embodiment of formula (I) compound, when n was 1, the spatial chemistry of α-carbon was (R) type.In another embodiment of formula (I) compound, when n was 2, the spatial chemistry of α-carbon was (S) type.In an embodiment of formula (II) compound, when n was 1, the spatial chemistry of α-carbon was (R) type.

In another embodiment, the R in described formula (II) compound ⁵" be the optional aryl (C that replaces ₂-C ₄Alkyl).

The conventional chemical term that is used for above structural formula described in the literary composition has their common implication.By way of example, term " alkyl " is meant the saturated hydrocarbon of straight chain or optional side chain, includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, 2-amyl group, 3-amyl group, neopentyl, hexyl, heptyl, octyl group etc.In addition, be understandable that the variant of the term alkyl that in other terms, uses, include but not limited to cycloalkyl, alkoxyl, haloalkyl, alkanoyl, alkylidene etc., and these other terms also comprise the variant of straight chain and optional side chain.

Term " aryl " is meant aromatic ring or heteroaromatic rings, and comprise such group, as furyl, pyrrole radicals, thienyl, pyridine radicals, thiazolyl,  azoles base, different  azoles base, isothiazolyl, imidazole radicals, pyrazolyl, phenyl, pyridazinyl, pyrimidine radicals, pyrazinyl, thiadiazolyl group,  di azoly, naphthyl, indanyl, fluorenyl, quinolyl, isoquinolyl, benzo two  alkyl, benzofuranyl, benzothienyl etc.

Term " optional replacement " is meant that one or more, preferred 1-3 hydrogen atom replaced by one or more substituting groups.Substituting group includes but not limited to group such as C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl, C ₁-C ₄Alkylthio group, hydroxyl, nitro, halogen, carboxyl, cyano group, C ₁-C ₄Haloalkyl, C ₁-C ₄Halogenated alkoxy, amino, carbamyl, formamido group, amino, alkyl amino, dialkyl amido, alkyl-alkyl amino, C ₁-C ₄Alkyl sulfonyl-amino etc.These optional substituting groups can be substituted on alkyl, thiazolinyl, heterocyclic radical, aryl, the heteroaryl etc.

Term " heterocycle " is meant the non-aromatic ring shape structure that contains one or more hetero atoms (as nitrogen, oxygen, sulphur etc.), and comprises group such as tetrahydrofuran base, morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, high piperazinyl, quininuclidinyl etc.

Term " acyl group " is meant the alkyl that connects by carbonyl, thiazolinyl, aryl etc., and comprises group such as formoxyl, acetyl group, propiono, bytyry, valeryl, hexamethylene acyl group, the optional benzoyl that replaces etc.

Term " shielded amino " is meant the amine of the blocking group protection that be can be used for protecting nitrogen (as the nitrogen of beta-lactam nucleus) in preparation or subsequent reaction.The example of such blocking group has benzyl, 4-methoxy-benzyl, 4-methoxyphenyl or trialkylsilkl (for example trimethyl silyl) etc.

Term " shielded carboxyl " is meant and is generally used for sealing the GPF (General Protection False radical protection of acid carboxyl or the carboxyl of sealing temporarily.The example of such blocking group comprises low alkyl group (for example tert-butyl group), junior alkyl halides (2-iodine ethyl and 2 for example; 2,2-three chloroethyls), the benzyl (for example 4-methoxy-benzyl and 4-nitrobenzyl) of benzyl, replacement, diphenyl methyl, thiazolinyl (for example pi-allyl), trialkylsilkl (for example trimethyl silyl and tert-butyl group diethylsilane base) and similarly carboxy protective group.

Used term " antagonist " is meant antagonist wholly or in part in the literary composition.Though all being useful, exemplary partial antagonist, the partial antagonist of any intrinsic activity shows at least about 50% antagonism, or at least about 80% antagonism.Term also is included as the compound of the complete antagonist of one or more vasopressins acceptors.Be understood that method exemplary described in the literary composition need treat the vasopressins receptor antagonist of effective dose; Therefore, performance can give by high dose the compound of one or more vasopressins acceptor portion antagonisms, suppresses the effect of vasopressins or vasopressin agonists to show enough antagonist activities.

Be understandable that in the described in the text embodiment, the variant of exemplary alkyl is C ₁-C ₆Alkyl is as methyl, ethyl, propyl group, third-2-base etc.; The variant of exemplary thiazolinyl is C ₂-C ₆Thiazolinyl is as vinyl, pi-allyl etc.; The variant of exemplary alkynyl is C ₂-C ₆Alkynyl is as acetenyl, propinyl etc.; The variant of exemplary alkoxyl is C ₁-C ₄Alkoxyl is as methoxyl group, penta-3-oxygen base etc.; The variant of exemplary alkylthio group is C ₁-C ₄Alkylthio group is as ethyl sulfenyl, 3-methyl fourth-2-base sulfenyl etc.; The variant of exemplary alkyl-carbonyl is C ₁-C ₃Alkyl-carbonyl is as acetyl group, propiono etc.; The variant of exemplary cycloalkyl is C ₃-C ₈Cycloalkyl; The variant of exemplary cycloalkenyl group is C ₃-C ₉Cycloalkenyl group is as lemon thiazolinyl, firpene base etc.; The variant of the aryl alkyl of exemplary optional replacement is the optional aryl (C that replaces ₁-C ₄Alkyl); The variant of the aryl alkenyl of exemplary optional replacement is the optional aryl (C that replaces ₂-C ₄Thiazolinyl); The variant of the aromatic yl polysulfide yl of exemplary optional replacement is the optional aryl (C that replaces ₂-C ₄Alkynyl); The variant of exemplary alkoxyalkyl is (C ₁-C ₄Alkoxyl)-(C ₁-C ₄Alkyl); The variant of the heteroaryl alkyl of exemplary optional replacement is the optional heteroaryl (C that replaces ₁-C ₄Alkyl); The variant of exemplary alkoxy carbonyl is C ₁-C ₄Alkoxy carbonyl.

Each the above-mentioned embodiment, variant and the aspect that also are understandable that compound described in the literary composition can combined in various manners.For example, R ³Be optional  oxazolidone base, the R that replaces ⁴For the compound of the optional aryl alkenyl that replaces is considered by the present invention.In addition, R ³Be optional  oxazolidone base, the R that replaces ⁴Be optional aryl alkenyl and the R that replaces ¹And R ²The compound that is hydrogen is considered by the present invention.In addition, R ³Be optional  oxazolidone base, the R that replaces ⁴Be optional aryl alkenyl, the R that replaces ¹And R ²Being the compound that hydrogen and A and A ' be the independent acid amides of selecting is considered by the present invention.

In another embodiment, following formula: compound has been described:

R wherein ¹, R ², R ⁴, A, A ', Q and R5 " such as in the literary composition definition, Ar ¹Be the optional aryl that replaces.

In another embodiment, following formula: compound has been described:

R wherein ¹, R ², A, A ', Q and R5 " as above definition, Ar ¹And Ar ²Independent separately aryl for optional replacement.

In another exemplary embodiment, following formula: compound has been described:

R wherein ¹, R ², Q and R5 be " as defining Ar in the literary composition ¹And Ar ²Be optional aryl or the heteroaryl that replaces, X independently selects and as define R when occurring in the literary composition at every turn when occurring at every turn ¹⁴Independent select and as defining in the literary composition, or be hydrogen.One exemplary aspect, Ar ¹And Ar ²Be the phenyl of the independent optional replacement of selecting separately.Another exemplary aspect, R ¹And R ²The hydrogen of respectively doing for oneself.

In another embodiment, following formula: compound has been described:

Ar wherein ¹And Ar ²Be optional aryl or the heteroaryl that replaces, R ¹And R ²As defining in the literary composition, X independently selects and as define R when occurring in the literary composition at every turn when occurring at every turn ¹⁴Independent select and as defining in the literary composition, or be hydrogen.One exemplary aspect, Ar ¹And Ar ²Be the phenyl of the independent optional replacement of selecting separately.Another exemplary aspect, R ¹And R ²The hydrogen of respectively doing for oneself.

Compound described in the literary composition has the aza cyclo-butanone core texture, and it is included in the asymmetric carbon atom on C (3) and the C (4), produces four kinds of alloisomerism configurations, as with shown in the following formula:

Therefore, compound described in the literary composition can single diastereomer, the form of mixtures of racemic mixture or different diastereomers exists.Be understood that in some applications the mixture of some stereoisomer or stereoisomer can be included in the different embodiments of the present invention, and in other were used, other stereoisomers or stereoisomer mixture can be included in wherein.One exemplary mixture is the racemic mixture of two kinds of isomer, and it is basically or fully without any other diastereomers.In other were used, single stereoisomer can be included in the different embodiments of the present invention.On the one hand, certain chiral centre is that spatial chemistry is pure in the described in the text compound, for example introduced corresponding to (3S, 4R)-single enantiomer of the aza cyclo-butanone core texture of diastereomer configuration.In a variant, be included in other chiral centres in the compound of this embodiment and be epimerism, there is each spatial configuration of equivalent like this.In another variant, some or all of other chiral centres in described compound are optical voidness.

Should be understood that and have R ¹α-carbon also have chirality.In addition, select as R ¹, R ², R ³, R ⁴, A, A ' group also can comprise chiral centre.For example, work as R ³During the  azoles alkane-2-ketone that replaces for 4--3-base, 4 of  oxazolidone ring have asymmetry.In addition, work as R ³Be 2, the dibasic  azoles alkane of 5--4-ketone-3-base or 1,2, when the trisubstituted imidazoline of 5--4-ketone-3-was basic, 2-on the imidazolone ring and 5-carbon had asymmetry separately.At last, work as R ³Be succinimide base and R ¹⁰And R ¹¹In one when being hydrogen, have non-hydrogen substituent carbon and also have asymmetry.Thereby the different structure formula described in the literary composition that is understandable that can be represented each single diastereomer, different racemic mixture and enantiomter and/or common different other mixtures of diastereomer.Though this specification considers to have the compound of the combination of all spatial chemistry purity, should be understood that beyond any doubt required in many cases vasopressin antagonists activity can be present in possible diastereomer subclass or even single diastereomer in.In an exemplary embodiment, compound described in the literary composition be (α R, 3S, 4R) and (α S, 3S, 4R) non-enantiomer mixture of absolute configuration.In another exemplary embodiment, compound described in the literary composition go up substantially into or only for (α R, 3S, absolute configuration 4R).In another exemplary embodiment, compound described in the literary composition go up substantially into or only for (α S, 3S, absolute configuration 4R).

Will be understood that above general formula represents at least 8 different alloisomerism configurations.Be understood that a certain stereoisomer can have more biologically active than other.Thereby, in the literary composition following formula considered might stereoisomer and the different mixtures of each stereoisomer.Introduce to following illustrative a pair of diastereomer of C (α):

Wherein the spatial chemistry of " α " carbon is (R) or (S).On the one hand, the spatial chemistry of " α " carbon is single (R), and the spatial chemistry of " α " carbon is single (S) on the other hand.

Compound described in the literary composition also can prepare or change into the derivative of pharmaceutically acceptable salt.The exemplary pharmaceutically acceptable salt that has the amino compound of alkalescence described in the literary composition includes but not limited to inorganic and organic acid salt.Exemplary inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid etc.Exemplary organic acid comprises p-methyl benzenesulfonic acid, methanesulfonic acid, ethanedioic acid, to bromo-benzene sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetate etc.The exemplary example of these pharmaceutically acceptable salts has sulphate, pyrosulfate, disulfate, sulphite, acid sulphite, phosphate, dibasic alkaliine, dihydric phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1, the 4-diacid salt, hexin-1, the 6-diacid salt, benzoate, the helium benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxy benzoic acid salt, phthalate, sulfonate, xylenesulfonate, phenylacetic acid salt, phenylpropionic acid salt, phenylbutyric acid salt, citrate, lactate, beta-hydroxy-butanoic acid salt, glycollate, tartrate, mesylate, propane sulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate etc.In one embodiment, pharmaceutically acceptable salt is the salt that forms with hydrochloric acid, trifluoroacetic acid, maleic acid or fumaric acid.

In another embodiment, the method for the treatment of the preceding illness of one or more menstruations has been described in the literary composition.Described method comprises β-Nei acylamino-alkanoic acid vasopressins V described in one or more literary compositions of patient that need the preceding illness of these menstruations of alleviation _1aReceptor antagonist comprises its pharmaceutically acceptable salt.In pharmaceutical composition as described herein, can comprise one or more β-Nei acylamino-alkanoic acid vasopressins V _1aReceptor antagonist and/or its pharmaceutically acceptable salt.Vasopressins V _1aThe antagonism of acceptor shows as and alleviates or prevent dysmenorrhoea anxiety (PMDD) and primary dysmenorrhea (PD) symptom before the menstruation.Referring to Brouard etc. described in the BritishJournal of Obstetrics and Gynecology 107:614-19 (2000).For example understand in menstruation one or more compounds or its pharmaceutical composition prophylactic treatment as premenstrual syndrome (PMS), illness, functional disorder and/or dysmenorrhoea takes place not long ago to give.The active V of patient's oral administration that report 18-35 year is arranged _1aPain significantly alleviates antagonist SR49059 menstrual period after three months.

In one embodiment, the method for illness comprises that primary dysmenorrhea (PD) is also referred to as cramp through (premenstrual) (PMD) before the described treatment menstruation.Primary dysmenorrhea (PD) comprises the symptom relevant with menstruation outbreak such as back pain, pelvis spasm, uterus pain, fluid retention (rising as stomach Qi) etc.This method comprises the step of arbitrary independent compound described in the literary composition for the treatment of effective dose or pharmaceutical composition.Be understood that in these methods and preferably adopt optionally or preferentially to the compound described in the activated literary composition of periphery vasopressins acceptor.

In another embodiment, the method for illness comprises the preceding dysmenorrhoea anxiety (PMDD) of menstruation before the described treatment menstruation.Dysmenorrhoea anxiety (PMDD) comprises observed many symptoms among the PD before the menstruation, and also can comprise the Secondary cases anxiety.PMDD can be used as treating depression.This method comprises the step of arbitrary independent compound described in the literary composition for the treatment of effective dose or pharmaceutical composition.Be understood that and in these methods, preferably adopt compound described in the literary composition that can pass blood-brain barrier.

In another embodiment, the pharmaceutical composition that comprises one or more β-Nei acylamino-alkanoic acid vasopressins receptor antagonist has been described in the literary composition.This pharmaceutical composition comprises one or more carriers, thinner and/or excipient.

Compound described in the literary composition can directly or with the part of pharmaceutical compositions that comprises one or more carriers, thinner and/or excipient give.These preparations can comprise a kind of or surpass compound described in a kind of literary composition.These pharmaceutical compositions can give by different conventional route by different dosage form, include but not limited to oral, rectum, outside skin, hypogloeeis, intestines and stomach, in subcutaneous, the vein, intramuscular, nose etc.Referring to Remington ' s PharmaceuticalSciences (the 16th edition, 1980).

Described in the preparation literary composition in the compound compositions, active component can with mixed with excipients, with the excipient dilution or be enclosed in the carrier that can become capsule, sachet, paper container or other vessel forms.Excipient can be used as thinner, and it can be solid, semisolid or fluent material, solvent, carrier or the medium of its action activity composition.Therefore, composition can be following form: the powder of tablet, pill, powder, lozenge, sachet, cachet, elixir, supensoid agent, emulsion, solution, syrup, aerosol (be solid or in liquid medium), ointment, soft and hard gelatine capsule, suppository, aseptic injectable solution agent and aseptic packaging.These compositions can comprise about active component of 0.1% to 99.9%, and this depends on selected dosage and formulation.

The part example of suitable excipient comprises lactose, glucose, sucrose, sorbitol, mannitol, starch, gum Arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose.In addition, preparation also can comprise: lubricant, for example talcum powder, dolomol and mineral oil; Wetting agent; Emulsifier and suspending agent; Preservative, for example methyl hydroxybenzoate and nipasol; Sweetener; And flavor enhancement.The present composition can be formulated as such preparation by methods known in the art: after giving the patient, provide fast, continue or postpone the active component that discharges.Be understood that the carrier, thinner and the excipient that are used to prepare composition described in the literary composition are preferably GRAS (Generally Regarded as Safe) compound.

Compound described in pulverous literary composition can be milled into desired particle size and the particle size range that is used for emulsion and/or solid dosage forms.Exemplary particle size range comprises and is lower than 200 purpose granularities, is lower than 40 purpose granularities etc.

The actual administered dose that is understandable that described compound will be determined according to relevant details by the attending doctor, comprise the disease of being treated, selected method of administration, actual one or more compounds that give, age, body weight and the reaction of individual patient and the order of severity of patient's symptom.Therefore, dosage range described in the literary composition is intended to illustrate rather than by any way to any restriction of the scope of the invention.In the text under the situation of the upper limit of described scope, the time point that this dosage prepared composition doses can be presetted at a day gives at dosage.Dosage under the situation of the lower limit of described scope, can be prepared into this dosage single dose and give at the time point that presets once a day in the text.Term " unit dosage forms " is meant the physically-isolated unit that is fit to human patients and other mammiferous unit dose, each unit comprises the active substance and the pharmaceutically acceptable carrier of the scheduled volume that calculates according to the required result of treatment of generation in the scheduled time that limits, and optional suitable pharmacy thinner and/or the excipient that combine.

In an exemplary embodiment, every day, single or total divided dose was treated the about 1 μ g of weight in patients to about 100mg scope at every kg.In another exemplary embodiment, every day, single or total divided dose was treated the about 25 μ g of weight in patients to about 25mg scope at every kg.Be understood that formula (I) compound preferably is slightly higher than TDD, as the about 5 μ g of every kg body weight to about 100mg scope, the about 25 μ g of every kg body weight are to about 25mg scope or about 25 μ g of every kg body weight extremely in about 5mg scope.It further is understood that formula (II) compound can preferably give to be lower than slightly TDD, as the about 1 μ g of every kg body weight to about 50mg scope, the about 5 μ g of every kg body weight are to about 25mg scope or about 5 μ g of every kg body weight extremely in about 5mg scope.Be understood that the external combination of compound described in the literary composition and to V _1aThe functional antagonism of vasopressins acceptor is relevant with giving effective unit dosage.

Below preparation and embodiment are intended to further illustrate the synthetic of The compounds of this invention but not limit invention scope by any way.Unless other explanations are arranged in addition, otherwise all reactions are carried out at room temperature and all evaporations are carried out in a vacuum.Following all compounds by standard analysis (comprise nuclear magnetic resoance spectrum ( ¹HNMR) and mass spectrum (MS)) characterized by techniques.Can prepare other embodiment and illustrate by synthesis path described in the literary composition and method following.Further described synthetic method in WO03/031407, this patent is bonded to herein by reference.

Embodiment

Compound embodiment

Embodiment 1. (4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride

1.0 (4 (S)-phenyl  azoles alkane-2-ketone-3-yl) acetate (Evans of equivalent, United States Patent (USP) 4,665,171) and the solution of the oxalyl chloride of 1.3 equivalents in the 200mL carrene handle with the anhydrous dimethyl formamide (the millinormal acetogenin of 85 μ L/) of catalytic amount and make and produce a large amount of gases.After 45 minutes, gas discharges and stops fully, and subsequently with this reactant mixture concentrating under reduced pressure, vacuum drying obtains the title compound of pale solid shape after 2 hours.

Embodiment 1A. (4 (R)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride

Adopt the method for embodiment 1 to prepare embodiment 1A, difference is to replace (4 (S)-phenyl  azoles alkane-2-ketone-3-yl) acetate (referring to Evans ﹠amp with (4 (R)-phenyl  azoles alkane-2-ketone-3-yl) acetate; Sjogren, Tetrahedron Lett.26:3783 (1985)).

Embodiment 1B. (4 (S)-phenyl  azoles alkane-2-ketone-3-yl) methyl acetate

Per hour handle (using 20 equivalents altogether) (4 (S)-phenyl  azoles alkane-2-ketone-3-yl) acetate (1g, 4.52mmol) (at United States Patent (USP) 4,665, method described in 171 prepares according to Evans) solution in the 20mL absolute methanol with 5 equivalent chloroacetic chlorides.The solution stirring that obtains is spent the night.Again be dissolved in 30mL CH with boiling off the residue that obtains behind the methyl alcohol ₂Cl ₂In and with 50mL saturated Na ₂CO ₃The aqueous solution is handled.With organic layer evaporation and dry (MgSO ₄), obtain the title compound (1.001g, 94%) of colorless oil;

¹H NMR(CDCl ₃)δ3.37(d，J＝18.0Hz，1H)，3，69(s，3H)，4.13(t，J＝8.3Hz，1H)，4.28(d，J＝18.0Hz，1H)，4.69(t，J＝8.8Hz，1H)，5.04(t，J＝8.4Hz，1H)，7.26-7.29(m，2H)，7.36-7.42(m，3H).

Embodiment 1C.2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) methyl propionate

Under-78 ℃, with two solution-treated (4 (S)-phenyl  azoles alkane-2-ketone-3-yl) methyl acetate (1g, 4.25mmol) the solution among 10mL anhydrous THFs of (trimethyl silyl) lithium amide in THF of 4.68mL (4.68mmol) 1M.This reactant mixture was stirred 1 hour down in-70 ℃, add subsequently MeI (1.59mL, 25.51mmol).After aza cyclo-butanone transformed fully, this reacted with saturated NH ₄The quencher of the Cl aqueous solution also distributes between EtOAc and water.Organic layer is used saturated aqueous solution of sodium bisulfite and saturated NaCl solution washing successively.With the organic layer drying (MgSO that obtains ₄) and evaporate, obtain the title compound (mixture of diastereoisomer) (1.06g, 93%) of white solid;

¹H

NMR(CDCl ₃)δ1.07/1.53(d/d，J＝7.5Hz，3H)，3.59/3.74(s/s，3H)，3.85/4.48(q/q，J＝7.5Hz，1H)，4.10-4.14(m，1H)，4.60-4.64/4.65-4.69(m/m，1H)，4.88-4.92/4.98-5.02(m/m，1H)，7.24-7.40(m，5H).

Embodiment 1D.2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) propionic acid

Under 0 ℃, (1g 4.01mmol) adds the solution of 14.3mL (12.04mmol) 0.84MLiOH in water in the solution in 35mL MeOH toward 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) methyl propionate.Subsequently this reactant mixture was stirred under room temperature 3 hours.After the aza cyclo-butanone complete hydrolysis, MeOH is removed in evaporation, and rough residue is dissolved in CH ₂Cl ₂In and with the processing of the saturated NaCl aqueous solution.With the organic layer drying (MgSO that obtains ₄) and evaporate, obtain the title compound (racemic mixture) (0.906g, 96%) of white solid;

¹H NMR(CDCl ₃)δ1.13/1.57(d/d，J＝7.5Hz，3H)，3.75/4.50(q/q，J＝7.5Hz，1H)，4.10-4.16(m，1H)，4.62-4.72(m，1H)，4.92-5.03(m，1H)，7.32-7.43(m，5H).

Embodiment 1E.2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) propionyl chloride

The embodiment 1D of 1 equivalent and the oxalyl chloride of 1.3 equivalents are at 200mL CH ₂Cl ₂In solution (150mL/g propanoic derivatives) handle with the dry DMF (85 μ L/mmol propanoic derivatives) of catalytic amount and produce a large amount of bubbles.After 45 minutes, gas discharges and stops fully, and subsequently with this reactant mixture concentrating under reduced pressure, vacuum drying obtains the title compound of pale solid shape after 2 hours.

