CN101279971A

CN101279971A - 4,4-difluoro-1,2,3,4-tetrahydro-5h-1-benzoazepine derivative or salt of the same

Info

Publication number: CN101279971A
Application number: CNA2008100999960A
Authority: CN
Inventors: 古盐裕之; 塚本一成; 掛札昭夫; 赤松清二郎; 斋藤亲
Original assignee: Yamanouchi Pharmaceutical Co Ltd
Current assignee: Yamanouchi Pharmaceutical Co Ltd
Priority date: 2003-04-28
Filing date: 2004-04-26
Publication date: 2008-10-08
Also published as: ZA200508080B; CN1780819A; CN100404511C; ES2366641T3

Abstract

A novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative or a pharmaceutically acceptable salt thereof, which is useful as an agent for treating or preventing nocturia and/or diabetes insipidus, is provided.

Description

4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-Azolobenzazepine derivs or its salt

Patent application of the present invention is that international application no is PCT/JP2004/005998, and international filing date is on April 26th, 2004, and the application number that enters the China national stage is " 200480011344.7 ", denomination of invention be " 4,4-two fluoro-1,2; 3,4-tetrahydrochysene-5H-1-benzo-aza Derivative or its salt " the dividing an application of application for a patent for invention.

Technical field

The present invention relates to a kind of medicine, specifically is 4 of a kind of novelty, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative or its salt, can be used as treatment central diabetes insipidus therapeutical agent or night frequent micturition medicine, also relate to and use the medicine of described compound as activeconstituents.

Technical background

Arginine vasopressin (AVP) is the peptide that hypothalamus-hypothalamic hypophysial system biosynthesizing, excretory are made up of 9 amino acid.The acceptor of AVP can be divided into V _1a, V _1bAnd V ₂Three hypotypes, known AVP to the end slightly the main pharmacological of system be through V _1aReceptor-mediated vasoconstriction effect and through V ₂Receptor-mediated antidiuretic activity.As V ₂The agonist of receptor-selective, synthesized Desmopressin as peptide (remove AVP 1 halfcystine amino and 8 arginine is become the peptide of d type), be used for the treatment (non-patent literature 1) of central diabetes insipidus.Yet the bioavailability of the oral dosage form of Desmopressin is very low, need use high dosage for obtaining effect.Therefore, the desmopressin preparation price is high, and usually owing to the absorption difference between individuality has side effects.Therefore wait in expectation and develop selective stimulating V ₂The non-peptide class antidiuretic that the bioavailability of acceptor is high.

On the other hand, along with the variation and the aging of medical treatment, medicine uses separately and is tailing off, and a lot of occasions give two or more medicines simultaneously, or the time of staggering give two or more medicines, like this too in the field of the medicine that stimulates AVP.Medicine is subjected to the effect of drug metabolism enzyme and inactivation is transformed into meta-bolites, and the most important thing is Terminal oxidase P450 (CYP) in this class drug metabolism enzyme.There is multiple molecular species in CYP, as striving unexpectedly on this metabolic enzyme through the metabolic a plurality of medicines of the CYP of same molecular species, thinks that then to the affinity of CYP metabolism different, to a certain degree can take place according to these medicines suppresses.The result occur that blood level rises and blood in drug interaction such as transformation period prolongation.

Such drug interaction except attempt obtains summation action, synergy and the occasion used, all is bad effect, because they occur unexpected side effect sometimes.Therefore wish the little pharmaceuticals of development possibility low to the CYP affinity, drug interaction.

So far, the tricyclic compound of expression is known to V by general formula (A), (B) with (C) ₂Receptor selective agonists also has the non-peptide compound (patent documentation 1, patent documentation 2, patent documentation 3) of antidiuretic activity.

(symbol is referring to patent documentation in the formula .)

Also known general formula (D) expression condense azepine

Derivative is V ₂Acceptor-selective agonist (patent documentation 4).

(symbol is referring to patent documentation in the formula .)

In addition, the benzo-aza of general formula (E) expression

Derivative (patent documentation 5, patent documentation 6) and general formula (F) or benzo-heterogeneous ring compound (patent documentation 7, patent documentation 8, patent documentation 9) of (G) representing are V ₂Acceptor-selective agonist.