Embodiment 2. is formed the universal method of acid amides by the ester derivant of activation

N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

Handle N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-N-hydroxy-succinamide ester (1.95g with 0.68mL (4.74mmol) 3-(trifluoromethyl) benzyl amine, 4.64mmol, Advanced ChemTech) and solution in the 20mL anhydrous tetrahydro furan.(TLC, 60 after reaction is finished; 40 hexane/ethyl acetate), with the evaporation of this mixture, subsequently the grease that obtains is distributed between carrene and saturated sodium bicarbonate aqueous solution.With the organic layer evaporation, obtain the title compound of 2.23g (quantitative yield) white solid;

¹H NMR(CDCl ₃)δ1.39(s，9H)，2.61(dd，J＝6.5Hz，J＝17.2Hz，1H)，2.98(dd，J＝3.7Hz，J＝17.0Hz，1H)，4.41(dd，J＝5.9Hz，J＝15.3Hz，1H)，4.50-4.57(m，2H)，5.15(δ，2H)，5.96-5.99(m，1H)，6.95(s，1H)，7.29-7.34(m，5H)，7.39-7.43(m，2H)，7.48-7.52(m，2H).

Prepare embodiment 2A-2C and 3-5 according to embodiment 2 methods, difference is to replace N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-N-hydroxy-succinamide ester with suitable amino acid derivativges, and uses suitable amine to replace 3-(trifluoromethyl) benzyl amine.

Embodiment 2A.N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide

N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-N-hydroxy-succinamide ester (5.0g, 12mmol, Advanced ChemTech) and 4-(phenylethyl) piperazine 2.27mL (11.9mmol) reaction, obtain the title compound of 5.89g (quantitative yield) canescence grease;

¹H NMR(CDCl ₃)δ1.40(s，9H)，2.45-2.80(m，10H)，3.50-3.80(m，4H)，4.874.91(m，1H)，5.08(s，2H)，5.62-5.66(m，1H)，7.17-7.33(m，10H).

Embodiment 2B.N-benzyl oxygen base carbonyl-L-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

N-benzyl oxygen base carbonyl-L-glutamic acid β-tert-butyl ester α-N-hydroxy-succinamide ester (4.83g, 11.1mmol, Advanced ChemTech) and 3-(trifluoromethyl) benzyl amine) 1.63mL (11.4mmol) reaction, obtain the title compound of 5.41g (98%) pale solid shape;

¹H NMR(CDCl ₃)δ1.40(s，9H)，1.88-1.99(m，1H)，2.03-2.13(m，1H)，2.23-2.33(m，1H)，2.38-2.47(m，1H)，4.19-4.25(s，1H) 4.46-4.48(m，2H)，5.05-5.08(m，2H)，5.67-5.72(m，1H)，7.27-7.34(m，5H)，7.39-7.43(m，2H)，7.48-7.52(m，2H).

Embodiment 2C.N-benzyl oxygen base carbonyl-L-glutamic acid gamma-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide

N-benzyl oxygen base carbonyl-L-glutamic acid gamma-tert-butyl ester α-N-hydroxy-succinamide ester (5.0g, 12mmol, Advanced ChemTech) and 4-(phenylethyl) piperazine 2.19mL (11.5mmol) reaction, obtain the title compound of 5.87g (quantitative yield) canescence grease;

¹H NMR(CDCl ₃)δ1.43(s，9H)；1.64-1.73(m，1H)；1.93-2.01(m，1H)；2.23-2.40(m，2H)；2.42-2.68(m，6H)；2.75-2.85(m，2H)；3.61-3.74(m，4H)；4.66-4.73(m，1H)；5.03-5.12(m，2H)；5.69-5.72(m，1H)；7.16-7.34(m，10H).

Embodiment 3.N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide

¹H NMR(CDCl ₃)δ1.40(s，9H)，2.45-2.80(m，10H)，3.50-3.80(m，4H)，4.87-4.91(m，1H)，5.08(s，2H)，5.62-5.66(m，1H)，7.17-7.33(m，10H).

Embodiment 4.N-benzyl oxygen base carbonyl-L-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

N-benzyl oxygen base carbonyl-L-glutamic acid β-tert-butyl ester α-N-hydroxy-succinamide ester (4.83g, 111mmol, Advanced ChemTech) and 3-(trifluoromethyl) benzyl amine 1.63mL (11.4mmol) reaction, obtain the title compound of 5.41g (98%) pale solid shape:

¹HNMR(CDCl ₃)δ1.40(s，9H)，1.88-1.99(m，1H)，2.03-2.13(m，1H)，2.23-2.33(m，1H)，2.38-2.47(m，1H)，4.19-4.25(s，1H)，4.46-4.48(m，2H)，5.05-5.08(m，2H)，5.67-5.72(m，1H)，7.27-7.34(m，5H)，7.39-7.43(m，2H)，7.48-7.52(m，2H).

Embodiment 5.N-benzyl oxygen base carbonyl-L-glutamic acid gamma-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide

Embodiment 5A.N-[(9H-fluorenes-9-yl) methoxycarbonyl]-O-(benzyl)-D-serine tert-butyl

Under 0 ℃, in the airtight flask with tert-butyl acetate (3mL) and the concentrated sulfuric acid (40 μ L) processing the N-[(9H-fluorenes-9-yl in carrene (8mL)) methoxycarbonyl]-O-(benzyl)-D-serine (0.710g, 1.70mmol).After reaction is finished (TLC), this reaction carrene (10mL) and saturated potassium bicarbonate aqueous solution (15mL) quencher.Organic layer also evaporates with distilled water wash.The residue that obtains obtains the title compound (0.292g, 77%) of colorless oil through rapid column chromatography purifying (98: 2 methylene chloride);

¹H NMR(CDCl ₃)δ1.44(s，9H)；3.68(dd，J＝2.9Hz，J＝9.3Hz，1H)；3.87(dd，J＝2.9Hz，J＝9.3Hz，1H)；4.22(t，J＝7.1Hz，1H)；4.30-4.60(m，5H)；5.64-5.67(m，1H)；7.25-7.39(m，9H)；7.58-7.61(m，2H)；7.73-7.76(m，2H).

Embodiment 5B.O-(benzyl)-D-serine tert-butyl

(0.620g 1.31mmol) handled 5 hours with three (2-amino-ethyl) amine (2.75mL) compound of embodiment 5A in carrene (5mL).The mixture that obtains with saturated potassium bicarbonate aqueous solution washing once, evaporates subsequently with phosphoric acid buffer agent (pH=5.5) washed twice, obtains the title compound of 0.329g (quantitative yield) pale solid shape;

¹H NMR(CD ₃OD)δ1.44(s，9H)；3.48(dd，J＝J′＝4.2Hz，1H)；3.61(dd，J＝4.0Hz，J＝9.2Hz，1H)；3.72(dd，J＝4.6Hz，J＝9.2Hz，1H)；4.47(d，J＝12.0Hz，1H)；4.55(d，J＝12.0Hz，1H)；7.26-7.33(m，5H).

Embodiment 6. is formed the universal method of acid amides by carboxylic acid

N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

1g (2.93mmol) the N-benzyl oxygen base carbonyl-D-aspartic acid β-solution of tert-butyl ester monohydrate (Novabiochem) in the 3-4mL carrene is by adding 0.46mL (3.21mmol) 3-(trifluoromethyl) benzyl amine, 0.44g (3.23mmol) 1-hydroxyl-7-BTA and 0.62g (3.23mmol) 1-[3-(dimethylamino) propyl group successively]-processing of 3-ethyl-carbodiimide hydrochloride.Room temperature at least 12 hours or after determined to react completely by thin-layer chromatography (eluent is 95: 5 methylene chloride), reactant mixture is used saturated sodium bicarbonate aqueous solution and distilled water wash successively.The organic layer evaporation is obtained the title compound of 1.41g (quantitative yield) pale solid shape;

¹H NMR(CDCl ₃)δ1.39(s，9H)；2.61(dd，J＝6.5Hz，J＝17.2Hz，1H)；2.98(dd，J＝4.2Hz，J＝17.2Hz，1H)；4.41(dd，J＝5.9Hz，J＝15.3Hz，1H)；4.50-4.57(m，2H)；5.10(s，2H)；5.96-6.01(m，1H)；6.91-7.00(m，1H)；7.30-7.36(m，5H)；7.39-7.43(m，2H)；7.48-7.52(m，2H).

Method according to embodiment 6 prepares embodiment 7-7H, and difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with suitable amino acid derivativges, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine.

Embodiment 7.N-benzyl oxygen base carbonyl-D-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

N-benzyl oxygen base carbonyl-D-glutamic acid gamma-tert-butyl ester (114g, 3.37mmol) and 0.53mL (3.70mmol, Novabiochem) 3-(trifluoromethyl) benzyl amine reaction obtain the compound of the embodiment 7 of 1.67g (quantitative yield) pale solid shape.The compound of embodiment 7 ¹The HNMR spectrum is consistent with specified structure.

Embodiment 7A.N-benzyl oxygen base carbonyl-L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl) piperazine amide

(1.36g 4.03mmol) and 0.746g (4.43mmol) 1-cyclohexyl piperazine reaction, obtains the compound of the embodiment 7A of 1.93g (98%) pale solid shape to N-benzyl oxygen base carbonyl-L-glutamic acid α-tert-butyl ester;

¹HNMR(CDCl ₃)δ1.02-1.12(m，5H)；1.43(s，9H)，1.60-1.64(m，1H)；1.80-1.93(m，5H)；2.18-2.52(m，8H)；3.38-3.60(m，4H)；4.20-4.24(m，1H)；5.03-5.13(m，2H)；5.53-5.57(m，1H)；7.28-7.34(m，5H).

Embodiment 7B.N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl) benzyl acid amides

N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (0.25g, 0.73mmol) and 0.12mL (2-fluoro-3-trifluoromethyl) benzyl amine reaction, obtain the compound of the embodiment 7B of 0.365g (quantitative yield) pale solid shape;

¹H NMR(CDCl ₃)δ1.38(s，9H)；2.59(dd，J＝6.5Hz，J＝17.0Hz，1H)；2.95(dd，J＝4.3Hz，J＝17.0Hz，1H)；4.46-4.56(m，3H)；5.11(s，2H)；5.94-5.96(m，1H)；7.15(t，J＝8.0Hz，1H)；7.30-7.36(m，5H)；7.47-7.52(m，2H).

Embodiment 7C.N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-and α-Jia Jibianji] acid amides

(0.25g 0.73mmol) and 0.094mL (S)-reaction of α-Jia Jibianji amine, obtains the compound of the embodiment 7C of 0.281g (90%) pale solid shape to N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem);

¹H NMR(CDCl ₃)δ1.41(s，9H)；1.44(d，J＝7.0Hz，3H)；2.61(dd，J＝7.0Hz，J＝17.0Hz，1H)；2.93(dd，J＝4.0Hz，J＝17.5Hz，1H)；4.50-4.54(m，1H)；5.04-5.14(m，3H)；5.94-5.96(m，1H)；6.76-6.80(m，1H)；7.21-7.37(m，10H).

Embodiment 7D.N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-and α-Jia Jibianji] acid amides

(0.25g 0.73mmol) and 0.094mL (R)-reaction of α-Jia Jibianji amine, obtains the compound of the embodiment 7D of 0.281g (90%) pale solid shape to N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem);

¹HNMR(CDCl ₃)δ1.38(s，9H)；1.43(d，J＝6.9Hz，3H)；2.54(dd，J＝7.3Hz，J＝17.2Hz，1H)；2.87(dd，J＝4.1Hz，J＝17.3Hz，1H)；4.46-4.50(m，1H)；4.99-5.15(m，3H)；5.92-5.96(m，1H)；6.78-6.82(m，1H)；7.21-7.33(m，10H).

Embodiment 7E.N-benzyl oxygen base carbonyl-D-aspartic acid γ-tert-butyl ester α-[N-methyl-N-(3-trifluoromethyl benzyl)] acid amides

N-benzyl oxygen base carbonyl-D-aspartic acid γ-tert-butyl ester (0.303g, 0.89mmol, Novabiochem) and 0.168g (0.89mmol) N-methyl-N-(3-trifluoromethyl benzyl) amine reaction, obtain the compound of the embodiment 7E of 0.287g (65%) pale solid shape;

¹HNMR(CDCI ₃)δ1.40(s，9H)；2.55(dd，J＝5.8Hz，J＝15.8Hz，1H)；2.81(dd，J＝7.8Hz，J＝15.8Hz，1H)；3.10(s，3H)；4.25(d，J＝15.0Hz，1H)；4.80(d，J＝15.5Hz，1H)；5.01-5.13(m，3H)；5.52-5.55(m，1H)；7.25-7.52(m，10H).

Embodiment 7F.N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-and 1-(3-trifluoromethyl) ethyl] acid amides

N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (84mg, 0.25mmol) and 47mg (S)-1-(3-trifluoromethyl) ethylamine reaction, obtain the compound of the embodiment 7F of 122mg (quantitative yield) pale solid shape.

The compound of embodiment 7F ¹The HNMR spectrum is consistent with specified structure.

Embodiment 7G.N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-and 1-(3-trifluoromethyl) ethyl] acid amides

N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (150mg, 0.44mmol) and 83mg (R)-1-(3-trifluoromethyl) ethylamine reaction, obtain the compound of the embodiment 7G of 217mg (quantitative yield) pale solid shape.The compound of embodiment 7G ¹The HNMR spectrum is consistent with specified structure.

Embodiment 7H.N-benzyl oxygen base carbonyl-D-glutamic acid α-methyl esters γ-(3-trifluoromethyl) benzyl acid amides

(508mg 1.72mmol) and 317mg (1.81mmol) 3-(trifluoromethyl) benzyl amine reaction, obtains the compound of the embodiment 7H of 662mg (85%) pale solid shape to N-benzyl oxygen base carbonyl-D-glutamic acid α-methyl esters.The compound of embodiment 7H ¹The HNMR spectrum is consistent with specified structure.

The universal method of embodiment 8. hydrogenation benzyl oxygen base carbonyl amine

L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

With 2.23g (4.64mmol) N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides and palladium (5% weight, on activated carbon, 0.642g) suspension in 30mL methyl alcohol places under the hydrogen atmosphere and determines to transform fully until thin-layer chromatography (eluent is 95: 5 methylene chloride).Reaction removed by filter palladium carbon and filtrate evaporation is obtained the title compound of 1.52g (96%) grease;

¹H NMR(CDCl ₃)δ1.42(s，9H)；2.26(brs，2H)；2.63-2.71(m，1H)；2.82-2.87(m，1H)；3.75-3.77(m，1H)；4.47-4.50(m，2H)；7.41-7.52(m，4H)；7.90(brs，1H).

Method according to embodiment 8 prepares embodiment 9-13P, and difference is to replace N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides with suitable amino acid derivativges.

Embodiment 9.L-aspartic acid β-tert-butyl ester α-4-(2-phenylethyl)] piperazine amide

β-(5.89g 11.9mmol), obtains the compound of the embodiment 9 of 4.24g (98%) canescence oily to tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide to adopt N-benzyl oxygen base cbz l aspartic acid;

¹H NMR(CDCl ₃)；δ1.42(s，9H)；2.61-2.95(m，10H)；3.60-3.90(m，4H)；4.35-4.45(m，1H)；7.17-7.29(m，5H).

Embodiment 10.D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

Carbonyl-(1.41g 2.93mmol), obtains the compound of the embodiment 10 of 0.973g (96%) canescence oily to D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides to adopt N-benzyl oxygen base;

¹H NMR(CDCl ₃)：δ1.42(s，9H)；2.21(brs，2H)；2.67(dd，J＝7.1Hz，J＝16.8Hz，1H)；2.84(dd，J＝3.6Hz，J＝16.7Hz，1H)；3.73-3.77(m，1H)；4.47-4.50(m，2H)；7.41-7.52(m，4H)；7.83-7.87(m，1H)

Embodiment 11.L-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

Carbonyl-(5.41g 10.9mmol), obtains the compound of the embodiment 11 of 3.94g (quantitative yield) canescence oily to L-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides to adopt N-benzyl oxygen base;

¹H NMR(CDCl ₃)：δ1.41(s，9H)；1.73-1.89(m，3H)；2.05-2.16(m，1H)；2.32-2.38(m，2H)；3.47(dd，J＝5.0Hz，J＝7.5Hz，1H)；4.47-4.49(m，2H)；7.36-7.54(m，4H)；7.69-7.77(m，1H).

Embodiment 12.L-glutamic acid gamma-, tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide

Carbonyl-(5.86g 11.50mmol), obtains the compound of the embodiment 12 of 4.28g (99%) canescence oily to L-glutamic acid gamma-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide to adopt N-benzyl oxygen base;

¹H NMR(CDCl ₃)δ1.39(s，9H)；2.00-2.08(m，1H)；2.38-2.46(m，1H)；2.55-2.90(m，9H)；3.61-3.82(m，4H)；4.48-4.56(m，1H)；7.17-7.26(m，5H).

Embodiment 13.D-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

Carbonyl-(1.667g 3.37mmol), obtains the compound of the embodiment 13 of 1.15g (94%) canescence oily to D-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides to adopt N-benzyl oxygen base;

¹H NMR(CDCl ₃)δ1.41(s，9H)；1.80-2.20(m，4H)；2.31-2.40(m，2H)；3.51-3.59(m，1H)；4.47-4.49(m，2H)；7.39-7.52(m，4H)；7.71-7.79(m，1H).

Embodiment 13A.L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl) piperazine amide

Carbonyl-(1.93g 3.96mmol), obtains the compound of the embodiment 13A of 1.30g (93%) canescence oily to L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl) piperazine amide to adopt N-benzyl oxygen base;

¹H NMR(CDCl ₃)δ1.02-1.25(m，5H)；1.41(s，9H)；1.45-1.50(m，1H)；1.56-1.60(m，1H)；1.69-1.80(m，6H)；3.30(dd，J＝4.8Hz，J＝8.5Hz，1H)；3.44(t，J＝9.9Hz，2H)；3.56(t，J＝9.9Hz，2H).

Embodiment 13B.D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl) benzyl acid amides

Carbonyl-(0.36g 0.72mmol), obtains the compound of the embodiment 13B of 0.256g (92%) canescence oily to D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl) benzyl acid amides to adopt N-benzyl oxygen base;

¹H NMR(CDCl ₃)δ1.39(s，9H)；2.50(brs，2H)；2.74(dd，J＝7.0Hz，J＝16.5Hz，1H)；2.86(dd，J＝4.8Hz，J＝16.8Hz，1H)；3.89(brs，2H)；4.47-4.57(m，2H)；7.16(t，J＝7.8Hz，1H)；7.48(t，J＝7.3Hz，1H)；7.56(t，J＝7.3Hz，1H)；7.97-8.02(m，1H).

Embodiment 13C.D-aspartic acid β-tert-butyl ester α-[(S)-and Alpha-Methyl] the benzyl acid amides

Employing N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-and α-Jia Jibianji] (0.275g 0.65mmol), obtains the compound of the embodiment 13C of 0.17g (90%) canescence oily to acid amides;

¹HNMR(CDCl ₃)δ1.40(s，9H)；1.47(d，J＝6.9Hz，3H)；1.98(brs，2H)；2.49(dd，J＝7.9Hz，J＝17.7Hz，1H)；2.83(dd，J＝3.6Hz，J＝16.7Hz，1H)；3.69(brs，1H)；4.99-5.10(m，1H)；7.19-7.33(m，5H)；7.65-7.68(m，1H).

Embodiment 13D.D-aspartic acid β-tert-butyl ester α-[(R)-and α-Jia Jibianji] acid amides

Employing N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-and α-Jia Jibianji] (0.273g 0.64mmol), obtains the compound of the embodiment 13D of 0.187g (quantitative yield) canescence oily to acid amides;

¹HNMR(CDCl ₃)δ1.38(s，9H)；1.46(d，J＝6.9Hz，3H)；1.79(brs，2H)；2.51(dd，J＝7.8Hz，J＝17.5Hz，1H)；2.87(dd，J＝3.6Hz，J＝16.9Hz，1H)；4.19(brs，1H)；4.99-5.11(m，1H)；7.18-7.34(m，5H)；7.86-7.90(m，1H).

Embodiment 13E.D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethyl benzyl)] acid amides

Carbonyl-(0.282g 0.57mmol), obtains the compound of the embodiment 13E of 0.195g (95%) canescence oily to D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethyl benzyl)] acid amides to adopt N-benzyl oxygen base.Embodiment 13E's ¹The HNMR spectrum is consistent with specified structure.

Embodiment 13F.L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide

β-(5.89g 11.9mmol), obtains the compound of 4.24g (98%) the embodiment 13F of canescence oily to tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide to adopt N-benzyl oxygen base cbz l aspartic acid;

¹H NMR(CDCl ₃)：δ1.42(s，9H)；2.61-2.95(m，10H)；3.60-3.90(m，4H)；4.35-4.45(m，1H)；7.17-7.29(m，5H).

Embodiment 13G.D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

Carbonyl-(1.41g 2.93mmol), obtains the compound of the embodiment 13G of 0.973g (96%) canescence oily to D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides to adopt N-benzyl oxygen base;

¹H NMR(CDCl ₃)：δ1.42(s，9H)；2.21(brs，2H)；2.67(dd，J＝7.1Hz，J＝16.8Hz，1H)；2.84(dd，J＝3.6Hz，J＝16.7Hz，1H)；3.73-3.77(m，1H)；4.47-4.50(m，2H)；7.41-7.52(m，4H)；7.83-7.87(m，1H).

Embodiment 13H.L-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

Carbonyl-(5.41g 10.9mmol), obtains the compound of the embodiment 13H of 3.94g (quantitative yield) canescence oily to L-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides to adopt N-benzyl oxygen base;

Embodiment 13I. L-glutamic acid gamma-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide

Carbonyl-(5.86g 11.50mmol), obtains the compound of the embodiment 13I of 4.28g (99%) canescence oily to L-glutamic acid gamma-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide to adopt N-benzyl oxygen base;

Embodiment 13J.D-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides

Carbonyl-(1.667g 3.37mmol), obtains the compound of the embodiment 13J of 1.15g (94%) canescence oily to D-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides to adopt N-benzyl oxygen base;

Embodiment 13K.L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl) piperazine amide

Carbonyl-(1.93g 3.96mmol), obtains the compound of the embodiment 13K of 1.30g (93%) canescence oily to L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl) piperazine amide to adopt N-benzyl oxygen base;

Embodiment 13L.D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl) benzyl acid amides

Carbonyl-(0.36g 0.72mmol), obtains the compound of the embodiment 13L of 0.256g (92%) canescence oily to D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl) benzyl acid amides to adopt N-benzyl oxygen base;

¹H NMR(CDCl ₃)δ1.39(s，9H)；2.50(brs，2H)；2.74(dd，J＝7.0Hz，J＝16.5Hz，1H)；2.86(dd，J＝4.8Hz，J＝16.8Hz，1H)；3.89(brs，2H)；4.47-4.57(m，2H)；7.16(t，J＝7.8 Hz，1H)；7.48(t，J＝7.3Hz，1H)；7.56(t，J＝7.3Hz，1H)；797-8.02(m，1H).

Embodiment 13M.D-aspartic acid β-tert-butyl ester α-[(S)-and 1-(3-trifluoromethyl) ethyl] acid amides

Employing N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-1-(3-trifluoromethyl) ethyl] acid amides (120mg 0.24mmol), obtains the compound of the embodiment 13M of 91mg (91%) canescence oily, and ¹The HNMR spectrum is consistent with specified structure.

Embodiment 13N.D-aspartic acid β-tert-butyl ester α-[(R)-and 1-(3-trifluoromethyl) ethyl] acid amides

Adopt N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-1-(3-trifluoromethyl) ethyl] acid amides (217mg, 0 44mmol), obtain the compound of the embodiment 13N of 158mg (quantitative yield) canescence oily, and ¹The HNMR spectrum is consistent with specified structure.

Embodiment 13O.D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethyl benzyl)] acid amides

Employing N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethyl benzyl)] acid amides (0.282g 0.57mmol), obtains the compound of 0.195g (95%) the embodiment 13O of canescence grease, and ¹The HNMR spectrum is consistent with specified structure.

Embodiment 13P.D-glutamic acid Alpha-Methyl ester γ-(3-trifluoromethyl) benzyl acid amides

Employing N-benzyl oxygen base carbonyl-D-glutamic acid Alpha-Methyl ester γ-(3-trifluoromethyl) benzyl acid amides (764mg 1.69mmol), obtains the compound of the embodiment 13P of g (516mg, 96%) canescence oily, and ¹The HNMR spectrum is consistent with specified structure.

Embodiment 14. is formed the universal method of 2-aza cyclo-butanone by imines and chloroacetic chloride

Step 1: the universal method that forms imines by amino acid derivativges

Solution in carrene uses suitable aldehyde of 1 equivalent and desiccant (for example magnesium sulfate or silica gel) to handle successively with 1 equivalent α-An Jisuanzhi or acid amides, the about 2g desiccant of every gram raw material α-An Jisuanzhi or acid amides.At room temperature reaction stirred is up to all reactant depletion (by the thin-layer chromatography monitoring).Usually this is reflected in 1 hour and finishes.The subsequent filtration reactant mixture, the filter cake washed with dichloromethane, concentrating under reduced pressure filtrate obtains required imines, is used for step subsequently.

Step 2: the universal method of the 2+2 cycloaddition of imines and chloroacetic chloride

Carrene (10mL carrene/1g imines) solution of imines is cooled to 0 ℃.In this cold soln, add the suitable amine (being generally triethylamine) of 1.5 equivalents, drip carrene (chloroacetic chloride that 10mL carrene/1g the is suitable) solution of the suitable chloroacetic chloride of 1.1 equivalents (example chloroacetic chloride as described in example 1 above) then.Allow reactant mixture in 1 hour, rise to room temperature, add the saturated aqueous ammonium chloride quencher then.The gained mixture distributes between water and carrene.Separate each layer, organic layer is successively with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing.The organic layer dried over mgso, concentrating under reduced pressure.Residue can be directly used in next step reaction, perhaps if desired, and by chromatographic purification or use the suitable solvent system crystallization and purification.In various situations, adopt described 2+2 reaction, the spatial chemistry of beta-lactam can be passed through circular dichroism spectra/rotatory dispersive (CD/ORD) and confirm.As an illustration, by previous synthetic (α R, 3S, 4R) and (4R) example of beta-lactam platform three-dimensional chemical configuration can be used as the CD/ORD reference material for α S, 3S.

Embodiment 15.[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] tert-butyl acetate

Adopt the method for embodiment 14, imines with 4.53g (34.5mmol) tert-butyl glycinate and cinnamic acid preparation mixes with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1), obtain the compound (recrystallization, positive chloro-butane) of the embodiment 15 of 5.5g (30%) anhydrous crystalline shape; Fusing point 194-195 ℃.

The universal method of embodiment 16. acidylate acetate (azetidine-2-ketone-1-yl) ester

The solution of acetate (azetidine-2-ketone-1-yl) ester in oxolane (the aza cyclo-butanone solution of 0.22M) is cooled to-78 ℃, adds two (trimethyl silyl) lithium amides (2.2 equivalent).The gained anion is handled with suitable acid halides (1.1 equivalent).After aza cyclo-butanone transformed fully, the saturated aqueous ammonium chloride quencher was used in this reaction, distributes between ethyl acetate and water subsequently.Organic facies is successively with 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing.With dried over mgso gained organic layer, evaporation then.Residue is through silica gel chromatography (with suitable eluant, eluent, for example 3: 2 hexane/ethyl acetate) purifying.

Embodiment 17.2 (RS)-(tert-butoxycarbonyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate 2,2, the 2-trichloro ethyl ester

Adopt the method for embodiment 16, the compound of 9.0g (20mmol) embodiment 15 is obtained the compound of 7.0g (56%) embodiment 17 with 4.2g (20mmol) trichloroethyl chloroformate acidylate; Fusing point 176-178 ℃.

Embodiment 18.2 (RS)-(tert-butoxycarbonyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Compound and the vlil of 52 μ L (0.36mmol) (3-trifluoromethyl benzyl) amine in THF with 0.20g (0.32mmol) embodiment 17.After conversion is finished (TLC),, obtain the compound of the embodiment 18 of 0.17g (82%) white solid with the solvent evaporation and with residue recrystallization (chloroform/hexane); Fusing point 182-184 ℃.

Embodiment 18A.2 (RS)-(tert-butoxycarbonyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(2-fluoro-3-trifluoromethyl benzyl) acid amides

Prepare the compound of embodiment 18A according to the method for embodiment 18, use 2-fluoro-3-(trifluoromethyl) benzyl amine to replace (3-trifluoromethyl benzyl) amine.Obtain the compound (140mg, 41%) of the embodiment 18A of white solid, and shown in ¹The HNMR spectrum is consistent with specified structure.

Method according to embodiment 14 prepares embodiment 19-25AF, wherein uses suitable amino acid derivativges and aldehyde in the step 1, uses suitable chloroacetic chloride in the step 2.

Embodiment 19.2 (S)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 1.52g (4.39mmol) L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides and cinnamic acid preparation, obtain the tenne grease of 2.94g, behind rapid column chromatography purifying (70: 30 hexane/ethyl acetate), obtain the compound of the embodiment 19 of 2.06g (70%) white solid;

¹HNMR(CDCl ₃)δ139(s，9H)；2.46(dd，J＝11.1Hz，J＝16.3Hz，1H)；3.18(dd，J＝3.8Hz，J＝16.4Hz，1H)；4.12-4.17(m，1H)；4.26(d，J＝5.0Hz，1H)；4.45(dd，J＝6.0Hz，J＝14.9Hz，1H)；4.54(dd，J＝5.3Hz，J＝9.8Hz，1H)；4.58-4.66(m，3H)；4.69-4.75(m，1H)；4.81(dd，J＝3.8Hz，J＝11.1Hz，1H)；6.25(dd，J＝9.6Hz，J＝15.8Hz，1H)；6.70(d，J＝15.8Hz，1H)；7.14-7.17(m，2H)；7.28-7.46(m，11H)；7.62(s，1H)；8.27-8.32(m，1H).

Embodiment 19A.2 (S)-(tert-butoxycarbonyl methyl)-2-[3 (R)-(4 (R)-phenyl  azoles alkane-2-ketone-3-yl)-4 (S)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Method according to embodiment 19 prepares embodiment 19A, and difference is to replace 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride with 2-(4 (R)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1A).Obtain the compound (41mg, 13%) of the embodiment 19A of white solid;

¹H NMR(CDCl ₃)δ1.37(8，9H)；3.11(dd，J＝3.7Hz，J＝17.8Hz，1H)；3.20(dd，J＝10.6Hz，J＝17.8Hz，1H)；4.02(dd，J＝3.7Hz，J＝10.6Hz，1H)；4.10-4.17(m，1H)；4.24(d，J＝4.9Hz，1H)；4.4652-4.574(dd，J＝5.9Hz，J＝15.1Hz，1H)；4.58-4.76(m，4H)；6.27(dd，J＝9.6Hz，J＝15.8Hz，1H)；6.79(d，J＝15.8Hz，1H)；7.23-7.53(m，13H)；7.63(s，1H)；8.51-8.55(m，1H).

Embodiment 20.2 (S)-(tert-butoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 394g (10.93mmol) L-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides and cinnamic acid preparation, by obtaining the compound of 5.53g (75%) embodiment 20 behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.36(s，9H)；1.85-1.96(m，1H)；2.18-2.49(m，3H)；4.14-4.19(m，1H)；4.30(d，J＝4.9Hz，2H)；4.44(dd，J＝6.1Hz，J＝14.9Hz，1H)；4.56-4.67(m，4H)；4.71-4.75(m，1H)；6.26(dd，J＝9.6Hz，J＝15.8Hz，1H)；6.71(d，J＝15.8Hz，1H)；7.16-7.18(m，2H)；7.27-7.49(m，11H)；7.60(s，1H)；8.08-8.12(m，1H).

Embodiment 21.2 (S)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[4-(2-phenylethyl)] piperazine amide

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 4.20g (11.6mmol) L-aspartic acid 3-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide and cinnamic acid preparation, by obtaining the compound of 4.37g (55%) embodiment 21 behind the rapid column chromatography purifying (50: 50 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.34(s，9H)；2.26-2.32(m，1H)；2.46-2.63(m，4H)；2.75-2.89(m，4H)；3.24-3.32(m，1H)；3.49-3.76(m，3H)；4.07-4.13(m，1H)；4.30(d，J＝4.6Hz，1H)；4.22-4.48(m，1H)；4.55-4.61(m，1H)；4.69-4.75(m，1H)；5.04-5.09(m，1H)；6.15(dd，J＝9.3Hz，J＝15.9Hz，1H)；6.63(d，J＝15.8Hz，1H)；7.18-7.42(m，15H).

Embodiment 22.2 (S)-(tert-butoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[4-(2-phenylethyl)] piperazine amide

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 2.54g (6.75mmol) L-glutamic acid gamma-tert-butyl ester α-[4-(2-phenylethyl)] piperazine amide and cinnamic acid preparation, by obtaining the compound of 3.55g (76%) embodiment 22 behind the rapid column chromatography purifying (50: 50 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.32(s，9H)；1.96-2.07(m，1H)；2.15-2.44(m，6H)；2.54-2.62(m，2H)；2.69-2.81(m，3H)；3.28-3.34(m，1H)；3.59-3.68(m，1H)；4.08-4.13(m，1H)；4.33-4.44(m，2H)；4.48-4.60(m，2H)；4.67-4.77(m，1H)；6.14(dd，J＝8.9Hz，J＝16.0Hz，1H)；6.62(d，J＝16.0Hz，1H)；7.16-7.42(m，15H).

Embodiment 23.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 0.973g (2.81mmol) D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides and cinnamic acid preparation, by obtaining the compound of 1.53g (82%) embodiment 23 behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.37(s，9H)；3.10(dd，J＝3.7Hz，J＝17.8Hz，1H)；3.20(dd，J＝10.7Hz，J＝17.8Hz，1H)；4.02(dd，J＝3.6Hz，J＝10.6Hz，1H)；4.11-4.17(m，1H)；4.24(d，J＝4.9Hz，1H)；4.46(dd，J＝5.8Hz，J＝15.1Hz，1H)；4.58-4.67(m，3H)；4.70-4.76(m，1H)；6.27(dd，J＝9.5Hz，J＝15.8Hz，1H)；6.79(d，J＝15.8Hz，1H)；7.25-7.50(m，13H)；7.63(s，1H)；8.50-8.54(m，1H).

Embodiment 23A.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (R)-(4 (R)-phenyl  azoles alkane-2-ketone-3-yl)-4 (S)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Method according to embodiment 23 prepares embodiment 23A, and difference is to replace 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride with 2-(4 (R)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1A).Obtain the compound (588mg, 49%) of the embodiment 23A of white solid;

¹H NMR(CDCl ₃)δ1.39(s，9H)；2.47(dd，J＝11.2Hz，J＝16.3Hz，1H)；3.18(dd，J＝3.8Hz，J＝16.3Hz，1H)；4.15(t，J＝8.25，HZ 1H)；4.26(d，J＝5.0Hz，1H)；4.45(dd，J＝6.0Hz，J＝15.0Hz，1H)；4.52-4.57(m，3H)；4.63(t，J＝9Hz，1H)；4.70(t，J＝8Hz，1H)；4.81(dd，J＝3.8Hz，J＝10.8Hz，1H)；6.25(dd，J＝9.8Hz，J＝15.8Hz，1H)；6.70(d，J＝15.8Hz，1H)；7.15-7.17(m，2H)；7.27-7.51(m，11H)；7.62(s，1H)；8.27-8.32(m，1H).

Embodiment 24.2 (R)-(tert-butoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Imines with 1.15g (3.20mmol) D-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides and cinnamic acid preparation mixes with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1), by obtaining the compound of 1.84g (85%) embodiment 24 behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.37(s，9H)；2.23-2.39(m，4H)；3.71-3.75(m，1H)；4.13-4.18(m，1H)；4.31(d，J＝4.9Hz，1H)；4.44-4.51(m，2H)；4.56-4.68(m，2H)；4.71-4.76(m，1H)；6.26(dd，J＝9.5Hz，J＝15.8Hz，1H)；6,71(d，J＝15.8Hz，1H)；7.25-7.52(m，13H)；7.63(s，1H)；8.25.8.30(m，1H).

Embodiment 25.2 (S)-(tert-butoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(4-cyclohexyl) piperazine amide

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 2.58g (5.94mmol) L-glutamic acid gamma-tert-butyl ester α-(4-cyclohexyl) piperazine amide and cinnamic acid preparation, by obtaining the compound of 3.27g (94%) embodiment 25 behind the rapid column chromatography purifying (95: 5 methylene chloride);

¹H NMR(CDCl ₃)δ1.32(s，9H)；1.10-1.18(m，1H)；1.20-1.31(m，2H)；1.38-1.45(m，2H)；1.61-1.66(m，1H)；1.84-1.89(m，2H)；1.95-2.01(m，1H)；2.04-2.14(m，3H)；2.20-2.24(m，1H)；2.29-2.35(m，1H)；2.85-2.92(m，1H)；3.24-3.32(m，1H)；3.36-3.45(m，2H)；3.80-3.86(m，1H)；4.08(t，J＝8.3Hz，1H)；4.27(d，J＝5.0Hz，1H)；4.31-4.55(m，4H)；4.71(t，J＝8.3Hz，1H)；4.83-4.90(m，1H)；6.18(dd，J＝9.1Hz，J＝15.9Hz，1H)；6.67(d，J＝15.9Hz，1H)；7.25-7.44(m，10H)；8.22(brs，1H).

Embodiment 25A.2 (S)-(2-(4-cyclohexyl piperazinyl carbonyl) ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] tert-butyl acetate

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 1.282g (3.63mmol) L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl) piperazine amide and cinnamic acid preparation, by obtaining the compound of 1.946g (80%) embodiment 25A behind the rapid column chromatography purifying (50: 50 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.15-1.26(m，6H)；1.39(s，9H)；1.55-1.64(m，2H)；1.77-1.83(m，3H)；2.22-2.35(m，2H)；2.40-2.50(m，6H)；2.75-2.79(m，1H)；3.43-3.48(m，1H)；3.56-3.60(m，2H)；3.75-3.79(m，1H)；4.10(t，J＝8.3Hz，1H)；4.31-4.35(m，2H)；4.58(t，J＝8.8Hz，1H)；4.73(t，J＝8.4Hz，1H)；6.17(dd，J＝8.6Hz，J＝16.0Hz，1H)；6.65(d，J＝16.0Hz，1H)；7.27-7.42(m，10H).

Embodiment 25B.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(2-fluoro-3-trifluoromethyl benzyl) acid amides

To mix with 2-(4 (S)-phenyl  oxazolidinyl-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 0.256g (0.70mmol) D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl) benzyl acid amides and cinnamic acid preparation, by obtaining the compound of 0.287g (60%) embodiment 25B behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹H NMR(CDCl ₃)δ1.38(s，9H)；3.12(dd，J＝4.0Hz，J＝17.8Hz，1H)；3.20(dd，J＝10.4Hz，J＝17.8Hz，1H)；4.05(dd，J＝3.9Hz，J＝10.4Hz，1H)；4.14(dd，J＝J′＝8.2Hz，1H)；4.25(d，J＝4.9Hz，1H)；4.59-4.67(m，4H)；4.74(t，J＝8.3Hz，1H)；6.36(dd，J＝9.6Hz，J＝15.8Hz，1H)；6.83(d，J＝15.8Hz，1H)；7.02-7.07(m，1H)；7.28-7.55(m，12H)；8.44-8.48(m，1H).

Embodiment 25C.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(S)-α-Jia Jibianji] acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 0.167g (0.57mmol) D-aspartic acid β-tert-butyl ester [(S)-α-Jia Jibianji] acid amides and cinnamic acid preparation, by obtaining the compound of 0.219g (63%) embodiment 25C behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.35(s，9H)；1.56(d，J＝7.0Hz，3H)；2.97(dd，J＝3.5Hz，J＝18.0Hz，1H)；3.15(dd，J＝11.0Hz，J＝17.5Hz，1H)；4.01(dd，J＝3.0Hz，J＝11.0Hz， 1H)；4.14(t，J＝8.5Hz，1H)；4.24(d，J＝5.0Hz，1H)；4.57(dd，J＝5.0Hz，J＝9.5Hz，1H)；4.64(t，J＝8.8Hz，1H)；5.07(t，J＝8.5Hz，1H)；5.03-5.09(m，1H)；6.43(dd，J＝9.5Hz，J＝16.0Hz，1H)；6.83(d，J＝16.0Hz，1H)；7.16-7.20(m，1H)；7.27-7.49(m，14H)；8.07-8.10(m，1H).

Embodiment 25D.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(R)-α-Jia Jibianji] acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 0.187g (0.46mmol) D-aspartic acid β-tert-butyl ester [(R)-α-Jia Jibianji] acid amides and cinnamic acid preparation, by obtaining the compound of 0.25g (64%) embodiment 25D behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.36(s，9H)；1.59(d，J＝7.1Hz，3H)；3.10(dd，J＝3.5Hz，J＝17.8Hz，1H)；3.22(d d，J＝10.9Hz，J＝17.8Hz，1H)；3.93(dd，J＝3.5Hz，J＝10.8Hz，1H)；4.14(t，J＝8.1Hz，1H)；4.24(d，J＝5.0Hz，1H)；4.58(dd，J＝5.0Hz，J＝9.5Hz，1H)；4.65(t，J＝8.7Hz，1H)；4.74(t，J＝8.2Hz，1H)；5.06-5.14(m，1H)；6.32(dd，J＝9.5Hz，J＝15.8Hz，1H)；6.74(d，J＝15.8Hz，1H)；7.19-7.43(m，15H)；8.15-8.18(m，1H).

Embodiment 25E.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-methyl-N-(3-trifluoromethyl benzyl) acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 0.195g (0.41mmol) D-aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethyl benzyl)] acid amides and cinnamic acid preparation, by obtaining the compound of 0.253g (69%) embodiment 25E behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹H NMR(CDCl ₃)δ1.36(s，9H)；2.53(dd，J＝4.0Hz，J＝17.0Hz，1H)；3.06(dd，J＝10.8Hz，J＝16.8Hz，1H)；3.13(s，3H)；4.12(dd，J＝8.0Hz，J＝9.0Hz，1H)；4.26(d，J＝5.0Hz，1H)；4.38(d，J＝15.0Hz，1H)；4.46(dd，J＝5.0Hz，J＝9.5Hz，1H)；4.56(t，J＝6.8Hz，1H)；4.70-4.79(m，2H)；5.27(dd，J＝4.0Hz，J＝11.0Hz，1H)；6.22(dd，J＝9.3Hz，J＝15.8Hz，1H)；6.73(d，J＝15.8Hz，1H)；7.33-7.45(m，14H).

Embodiment 25F.2 (S)-(tert-butoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-chlorostyrene-2-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 1.62g (4.44mmol) L-glutamic acid gamma-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides and α-chlorocinnamaldehyde preparation, by obtaining the compound of 0.708g (22%) embodiment 25F behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹H NMR(CDCl ₃)δ1.35(s，9H)；1.68(brs，1H)；2.19-2.35(m，2H)；2.40-2.61(m，2H)；4.13(dd，J＝7.5Hz，J＝9.0Hz，1H)；4.22(t，J＝7.0Hz，1H)；4.34(d，J＝4.5Hz，1H)；4.45(dd，J＝5.5Hz，J＝15.0Hz，1H)；4.51-4.60(m，3H)；4.89(dd，J＝7.5Hz，J＝8.5Hz，1H)；6.89(s，1H)；7.28-7.54(m，14H).

Embodiment 25G.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2 '-methoxy styrene-2-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Will by 0.34g (0.98mmol) D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl benzyl) acid amides and 2 '-imines of methoxycinnamic aldehyde preparation mixes with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1), by obtaining the compound of 0.402g (59%) embodiment 25G behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹H NMR(CDCl ₃)δ1.35(s，9H)；1.68(brs，1H)；2.19-2.35(m，2H)；2.40-2.61(m，2H)；4.13(dd，J＝7.5Hz，J＝9.0Hz，1H)；4.22(t，J＝7.0Hz，1H)；4.34(d，J＝4.5Hz，1H)；4.45(dd，J＝5.5Hz，J＝15.0Hz，1H)；4.51-4.60(m，3H)；4.89(dd，J＝7.5 Hz，J＝8.5Hz，1H)；6.89(s，1H)；7.28-7.54(m，14H).

Embodiment 25H. (2R)-(benzyl oxygen ylmethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] tert-butyl acetate

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 0.329g (1.31mmol) O-(benzyl)-D-serine tert-butyl (embodiment 5B) and cinnamic acid preparation, by obtaining the compound of 0.543g (73%) embodiment 25H behind the rapid column chromatography purifying (90: 10 hexane/ethyl acetate);

¹H NMR(CDCl ₃)δ1.39(s，9H)；3.56(dd，J＝2.7Hz，J＝9.5Hz，1H)；3.82(dd，J＝4.8Hz，J＝9.5Hz，1H)；4.11(t，J＝8.3Hz，1H)；4.21-4.29(m，2H)；4.50-4.58(m，3H)；4.71-4.78(m，2H)；6.19(dd，J＝9.1Hz，J＝16.0Hz，1H)；6.49(d，J＝16.0Hz，1H)；7.07-7.11(m，1H)；7.19-7.40(m，14H).

Embodiment 25I.2 (S)-(2-(4-cyclohexyl piperazinyl carbonyl) methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] tert-butyl acetate

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 0.3g (0.88mmol) L-aspartic acid α-tert-butyl ester γ-(4-cyclohexyl) piperazine amide and cinnamic acid preparation, by obtaining the compound of the embodiment 25I of 464mg (80%) white solid behind the rapid column chromatography purifying (50: 50 hexane/ethyl acetate).The compound of embodiment 25I ¹The HNMR spectrum is consistent with specified structure.

Embodiment 25J.3 (R)-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-3-methyl-4 (R)-(styrene-2-yl) azetidine-2-ketone-1-yl]-3-[(3-trifluoromethyl) phenyl methyl amino carbonyl] the propionic acid tert-butyl ester

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) propionyl chloride (embodiment 1E) by the imines of 0.307g (0.89mmol) D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides (embodiment 20) and cinnamic acid preparation, by obtaining 120mg (20%) behind the rapid column chromatography purifying (hexane 70%/EtOAc30%);

¹HNMR(CDCl ₃)δ1.25(s，3H)，1.38(s，9H)；3.09(dd，J＝3.0Hz，J＝18.0Hz，1H)；3.33(dd，J＝12.5Hz，J＝18.0Hz，1H)；4.01(dd，J＝3.0Hz，J＝11.5Hz，1H)；4.04(dd，J＝3.5Hz，J＝8.8Hz，1H)；4.42(d，J＝9.0Hz，1H)；4.45-4.51(m，3H)；4.61-4.66(m，1H)；4.75(dd，J＝3.5Hz，J＝8.5Hz，1H)；6.23(dd，J＝9.0Hz，J＝15.5Hz，1H)；6.78(d，J＝15.5Hz，1H)；7.23-7.53(m，13H)；7.64(s，1H).

Embodiment 25K.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  oxazolidinyl-2-ketone-3-yl)-4 (R)-(propylene-1-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 0.289g (0.83mmol) D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides and crotonaldehyde preparation, by rapid column chromatography purifying (99: 1 CH ₂Cl ₂/ obtain the compound of 381mg (76%) embodiment 25K after MeOH);

¹HNMR(CDCl ₃)δ1.36(s，9H)，1.69(dd，J＝2Hz，J＝6.5Hz，3H)；3.08(dd，J＝3.3Hz，J＝17.8Hz，1H)；3.18(dd，J＝11Hz，J＝17.5Hz，1H)；3.94(dd，J＝3.5Hz，J＝11Hz，1H)；4.12(d，J＝5Hz，1H)；4.15(dd，J＝7Hz，J＝8Hz，1H)；4.35(dd，J＝4.8Hz，J＝9.8Hz，1H)；4.44(dd，J＝6Hz，J＝15Hz，1H)；4.61(dd，J＝6Hz，J＝15Hz，1H)；4.67-4.75(m，2H)；5.52-5.58(m，1H)；5.92-6.00(m，1H)；7.33-7.60(m，9H)；8.47-8.50(m，1H).