(symbol is referring to patent documentation in the formula .)

Yet these patent documentations are to not just of the present invention 4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

The description of derivative.

Although known 4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative has antagonistic action to AVP acceptor or ocytocin receptor, and unmatchful any V ₂The agonism of acceptor and central diabetes insipidus and the relevant aspect record of frequent micturition at night.(patent documentation 10, patent documentation 11, patent documentation 12).This respect, patent documentation 10 and patent documentation 12 are unexposed of the present invention 4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative, wherein CF ₃Or halogen is displaced at benzo-aza

On the 2-position benzoyl that replaces on the 1-position.In addition, the open a kind of like this compounds of 11 of patent documentations, one of them aromatic ring is directly connected on the heteroaryl, and heteroaryl is connected to and is substituted in benzo-aza

On the carbonyl of 1-position, but and unexposed of the present invention 4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative wherein, is connected to and is substituted in benzo-aza

Ring on the carbonyl of 1-position has-O-,-S-,-NH-or contain-N (low alkyl group)-substituting group.

Under this situation, urgent wish exploitation with the treatment central diabetes insipidus and/or night frequent micturition be the high non-peptide class antidiuretic of bioavailability of purpose.

[non-patent literature 1] Journal of Japan Endocrine Society, 54,676-691,1978

[patent documentation 1] international monopoly publication No.99/06409

[patent documentation 2] international monopoly publication No.99/06403

[patent documentation 3] international monopoly publication No.00/46224

[patent documentation 4] international monopoly publication No.01/49682

[patent documentation 5] international monopoly publication No.97/22591

[patent documentation 6] Japanese Patent No.2926335

[patent documentation 7] Japanese Patent No.3215910

[patent documentation 8] Japanese patent gazette JP-A-11-349570

[patent documentation 9] Japanese patent gazette JP-A-2000-351768

[patent documentation 10] international monopoly publication No.95/06035

[patent documentation 11] international monopoly publication No.98/39325

[patent documentation 12] Japanese patent gazette JP-A-9-221475

Summary of the invention

The present inventor for the expection to central diabetes insipidus and/or night frequent micturition effectively have V ₂The compound of receptor agonism is furtherd investigate, and finds 4 of novelty, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative has good described effect, thereby has finished the present invention.In addition, find The compounds of this invention and previously knownly have a V ₂The benzo-aza of receptor agonism

Derivative is compared, and is extremely low to the restraining effect of drug metabolism enzyme CYP3A4 and CYP2C9, thereby finished the present invention.

That is,, provide a kind of novelty 4 of following general formula (I) representative, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza according to the present invention

Derivative or its pharmacy acceptable salt, can be used as central diabetes insipidus and/or night frequent micturition therapeutical agent, also provide and be the medicine of effective constituent with in these compounds any, provide especially as the central diabetes insipidus therapeutical agent or night the frequent micturition therapeutical agent medicine, as arginine vasopressin V ₂The medicine of receptor stimulant.

[symbol has following implication in the formula:

R ¹: can substituted amino ,-OH or-the O-low alkyl group,

R ²: CF ₃Or halogen,

R ³: H or halogen,

A, b: represent singly-bound or two key separately, one of them is a singly-bound, another is two keys ,-X-:

(1)-CH=CH-,-CH=N-,-N=CH-,-N=N-or-S-, when a is singly-bound and b when being two key,

(2)-and N-, when a is two keys and b when being singly-bound,

Y：

(1) CH or N, when a is singly-bound and b when being two key,

(2) S, when a is two keys and b when being singly-bound,

-A-:-O-,-S-,-NH-or-N (low alkyl group),

B: low alkyl group, low-grade alkenyl, low-grade alkynyl, cyclic hydrocarbon radical or aryl, they can be substituted separately.]

The compounds of this invention has following feature on chemical structure, i.e. the benzo-aza that replaces at substituted methylene radical

Have two fluorine-basedly on the adjacent ring carbon atom of ring carbon atom, this is different from common known V fully ₂Acceptor-selective agonist.Under this situation, because The compounds of this invention has difluoride group, the isomerization with the two keys of carbonyl conjugated does not take place, therefore have enough stability in vivo.