Embodiment 25O.2 (S)-(tert-butoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] methyl acetate

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 433mg (1.99mmol) L-glutamic acid gamma-tert-butyl ester α-methyl esters and cinnamic acid preparation, by obtaining the compound of 682mg (64%) embodiment 25O behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹H NMR(CDCl ₃)δ1.32(s，9H)；2.10-2.26(m，1H)；2.30-2.41(m，3H)；3.66(s，3H)；3.95-3.99(m，1H)；4.16(dd，J＝7.5Hz，J＝9Hz，1H)；4.38(dd，J＝5Hz，J＝9Hz，1H)；4.55(d，J＝5Hz 1H)；4.61(t，J＝9Hz，1H)；4.86(dd，J＝7.5Hz，J＝9Hz，1H)；6.00(dd，J＝9Hz，J＝16Hz，1H)；6.60(d，J＝16Hz，1H)；7.26-7.43(m，10H).

Embodiment 25M.2 (S)-(methoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] tert-butyl acetate

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 428mg (1.97mmol) L-glutamic acid gamma-tert-butyl ester α-methyl esters and cinnamic acid preparation, by obtaining the compound of 864mg (82%) embodiment 25M behind the rapid column chromatography purifying (70: 30 hexane/ethyl acetate);

¹HNMR(CDCl ₃)δ1.40(s，9H)；2.12-2.27(m，1H)；2.32-2.55(m，3H)；3.50(s，3H)；3.72(dd，J＝4.6Hz，J＝10.4Hz，1H)；4.12-4.17(m，1H)；4.34(dd，J＝5Hz，J＝9Hz，1H)；4.50(d，J＝5Hz，1H)；4.60(t，J＝8.9Hz，1H)；4.81-4.86(m，1H)；6.06(dd，J＝9Hz，J＝16Hz，1H)；6.59(d，J＝1.6Hz，1H)；7.25-7.42(m，10H).

Embodiment 25P.2 (S)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] methyl acetate

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 424mg (2.09mmol) L-aspartic acid γ-tert-butyl ester α-methyl esters and cinnamic acid preparation, using CH ₂Cl ₂Obtain the compound of 923mg (85%) embodiment 25P behind the/hexane recrystallization;

¹HNMR(CDCl ₃)δ1.41(s，9H)；2.77(dd，J＝7.5Hz，J＝16.5Hz，1H)；3.00(dd，J＝7Hz，J＝16.5Hz，1H)；4.16(dd，J＝7.5Hz，J＝9Hz，1H)；4.41-48(m，2H)；4.55(d，J＝5Hz，1H)；4.60(t，J＝8.8Hz，1H)；4.86(dd，J＝7.5Hz，J＝9Hz，1H)；5.93(dd，J＝9.5Hz，J＝15.5Hz，1H)；6.61(d，J＝15.5Hz，1H)；7.25-7.43(m，10H).

Embodiment 25L.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(R)-1-(3-trifluoromethyl) ethyl] acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 160mg (0.44mmol) D-aspartic acid β-tert-butyl ester α-[(R)-1-(3-trifluoromethyl) ethyl] acid amides and cinnamic acid preparation, (obtain the compound of 166mg (55%) embodiment 25L behind 70: 30 hexanes/EtOAc) by the rapid column chromatography purifying.The compound of embodiment 25L ¹The HNMR spectrum is consistent with specified structure.

Embodiment 25N.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(S)-1-(3-trifluoromethyl) ethyl] acid amides

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 120mg (0.22mmol) D-aspartic acid β-tert-butyl ester α-[(S)-1-(3-trifluoromethyl) ethyl] acid amides and cinnamic acid preparation, (obtain the compound of 75mg (50%) embodiment 25N behind 70: 30 hexanes/EtOAc) by the rapid column chromatography purifying.The compound of embodiment 25N ¹The HNMR spectrum is consistent with specified structure.

Embodiment 25Q.2 (R)-(2-(3-trifluoromethyl benzyl) amino carbonyl) ethyl)-and 2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] methyl acetate

To mix with 2-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl) chloroacetic chloride (embodiment 1) by the imines of 517mg (1.62mmol) D-glutamic acid α-methyl esters γ-(3-trifluoromethyl) benzyl acid amides and cinnamic acid preparation, (obtain the compound of 527mg (51%) embodiment 25Q behind 50: 50 hexanes/EtOAc) by the rapid column chromatography purifying.The compound of embodiment 25Q ¹The HNMR spectrum is consistent with specified structure.

Prepare following compound according to method described in the literary composition:

Embodiment	Y	C (3)-C (4) spatial chemistry
Embodiment	Y	C (3)-C (4) spatial chemistry	25R	F	(3S，4R)
25S	F	Do not determine	25R	F	(3S，4R)
25S	F	Do not determine	25T	Br	Do not determine
25U	Br	Do not determine	25T	Br	Do not determine

Embodiment	A
Embodiment	A	25V	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino (amide)

25W	1-phenyl-cyclopenta amino (amide)

Embodiment	C (3)-C (4) spatial chemistry	R
Embodiment	C (3)-C (4) spatial chemistry	R	25X	(3S)-cis	Me
25Y	Do not determine	H	25X	(3S)-cis	Me

Embodiment	A
Embodiment	A	25Z	1-phenyl-ring penta-1-base is amino
25AA	(R)-1-phenyl second-1-amino	25Z	1-phenyl-ring penta-1-base is amino

Embodiment	C (3)-C (4) spatial chemistry	A	A′
Embodiment	C (3)-C (4) spatial chemistry	A	A′	25AB	(3S，4R)	α, α-Er Jiajibianji amino	The tert-butyl ester
25AC	Do not determine	N-methyl-3-CF3-benzylamino	The tert-butyl ester	25AB	(3S，4R)	α, α-Er Jiajibianji amino	The tert-butyl ester
25AC	Do not determine	N-methyl-3-CF3-benzylamino	The tert-butyl ester	25AD	Do not determine	(R)-alpha-methyl benzyl amino	The tert-butyl ester
25AE	(3S，4R)	(R)-and α, N-dimethyl benzyl amino	The tert-butyl ester	25AD	Do not determine	(R)-alpha-methyl benzyl amino	The tert-butyl ester

Embodiment 25AF.2 (S)-(2-(3-trifluoromethyl benzyl) amino carbonyl) ethyl)-and 2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] tert-butyl acetate

The universal method of the embodiment 26. hydrolysis tert-butyl esters

The solution (be generally 1g/10mL) of tert-butyl ester derivative in formic acid stirred under room temperature until thin-layer chromatography (carrene 95%/methyl alcohol 5%) no longer detect more ester, the reaction time is about 3 hours usually.Pressure reducing and steaming formic acid; The solid residue that obtains is distributed between carrene and saturated sodium bicarbonate aqueous solution.The organic layer evaporation is obtained pale solid, and it can be directly used in other reactions, or as need be recrystallized with proper solvent system.

Prepare embodiment 27-34AE according to method therefor among the embodiment 26 by the suitable tert-butyl ester.

Embodiment 27.2 (R, S)-(carboxyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(0.30g, 0.46mmol) hydrolysis obtain the compound of the embodiment 27 of 0.27g (quantitative yield) pale solid shape with the compound of embodiment 18;

¹H NMR(CDCl ₃)δ4.17-5.28(m，9H)；6.21-6.29(m，1H)，6.68-6.82(m，1H)；7.05-7.75(m，13H)；9.12-9.18(m，1H).

Embodiment 28.2 (S)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(1.72g, 2.59mmol) hydrolysis obtain the compound of the embodiment 28 of 1.57g (quantitative yield) pale solid shape with the compound of embodiment 19;

¹H NMR(CDCl ₃)δ2.61(dd，J＝9.3Hz，J＝16.6Hz，1H)；3.09-3.14(m，1H)；4.10-4.13(m，1H)；4.30(d，J＝4.5Hz，1H)；4.39-4.85(m，6H)；6.20(dd，J＝9.6Hz，J＝15.7Hz，1H)；6.69(d，J＝15.8Hz，1H)；7.12-7.15(m，2H)；7.26-7.50(m，11H)；7.61(s，1H)；8.41-8.45(m，1H).

Embodiment 28A.2 (S)-(carboxymethyl)-2-[3 (R)-(4 (R)-phenyl  azoles alkane-2-ketone-3-yl)-4 (S)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(41mg, 0.06mmol) hydrolysis obtain the compound of the embodiment 28A of 38mg (quantitative yield) pale solid shape with the compound of embodiment 19A;

¹H NMR(CDCl ₃)δ2.26(d，J＝7Hz，1H)；4.03(t，J＝7Hz，1H)；4.16(t，J＝8Hz，1H)；4.26(d，J＝4.3Hz，1H)；4.46(dd，J＝5.7Hz，J＝15.1，1H)；4.53-4.75(m，5H)；6.25(dd，J＝9.5Hz，J＝15.7Hz，1H)；6.77(d，J＝15.7Hz，1H)；7.28-7.53(m，13H)；7.64(s，1H)；8.65-8.69(m，1H).

Embodiment 29.2 (S)-(carboxy ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(4.97g, 7.34mmol) hydrolysis obtain the compound of the embodiment 29 of 4.43g (97%) pale solid shape with the compound of embodiment 20;

¹H NMR(CDCl ₃)δ1.92-2.03(m，1H)；2.37-2.51(m，3H)；4.13-4.19(m，1H)；3.32(d，J＝4.9Hz，1H)；4.35-4.39(m，1H)；4.44(dd，J＝5.9Hz，J＝14.9Hz，1H)；4.50-4.57(m，2H)；4.61-4.67(m，1H)；4.70-4.76(m，1H)；6.24(dd，J＝9.6Hz，J＝15.8Hz，1H)；6.70(d，J＝15.8Hz，1H)；7.18-7.47(m，14H).

Embodiment 30.2 (S)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[4-(2-phenylethyl)] piperazine amide

(1.88g, 2.78mmol) hydrolysis obtain the compound of the embodiment 30 of 1.02g (60%) pale solid shape with the compound of embodiment 21;

¹H NMR(CDCl ₃)δ2.63(dd，J＝6.0Hz，J＝16.5Hz，1H)；2.75-2.85(m，1H)；3.00(dd，J＝8.2Hz，J＝16.6Hz，1H)；3.13-3.26(m，4H)；3.37-3.56(m，4H)；3.86-4.00(m，1H)；4.05-4.11(m，1H)；4.24(d，J＝5.0Hz，1H)；4.46-4.66(m，1H)；4.65-4.70(m，1H)；5.10-5.15(m，1H)；6.14(dd，J＝9.3Hz，J＝5.9Hz，1H)；6.71(d，J＝15.9Hz，1H)；7.22-7.41(m，15H)；12.02(s，1H).

Embodiment 31.2 (S)-(carboxy ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[4-(2-phenylethyl)] piperazine amide

(0.383g, 0.55mmol) hydrolysis obtain the compound of the embodiment 31 of 0.352g (quantitative yield) pale solid shape with the compound of embodiment 22;

¹H NMR(CDCl ₃)δ1.93-2.01(m，1H)；2.07-2.36(m，6H)；2.82-2.90(m，1H)；3.00-3.20(m，4H)；3.36-3.54(m，4H)；3.74-3.82(m，1H)；4.06-4.11(m，1H)；4.29(d，J＝4.9Hz，1H)；4.33-4.46(m，2H)；4.50-4.58(m，2H)；4.67-4.72(m，1H)；4.95-5.00(m，1H)；6.18(dd，J＝9.2Hz，J＝16.0Hz，1H)；6.67(d，J＝15.9Hz，1H)；7.19-7.42(m，15H)；8.80(brs，1H).

Embodiment 32.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(1.51g, 2.27mmol) hydrolysis obtain the compound of the embodiment 32 of 1.38g (quantitative yield) pale solid shape with the compound of embodiment 23.

Embodiment 32A.2 (R)-(carboxymethyl)-2-[3 (R)-(4 (R)-phenyl  azoles alkane-2-ketone-3-yl)-4 (S)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(550mg, 0.83mmol) hydrolysis obtain the compound of the embodiment 32A of 479mg (95%) pale solid shape with the compound of embodiment 23A.The compound of embodiment 32A ¹The HNMR spectrum is consistent with specified structure.

Embodiment 33.2 (R)-(carboxy ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(0.604g, 0.89mmol) hydrolysis obtain the compound of the embodiment 33 of 0.554g (quantitative yield) pale solid shape with the compound of embodiment 24.

Embodiment 34.2 (S)-(carboxy ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) ammonia heterocycle butane-2-ketone-1-yl] acetate N-(4-cyclohexyl) piperazine amide

(0.537g, 0.80mmol) hydrolysis obtain the compound of the embodiment 34 of 0.492g (quantitative yield) pale solid shape with the compound of embodiment 25;

¹H NMR(CDCl ₃)δ1.09-1.17(m，1H)；1.22-1.33(m，2H)；1.40-1.47(m，2H)；1.63-1.67(m，1H)；1.85-1.90(m，2H)；1.95-2.00(m，1H)；2.05-2.15(m，3H)；2.20-2.24(m，1H)；2.30-2.36(m，1H)；2.85-2.93(m，1H)；3.25-3.33(m，1H)；3.36-3.46(m，2H)；3.81-3.87(m，1H)；4.08(t，J＝8.3Hz，1H)；4.28(d，J＝5.0Hz，1H)；4.33-4.56(m，4H)；4.70(t，J＝8.3Hz，1H)；4.834.91(m，1H)；6.17(dd，J＝9.1Hz，J＝15.9Hz，1H)；6.67(d，J＝15.9Hz，1H)；7.25-7.44(m，10H)；8.22(brs，1H).

Embodiment 34A.2 (S)-(2-(4-cyclohexyl piperazinyl carbonyl) ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate

(0.787g, 1.28mmol) hydrolysis obtain the compound of the embodiment 34A of 0.665g (92%) pale solid shape with the compound of embodiment 25A;

¹H NMR(CDCl ₃)δ1.05-1.13(m，1H)；1.20-1.40(m，5H)；1.60-1.64(m，1H)；1.79-1.83(m，2H)；2.00-2.05(m，2H)；2.22-2.44(m，3H)；2.67-2.71(m，1H)；2.93-3.01(m，4H)；3.14-3.18(m，1H)；3.38-3.42(m，1H)；3.48-3.52(m，1H)；3.64-3.69(m，1H)；4.06-4.14(m，2H)；4.34-4.43(m，2H)；4.56(t，J＝8.8Hz，1H)；4.73(t，J＝8.4Hz，1H)；6.15(dd，J＝9.1Hz，J＝16.0Hz，1H)；6.65(d，J＝16.0Hz，1H)；7.25-7.42(m，10H).

Embodiment 34B.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(2-fluoro-3-trifluoromethyl benzyl) acid amides (carboxamide)

(0.26g, 0.38mmol) hydrolysis obtain the compound of the embodiment 34B of 0.238g (quantitative yield) pale solid shape with the compound of embodiment 25B;

¹H NMR(CDCl ₃)δ3.27(d，J＝7.2Hz，lH)；4.06(t，J＝7.2Hz，1H)；4.15(t，J＝8.1Hz，1H)；4.27(d，J＝4.8Hz，1H)；4.56-4.76(m，5H)；634(dd，J＝9.5Hz.J＝15.7Hz，1H)；6.80(d，J＝15.7Hz，1H)；7.06(t，J＝7.7Hz，1H)；7.31-7.54(m，12H)；8.58(t，J＝5.9Hz，1H).

Embodiment 34C.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(S)-α-Jia Jibianji] acid amides

(0.215g, 0.35mmol) hydrolysis obtain the compound of the embodiment 34C of 0.195g (quantitative yield) pale solid shape with the compound of embodiment 25C;

¹H NMR(CDCl ₃)δ1.56(d，J＝7.0Hz，1H)；3.10(dd，J＝4.5Hz，J＝17.9Hz，1H)；3.18(dd，J＝9.8Hz，J＝17.9Hz，1H)；4.00(dd，J＝4.5Hz，J＝9.7Hz，1H)；4.14(t，J＝8.2Hz，1H)；4.26(d，J＝4.7Hz，1H)；5.02-5.09(m，1H)；6.41(dd，J＝9.4Hz，J＝15.8Hz，1H)；6.78(d，J＝15.8Hz，1H)；7.18(t，J＝7.3Hz，1H)；7.26-7.43(m，12H)；8.29(d，J＝8.2Hz，1H)，

Embodiment 34D.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(R)-α-Jia Jibianji] acid amides

(0.22g, 0.35mmol) hydrolysis obtain the compound of the embodiment 34D of 0.20g (quantitative yield) pale solid shape with the compound of embodiment 25D;

¹H NMR(CDCl ₃)δ1.59(d，J＝7.0Hz，1H)；3.25(d，J＝7.0Hz，2H)；3.92(t，J＝7.3Hz，1H)；4.15(t，J＝8.3Hz，1H)；4.26(d，J＝5.0Hz，1H)；4.52(dd，J＝4.8Hz，J＝9.3Hz，1H)；4.65(t，J＝8.8Hz，1H)；4.72(t，J＝8.3Hz，1H)；5.07-5.28(m，1H)；6.29(dd，J＝9.5Hz，J＝15.6Hz，1H)；6.71(d，J＝16.0Hz，1H)；7.20-7.43(m，13H)；8.31(d，J＝8.0Hz，1H).

Embodiment 34E.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-methyl-N-(3-trifluoromethyl benzyl) acid amides

(0.253g, 0.37mmol) hydrolysis obtain the compound of the embodiment 34E of 0.232g (quantitative yield) pale solid shape with the compound of embodiment 25E;

¹H NMR(CDCl ₃)δ3.07-3.15(m，4H)；4.13(t，J＝8.2Hz，1H)；4.30(d，J＝4.9Hz，1H)；4.46-4.78(m，5H)；5.23(dd，J＝4.6Hz，J＝9.7Hz，1H)；6.20(dd，J＝9.4Hz，J＝15.9Hz，1H)；6.73(d，J＝15.9Hz，1H)；7.25-7.43(m，15H).

Embodiment 34F.2 (S)-(carboxy ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-chlorostyrene-2-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(0.707g, 0.99mmol) hydrolysis obtain the compound of the embodiment 34F of 0.648g (99%) pale solid shape with the compound of embodiment 25F;

¹H NMR(CDCl ₃)δ2.22-2.28(m，2H)；2.49-2.64(m，2H)；4.09(t，J＝8.0Hz，1H)；4.25-4.62(m，6H)；4.87(t，J＝8.0Hz，1H)；6.88(s，1H)；7.25-7.66(m，15H).

Embodiment 34G.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2 '-methoxy styrene-2-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

(0.268g, 0.39mmol) hydrolysis obtain the compound of the embodiment 34G of 0.242g (98%) pale solid shape with the compound of embodiment 25G;

¹H NMR(CDCl ₃)δ3.26(d，J＝7.1Hz，1H)；3.79(s，3H)；4.14(t，J＝8.2Hz，1H)；4.25(d，J＝4.5Hz，1H)；4.51(dd，J＝5.9Hz，J＝15.5Hz，1H)；4.53-4.66(m，4H)；6.36(dd，J＝9.4Hz，J＝15.8Hz，1H)；8.88(t，J＝8.2Hz，1H)；6.70(d，J＝15.8Hz，1H)；7.18(d，J＝6.5Hz，1H)；7.25-7.48(m，10H)；7.48(s，1H)；8.66-8.69(m1H).

Embodiment 34H. (2R)-(benzyl oxygen ylmethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate

(0.16g, 0.28mmol) hydrolysis obtain the compound of the embodiment 34H of 0.144g (quantitative yield) pale solid shape with the compound of embodiment 25H;

¹HNMR(CDCl ₃)δ3.65(dd，J＝4.0Hz，J＝9.5Hz，1H)；3.82(dd，J＝5.5Hz，J＝9.5Hz，1H)；4.11(dd，J＝7.8Hz，J＝8.8Hz，1H)；4.33(s，2H)；4.50(d，J＝5.0Hz，1H)；4.57(t，J＝9.0Hz，1H)；4.67(dd，J＝4.0Hz，J＝5.0Hz，1H)；4.69(dd，J＝5.0Hz，J＝9.5Hz，1H)；4.75(t，J＝8.0Hz，1H)；6.17(dd，J＝9.3Hz，J＝15.8Hz，1H)；6.55(d，J＝16.0Hz，1H)；7.09-7.12(m，2H)；7.19-7.42(m，13H).

Embodiment 34I.2 (S)-(2-(4-cyclohexyl piperazinyl carbonyl) methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate

(737mg, 1.12mmol) hydrolysis obtains the compound of the embodiment 34I of 640mg (95%) pale solid shape with the compound of embodiment 25I.The compound of embodiment 34I ¹H NMR spectrum is consistent with specified structure.

Embodiment 34J.3 (R)-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-3-methyl-4 (R)-(styrene-2-yl) azetidine-2-ketone-1-yl]-3-[(3-trifluoromethyl) phenyl methyl amino carbonyl] propionic acid

Adopt the universal method of embodiment 26,, obtain the compound of the embodiment 34J of 108mg (98%) pale solid shape the compound hydrolysis of 120mg (0.18mmol) embodiment 25J;

¹HNMR(CDCl ₃)δ1.22(s，3H)；3.25(dd，J＝3.5Hz，J＝18.0Hz，1H)；3.36(dd，J＝10.8Hz，J＝18.2Hz，1H)；4.01(dd，J＝4.0Hz，J＝10.5Hz，1H)；4.05(dd，J＝3.8Hz，J＝8.8Hz，1H)；4.33(d，J＝9.0Hz，1H)；4.44-4.51(m，3H)；4.61-4.66(m，1H)；4.73(dd，J＝3.8Hz，J＝8.8Hz，1.H)；6.19(dd，J＝9.0Hz，J＝16.0Hz，1H)；6.74(d，J＝16.0Hz，1H)；7.22-7.54(m，13H)；7.65(s，1H).

Embodiment 34K.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(propylene-1-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the universal method of embodiment 26,, obtain the compound of the embodiment 34K of 131mg (90%) pale solid shape the compound hydrolysis of 160mg (0.27mmol) embodiment 25K.

¹H NMR(CDCl ₃)δ1.69(dd，J＝1Hz，J＝6.5Hz，3H)；3.23(d，J＝7Hz，1H)；3.93(t，J＝7.3Hz，1H)；4.14-4.20(m，3H)；4.29(dd，J＝5Hz，J＝9.5Hz，1H)；4.43(dd，J＝6Hz，J＝15Hz，1H)；4.61(dd，J＝6.5Hz，J＝15Hz，1H)；4.66-4.74(m，2H)；5.50-5.55(m，1H)；5.90-5.98(m，1H)；7.32-7.60(m，9H)；8.60-8.64(m，1H).

Embodiment 34L.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(R)-1-(3-trifluoromethyl) ethyl] acid amides

(166mg, 0.24mmol) hydrolysis obtain the compound of the embodiment 34L of 152mg (quantitative yield) pale solid shape with the compound of embodiment 25L; And shown in ¹The HNMR spectrum is consistent with specified structure.

Embodiment 34M.2 (S)-(methoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate

With embodiment 25M (875mg, compound hydrolysis 1.64mmol) obtain the compound of the embodiment 34M of 757mg (97%) pale solid shape, and shown in ¹The HNMR spectrum is consistent with specified structure.

Embodiment 34N.2 (R)-(carboxymethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(S)-1-(3-trifluoromethyl) ethyl] acid amides

With the compound of embodiment 25N (38.5mg, 0.057mmol) hydrolysis obtain the compound of the embodiment 34N of 35mg (quantitative yield) pale solid shape, and shown in ¹The HNMR spectrum is consistent with specified structure.

Embodiment 34O.2 (S)-(tert-butoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate

With the compound of embodiment 25O (97mg, 0.18mmol) be dissolved in methyl alcohol/oxolane (2.5mL/2mL) and under room temperature with lithium hydroxide (the 0.85mL 0.85M aqueous solution; 0.72mmol) reacted 6 hours.This reaction adds aqueous hydrochloric acid solution (1M) until water layer pH to 5 (standard pH test paper mensuration) subsequently with the dilution of 15mL carrene.Subsequently organic layer is separated and evaporate to dryness obtains the compound of the embodiment 34O of 84mg (89%) pale solid shape, and shown in ¹The HNMR spectrum is consistent with specified structure.