In these compounds, preferably by the novelty 4 of above-mentioned general formula (I) representative, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative, wherein R ¹Be the group of formula (II) expression, the group of formula (III) expression ,-OH or-the O-low alkyl group, or its pharmacy acceptable salt, wherein preferably by the novelty 4 of general formula (I) expression, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative, wherein R ¹Be group by formula (II) or formula (III) expression, or its pharmacy acceptable salt.

[symbol has following implication in the formula:

Z ¹: singly-bound, low-grade alkylidene or-low-grade alkylidene-C (=O)-,

R ¹¹: can be selected from-OH ,-the O-low alkyl group ,-CO ₂H ,-CO ₂The low alkyl group that the group of-low alkyl group and the formamyl that can be replaced by 1 or 2 low alkyl groups replaces or-H.

R ¹²：

(1) when Z represents singly-bound or low-grade alkylidene,

For-H ,-OH ,-the O-low alkyl group ,-CO ₂H ,-CO ₂-low alkyl group, the formamyl that can be replaced by one or two low alkyl group, can substituted aryl, can substituted cyclic hydrocarbon radical, can substituted aromatic heterocycle or can substituted non-aromatic heterocyclic,

(2) work as Z ¹Expression-low-grade alkylidene-C (=O)-time,

For formula (III) or (IV) expression group.

[symbol has following implication in the formula

Z ²: singly-bound or low-grade alkylidene and

R ¹⁵:-H ,-OH ,-the O-low alkyl group ,-CO ₂H ,-CO ₂-low alkyl group, the formamyl that can be replaced by one or two low alkyl group, can substituted aryl, can substituted cyclic hydrocarbon radical, can substituted aromatic heterocycle ring can substituted non-aromatic heterocyclic,

R ¹³, R ¹⁴: with adjacent nitrogen atom, be non-aromatics cyclic amino].

Be more preferably the novelty 4 of top general formula (I) expression, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative, or its pharmacy acceptable salt, wherein, R ¹Be by by formula (II) or (III) expression group; A is a singly-bound; B is two keys;-X-is-CH=CH-;-Y-is-CH-.

Be preferably top general formula (I) expression novelty 4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative, or its pharmacy acceptable salt, wherein R ¹It is group by formula (II) expression; A is a singly-bound; B is two keys;-X-is-CH=CH-;-Y-is-CH-.

Be more preferably top general formula (I) expression novelty 4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative, or its pharmacy acceptable salt,, wherein, R ¹It is group by formula (II) expression; A is a singly-bound; B is two keys;-X-is-CH=CH-;-Y-is-CH-;-A-is-O-.

4 of the novelty of top general formula (I) expression that best is, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

Derivative, or its pharmacy acceptable salt, wherein, R ¹It is group by formula (II) expression; A is a singly-bound; B is two keys;-X-is-CH=CH-;-Y-is-CH-that-A-is-O-; With

-B is can substituted low alkyl group.

Wherein, best is 4 of novelty, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza Derivative, or its pharmacy acceptable salt, wherein R ²It is trifluoromethyl; R ³Be-H or-F.

In these compounds, best compound is to be selected from the compound of P group and the compound of Q group, or its pharmacy acceptable salt, wherein is preferably the compound that is selected from the P group, or its pharmacy acceptable salt.

In this case, " P organizes compound " comprises following compound:

(2Z)-and N-(2-amino-2-oxoethyl)-2-{4,4,7-three fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide,

(2Z)-and N-(2-hydroxyethyl)-2-{4,4,7-three fluoro-1-[4-{[(2S)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide,

(2Z)-and N-(2-hydroxyethyl)-2-{4,4,7-three fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide,

(2Z)-and 2-{4,4-two fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza -5-subunit }-N-[(2S)-2, and the 3-dihydroxypropyl] ethanamide,

3-[((2Z)-and 2-{4,4,7-three fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanoyl) amino] propionic acid amide and

(2Z)-N-[(2R)-2, the 3-dihydroxypropyl]-2-{4,4,7-three fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza -5-subunit } ethanamide, " Q organizes compound " comprises following compound:

(2Z)-and N-(2-amino-2-oxoethyl)-2-{4,4,7-three fluoro-1-[4-{[(2S)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide,

(2Z)-and 2-{1-[4-(2,2-difluoro propoxy-)-2-(trifluoromethyl) benzoyl]-4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit }-N-(2-hydroxyethyl) ethanamide,

(2Z)-and 2-{4,4-two fluoro-1-[4-{[(2S)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza -5-subunit }-N-(2-hydroxyethyl) ethanamide,

(2Z)-and 2-{4,4-two fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit }-N-(2-hydroxyethyl) ethanamide,

(2Z)-and 2-{1-[4-(2,2-difluoro propoxy-)-2-(trifluoromethyl) benzoyl]-4,4,7-three fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit }-N-(2-hydroxyethyl) ethanamide,

(2Z)-N-[(2R)-2, the 3-dihydroxypropyl]-2-{4,4,7-three fluoro-1-[4-propoxy--2-(trifluoromethyl) benzoyls]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide,

(2Z)-and 2-{4,4-two fluoro-1-[4-{[(2S)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit }-N-[(2S)-2, and the 3-dihydroxypropyl] ethanamide,

(2Z)-and 2-{4,4-two fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza -5-subunit }-N-[(2R)-2, and the 3-dihydroxypropyl] ethanamide,

3-[((2Z)-and 2-{4,4,7-three fluoro-1-[4-{[(2S)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanoyl) amino] propionic acid amide,

(2Z)-N-[(2R)-2, the 3-dihydroxypropyl]-2-{4,4,7-three fluoro-1-[4-{[(2S)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide,

3-[((2Z)-and 2-{1-[4-(2,2-difluoro propoxy-)-2-(trifluoromethyl) benzoyl]-4,4,7-three fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanoyl) amino] propionic acid amide,

(2Z)-and 2-{4,4-two fluoro-1-[4-propoxy--2-(trifluoromethyl) benzoyls]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit }-N-[(2R)-2, the 3-dihydroxypropyl] ethanamide and

-5-subunit }-N-[(2S)-2, and the 3-dihydroxypropyl] ethanamide.

In the case, about R ¹, better be following formula (II) or (III) expression group; Be more preferably the group of following formula (II) expression, wherein Z ¹Be singly-bound, R ¹²Be-H R ¹¹Be can substituted low alkyl group; The preferably group of following formula (II) expression, wherein Z ¹Be singly-bound, R ¹²Be-H R ¹¹Be can be by the low alkyl group of one or more being selected from-OH and formamyl replacement.

About R ², better be trifluoromethyl or chlorine; Trifluoromethyl preferably.

About R ³, better be-H or fluorine; Preferably-H or 7-fluorine.

About a, b ,-X-and-Y-, preferably, a is a singly-bound, b is two keys ,-X-is-CH=CH-that-Y-is-CH-.

Better-A-is-O-.

In addition, right-B, better be can substituted low alkyl group; The low alkyl group that is replaced by F preferably.

Below The compounds of this invention is further detailed.

In this specification sheets, " low alkyl group " refers to C _1-6The unit price base of carbochain of straight or branched, but concrete exemplified by methyl, ethyl, propyl group, butyl, amyl group and hexyl, sec.-propyl, the tertiary butyl and similar constitutional isomer better are C _1-4The methyl of alkyl, ethyl, propyl group, butyl and isobutyl-.

" low-grade alkylidene " refers to C _1-6The divalent radical of carbochain of straight or branched, specifically can exemplify methylene radical, ethylidene, propylidene, methyl methylene radical, methyl ethylidene, dimethylated methylene base etc.

" low-grade alkenyl " refers to C _2-6The unit price base of the carbochain that at least one two key is arranged of straight or branched, but concrete exemplified by vinyl, allyl group, 1-butylene base, crotyl, 1-hexenyl or 3-hexenyl, or 2-methacrylic and similar constitutional isomer, better be allyl group and 2-methyl isophthalic acid-propylene-3-base.