Embodiment 34P.2 (S)-(tert-butoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate

According to embodiment 34O method therefor, (200mg, 0.39mmol) hydrolysis obtain the compound of the embodiment 34P of 155mg (88%) pale solid shape with the compound of embodiment 25P; And shown in ¹The HNMR spectrum is consistent with specified structure.

Embodiment 34Q.2 (R)-(2-(3-trifluoromethyl benzyl) amino-1-base carbonyl) ethyl)-and 2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate

According to embodiment 34O method therefor, with the compound of embodiment 25Q (150mg, 0.24mmol) hydrolysis obtain the compound of the embodiment 34Q of 143mg (97%) pale solid shape, and ¹The HNMR spectrum is consistent with specified structure.

Embodiment 34R.2 (R)-(tert-butoxycarbonyl methyl)-2-[3 (RS)-2-thienyl methyl]-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

To mix with 2-thiophene-chloroacetic chloride by the imines of 290mg (0.84mmol) D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides and cinnamic acid preparation, behind rapid column chromatography purifying (70: 30 hexane/ethyl acetate), obtain the compound of 42mg (8%) embodiment 34R, and shown in ¹The HNMR spectrum is consistent with specified structure.

Embodiment	Y	C (3)-C (4) spatial chemistry
Embodiment	Y	C (3)-C (4) spatial chemistry	34S	F	(3S，4R)
34T	F	Do not determine	34S	F	(3S，4R)
34T	F	Do not determine	34U	Br	Do not determine

Embodiment	A
Embodiment	A	34V	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino (amide)
34W	1-phenyl-cyclopenta amino (amide)	34V	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino (amide)

Embodiment	C (3)-C (4) spatial chemistry	R
Embodiment	C (3)-C (4) spatial chemistry	R	34X	(3S，4R)	Me
34Y	Do not determine	H	34X	(3S，4R)	Me

Embodiment	A
Embodiment	A	34Z	1-phenyl-ring penta-1-base is amino
34AA	(R)-1-phenylethyl-1-base is amino	34Z	1-phenyl-ring penta-1-base is amino

Embodiment	C (3)-C (4) spatial chemistry	A
Embodiment	C (3)-C (4) spatial chemistry	A	34AB	(3S，4R)	α, α-Er Jiajibianji amino
34AC	Do not determine	N-methyl-3-CF3-benzylamino	34AB	(3S，4R)	α, α-Er Jiajibianji amino
34AC	Do not determine	N-methyl-3-CF3-benzylamino	34AD	Do not determine	(R)-alpha-methyl benzyl amino
34AE	(3S，4R)	(R)-and α, N-dimethyl benzyl amino	34AD	Do not determine	(R)-alpha-methyl benzyl amino

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 36-42A, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate and replace 3-(trifluoromethyl) benzyl amine with suitable amine with the compound of embodiment 27; The compound of listed embodiment ¹The HNMR spectrum is consistent with specified structure.

Embodiment	A′
Embodiment	A′	36	2-(piperidyl) ethylamino
37	4-(piperidyl) piperidyl	36	2-(piperidyl) ethylamino
37	4-(piperidyl) piperidyl	38	4-(2-phenylethyl) piperazinyl
39	1-benzyl piepridine-4-base is amino	38	4-(2-phenylethyl) piperazinyl
39	1-benzyl piepridine-4-base is amino	40	4-butyl piperazinyl
41	4-isopropyl piperazinyl	40	4-butyl piperazinyl
41	4-isopropyl piperazinyl	42	The 4-cyclohexyl piperazinyl
42A	4-[2-(piperidyl) ethyl] piperidyl	42	The 4-cyclohexyl piperazinyl

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 43-86A, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate and replace 3-(trifluoromethyl) benzyl amine with suitable amine with the compound of embodiment 28; The compound of listed embodiment ¹The HNMR spectrum is consistent with specified structure.

Embodiment	A′
Embodiment	A′	43	2-(piperidyl) ethylamino
44	4-(piperidyl) piperidyl	43	2-(piperidyl) ethylamino
44	4-(piperidyl) piperidyl	45	4-(phenylethyl) piperazinyl
46	Furans-2-ylmethyl amino	45	4-(phenylethyl) piperazinyl
46	Furans-2-ylmethyl amino	47	4-(pyrrolidinyl) piperazinyl
48	4-(3-trifluoromethyl) piperazinyl	47	4-(pyrrolidinyl) piperazinyl

Embodiment	A′
Embodiment	A′	49	4-(benzyl oxygen base carbonyl) piperazinyl
50	4-[2-(2-hydroxyl-oxethyl) ethyl] piperazinyl	49	4-(benzyl oxygen base carbonyl) piperazinyl
50	4-[2-(2-hydroxyl-oxethyl) ethyl] piperazinyl	51	4-benzyl diethylenediamine base
52	4-(3,4-methylene dioxy base benzyl) piperazinyl	51	4-benzyl diethylenediamine base
52	4-(3,4-methylene dioxy base benzyl) piperazinyl	53	The 4-Phenylpiperazinyl
54	4-(3-phenyl third-2-thiazolinyl) piperazinyl	53	The 4-Phenylpiperazinyl
54	4-(3-phenyl third-2-thiazolinyl) piperazinyl	55	4-ethyl piperazidine base
56	2-(dimethylamino) ethylamino	55	4-ethyl piperazidine base
56	2-(dimethylamino) ethylamino	57	4-(pyrrolidinyl carbonyl methyl) piperazinyl
58	4-(1-methyl piperidine-4-yl) piperazinyl	57	4-(pyrrolidinyl carbonyl methyl) piperazinyl
58	4-(1-methyl piperidine-4-yl) piperazinyl	59	4-butyl piperazinyl
60	4-isopropyl piperazinyl	59	4-butyl piperazinyl
60	4-isopropyl piperazinyl	61	4-pyridylmethyl amino
62	3-(dimethylamino) propyl group amino	61	4-pyridylmethyl amino
62	3-(dimethylamino) propyl group amino	63	1-benzyl piepridine-4-base is amino
64	N-benzyl-2-(dimethylamino) ethylamino	63	1-benzyl piepridine-4-base is amino
64	N-benzyl-2-(dimethylamino) ethylamino	65	3-pyridylmethyl amino
66	4-(cyclohexyl) piperazinyl	65	3-pyridylmethyl amino
66	4-(cyclohexyl) piperazinyl	67	4-(2-cyclohexyl ethyl) piperazinyl
68	4-[2-(morpholine-4-yl) ethyl] piperazinyl	67	4-(2-cyclohexyl ethyl) piperazinyl
68	4-[2-(morpholine-4-yl) ethyl] piperazinyl	69	4-(4-tert-butyl group benzyl) piperazinyl
70	4-[2-(piperidyl) ethyl] piperazinyl	69	4-(4-tert-butyl group benzyl) piperazinyl
70	4-[2-(piperidyl) ethyl] piperazinyl	71	4-[3-(piperidyl) propyl group] piperazinyl
72	4-[2-(N, N-dipropyl amino) ethyl] piperazinyl	71	4-[3-(piperidyl) propyl group] piperazinyl
72	4-[2-(N, N-dipropyl amino) ethyl] piperazinyl	73	4-[3-(N, N-diethylamino) propyl group] piperazinyl
74	4-[2-(dimethylamino) ethyl] piperazinyl	73	4-[3-(N, N-diethylamino) propyl group] piperazinyl
74	4-[2-(dimethylamino) ethyl] piperazinyl	75	4-[3-(pyrrolidinyl) propyl group] piperazinyl
76	4-(cyclohexyl methyl) piperazinyl	75	4-[3-(pyrrolidinyl) propyl group] piperazinyl
76	4-(cyclohexyl methyl) piperazinyl	77	4-cyclopentyl-based piperazine base
78	4-[2-(pyrrolidinyl) ethyl] piperazinyl	77	4-cyclopentyl-based piperazine base
78	4-[2-(pyrrolidinyl) ethyl] piperazinyl	79	4-[2-(thiophene-2-yl) ethyl] piperazinyl
80	4-(3-phenyl propyl) piperazinyl	79	4-[2-(thiophene-2-yl) ethyl] piperazinyl
80	4-(3-phenyl propyl) piperazinyl	81	4-[2-(N, N-diethylamino) ethyl] piperazinyl
82	The high piperazinyl of 4-benzyl	81	4-[2-(N, N-diethylamino) ethyl] piperazinyl
82	The high piperazinyl of 4-benzyl	83	4-(diphenyl methyl) piperazinyl

Embodiment	A′
Embodiment	A′	84	3-(4-methyl piperazine base) propyl group amino
85	(+)-3 (S)-1-benzyl-pyrrole alkane-3-base is amino	84	3-(4-methyl piperazine base) propyl group amino
85	(+)-3 (S)-1-benzyl-pyrrole alkane-3-base is amino	86	2-pyridylmethyl amino
86A	4-[2-(piperidyl) ethyl] piperidyl	86	2-pyridylmethyl amino
86A	4-[2-(piperidyl) ethyl] piperidyl	86B	1-benzyl piepridine-4-base amino N-oxide

Embodiment 86B.

(44mg 0.06mmol) is dissolved in the 4mL carrene, and (12mg, 0.07mmol) reaction is finished (by the TLC monitoring, carrene 94%/methyl alcohol 6%, UV detection) until reaction with the 3-chloroperoxybenzoic acid subsequently with embodiment 63.Sodium sulfite aqueous solution quencher is used in this reaction, and dichloromethane layer is with 5% sodium bicarbonate aqueous solution and distilled water wash.Dichloromethane layer is boiled off, obtain the compound (35mg, 78%) of the embodiment 86B of pale solid shape, and shown in ¹The HNMR spectrum is consistent with specified structure.

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 121-132, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 30, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; The compound of listed embodiment ¹The HNMR spectrum is consistent with specified structure.

Embodiment	A′
Embodiment	A′	121	3-trifluoromethyl benzyl amino
122	Morpholine-4-base is amino	121	3-trifluoromethyl benzyl amino
122	Morpholine-4-base is amino	123	2-(dimethylamino) ethylamino
124	3-(dimethylamino) propyl group amino	123	2-(dimethylamino) ethylamino
124	3-(dimethylamino) propyl group amino	125	Cyclohexyl amino

Embodiment	A′
Embodiment	A′	126	Piperidyl
127	2-methoxy ethyl amino	126	Piperidyl
127	2-methoxy ethyl amino	128	Isopropyl amino
129	Isobutylamino	128	Isopropyl amino
129	Isobutylamino	130	Ethylamino
131	Dimethylamino	130	Ethylamino
131	Dimethylamino	132	Methylamino

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 132A-132B, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34I, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; Listed embodiment's ¹The HNMR spectrum is consistent with specified structure.

Embodiment	A
Embodiment	A	132A	(2, the 3-dichloro benzyl) amino
132B	1-benzyl ring hexyl amino	132A	(2, the 3-dichloro benzyl) amino

Embodiment 132C.2 (S)-(tert-butoxycarbonyl methyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(4-cyclohexyl) piperazine amide

Adopt the method for embodiment 6 to prepare embodiment 132C, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34P, and replaces 3-(trifluoromethyl) benzyl amine with 1-cyclohexyl-piperazine.The compound of embodiment 132C ¹The HNMR spectrum is consistent with specified structure.

Prepare compound shown in the following table according to method described in the literary composition:

Embodiment	A	A′
Embodiment	A	A′	132D	1-phenyl-ring penta-1-base is amino	4-(piperidyl) piperidyl
132E	1-phenyl-ring penta-1-base is amino	1-benzyl piepridine-4-base is amino	132D	1-phenyl-ring penta-1-base is amino	4-(piperidyl) piperidyl
132E	1-phenyl-ring penta-1-base is amino	1-benzyl piepridine-4-base is amino	132F	(R)-1-phenyl second-1-base is amino	4-(piperidyl) piperidyl

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 133-134G, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 32, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; The compound of listed embodiment ¹The HNMR spectrum is consistent with specified structure.

Embodiment	A′
Embodiment	A′	133	4-(piperidyl) piperidyl
134	4-(2-phenylethyl) piperazinyl	133	4-(piperidyl) piperidyl
134	4-(2-phenylethyl) piperazinyl	134A	4-[2-(piperidyl) ethyl] piperidyl
134B	4-(pyrrolidinyl) piperazinyl	134A	4-[2-(piperidyl) ethyl] piperidyl
134B	4-(pyrrolidinyl) piperazinyl	134C	1-benzyl piepridine-4-base is amino
134D	(pyridin-3-yl methyl) amino	134C	1-benzyl piepridine-4-base is amino
134D	(pyridin-3-yl methyl) amino	134E	3-(dimethylamino) propyl group amino
134F	3-(S)-(1-benzyl-pyrrole alkane-3-yl) amino	134E	3-(dimethylamino) propyl group amino
134F	3-(S)-(1-benzyl-pyrrole alkane-3-yl) amino	134G	The 4-[(piperidyl) methyl] piperidyl
134H	4-(piperidyl) piperidyl N-oxide	134G	The 4-[(piperidyl) methyl] piperidyl

Embodiment 134H. adopts the method for embodiment 86B to prepare embodiment 134H, and difference is to replace embodiment 133 with the compound of embodiment 110.Obtain the compound (48mg, 94%) of the embodiment 134H of pale solid shape, and shown in ¹The HNMR spectrum is consistent with specified structure.

Embodiment 134I.2 (R)-[[4-(piperidyl) piperidyl] carboxymethyl]-2-[3 (S)-(4 (R)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 6 to prepare embodiment 134I, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 32A, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines, and shown in ¹The HNMR spectrum is consistent with specified structure.

Embodiment	C (3)-C (4) spatial chemistry	A	A′
Embodiment	C (3)-C (4) spatial chemistry	A	A′	134J	(3S，4R)	α, α-Er Jiajibianji amino	4-(piperidyl) piperidyl
134K	(3S，4R)	α, α-Er Jiajibianji amino	1-benzyl piepridine-4-base is amino	134J	(3S，4R)	α, α-Er Jiajibianji amino	4-(piperidyl) piperidyl
134K	(3S，4R)	α, α-Er Jiajibianji amino	1-benzyl piepridine-4-base is amino	134L	Do not determine	N-methyl-3-CF3-benzylamino	4-(piperidyl) piperidyl
134M	(3S，4R)	N-methyl-3-CF3-benzylamino	3-(pyrrolidinyl) piperidyl	134L	Do not determine	N-methyl-3-CF3-benzylamino	4-(piperidyl) piperidyl
134M	(3S，4R)	N-methyl-3-CF3-benzylamino	3-(pyrrolidinyl) piperidyl	134N	Do not determine	(R)-alpha-methyl benzyl amino	4-(piperidyl) piperidyl
134O	(3S，4R)	(R)-and α, N-dimethyl benzyl amino	4-(piperidyl) piperidyl	134N	Do not determine	(R)-alpha-methyl benzyl amino	4-(piperidyl) piperidyl

Embodiment 222.2 (R)-[[4-(piperidyl) piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(2-fluoro-3-trifluoromethyl benzyl) acid amides (carboxamide)

Adopt the method for embodiment 6 to prepare embodiment 222, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34B, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines; The compound of embodiment 222 ¹The HNMR spectrum is consistent with specified structure.

Embodiment 223.2 (R)-[[4-(piperidyl) piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(S)-α-Jia Jibianji] acid amides

Adopt the method for embodiment 6 to prepare embodiment 223, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34C, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines; The compound of embodiment 223 ¹The HNMR spectrum is consistent with specified structure.

Embodiment 224.2 (R)-[[4-(piperidyl) piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  oxazolidinyl-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(R)-α-Jia Jibianji] acid amides

Adopt the method for embodiment 6 to prepare embodiment 224, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34D, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines; The compound of embodiment 223 ¹The HNMR spectrum is consistent with specified structure.

Embodiment 225.2 (R)-[[4-(piperidyl) piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-methyl-N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 6 to prepare embodiment 225, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34E, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines; The compound of embodiment 223 ¹The HNMR spectrum is consistent with specified structure; C ₄₃H ₄₈F ₃N ₅O ₅Calculated value be: C, 66.91; H, 6.27; N, 9.07; Measured value is: C, 66.68; H, 6.25; N, 9.01.

Embodiment 225 hydrochlorides

The compound (212.5mg) of embodiment 225 is dissolved in the anhydrous Et of 30mL ₂Among the O.Bubbling feeds dry HCl gas in this solution, and the result forms pale precipitation fast.(about 5 minutes) no longer add HCl when finding no longer to form more precipitations.By suction filtration this solid is separated, with the anhydrous Et of 15mL ₂The O washed twice is also dry, obtains 213.5mg (productive rate 96%) pale solid; C ₄₃H ₄₉ClF ₃N ₅The calculated value of O is ₅: C, 63.89; H, 6.11; N, 8.66; Cl, 4.39; Measured value is: C, 63.41; H, 5.85; N, 8.60; Cl, 4.86.

Embodiment 225A.2 (R)-[[4-[2-(piperidyl) ethyl] piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(S)-α-Jia Jibianji] acid amides

Adopt the method for embodiment 6 to prepare embodiment 225A, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34C, and with 4-[2-(piperidyl) ethyl] piperidines replacement 3-(trifluoromethyl) benzyl amine.The compound of embodiment 225A ¹The HNMR spectrum is consistent with specified structure.

Embodiment 225B.2 (R)-[[4-[2-(piperidyl) ethyl] piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(R)-α-Jia Jibianji] acid amides

Adopt the method for embodiment 6 to prepare embodiment 225B, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34D, and with 4-[2-(piperidyl) ethyl] piperidines replacement 3-(trifluoromethyl) benzyl amine.The compound of embodiment 225B ¹The HNMR spectrum is consistent with specified structure.

Embodiment 225C.2 (R)-[[4-(piperidyl) piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(R)-1-(3-trifluoromethyl) ethyl] acid amides

Adopt the method for embodiment 6 to prepare embodiment 225C, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34L, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines.Embodiment 225C's ¹The HNMR spectrum is consistent with specified structure.

Embodiment 225D.2 (R)-[[4-(piperidyl) piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  oxazolidinyl-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[(S)-1-(3-trifluoromethyl) ethyl] acid amides

Adopt the method for embodiment 6 to prepare embodiment 225D, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34N, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines.Embodiment 225D's ¹The HNMR spectrum is consistent with specified structure.

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 87-120E, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 29, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; The compound of listed embodiment ¹The HNMR spectrum is consistent with specified structure.

Embodiment	A′
Embodiment	A′	87	2-(piperidyl) ethylamino
88	4-(piperidyl) piperidyl	87	2-(piperidyl) ethylamino
88	4-(piperidyl) piperidyl	89	2-(pyridine-2-yl) ethylamino
90	Morpholine-4-base is amino	89	2-(pyridine-2-yl) ethylamino
90	Morpholine-4-base is amino	91	4-(pyrrolidinyl) piperazinyl
92	4-(3-trifluorophenyl) piperazinyl	91	4-(pyrrolidinyl) piperazinyl
92	4-(3-trifluorophenyl) piperazinyl	93	4-(benzyl oxygen base carbonyl) piperazinyl
94	4-[2-(2-hydroxyl-oxethyl) ethyl] piperazinyl	93	4-(benzyl oxygen base carbonyl) piperazinyl
94	4-[2-(2-hydroxyl-oxethyl) ethyl] piperazinyl	95	4-benzyl diethylenediamine base
96	4-(3,4-methylene dioxy base benzyl) piperazinyl	95	4-benzyl diethylenediamine base
96	4-(3,4-methylene dioxy base benzyl) piperazinyl	97	The 4-Phenylpiperazinyl
98	4-(3-phenyl third-2-thiazolinyl) piperazinyl	97	The 4-Phenylpiperazinyl
98	4-(3-phenyl third-2-thiazolinyl) piperazinyl	99	4-ethyl piperazidine base
100	2-(dimethylamino) ethylamino	99	4-ethyl piperazidine base

Embodiment	A′
Embodiment	A′	101	4-(pyrrolidinyl carbonyl methyl) piperazinyl
102	4-(1-methyl piperidine-4-yl) piperazinyl	101	4-(pyrrolidinyl carbonyl methyl) piperazinyl
102	4-(1-methyl piperidine-4-yl) piperazinyl	103	4-butyl piperazinyl
104	4-isopropyl piperazinyl	103	4-butyl piperazinyl
104	4-isopropyl piperazinyl	105	4-pyridylmethyl amino
106	3-(dimethylamino) propyl group amino	105	4-pyridylmethyl amino
106	3-(dimethylamino) propyl group amino	107	1-benzyl piepridine-4-base is amino
108	N-benzyl-2-(dimethylamino) ethylamino	107	1-benzyl piepridine-4-base is amino
108	N-benzyl-2-(dimethylamino) ethylamino	109	3-pyridylmethyl amino
110	The 4-cyclohexyl piperazinyl	109	3-pyridylmethyl amino
110	The 4-cyclohexyl piperazinyl	111	4-(2-cyclohexyl ethyl) piperazinyl
112	4-[2-(morpholine-4-yl) ethyl] piperazinyl	111	4-(2-cyclohexyl ethyl) piperazinyl
112	4-[2-(morpholine-4-yl) ethyl] piperazinyl	113	4-(4-tert-butyl group benzyl) piperazinyl
114	4-[2-(piperidyl) ethyl] piperazinyl	113	4-(4-tert-butyl group benzyl) piperazinyl
114	4-[2-(piperidyl) ethyl] piperazinyl	115	4-[3-(piperidyl) propyl group] piperazinyl
116	4-[2-(diisopropylaminoethyl) ethyl] piperazinyl	115	4-[3-(piperidyl) propyl group] piperazinyl
116	4-[2-(diisopropylaminoethyl) ethyl] piperazinyl	117	4-[3-(diethylamino) propyl group] piperazinyl
118	4-(2-dimethyl aminoethyl) piperazinyl	117	4-[3-(diethylamino) propyl group] piperazinyl
118	4-(2-dimethyl aminoethyl) piperazinyl	119	4-[3-(pyrrolidinyl) propyl group] piperazinyl
120	4-(cyclohexyl methyl) piperazinyl	119	4-[3-(pyrrolidinyl) propyl group] piperazinyl
120	4-(cyclohexyl methyl) piperazinyl	120A	4-[2-(piperidyl) ethyl] piperidyl
120B	4-propyl group-piperazinyl	120A	4-[2-(piperidyl) ethyl] piperidyl
120B	4-propyl group-piperazinyl	120C	4-[N-(isopropyl) acetyl ammonia (acetamid)-2-yl] piperazinyl
120D	3-benzyl-six hydrogen-(1H)-1,3-diazacyclo heptenyl	120C
120D	3-benzyl-six hydrogen-(1H)-1,3-diazacyclo heptenyl	120E	4-(piperidino methyl) piperidyl
120F	4-cyclohexyl piperazinyl N-oxide	120E	4-(piperidino methyl) piperidyl
120F	4-cyclohexyl piperazinyl N-oxide	120G	Methoxyl group
120H	The 4-cyclohexyl piperazinyl	120G	Methoxyl group

Embodiment 120F.

Adopt the method for embodiment 86B to prepare embodiment 120F, difference is to replace with embodiment 110 compound of embodiment 63, obtains pale solid (54.5mg, 98%).The compound of embodiment 120F ¹The HNMR spectrum is consistent with specified structure.

Embodiment 120G.2 (S)-(methoxycarbonyl ethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 6 to prepare embodiment 120G, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34M, and ¹The HNMR spectrum is consistent with specified structure.

Embodiment 35.2 (S)-[4-(2-phenylethyl) piperazinyl-carbonyl ethyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 6, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the carboxylic acid of embodiment 29, and replaces 3-(trifluoromethyl) benzyl amine to prepare title compound with 4-(2-phenylethyl) piperazine;

¹H NMR(CDCl ₃)δ2.21-2.23(m，1H)；2.25-2.45(m，6H)；2.52-2.63(m，3H)；2.72-2.82(m，2H)；3.42-3.48(m，2H)；3.52-3.58(m，1H)；4.13-4.18(m，1H)；4.26(dd，J＝5.1Hz，J＝8.3Hz，1H)；4.29(d，J＝5.0Hz，1H)；4.44(dd，J＝6.0Hz，J＝15.0Hz，1H)；4.54(dd，J＝6.2Hz，J＝14.9Hz，1H)；4.61-4.68（m，2H)；4.70-4.75(m，1H)；6.27(dd，J＝9.6Hz，J＝15.8Hz，1H)；6.73(d，J＝15.8Hz，1H)；7.16-7.60(m，19H)；8.07-8.12(m，1H)；FAB ⁺(M+H) ⁺/z 794；

C ₄₅H ₄₆F ₃N ₅0 ₅The calculated value of elementary analysis: C, 68.08; H, 5.84; N, 8.82; Measured value: C, 67.94; H, 5.90; N, 8.64.

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 141-171, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; Listed embodiment's ¹The HNMR spectrum is consistent with specified structure.

Embodiment	A′
Embodiment	A′	141	Benzylamino
142	(2-methyl-benzyl) amino	141	Benzylamino
142	(2-methyl-benzyl) amino	143	(3-methyl-benzyl) amino
144	(4-methyl-benzyl) amino	143	(3-methyl-benzyl) amino
144	(4-methyl-benzyl) amino	145	(α-Jia Jibianji) amino
146	N-benzyl-N-methylamino	145	(α-Jia Jibianji) amino
146	N-benzyl-N-methylamino	147	N-benzyl-N-(tert-butyl group) amino
148	N-benzyl-N-butyl amino	147	N-benzyl-N-(tert-butyl group) amino
148	N-benzyl-N-butyl amino	149	(3, the 5-dimethyl benzyl) amino
150	(2-phenylethyl) amino	149	(3, the 5-dimethyl benzyl) amino
150	(2-phenylethyl) amino	151	Dimethylamino
152	(3-trifluoro-methoxybenzyl) amino	151	Dimethylamino
152	(3-trifluoro-methoxybenzyl) amino	153	(3, the 4-difluorobenzyl) amino
154	(3, the 5-dichloro benzyl) amino	153	(3, the 4-difluorobenzyl) amino
154	(3, the 5-dichloro benzyl) amino	155	(2, the 5-dichloro benzyl) amino
156	(2, the 3-dichloro benzyl) amino	155	(2, the 5-dichloro benzyl) amino
156	(2, the 3-dichloro benzyl) amino	157	(2-fluoro-5-trifluoromethyl benzyl) amino
158	(4-fluoro-3-trifluoromethyl benzyl) amino	157	(2-fluoro-5-trifluoromethyl benzyl) amino
158	(4-fluoro-3-trifluoromethyl benzyl) amino	159	(3-fluoro-5-trifluoromethyl benzyl) amino
160	(2-fluoro-3-trifluoromethyl benzyl) amino	159	(3-fluoro-5-trifluoromethyl benzyl) amino
160	(2-fluoro-3-trifluoromethyl benzyl) amino	161	(4-chloro-3-trifluoromethyl benzyl) amino
162	Indane-1-base is amino	161	(4-chloro-3-trifluoromethyl benzyl) amino
162	Indane-1-base is amino	163	4-(2-hydroxy benzo imidazoles-1-yl)-piperidyl
164	3 (S)-(tert-butyl group amino carbonyl)-1,2,3,4-tetrahydroisoquinoline-2-base	163	4-(2-hydroxy benzo imidazoles-1-yl)-piperidyl
164		165	(3, the 3-dimethylbutyl) amino
166	4-hydroxy-4-phenyl piperidine base	165	(3, the 3-dimethylbutyl) amino
166	4-hydroxy-4-phenyl piperidine base	167	(cyclohexyl methyl) amino

Embodiment	A′
Embodiment	A′	168	(2-phenoxy group ethyl) amino
169	3,4-methylene dioxy base benzylamino	168	(2-phenoxy group ethyl) amino
169	3,4-methylene dioxy base benzylamino	170	4-benzyl piepridine base
171	(3-trifluoromethyl) amino	170	4-benzyl piepridine base

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 172-221R, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34A, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; The compound of listed embodiment ¹The HNMR spectrum is consistent with specified structure.

Embodiment	A
Embodiment	A	172	(3-trifluoro-methoxybenzyl) amino
173	(3, the 4-dichloro benzyl) amino	172	(3-trifluoro-methoxybenzyl) amino
173	(3, the 4-dichloro benzyl) amino	174	(3, the 5-dichloro benzyl) amino
175	(2, the 5-dichloro benzyl) amino	174	(3, the 5-dichloro benzyl) amino
175	(2, the 5-dichloro benzyl) amino	176	(2, the 3-dichloro benzyl) amino
177	(2-fluoro-5-trifluoromethyl benzyl) amino	176	(2, the 3-dichloro benzyl) amino
177	(2-fluoro-5-trifluoromethyl benzyl) amino	178	(4-fluoro-3-trifluoromethyl benzyl) amino
179	(3-fluoro-5-trifluoromethyl benzyl) amino	178	(4-fluoro-3-trifluoromethyl benzyl) amino
179	(3-fluoro-5-trifluoromethyl benzyl) amino	180	(2-fluoro-3-trifluoromethyl benzyl) amino
181	(4-chloro-3-trifluoromethyl benzyl) amino	180	(2-fluoro-3-trifluoromethyl benzyl) amino
181	(4-chloro-3-trifluoromethyl benzyl) amino	182	(2-trifluoromethyl benzyl) amino
183	(3-methoxy-benzyl) amino	182	(2-trifluoromethyl benzyl) amino
183	(3-methoxy-benzyl) amino	184	(3-luorobenzyl) amino
185	(3, the 5-difluorobenzyl) amino	184	(3-luorobenzyl) amino
185	(3, the 5-difluorobenzyl) amino	186	(3-chloro-4-luorobenzyl) amino
187	(3-benzyl chloride base) amino	186	(3-chloro-4-luorobenzyl) amino

Embodiment	A
Embodiment	A	188	[3, two (trifluoromethyl) benzyls of 5-] amino
189	(3-nitrobenzyl) amino	188	[3, two (trifluoromethyl) benzyls of 5-] amino
189	(3-nitrobenzyl) amino	190	(3-bromobenzyl) amino
191	Benzylamino	190	(3-bromobenzyl) amino
191	Benzylamino	192	(2-methyl-benzyl) amino
193	(3-methyl-benzyl) amino	192	(2-methyl-benzyl) amino
193	(3-methyl-benzyl) amino	194	(4-methyl-benzyl) amino
195	(α-Jia Jibianji) amino	194	(4-methyl-benzyl) amino
195	(α-Jia Jibianji) amino	196	(N-methyl-benzyl) amino
197	(N-tert-butyl group benzyl) amino	196	(N-methyl-benzyl) amino
197	(N-tert-butyl group benzyl) amino	198	(N-butyl benzyl) amino
199	(3, the 5-dimethyl benzyl) amino	198	(N-butyl benzyl) amino
199	(3, the 5-dimethyl benzyl) amino	200	(2-phenylethyl) amino
201	(3, the 5-dimethoxy-benzyl) amino	200	(2-phenylethyl) amino
201	(3, the 5-dimethoxy-benzyl) amino	202	(1R)-(3-methoxyphenyl) ethylamino
203	(1S)-(3-methoxyphenyl) ethylamino	202	(1R)-(3-methoxyphenyl) ethylamino
203	(1S)-(3-methoxyphenyl) ethylamino	204	(α, α-Er Jiajibianji) amino
205	N-methyl-N-(3-trifluoromethyl benzyl) amino	204	(α, α-Er Jiajibianji) amino
205	N-methyl-N-(3-trifluoromethyl benzyl) amino	206	[(S)-and α-Jia Jibianji] amino
207	(1-benzyl ring third-1-yl) amino	206	[(S)-and α-Jia Jibianji] amino
207	(1-benzyl ring third-1-yl) amino	208	(pyridine-2-ylmethyl) amino
209	(pyridin-3-yl methyl) amino	208	(pyridine-2-ylmethyl) amino
209	(pyridin-3-yl methyl) amino	210	(pyridin-4-yl methyl) amino
211	(furans-2-ylmethyl) amino	210	(pyridin-4-yl methyl) amino
211	(furans-2-ylmethyl) amino	212	[(5-methylfuran-2-yl) methyl] amino
213	(thiophene-2-ylmethyl) amino	212	[(5-methylfuran-2-yl) methyl] amino
213	(thiophene-2-ylmethyl) amino	214	[(S)-1,2,3,4-tetrahydrochysene-1-naphthalene-1-yl] amino
215	[(R)-1,2,3,4-tetrahydrochysene-1-naphthalene-1-yl] amino	214	[(S)-1,2,3,4-tetrahydrochysene-1-naphthalene-1-yl] amino
215	[(R)-1,2,3,4-tetrahydrochysene-1-naphthalene-1-yl] amino	216	(indane-1-yl) amino
217	(1-benzyl ring penta-1-yl) amino	216	(indane-1-yl) amino
217	(1-benzyl ring penta-1-yl) amino	218	(α, alpha-alpha-dimethyl-3,5-dimethoxy-benzyl) amino
219	(2, the 5-dimethoxy-benzyl) amino	218	(α, alpha-alpha-dimethyl-3,5-dimethoxy-benzyl) amino
219	(2, the 5-dimethoxy-benzyl) amino	220	(2-methoxy-benzyl) amino
221	(α, α, 2-trimethyl benzyl) amino	220	(2-methoxy-benzyl) amino
221	(α, α, 2-trimethyl benzyl) amino	221A	N-methyl-3-methyl-benzylamino (amide)

Embodiment	A
Embodiment	A	221B	N-methyl-2,3-chloro-benzylamino (amide)
221C	N-methyl-3-chloro-benzylamino (amide)	221B	N-methyl-2,3-chloro-benzylamino (amide)
221C	N-methyl-3-chloro-benzylamino (amide)	221D	N-methyl-3-bromo-benzylamino (amide)
221E	N-methyl-3,5-chloro-benzylamino (amide)	221D	N-methyl-3-bromo-benzylamino (amide)
221E	N-methyl-3,5-chloro-benzylamino (amide)	221F	(R)-1-(3-trifluorophenyl) ethylamino (amide)
221G	1-phenyl-cyclohexyl amino (amide)	221F	(R)-1-(3-trifluorophenyl) ethylamino (amide)
221G	1-phenyl-cyclohexyl amino (amide)	221H	1-(2-fluorophenyl)-cyclopenta amino (amide)
221I	1-(4-fluorophenyl)-cyclopenta amino (amide)	221H	1-(2-fluorophenyl)-cyclopenta amino (amide)
221I	1-(4-fluorophenyl)-cyclopenta amino (amide)	221J	4-trifluoromethyl-benzylamino (amide)
221K	α-phenyl-benzylamino (amide)	221J	4-trifluoromethyl-benzylamino (amide)
221K	α-phenyl-benzylamino (amide)	221L	3-phenyl-benzylamino (amide)
221M	Dibenzyl amino (amide)	221L	3-phenyl-benzylamino (amide)
221M	Dibenzyl amino (amide)	221N	1-naphthalene-methylamino (amide)
221O	1,2,3,4-tetrahydrochysene-isoquinolin amino (amide)	221N	1-naphthalene-methylamino (amide)
221O	1,2,3,4-tetrahydrochysene-isoquinolin amino (amide)	221P	Indane-2-base is amino
221Q	α-(2-hydroxyl-ethyl) benzylamino (amide)	221P	Indane-2-base is amino
221Q	α-(2-hydroxyl-ethyl) benzylamino (amide)	221R	(S)-indane-1-base is amino

Embodiment	A	A′
Embodiment	A	A′	221S	(R)-1-indanyl amino	The 4-cyclohexyl piperazinyl
221T	(α R)-α-(tert-butoxycarbonyl methyl) benzylamino	The 4-cyclohexyl piperazinyl	221S	(R)-1-indanyl amino	The 4-cyclohexyl piperazinyl
221T	(α R)-α-(tert-butoxycarbonyl methyl) benzylamino	The 4-cyclohexyl piperazinyl	221U	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(2-morpholino ethyl)-piperazinyl
221V	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	2-dimethyl aminoethyl amino	221U	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(2-morpholino ethyl)-piperazinyl
221V	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	2-dimethyl aminoethyl amino	221W	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(2-phenylethyl)-Gao piperazinyl
221X	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	2-(1-piperidyl) ethylamino	221W	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(2-phenylethyl)-Gao piperazinyl
221X	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	2-(1-piperidyl) ethylamino	221Y	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(S)-2-(1-pyrrolidinyl methyl) pyrrolidinyl
221Z	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	2-(1-pyrrolidinyl) ethylamino	221Y	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(S)-2-(1-pyrrolidinyl methyl) pyrrolidinyl

221AA	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(1-piperidyl) piperidyl
221AA	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(1-piperidyl) piperidyl	221AB	3-trifluoromethyl-benzylamino	4-just-the butyl piperazinyl
221AC	3-trifluoromethyl-benzylamino	4-ethyl piperazidine base	221AB	3-trifluoromethyl-benzylamino	4-just-the butyl piperazinyl
221AC	3-trifluoromethyl-benzylamino	4-ethyl piperazidine base	221AD	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(R)-1-benzyl-pyrrole alkane-3-base is amino
221AE	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	Quinuclidine-3-base is amino	221AD	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(R)-1-benzyl-pyrrole alkane-3-base is amino
221AE	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	Quinuclidine-3-base is amino	221AF	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	The high piperazinyl of 4-methyl
221AG	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	2-pyrrole radicals phenyl amino	221AF	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	The high piperazinyl of 4-methyl
221AG	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	2-pyrrole radicals phenyl amino	221AH	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	Morpholine-4-base ethylamino
221AI	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(S)-1-ethyl pyrrolidine-2-base amino methyl	221AH	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	Morpholine-4-base ethylamino
221AI	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(S)-1-ethyl pyrrolidine-2-base amino methyl	221AJ	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(R)-1-ethyl pyrrolidine-2-base amino methyl
221AK	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(S)-1-butoxy carbonyl pyrrolidines-3-base is amino	221AJ	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(R)-1-ethyl pyrrolidine-2-base amino methyl
221AK	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	(S)-1-butoxy carbonyl pyrrolidines-3-base is amino	221AL	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	Quinoline-3-base is amino
221AM	1-(3-fluorophenyl)-cyclopenta amino	The 4-cyclohexyl piperazinyl	221AL	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	Quinoline-3-base is amino
221AM	1-(3-fluorophenyl)-cyclopenta amino	The 4-cyclohexyl piperazinyl	221AN	1-(4-chlorphenyl)-cyclopropyl amino	The 4-cyclohexyl piperazinyl
221AO	1-(4-methoxyphenyl)-cyclopropyl amino	The 4-cyclohexyl piperazinyl	221AN	1-(4-chlorphenyl)-cyclopropyl amino	The 4-cyclohexyl piperazinyl
221AO	1-(4-methoxyphenyl)-cyclopropyl amino	The 4-cyclohexyl piperazinyl	221AP	1-(4-aminomethyl phenyl)-cyclopropyl amino	The 4-cyclohexyl piperazinyl
221AQ	1-(4-chlorphenyl)-cyclopenta amino	The 4-cyclohexyl piperazinyl	221AP	1-(4-aminomethyl phenyl)-cyclopropyl amino	The 4-cyclohexyl piperazinyl
221AQ	1-(4-chlorphenyl)-cyclopenta amino	The 4-cyclohexyl piperazinyl	221AS	1-(4-aminomethyl phenyl)-cyclopenta amino	The 4-cyclohexyl piperazinyl
221AT	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	The different  azoles quinoline of 3-(4-chlorphenyl)-5-base is amino	221AS	1-(4-aminomethyl phenyl)-cyclopenta amino	The 4-cyclohexyl piperazinyl
221AT	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino		221AU	1-benzyl ring amyl group amino	4-(1-pyrrolidinyl) piperidyl
221AV	Indolinyl	The 4-cyclohexyl piperazinyl	221AU	1-benzyl ring amyl group amino	4-(1-pyrrolidinyl) piperidyl
221AV	Indolinyl	The 4-cyclohexyl piperazinyl	221AW	5-indanyl amino	The 4-cyclohexyl piperazinyl
221AX	1-benzyl ring amyl group amino	4-[3-((R)-tert-butoxycarbonyl-amino)-1-pyrrolidinyl) piperidyl	221AW	5-indanyl amino	The 4-cyclohexyl piperazinyl
221AX	1-benzyl ring amyl group amino		221AY	4-indanyl amino	The 4-cyclohexyl piperazinyl
221AZ	1-benzyl ring amyl group amino	(3R)-4-(3-oronain pyrrolidinyl) piperidyl	221AY	4-indanyl amino	The 4-cyclohexyl piperazinyl
221AZ	1-benzyl ring amyl group amino	(3R)-4-(3-oronain pyrrolidinyl) piperidyl	221BA	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(2-fluorophenyl) piperazinyl
221BB	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(3-chlorphenyl) piperazinyl	221BA	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(2-fluorophenyl) piperazinyl
221BB	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(3-chlorphenyl) piperazinyl	221BC	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(4-fluorophenyl) piperazinyl
221BD	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-ethyl piperazidine base	221BC	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(4-fluorophenyl) piperazinyl
221BD	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-ethyl piperazidine base	221BE	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	The 4-Phenylpiperazinyl
221BF	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-benzyl diethylenediamine base	221BE	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	The 4-Phenylpiperazinyl
221BF	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-benzyl diethylenediamine base	221BG	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-methyl piperazine base
221BH	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(2-methoxyphenyl) piperazinyl	221BG	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-methyl piperazine base
221BH	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(2-methoxyphenyl) piperazinyl	221BI	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(3-hydroxyl n-pro-pyl) piperazinyl
221BJ	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(4-hydroxy phenyl) piperazinyl	221BI	(R)-1,2,3,4-tetrahydrochysene-1-naphthyl amino	4-(3-hydroxyl n-pro-pyl) piperazinyl

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 135-140, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 33, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; The compound of listed embodiment ¹The HNMR spectrum is consistent with the structure of appointment.

Embodiment	A′
Embodiment	A′	135	4-(piperidyl) piperidyl
136	4-(2-phenylethyl) piperazinyl	135	4-(piperidyl) piperidyl
136	4-(2-phenylethyl) piperazinyl	137	4-butyl piperazinyl
138	4-isopropyl piperazinyl	137	4-butyl piperazinyl
138	4-isopropyl piperazinyl	139	The 4-cyclohexyl piperazinyl
140	4-(cyclohexyl methyl) piperazinyl	139	The 4-cyclohexyl piperazinyl

Embodiment 140A.2 (R)-(2-(3-trifluoromethyl benzyl) amino-1-base carbonyl) ethyl)-and 2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(4-cyclohexyl) piperazine amide

Adopt the method for embodiment 6 to prepare embodiment 140A, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34Q, and replaces 3-(trifluoromethyl) benzyl amine with 1-cyclohexyl-piperazine, and shown in ¹The HNMR spectrum is consistent with the structure of appointment.

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 226-230C, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34F, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; The compound of listed embodiment ¹The HNMR spectrum is consistent with the structure of appointment.

Embodiment	A′
Embodiment	A′	226	The 4-cyclohexyl piperazinyl
227	4-(pyrrolidinyl) piperazinyl	226	The 4-cyclohexyl piperazinyl
227	4-(pyrrolidinyl) piperazinyl	227A	4-[2-(2-hydroxyethyl oxygen base) ethyl] piperazinyl
227B	4-benzyl diethylenediamine base	227A	4-[2-(2-hydroxyethyl oxygen base) ethyl] piperazinyl
227B	4-benzyl diethylenediamine base	227C	4-(3,4-methylene dioxy base benzyl) piperazinyl
228	4-ethyl piperazidine base	227C	4-(3,4-methylene dioxy base benzyl) piperazinyl
228	4-ethyl piperazidine base	229	4-normal-butyl piperazinyl
230	4-isopropyl piperazinyl	229	4-normal-butyl piperazinyl
230	4-isopropyl piperazinyl	230A	1-benzyl piepridine-4-base is amino
230B	4-(2-cyclohexyl ethyl) piperazinyl	230A	1-benzyl piepridine-4-base is amino
230B	4-(2-cyclohexyl ethyl) piperazinyl	230C	4-[2-(morpholine-4-yl) ethyl] piperazinyl

Embodiment	Y	C (3)-C (4) spatial chemistry	A′
Embodiment	Y	C (3)-C (4) spatial chemistry	A′	230D	F	Do not determine	4-normal-butyl piperazinyl
230E	F	Do not determine	(R)-1-benzyl-pyrrole alkane-3-amino	230D	F	Do not determine	4-normal-butyl piperazinyl
230E	F	Do not determine	(R)-1-benzyl-pyrrole alkane-3-amino	230F	F	Do not determine	Quininuclidinyl-3-base is amino
230G	F	(3S，4R)	(S)-1-benzyl-pyrrole alkane-3-amino	230F	F	Do not determine	Quininuclidinyl-3-base is amino
230G	F	(3S，4R)	(S)-1-benzyl-pyrrole alkane-3-amino	230H	Cl	Do not determine	(R)-1-benzyl-pyrrole alkane-3-amino
230I	Cl	(3S，4R)	(R)-1-benzyl-pyrrole alkane-3-amino	230H	Cl	Do not determine	(R)-1-benzyl-pyrrole alkane-3-amino
230I	Cl	(3S，4R)	(R)-1-benzyl-pyrrole alkane-3-amino	230J	Cl	(3S，4R)	(S)-1-benzyl-pyrrole alkane-3-amino

230K	Cl	Do not determine	(S)-1-benzyl-pyrrole alkane-3-amino
230K	Cl	Do not determine	(S)-1-benzyl-pyrrole alkane-3-amino	230L	Br	Do not determine	4-normal-butyl piperazinyl
230M	Br	Do not determine	4-ethyl piperazidine base	230L	Br	Do not determine	4-normal-butyl piperazinyl

Embodiment 86C.2 (S)-[[4-(piperidyl) piperidyl] carbonyl methyl (carbonylmethyl)]-2-[3 (S)-(4 (R)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 6 to prepare embodiment 86C, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 28A, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines, and shown in ¹The HNMR spectrum is consistent with the structure of appointment.

Embodiment 231.2 (R)-[[4-(piperidyl) piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2 '-methoxy styrene-2-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 6 to prepare embodiment 231, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34G, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines, and ¹The HNMR spectrum is consistent with the structure of appointment.

Adopt the method for embodiment 6 to prepare following table illustrated embodiment 232-233A, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34H, and replaces 3-(trifluoromethyl) benzyl amine with suitable amine; The compound of listed embodiment ¹The HNMR spectrum is consistent with the structure of appointment.

Embodiment

A′

α

232	4-(piperidyl) piperidyl	D
232	4-(piperidyl) piperidyl	D	232A	(3-trifluoro-benzyl) amino	D
232B	4-(3-trifluoromethyl) piperazinyl	D or L	232A	(3-trifluoro-benzyl) amino	D
232B	4-(3-trifluoromethyl) piperazinyl	D or L	232C	4-(3-trifluoromethyl) piperazinyl	D or L
232D	The 4-cyclohexyl piperazinyl	DL	232C	4-(3-trifluoromethyl) piperazinyl	D or L
232D	The 4-cyclohexyl piperazinyl	DL	232E	4-(piperidino methyl) piperidyl	D
233	4-[2-(piperidyl) ethyl] piperidyl	D	232E	4-(piperidino methyl) piperidyl	D
233	4-[2-(piperidyl) ethyl] piperidyl	D	233A	The 4-[(1-piperidyl) methyl] the piperidines acid amides	D

Embodiment 234. (2RS)-[4-(piperidyl) piperidino carbonyl]-2-methyl-2-[3 (S)-(4 (S)-phenyl  azoles-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

In the compound of the embodiment 37 in oxolane (4mL) under-78 ℃ (50mg, 0.067mmol) use successively sodium hydride (4mg, 0.168mmol) and methyl iodide (6 μ L 0.094mmol) handle.The mixture that obtains is slowly risen to room temperature, subsequently evaporation.The residue that obtains is distributed between carrene and water, subsequently organic layer is evaporated.The residue that obtains obtains the title compound of 28mg (55%) pale solid shape through silica gel column chromatography purifying (95: 5 chloroform/methanol); MS (ES ⁺): m/z=757 (M ⁺).

Embodiment 234A.3 (R)-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-3-methyl-4 (R)-(styrene-2-yl) azetidine-2-ketone-1-yl]-3-[(3-trifluoromethyl) phenyl methyl amino carbonyl] propionic acid 4-(piperidyl)-piperidines acid amides

Adopt the method for embodiment 6, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the carboxylic acid of embodiment 34J, and replaces 3-(trifluoromethyl) benzyl amine to prepare the title compound of quantitative yield with 4-(piperidyl) piperidines; MS (m+H) ⁺772.

C (3)-C (4) spatial chemistry	R	A′
C (3)-C (4) spatial chemistry	R	A′	(3S，4R)	H	4-(piperidyl) piperidyl
(3S，4R)	Me	4-(piperidyl) piperidyl	(3S，4R)	H	4-(piperidyl) piperidyl
(3S，4R)	Me	4-(piperidyl) piperidyl	Do not determine	H	4-(piperidyl) piperidyl

Embodiment 235.2 (S)-[[(1-benzyl piepridine-4-yl) amino] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-phenyl second-1-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 8 to prepare embodiment 235, difference is the compound (50mg with embodiment 63,0.064mmol) replace N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides, obtain the compound of the embodiment 235 of 40mg (80%) pale solid shape; The compound of embodiment 235 ¹The HNMR spectrum is consistent with the structure of appointment.

Embodiment 236. (2S)-[(4-cyclohexyl piperazinyl) carbonyl ethyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-phenyl second-1-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 8 to prepare embodiment 236, difference is the compound (50mg with embodiment 110,0.065mmol) replace N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides, obtain the compound of the embodiment 236 of 42mg (84%) pale solid shape; The compound of embodiment 236 ¹The HNMR spectrum is consistent with the structure of appointment.

Embodiment 236A. (2S)-[(4-cyclohexyl piperazinyl) carbonyl ethyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-phenyl second-1-yl) azetidine-2-ketone-1-yl] acetate N-[(R)-1,2,3,4-naphthane-1-yl] acid amides

Adopt the method for embodiment 8 to prepare embodiment 236A, difference is the compound (76mg with embodiment 215,0.10mmol) replace N-benzyl oxygen base cbz l aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzyl acid amides, obtain the compound of the embodiment 236A of 69mg (90%) pale solid shape.The compound of embodiment 236A ¹The HNMR spectrum is consistent with the structure of appointment.

Embodiment 237.2 (R)-[[4-(piperidyl) piperidyl] carbonyl methyl]-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(propylene-1-yl) azetidine-2-ketone-1-yl] acetate N-(3-trifluoromethyl benzyl) acid amides

Adopt the method for embodiment 6 to prepare embodiment 237, difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the compound of embodiment 34K, and replaces 3-(trifluoromethyl) benzyl amine with 4-(piperidyl) piperidines.The compound of embodiment 237 ¹The HNMR spectrum is consistent with the structure of appointment.

Embodiment 238. (2S)-(dibenzylsulfide ylmethyl)-2-[3 (S)-(4 (S)-phenyl  azoles alkane-2-ketone-3-yl)-4 (R)-(2-styryl) azetidine-2-ketone-1-yl] acetate N-[4-[2-(piperidines-1-yl) ethyl] piperidines-1-yl] acid amides

Adopt the method for embodiment 6 to prepare this embodiment; difference is to replace N-benzyl oxygen base carbonyl-D-aspartic acid β-tert-butyl ester monohydrate with the cysteine analogs of corresponding benzyl protection, and with 4-[2-(piperidines-1-yl) ethyl] piperidines replacement 3-(trifluoromethyl) benzyl amine.

Step 1.N-tert-butyl group oxygen base carbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl) ethyl)] piperidines acid amides

N-tert-butyl group oxygen base carbonyl-(S)-benzyl-N-(tert-butyl group oxygen base carbonyl)-D-cysteine (0.289g, 0.93mmol) and 4-[2-(1-piperidyl) ethyl] piperidines (0.192g, 0.98mmol) in carrene (20mL), react, obtain the compound of the embodiment X of 0.454g (quantitative yield) pale solid shape.

¹H NMR(CDCl ₃)δ0.89-1.15(m，2H)；1.39-1.44(m，16H)；1.54-1.61(m，4H)；1.62-1.71(m，1H)；2.21-2.35(m，5H)；2.49-2.58(m，2H)；2.66-2.74(m，1H)；2.79-2.97(m，1H)；3.67-3.76(m，3H)；4.48-4.51(m，1H)；4.72-4.75(m，1H)；5.41-5.44(m，1H)；7.19-7.34(m，5H).

Step 2. (S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl) ethyl)] piperidines acid amides dihydrochloride

(0.453g, 0.93mmol) (0.78mL 13.80mmol) reacts in absolute methanol (15mL) and spends the night N-tert-butyl group oxygen base carbonyl-(S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl) ethyl)] piperidines acid amides with chloroacetic chloride.By this reactant mixture evaporate to dryness being obtained the title compound (0417g, 97%) of pale solid shape.

¹HNMR(CD ₃OD)δ0.94-1.29(m，2H)；1.49-1.57(m，1H)；1.62-1.95(m，10H)；2.65-2.80(m，2H)；2.81-2.97(m，4H)；3.01-3.14(m，2H)；3.50-3.60(m，3H)；3.81-3.92(m，2H)；4.41-4.47(m，2H)；7.25-7.44(m，5H).

Step 3. adopts universal method described in the literary composition, at triethylamine (0.26mL, 1.87mmol) exist down by (S)-(benzyl)-D-cysteine-[4-(2-(1-piperidyl) ethyl)] piperidines acid amides dihydrochloride (0.417g, 0.90mmol) and the imines of cinnamic acid preparation mix with 2-(4 (S)-phenyl  oxazolidinyl-2-ketone-3-yl) chloroacetic chloride (embodiment 1), after being recrystallized, obtain the compound of the embodiment 238 of 0.484g (76%) pale solid shape with dichloromethane/hexane.

¹H NMR(CDCl ₃)δ0.89-1.06(m，2H)；1.40-1.44(m，5H)；1.57-1.67(m，6H)；2.25-2.43(m，6H)；2.45-2.59(m，2H)；2.71-2.88(m，2H)；3.55-3.70(m，3H)；4.11-4.17(m，1H)；4.37-4.47(m，2H)；4.54-4.61(m，1H)；4.64-4.69(m，1H)；4.76-4.84(m，2H)；6.05-6.19(m，1H)；6.66-6.71(m，1H)；7.12-7.40(m，15H).

Table 16 expression selected compounds obtains (M+H) accordingly by the FAB+ mass spectral analysis ⁺Parent ion further characterizes.

Table 16.

Embodiment	(m+H) ⁺/z
Embodiment	(m+H) ⁺/z	37	744
38	766	37	744
38	766	39	766
40	718	39	766
40	718	41	704
42	744	41	704
42	744	42A	772
44	758	42A	772
44	758	63	780
85	766	63	780
85	766	86A	786
86C	758	86A	786
86C	758	88	772
91	759	88	772
91	759	95	780
96	824	95	780
96	824	104	732
110	772	104	732
110	772	111	800
112	803	111	800
112	803	120	786
120A	800	120	786
120A	800	120B	732
120E	788	120B	732
120E	788	132B	758
133	758	132B	758
133	758	134A	786
134C	780	134A	786
134C	780	134H	772
136	794	134H	772
136	794	137	746

Embodiment	(m+H) ⁺/z
Embodiment	(m+H) ⁺/z	138	732
139	772	138	732
139	772	174	772
175	772	174	772
175	772	176	772
177	790	176	772
177	790	179	790
180	790	179	790
180	790	182	772
183	734	182	772
183	734	184	722
185	740	184	722
185	740	186	756
187	738	186	756
187	738	188	840
189	749	188	840
189	749	190	782
191	704	190	782
191	704	192	718
193	718	192	718
193	718	199	732
200	718	199	732
200	718	201	764
202	748	201	764
202	748	203	748
205	786	203	748
205	786	206	718
207	730	206	718
207	730	208	705
209	705	208	705
209	705	210	705

Embodiment	(m+H) ⁺/z
Embodiment	(m+H) ⁺/z	211	694
212	708	211	694
212	708	213	710
214	744	213	710
214	744	215	744
216	7530	215	744
216	7530	217	758
218	792	217	758
218	792	219	764
220	734	219	764
220	734	221	746
222	776	221	746
222	776	224	704

Embodiment	(m+H) ⁺/z
Embodiment	(m+H) ⁺/z	225	772
226	806	225	772
226	806	227	792
228	752	227	792
228	752	229	780
230	766	229	780
230	766	231	788
232	663	231	788
232	663	233	691
234	758	233	691
234	758	235	782
236	774	235	782

Method embodiment

Method embodiment 1. people's vasopressins V _1aReceptors bind is measured

At expressing cho cell people V _1aThe cell-line of acceptor is (hereinafter referred to as hV _1aCell-line) from Dr.Michael Brownstein, NIMH, Bethesda, MD, USA obtains.Thibonnier etc. (Journal of Biological Chemistry, 269,3304-3310 (1994)) have described hV _1aThe cDNA sequence, and (1992) such as expression and Morel introduce identical.HV _1a(NY's cell-line grows among α-MEM USA) for Gibco, Grand Island containing 10% hyclone and 250 μ g/ml G418.For competitive binding assay, with hV _1aCell is inoculated in 6 well culture plates from merging flask with 1: 10 dilution factor, maintains in the culture at least two days.Remove culture medium then, with 2ml binding buffer liquid (25mM Hepes, 0.25%BSA, 1xDMEM, PH=7.0) washed cell.In each hole, add the binding buffer liquid that 990 μ l contain 1nM 3H-AVP, add the DMSO solution of the embodiment compound of 10 μ l serial dilutions then.All incubations are triplicate, and dosage suppresses curve and comprises total binding (DMSO) and contain IC ₅₀5 concentration (0.1,1.0,10,100 and 1000nM) agent of being had a try.The cold AVP of 100nM (Sigma) is used to estimate non-specific binding.Cell shifts out analysis of mixtures 37 ℃ of incubations 45 minutes, and each hole is with PBS (pH=7.4) washing three times subsequently.Add 1ml2%SDS in each hole, allow plate leave standstill 30 minutes.All inclusions in hole are transferred to the flicker bottle.Each hole adds flushing liquor corresponding bottle then with 0.5ml PBS flushing.Add again in each bottle the 3ml scintillation solution (Ecoscint, National Diagnostics, Atlanta, Georgia).Sample is counted with liquid scintillation counter (Beckman LS3801).IC ₅₀Value is calculated with Prism Curve match software.

All the chain docosandioic acid esters and the acid amides of illustration all is dissolved among the DMSO in all the foregoing descriptions in this assay method.Obtain binding curve according to (1994) described methods such as Thibonnier.In the hVla cell culture, add [ ³H]-AVP after with 10 times of each test compound dilutions.All reactive compounds show dosage and rely on the competition binding curve, have at expressing human V _1aV in the Chinese hamster ovary celI of acceptor (hV1a cell-line) _1aThe IC of acceptor high-affinity ₅₀And K _iThe value characteristic.Embodiment 225 shows dosage and relies on the competition binding curve, has IC ₅₀(1.86-2.13nM) and K _i(1.14-1.30nM) value.In table 17, summed up the binding affinity of exemplary compound.

Table 17.

Embodiment	V _1aBinding affinity (IC ₅₀(nM))
Embodiment	V _1aBinding affinity (IC ₅₀(nM))	18	35
19	35	18	35
19	35	20	35
35	1.9	20	35
35	1.9	37	5.5
38	＜25	37	5.5
38	＜25	39	23
40	11	39	23
40	11	41	＜20
42	＜20	41	＜20
42	＜20	42A	1.77
44	3.1	42A	1.77
44	3.1	47	～50
59	＜100	47	～50
59	＜100	63	1.84
66	～50	63	1.84
66	～50	77	＜100
78	＜100	77	＜100
78	＜100	81	＜100
82	＜50	81	＜100
82	＜50	85	5.87
86A	9.79	85	5.87
86A	9.79	87	15
88	2.4	87	15
88	2.4	91	3.24
95	1.76	91	3.24
95	1.76	96	4.35
100	＜100	96	4.35

Embodiment	V _1aBinding affinity (IC ₅₀(nM))
Embodiment	V _1aBinding affinity (IC ₅₀(nM))	101	～100
102	＜100	101	～100
102	＜100	103	0.81
104	1.85	103	0.81
104	1.85	106	～100
107	＜50	106	～100
107	＜50	108	～100
109	～100	108	～100
109	～100	110	0.49
111	1.31	110	0.49
111	1.31	112	1.34
120	0.75	112	1.34
120	0.75	120A	16.2
120B	2.93	120A	16.2
120B	2.93	120E	3.2
120H	2.75	120E	3.2
120H	2.75	132D	6.3
132F	4.8	132D	6.3
132F	4.8	133	2.43
134A	12.9	133	2.43
134A	12.9	134B	44.8
134C	9.1	134B	44.8
134C	9.1	134G	6
134J	5.29	134G	6
134J	5.29	135	～50
136	11	135	～50
136	11	137	17
138	21	137	17

Embodiment	V _1aBinding affinity (IC ₅₀(nM)
Embodiment	V _1aBinding affinity (IC ₅₀(nM)	139	9.5
172	4.5	139	9.5
172	4.5	173	＜100
174	1.46	173	＜100
174	1.46	175	4.56
176	0.61	175	4.56
176	0.61	177	0.67
178	＜50	177	0.67
178	＜50	179	0.81
180	0.33	179	0.81
180	0.33	181	＜50
182	1.52	181	＜50
182	1.52	183	＜10
184	＜10	183	＜10
184	＜10	185	1.27
186	＜10	185	1.27
186	＜10	187	1
188	7.26	187	1
188	7.26	189	1.7
190	0.88	189	1.7
190	0.88	191	2.92
192	＜10	191	2.92
192	＜10	193	1.17
194	＜100	193	1.17
194	＜100	195	＜50
196	＜100	195	＜50
196	＜100	198	～100
199	＜10	198	～100
199	＜10	200	5.08

Embodiment	V _1aBinding affinity (IC ₅₀(nM)
Embodiment	V _1aBinding affinity (IC ₅₀(nM)	201	10.5
203	2.46	201	10.5
203	2.46	204	6
205	0.34	204	6
205	0.34	206	1.58
207	4.48	206	1.58
207	4.48	208	16.3
209	16	208	16.3
209	16	210	29.5
211	5.37	210	29.5
211	5.37	212	0.95
213	0.78	212	0.95
213	0.78	214	1.86
215	0.61	214	1.86
215	0.61	216	1.83
217	3.17	216	1.83
217	3.17	218	7.7
219	0.63	218	7.7
219	0.63	220	53
221	5.1	220	53
221	5.1	221A	2.71
221B	0.59	221A	2.71
221B	0.59	221C	3
221D	2.41	221C	3
221D	2.41	221E	20.2
221F	1.7	221E	20.2
221F	1.7	221G	1.5
221H	4	221G	1.5
221H	4	221I	12

Embodiment	V _1aBinding affinity (IC ₅₀(nM))
Embodiment	V _1aBinding affinity (IC ₅₀(nM))	221K	～5
221O	8.4	221K	～5
221O	8.4	221P	1.7
221Q	18.1	221P	1.7
221Q	18.1	221R	5.13
221S	5.03	221R	5.13
221S	5.03	221X	11.6
221Y	7.6	221X	11.6
221Y	7.6	221AB	＜10
221AC	＜10	221AB	＜10
221AC	＜10	221AD	～50
221AE	～50	221AD	～50
221AE	～50	221AI	～50
221AL	～100	221AI	～50
221AL	～100	221AO	～100
221AQ	～50	221AO	～100
221AQ	～50	221AS	～20
221AX	83	221AS	～20
221AX	83	221AY	～30
221BD	2.7	221AY	～30
221BD	2.7	221BI	56
222	1.83	221BI	56
222	1.83	224	0.49
225	1.08	224	0.49
225	1.08	226	0.49
227	11	226	0.49
227	11	228	13.6
229	1.53	228	13.6
229	1.53	230	7.07

Embodiment	V _1aBinding affinity (IC ₅₀(nM))
Embodiment	V _1aBinding affinity (IC ₅₀(nM))	230F	～100
230L	12.7	230F	～100
230L	12.7	231	6.12
232	1.37	231	6.12
232	1.37	232D	2.04
232E	0.28	232D	2.04
232E	0.28	233	0.56
234	2.37	233	0.56
234	2.37	234A	8.6
235	37	234A	8.6
235	37	236	1.68
236A	9	236	1.68
236A	9	238	0.11

Table 18.

Embodiment	V _1a K _i (nM)
Embodiment	V _1a K _i (nM)	35	1.17
37	3.39	35	1.17
37	3.39	38	85
39	13.3	38	85
39	13.3	40	6.5
41	18.2	40	6.5
41	18.2	42	26.4
42A	1.17	42	26.4
42A	1.17	44	1.89
63	1.13	44	1.89
63	1.13	82	5.12
85	3.6	82	5.12
85	3.6	86A	6
88	1.45	86A	6
88	1.45	91	1.99
95	1.08	91	1.99
95	1.08	96	2.66
103	0.49	96	2.66
103	0.49	104	1.13
110	0.27	104	1.13
110	0.27	111	0.82
112	0.8	111	0.82
112	0.8	120	0.46
120A	9.9	120	0.46
120A	9.9	120B	1.79
120E	1.95	120B	1.79
120E	1.95	120H	1.68
132D	3.9	120H	1.68
132D	3.9	132F	3
133	1.49	132F	3
133	1.49	134A	7.9
134B	27.5	134A	7.9
134B	27.5	134C	5.58
134G	3.7	134C	5.58

Embodiment	V _1a K _i (nM)
Embodiment	V _1a K _i (nM)	134J	3.25
136	33	134J	3.25
136	33	137	10.5
138	13	137	10.5
138	13	139	5.84
172	2.78	139	5.84
172	2.78	174	0.89
175	2.79	174	0.89
175	2.79	176	0.38
177	0.41	176	0.38
177	0.41	179	0.51
180	0.2	179	0.51
180	0.2	182	0.93
185	0.82	182	0.93
185	0.82	187	0.66
188	4.45	187	0.66
188	4.45	189	1.04
190	0.54	189	1.04
190	0.54	191	1.79
193	0.72	191	1.79
193	0.72	200	3.11
201	6.43	200	3.11
201	6.43	203	1.5
204	3.7	203	1.5
204	3.7	205	0.21
206	0.97	205	0.21
206	0.97	207	2.74
208	10	207	2.74
208	10	209	9.8
210	18.1	209	9.8
210	18.1	211	3.29
212	0.58	211	3.29
212	0.58	213	0.48
214	1.14	213	0.48

Embodiment	V _1a K _i (nM)
Embodiment	V _1a K _i (nM)	215	0.38
216	1.12	215	0.38
216	1.12	217	1.94
218	4.7	217	1.94
218	4.7	219	0.39
220	3.26	219	0.39
220	3.26	221	3.1
221A	1.66	221	3.1
221A	1.66	221B	0.36
221C	1.84	221B	0.36
221C	1.84	221D	1.48
221E	12.4	221D	1.48
221E	12.4	221F	1.04
221G	0.93	221F	1.04
221G	0.93	221H	2.5
221I	7.4	221H	2.5
221I	7.4	221O	5.1
221P	1.1	221O	5.1
221P	1.1	221Q	11.1
221R	3.14	221Q	11.1
221R	3.14	221S	3.08
221X	7.2	221S	3.08
221X	7.2	221Y	4.7
221AM	2.7	221Y	4.7
221AM	2.7	221AP	3.8
221AX	51	221AP	3.8
221AX	51	221BD	1.66
221BI	35	221BD	1.66
221BI	35	222	1.13
224	0.3	222	1.13
224	0.3	225	0.66
225-HCl	1.36	225	0.66
225-HCl	1.36	226	0.3
227	6.71	226	0.3
227	6.71	228	8.35

Embodiment	V _1a K _i (nM)
Embodiment	V _1a K _i (nM)	229	0.94
230	4.33	229	0.94
230	4.33	230L	7.8
231	3.75	230L	7.8
231	3.75	232	0.84
232D	1.25	232	0.84
232D	1.25	232E	0.17
233	0.34	232E	0.17
233	0.34	233A	11.6
234	1.45	233A	11.6
234	1.45	234A	5.25
235	23	234A	5.25
235	23	236	1.03
236A	5.5	236	1.03
236A	5.5	238	0.07

The inhibitory action of method embodiment 2. phosphatidylinositols turnover

The physiological effect of vasopressins is by the mediation of specificity G-G-protein linked receptor.Vasopressins V _1aAcceptor is coupled to the G of G albumen _q/ G ₁₁Family, and the turnover of mediation phosphatidylinositols.The activator of The compounds of this invention or antagonist feature can determine that detection method is introduced by the ability of the phosphatidylinositols turnover that suppresses the vasopressins mediation in following paragraph.Representative compounds of the present invention is that the compound of embodiment 35,44,88,110 and 133 is tested with this analytical method, is found to be vasopressins V _1aAntagonist.

Cell culture and labeled cell

Analyzing first three day, separate near the hV that merges _1aCell culture is inoculated into 6 hole tissue culturing plates, by each 75cm ²Flask is inoculated about 100 holes (being equivalent to 12: 1 split ratios).There is 1mL to contain 2 μ Ci[in each hole ³H] inositol (American Radiolabeled Chemicals, St.Louis, MO, growth medium USA).

Incubation

Except basis (basal) and 10nM AVP (both n=6), all the other analyze triplicate.AVP ((arginine vasopressin), Peninsula Labs, Belmont, CA, USA (#8103)) is dissolved in 0.1N acetate.The agent of will being had a try is dissolved in DMSO, obtains final test concentration for 200 times with the DMSO dilution.To be had a try agent and AVP (or DMSO of respective volume) joins separately with the DMSO solution of 5 μ L 1mL analysis buffer (TyrodeShi balanced salt solution is housed, wherein comprise 50mM glucose, 10mM LiCl, 15mM HEPES pH7.4,10 μ M phosphoramidons and 100 μ M bacitracins) 12 * 75mm teat glass in.Incubation order randomized arrangement.Following beginning incubation: remove the medium of mark in advance, with 1mL0.9%NaCl washing individual layer once, the inclusion of transfer analysis pipe is in corresponding hole then.With plate 37 ℃ of incubations 1 hour.Remove the incubation medium, add 5% ice-cold (w/v) trichloroacetic acid of 500 μ L and allow each hole leave standstill 15 minutes to end incubation.

[ ³H] detection method of myo-inositol phosphates

Load the resin of 0.3mL AG 1X-8100-200 formic acid esters form among the BioRad Poly-Prep Econo-Columns.Resin was mixed with water with 1: 1, and in each post, add 0.6mL.Use 10mL water washing pillar then.Flicker bottle (20mL) is positioned under each post.For each hole, content is transferred to micro-column, then the hole is used the 0.5mL distilled water wash, and cleaning solution is also added micro-column.To eluent, there is not inositol twice with 5mL 5mM inositol washing pillar then.Aliquot (1mL) is transferred to 20mL flicker bottle, adds 10mLBeckman Ready Protein Plus.After inositol washing is finished, the flicker bottle of sky is placed under the post, add for three times the 1mL 0.5M ammonium formate wash-out that contains 0.1N formic acid [ ³H] myo-inositol phosphates.Optimize elution requirement reclaiming inositol one, two and triguaiacyl phosphate, and four, five and six-phosphate that can the more metabolism inertia of wash-out.The scintillation solution that in each sample, adds the high salt capacity of 10mL, for example Tru-Count High Salt Capacity or Packard Hionic-Fluor.Following detection inositol lipid: in each hole, add 1mL 2% lauryl sodium sulfate (SDS), allow each hole leave standstill at least 30 minutes, then solution is transferred to 20mL flicker bottle, then to wherein adding 10mL Beckman Ready Protein Plus scintillation solution.Sample was counted 10 minutes with Beckman LS 3801 liquid scintillation counters.Total inositol binding capacity in each hole is calculated as free inositol, myo-inositol phosphates and inositol lipid sum.

Data analysis: concentration suppresses experiment

The concentration-response curve of AVP and the agent of being had a try are analyzed the logical function of concentration inhibition curve negotiating nonlinear least square method curve match to 4 parameter of 10nMAVP.Change basis and maximum myo-inositol phosphates, EC ₅₀Or IC ₅₀And the parameter of Hill coefficient realizes best fit.Weighted curve match under following hypothesis: standard deviation and radioactivity dpm are proportional.Each test all prepares the full concentration-response curve of AVP, based on the EC of AVP in the same test ₅₀, use the Cheng-Prusoff equation with IC ₅₀Value is converted into K _iValue.Myo-inositol phosphates is expressed as dpm/10 ⁶The total inositol combination of dpm.

Data analysis: competitive trials

The emulative test of agent of being had a try comprises that AVP is not being had a try agent and have concentration-response curve under the agent of being had a try of two or more concentration.Data fitting becomes competitive logical equation:

Y = B + \frac{M \times {A / [E + (D / K)]}^{Q}}{1 + {A / [E + (D / K)]}^{Q}}

Wherein Y is the dpm of myo-inositol phosphates, and B is basic inositol monophosphate ester concentration, and M is the maximal increment of inositol monophosphate ester concentration, and A is activator (AVP) concentration, and E is the EC of activator ₅₀, D is antagonist (agent of a being had a try) concentration, K is the K of antagonist _i, Q is concertedness (a Hill coefficient).

Has IC ₅₀(2.68nM) and K _iThe compound of embodiment 225 (0.05nM) produces dose-dependent inhibition AVP effect.These values and the compound of embodiment 225 high affine combine with its through people V _1aIt is synthetic consistent that acceptor suppresses inositol lipid.

Method embodiment 3. shows optionally relatively combining of acceptor with other

To vasopressins V _1aThe compound of the embodiment 225 of the selective binding of acceptor by 100nM to one group 63 kinds by NOVASCREEN (Hanover, MD, other acceptors that USA) provide in conjunction with proof.The result has shown high degree of specificity; Embodiment 225 is only in conjunction with V _1aThe vasopressins acceptor.

Method embodiment 4. treatment premenstrual syndrome (PMS)

Vasopressins V _1aReceptor antagonism also shows as the symptom that alleviates or prevent preceding dysmenorrhoea anxiety (PMDD) of menstruation and primary dysmenorrhea (PD).Referring to Brouard etc. described in the BJOG107:614-19 (in May, 2000).Before being about to begin menstruation, treat prophylactic treatment as dysmenorrhoea.

Vasopressins V has been described in the literary composition _1aAntagonist is used for the treatment of the exemplary assay method of PMS, and comprise double blinding, at random. placebo-control, the cross matching (as comprising three stages and three kinds of treatments) of district base design fully.The treatment group for example comprises that the age is the 18-35 women who suffers from primary dysmenorrhea in year.Daily dose is made up of placebo or medicine, wherein drug dose for example for every day single dose give or be divided into about 0.5mg that a plurality of dosage give to about 300mg or about 10mg compound described in about 200mg literary composition extremely.This dosage gave in hemorrhage and/or dysmenorrhoea outbreak precontract in 4 hours to about 3 days.Perhaps, also available second daily dose of patient is treated.

Successful result comprises the dysmenorrhoea symptom relevant with physical efficiency (comprise and carrying on the back and pelycalgia) of dysmenorrhoea degree by the visual analogue scales readme, self-appraisal (adopting the Sultan scoring) and at the MBL of the self-assessment of being write down.

On the one hand, by 5-7 days every month, orally give patient doses treatment primary dysmenorrhea once a day or repeatedly.In this method on the other hand, human patients be the range of age about 18 to about 40 years old women.

Method embodiment 5. rat blood pressure pharmacology

Vascular smooth muscle is shunk compound described in the literary composition and the effect of blood pressure shows arginine vasopressin (AVP) V _1aAcceptor is the important medium of pain before the menstruation.Before menstruation, the blood vessel in the uterine wall is by blood engorgement.Pass through V _1aWhat the vasopressins of receptor acting caused that the contraction of uterus and vascular smooth muscle causes primary dysmenorrhea does not accommodate pain.Vasopressins is for keeping the endogenous factors of vascular tone.V on the blocking-up smooth muscle _1aAcceptor can improve the symptom of primary dysmenorrhea.Pass through V _1aWhat the concentration increase of the vasopressins of receptor acting caused that the contraction of uterus and vascular smooth muscle causes primary dysmenorrhea does not accommodate pain.There is not animal model to be used to assess receptor antagonist for dysmenorrhoea.On the contrary, simple blood pressure measuring method can be used for testing the effect of compound described in the literary composition to the whole body vascular system.The reasonability of this method is to find vasopressins V _1aAcceptor concentrates on the blood vessel of the circulatory system.When the endogenous AVP that is subjected to be obtained by hypophysis stimulates, the vessel retraction of these receptor-mediated smooth muscles causes that resistance increases and elevation of blood pressure, described in the Acta Obstetricia et Gynecologica 85:207-211 (2006), the disclosure is combined in herein by reference as Liedman etc.Show in the literary composition that vasoconstrictive this identical AVP of mediation appears at the uterus.As a result, use optionally V _1aReceptor antagonist block the expectation of these acceptors be used for the treatment of the female primary dysmenorrhoea (also referring to Brouard etc., British Journal of Obstetrics and Gynecology 107:614-19 (2000).French is at American Family Physician 71 (2): described about vasopressins V in 285 (2005) _1aOther information of acceptor effect in the illness before menstruation.

Male rat is divided into five groups, and each group is respectively with a kind of test in four kinds of dosage of compound described in placebo or one or more literary compositions, as being 0.16,0.4,1.0 and the compound of the embodiment 225 of 2.5mg/kg with dosage.Handle as follows for rat: the described compound of orally give, after giving 90-150 minute, measure its effect subsequently to blood pressure.Under isoflurane anesthesia, pass through the femoral arteriography recording blood pressure.Give AVP (25ng/kg) for increasing systemic blood pressure by femoral venous catheter; Injecting AVP writes down mean blood pressure after two minutes variation.Producing AVP-with the pretreated rat of the compound of embodiment 225 induces the dose dependent of elevation of blood pressure to suppress.With 1 and the rat of the compound treatment of 2.5mg/kg embodiment 225 rat of handling with the antagonist of carrier and two kinds of low dosages show blood pressure and significantly reduce (p＜0.01).These data show that the compound of oral embodiment 225 is capable of blocking by V _1aThe elevation of blood pressure that receptor activation causes, and supported that other compounds will produce identical effect in proper dosage described in the literary composition, described other compounds have Orally active and can block the V at experimenter uterus and vascular smooth muscle place _1aAcceptor.

Example of formulations 1. preparations contain the hard gelatin capsule of following composition:

Composition	Quantity (mg/ capsule)
Composition	Quantity (mg/ capsule)	Vasopressin antagonists	3.0-30
Starch	337-305	Vasopressin antagonists	3.0-30
Starch	337-305	Magnesium stearate	5.0

Above composition mixed and be filled in the hard gelatin capsule with the amount of 340mg.

Example of formulations 2. uses following composition to prepare tablet:

Composition	Quantity (mg/ sheet)
Composition	Quantity (mg/ sheet)	Vasopressin antagonists	2-25
Microcrystalline cellulose	222-200	Vasopressin antagonists	2-25
Microcrystalline cellulose	222-200	Cataloid	10
Stearic acid	5.0	Cataloid	10

To be pressed into tablet after all the components mixing, every heavy 240mg.

The anhydrous powder that example of formulations 3. preparations comprise following composition sucks preparation:

Composition	Weight %
Composition	Weight %	Vasopressin antagonists
	5	Vasopressin antagonists
	5	Lactose	95

Active mixture is mixed with lactose, will in the anhydrous powder suction apparatus, add mixture.

Example of formulations 4. is prepared as follows tablet, and every comprises the 30mg active component:

Composition	Quantity (mg/ sheet)
Composition	Quantity (mg/ sheet)	Vasopressin antagonists	3-30mg
Starch	72-45mg	Vasopressin antagonists	3-30mg
Starch	72-45mg	Microcrystalline cellulose	62-35mg
Polyvinylpyrrolidone (10% aqueous solution)	4.0mg	Microcrystalline cellulose	62-35mg
Polyvinylpyrrolidone (10% aqueous solution)	4.0mg	Sodium carboxymethyl starch	4.5mg
Magnesium stearate	0.5mg	Sodium carboxymethyl starch	4.5mg
Magnesium stearate	0.5mg	Talcum powder	1.0mg
Amount to	120mg	Talcum powder	1.0mg

Active component, starch and cellulose by 20 order U.S. sieve, are fully mixed.With the solution and the gained powder of polyvinylpyrrolidone, then it is sieved by 16 order U.S..With the particle of so preparation 50-60 ℃ of drying, then by 16 order U.S. sieve.Sodium carboxymethyl starch, dolomol and the talcum powder that will sieve by 30 order US. in advance adds in the above particle then, it is compressed to the tablet of every 120mg after mixing with pelleter.

Example of formulations 5. is prepared as follows the capsule that comprises the 40mg medicine:

Composition	Quantity (mg/ capsule)
Composition	Quantity (mg/ capsule)	Vasopressin antagonists	4-40mg
Starch	145-109mg	Vasopressin antagonists	4-40mg
Starch	145-109mg	Magnesium stearate	1.0mg
Amount to	150mg	Magnesium stearate	1.0mg

Active component, cellulose, starch and dolomol are mixed, and by 20 order U.S. sieve, the quantity with 150mg is filled into hard gelatine capsule then.

Example of formulations 6. is prepared as follows the suppository that comprises the 25mg active component:

Composition

Quantity (mg)

Vasopressin antagonists	2-25mg
Vasopressin antagonists	2-25mg	Saturated fatty acid glyceride	To 2,000mg

Active component is suspended in it in saturated fatty acid glyceride of using minimum necessary heat fusion in advance by 60 order U.S. sieve.Then with the suppository mould of the specified 2.0g capacity of this mixture impouring, allow its cooling.

The supensoid agent that example of formulations 7. every 5.0ml dosage contain the 50mg medicine is prepared as follows:

Composition	Quantity (mg)
Composition	Quantity (mg)	Vasopressin antagonists	5-50mg
Xanthans	4.0mg	Vasopressin antagonists	5-50mg
Xanthans	4.0mg	Sodium carboxymethylcellulose (11%) microcrystalline cellulose (89%)	95-50mg
Sucrose	1.75g		95-50mg
Sucrose	1.75g	Sodium Benzoate	10.0mg
Flavor enhancement and colouring agent	In right amount	Sodium Benzoate	10.0mg
Flavor enhancement and colouring agent	In right amount	Purified water	To 5.0ml

Medicine, sucrose and xanthans are mixed, by 10 order U.S. sieve, then with the aqueous solution of previously prepared microcrystalline cellulose and sodium carboxymethylcellulose.Sodium Benzoate, flavor enhancement and colouring agent with the dilution of part water, are under agitation added.The water that adds capacity then obtains volume required.

Example of formulations 8. is prepared as follows the capsule that contains the 15mg medicine:

Composition	Quantity (mg/ capsule)
Composition	Quantity (mg/ capsule)	Vasopressin antagonists	1.5-15mg
Starch	421-407mg	Vasopressin antagonists	1.5-15mg
Starch	421-407mg	Magnesium stearate	3.0mg
Amount to	425mg	Magnesium stearate	3.0mg

Active component, cellulose, starch and dolomol are mixed, and by 20 order U.S. sieve, the quantity with 425mg is filled in the hard gelatine capsule then.

Example of formulations 9. can be prepared as follows iv formulation:

Composition	Quantity (mg)
Composition	Quantity (mg)	Vasopressin antagonists	25-250mg
Isotonic saline solution	1000ml	Vasopressin antagonists	25-250mg

Example of formulations 10. can be prepared as follows topical formulations:

Composition	Quantity (mg)
Composition	Quantity (mg)	Vasopressin antagonists	0.1-1g
Emulsifying wax	30g	Vasopressin antagonists	0.1-1g
Emulsifying wax	30g	Atoleine	20g
Albolene	To 100g	Atoleine	20g

Heating white vaseline is to fusing.Mixing material paraffin and emulsifying wax also stir until dissolving.Add active component, continuous stirring is until dispersion.Then mixture is cooled to solid.

Example of formulations 11. can be prepared as follows the hypogloeeis that contains the 10mg active component or contain the clothes tablet:

Composition	Quantity (mg/ sheet)
Composition	Quantity (mg/ sheet)	Vasopressin antagonists	1-10mg
Glycerine	210mg	Vasopressin antagonists	1-10mg
Glycerine	210mg	Water	143mg
Sodium citrate	4.5mg	Water	143mg
Sodium citrate	4.5mg	Polyvinyl alcohol	26.5mg
Polyvinylpyrrolidone	15.5mg	Polyvinyl alcohol	26.5mg
Polyvinylpyrrolidone	15.5mg	Amount to	401-410mg

Continuous stirring mixes glycerine, water, sodium citrate, polyvinyl alcohol and polyvinylpyrrolidone, and keeping temperature is about 90 ℃.Behind the polymer pass into solution, gained solution is cooled to about 50-55 ℃, slowly hybrid medicine.In the mould with the preparation of homogeneous mixture impouring inert material, produce the diffusion matrix that contains medicine of thickness for about 2-4mm.Again this diffusion matrix is cut into the single tablet of suitable size.

The another kind of exemplary formulation of compound described herein comprises transdermal delivery device (" patch ").Such transdermal patch can be used for the continuous or interruption infusion The compounds of this invention with controlled quentity controlled variable.Structure and the transdermal patch that is used to transmit medicine are well known in the art.Open on June 11st, 5,023,252,1991 referring to for example United States Patent (USP), this patent is attached to this paper by reference.Can construct such patch be used for continuously, pulse administration or release as requested.

Another exemplary formulation of The compounds of this invention comprises directly or indirectly introduces brain with medicine.Direct technology can comprise delivery catheter is placed into host's ventricular system to walk around blood-brain barrier.A kind of exemplary portable delivery system is used for biotic factor is transferred to the particular anatomical zone of health, United States Patent (USP) 5,011, and 472 have introduced such delivery system, and this patent is attached to this paper by reference.

Indirection techniques can comprise and hydrophilic drugs is converted into fat-soluble medicine or pro-drug comes compositions formulated, imitates thereby provide medicine to dive.Dive to imitate common following realization: it is bigger fat-soluble and can transport and pass blood-brain barrier that hydroxyl, carbonyl, sulfuric ester and the primary amine group that exists on the sealing medicine makes that medicine has.Perhaps, can strengthen giving of hydrophilic medicament by the hypertonic solution that endoarterial infusion can temporarily be opened blood-brain barrier.

The preparation type that is used to give the compound that the inventive method uses may depend on characteristics of pharmacokinetics type that employed particular compound, method of administration and compound require and patient's state.

Though in the specification in front the present invention has been done to specify and describe, but such explanation and description are considered to exemplary, rather than it is restrictive, be to be understood that only to illustrate and described exemplary embodiment, but also consider other embodiments all belong to the variation and the change of essence of the present invention.

Claims

1. method for the treatment of illness before the menstruation, described method comprise the step of the patient's effective dose compound that needs to alleviate described illness, and wherein said compound is following formula: compound and pharmaceutically acceptable salt thereof:

Wherein

A is carboxylic acid, ester or acid amides;

B is a carboxylic acid, or its ester or its amide derivatives; Perhaps B is alcohol or mercaptan, or derivatives thereof;

R ¹Be hydrogen or C ₁-C ₆Alkyl;

R ²For hydrogen, alkyl, alkoxyl, alkylthio group, cyano group, formoxyl, alkyl-carbonyl or be selected from-CO ₂R ⁸With-CONR ⁸RR ⁸' substituting group; R wherein ⁸And R ⁸' be selected from hydrogen and alkyl independently of one another;

2. the process of claim 1 wherein that described compound is following formula: compound and pharmaceutically acceptable salt thereof:

Wherein

A and A ' are selected from-CO independently of one another ₂H, or its ester or its amide derivatives;

N is selected from 0 to about 3 integer;

R ¹Be hydrogen or C ₁-C ₆Alkyl;

R ²For hydrogen, alkyl, alkoxyl, alkylthio group, cyano group, formoxyl, alkyl-carbonyl or be selected from-CO ₂R ⁸With-CONR ⁸R ⁸' substituting group, R wherein ⁸And R ⁸' be selected from hydrogen and alkyl independently of one another;

R ³Be optional amino, carbamoyl, acyl amino formoxyl or the urea groups that replaces; Or R ³Be the nitrogen heterocyclic ring group that connects by nitrogen-atoms; With

3. the process of claim 1 wherein that described compound is following formula: compound and pharmaceutically acceptable salt thereof:

Wherein

A is-CO ₂H, or its ester or its amide derivatives;

Q is an oxygen; Or Q is sulphur or disulfide bond, or its oxidized derivatives;

N is the integer of 1-3;

R ¹Be hydrogen or C ₁-C ₆Alkyl;

R ³Be optional amino, carbamoyl, acyl amino formoxyl or the urea groups that replaces; Or R ³Be the nitrogen heterocyclic ring group that connects by nitrogen-atoms;

R ⁴Be alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, alkyl-carbonyl, the optional aryl that replaces, the optional aryl alkyl that replaces, the optional aryl halide substituted alkyl that replaces, the optional alkoxy aryl alkyl that replaces, the optional aryl alkenyl that replaces, the optional aryl haloalkenyl group that replaces or the optional aromatic yl polysulfide yl that replaces; With

4. each method, wherein R among the claim 1-3 ¹Be hydrogen or methyl.

5. each method, wherein R among the claim 1-3 ¹Be hydrogen.

6. each method, wherein R among the claim 1-3 ²Be hydrogen or methyl.

7. each method, wherein R among the claim 1-3 ²Be hydrogen.

8. each method, wherein R among the claim 1-3 ³Be selected from following group:

9. the method for claim 8, wherein R ³Be selected from following group:

10. the method for claim 8, wherein R ³Be selected from following group:

11. the method for claim 8, wherein R ³For

12. the method for claim 8, wherein R ¹⁰Be the optional aryl that replaces, R ¹¹Be hydrogen.

13. each method, wherein R among the claim 1-3 ⁴Be selected from following group:

Wherein Y is an electron-withdrawing group, and R is hydrogen, halogen, alkyl or alkoxyl.

14. the method for claim 13, wherein Y is a halogen.

15. the method for claim 13, wherein R is hydrogen or methoxyl group.

16. each method among the claim 1-3, wherein A is-CO ₂R ⁵R wherein ⁵Be selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optional aryl alkyl, heterocyclic radical, the heterocyclic radical (C that replaces ₁-C ₄Alkyl) and R ⁶R ⁷N-(C ₂-C ₄Alkyl); R wherein ⁶And R ⁷In various situations, select independently of one another, wherein R ⁶Be selected from hydrogen or alkyl; R ⁷Be selected from alkyl, cycloalkyl, the optional aryl that replaces or the optional aryl alkyl that replaces; Or R ⁶And R ⁷Connected nitrogen-atoms forms the optional heterocycle that replaces together.

17. the method for claim 16, the heterocycle of wherein said optional replacement are selected from pyrrolidinyl, piperidyl, morpholinyl, piperazinyl and high piperazinyl; Wherein said piperazinyl or high piperazinyl also can be chosen wantonly by R on N ¹³Replace; R in various situations wherein ¹³Independently be selected from following group: hydrogen, alkyl, cycloalkyl, alkoxy carbonyl, the optional aryloxycarbonyl that replaces, the optional aryl alkyl that replaces and the optional aroyl that replaces.

18. each method among the claim 1-3, wherein A is mono-substituted carbamoyl, dibasic carbamoyl or the optional nitrogen heterocycle carbamoyl that replaces.

19. the method for claim 18, wherein heterocyclic radical is selected from tetrahydrofuran base, morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, high piperazinyl or quininuclidinyl; Wherein said morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, high piperazinyl or quininuclidinyl are optional by C on N ₁-C ₄Alkyl or the optional aryl (C that replaces ₁-C ₄Alkyl) replaces.

20. each method among the claim 1-3, wherein A is C (O) NR ¹⁴X-, wherein R ¹⁴Be hydrogen, hydroxyl, alkyl, alkoxy carbonyl or benzyl; X is alkyl, cycloalkyl, alkoxyalkyl, the optional aryl that replaces, optional aryl alkyl, heterocyclic radical, the heterocyclic radical-(C that replaces ₁-C ₄Alkyl), R ⁶R ⁷N-and R ⁶R ⁷N-(C ₂-C ₄Alkyl).

21. each method among the claim 1-3, wherein A is the nitrogen heterocyclic ring by the optional replacement of nitrogen-atoms connection.

22. the method for claim 21, wherein said nitrogen heterocyclic ring is selected from pyrrolidinyl, piperidyl, piperazinyl, high piperazinyl, triazolidinyl, triazinyl,  oxazolidinyl, different  oxazolidinyl, thiazolidinyl, isothiazole alkyl, 1,2- piperazine base, 1,3- piperazine base, morpholinyl,  two oxazolidinyls and thiadiazoles alkyl.

23. the method for claim 21, wherein said nitrogen heterocyclic ring is by R ¹⁰, R ¹², R ⁶R ⁷N-or R ⁶R ⁷N-(C ₁-C ₄Alkyl) replaces.

24. the method for claim 21, wherein said nitrogen heterocyclic ring are selected from pyrrolidone-base, piperidone base, 2-(pyrrolidines-1-ylmethyl) pyrrolidines-1-base or 1,2,3,4-tetrahydroisoquinoline-2-base.

25. the method for claim 2, wherein A ' is C (O) NR ¹⁴X-, wherein R ¹⁴Be hydrogen, hydroxyl, alkyl, alkoxy carbonyl or benzyl; X is alkyl, cycloalkyl, alkoxyalkyl, the optional aryl that replaces, optional aryl alkyl, heterocyclic radical, the heterocyclic radical-(C that replaces ₁-C ₄Alkyl), R ⁶R ⁷N-and R ⁶R ⁷N-(C ₂-C ₄Alkyl).

26. the method for claim 2, wherein A ' is the nitrogen heterocyclic ring by the optional replacement of nitrogen-atoms connection.

27. the method for claim 26, wherein said nitrogen heterocyclic ring is selected from pyrrolidinyl, piperidyl, piperazinyl, high piperazinyl, triazolidinyl, triazinyl,  oxazolidinyl, different  oxazolidinyl, thiazolidinyl, isothiazole alkyl, 1,2- piperazine base, 1,3- piperazine base, morpholinyl,  two oxazolidinyls and thiadiazoles alkyl.

28. the method for claim 26, wherein said nitrogen heterocyclic ring is by R ¹⁰, R ¹², R ⁶R ⁷N-or R ⁶R ⁷N-(C ₁-C ₄Alkyl) replaces.

29. the method for claim 26, wherein said nitrogen heterocyclic ring are selected from pyrrolidone-base, piperidone base, 2-(pyrrolidines-1-ylmethyl) pyrrolidines-1-base or 1,2,3,4-tetrahydroisoquinoline-2-base.

30. the method for claim 3, wherein R ⁵" be the optional aryl alkyl that replaces.

31. the method for claim 2, wherein n is 0.

32. the method for claim 2, wherein n is 1 or 2.

33. the method for claim 3, wherein n is 1.