" low-grade alkynyl " refers to C _2-6The unit price base that at least one triple-linked carbochain is arranged of straight or branched, specifically can exemplify ethynyl, proyl, the ethyl acetylene base, 3-butynyl, 1-hexin base and 3-hexin base, 3-methyl isophthalic acid-butynyl and its similar constitutional isomer, wherein preferred proyl and ethyl acetylene-4-base.

" cyclic hydrocarbon radical " refers to C _3-8The unit price base of non-aromatic hydrocarbon ring, can partly have unsaturated link(age), group can be enumerated cyclopropyl, cyclopentyl, cyclohexenyl, ring octyl group, cyclohexyl, cyclooctadiene base etc.

" aryl " refers to the C of monocycle to 3 ring _6-14The unit price base of aromatic hydrocarbon ring, but concrete exemplified by phenyl, naphthyl etc. better are phenyl.

" aromatic heterocycle " refers to the unit price base of heteroatomic aromatic nucleus such as nitrogenous, the oxygen, sulphur of monocycle to 3 ring, specifically can enumerate pyridyl, thienyl, furyl, pyrazinyl, pyridazinyl, thiazolyl, pyrimidyl, pyrazolyl, pyrryl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl etc., better be pyridyl.

" non-aromatic heterocyclic " refer to contain the part unsaturated link(age), can be nitrogenous with aryl or aromatic heterocycle condensed, the unit price base of heteroatomic 5 to 7 yuan of rings such as oxygen, sulphur, specifically can exemplify pyrrolidyl, imidazolidyl, piperidyl, piperazinyl, azepine Base, morpholinyl, thio-morpholinyl, tetrahydrofuran base, tetrahydro-thienyl etc. better are pyrrolidyl, piperidyl and morpholinyl.

" non-aromatics cyclic amino " refers to contain nitrogenous, oxygen, sulphur 3 to 10 yuan of part unsaturated link(age), and the unit price base of the non-aromatics cyclammonium of better 5 to 7 yuan of rings specifically can exemplify pyrrolidyl, piperidyl, azepine

Base, morpholinyl, thio-morpholinyl, piperazinyl, pyrazolidyl, pyrrolin base etc. better are pyrrolidyl, piperidyl and morpholinyl.

The unit price base of " halogen " halogen atom specifically can be enumerated fluorine, chlorine, bromine, iodine etc.

According to this specification sheets, the substituting group that term " can be substituted " is allowed is the substituent any substituting group that is used as each base usually, and each base also can have one or more substituting groups.

To R ¹In " can substituted amino ", specifically can enumerate the top general formula (II) and (III) group of expression.

The group shown in (a) to (h) is as the substituting group of the permission of " can substituted cyclic hydrocarbon radical " among the B and " can substituted aryl " below enumerating; R ¹²And R ¹⁵In " can substituted aryl ", " can substituted cyclic hydrocarbon radical ", " can substituted aromatic heterocycle " and " can substituted non-aromatic heterocyclic "; And R ¹³And R ¹⁴In " can substituted non-aromatic amine ".And, R ^ZThe low alkyl groups that expression can be replaced by one or more substituting groups that are selected from down group :-OH ,-O-low alkyl group, the amino that can be replaced by one or two low alkyl group, formamyl, aryl, aromatic heterocycle and the halogen that can be replaced by one or two low alkyl group.

(a) halogen;

(b)-and OH ,-O-R ^Z,-O-aryl ,-OCO-R ^Z, oxo (=O);

(c)-and SH ,-S-R ^Z,-S-aryl ,-SO-R ^Z,-SO-aryl ,-SO ₂-R ^Z,-SO ₂-aryl is by one or two R ^ZThe sulfamyl that replaces;

(d) can be by 1 or 2 R ^ZThe amino that replaces ,-NHCO-R ^Z,-NHCO-aryl ,-NHSO ₂-R ^Z,-NHSO ₂-aryl, nitro;

(e)-and CHO ,-CO-R ^Z,-CO ₂H ,-CO ₂-R ^Z, can be by 1 or 2 R ^ZThe formamyl that replaces, cyano group;

(f) aryl or the cyclic hydrocarbon radical that can be respectively replaced by one or more groups that are selected from down group :-OH ,-O-low alkyl group, the amino that can be replaced by one or two low alkyl group; the formamyl that can be replaced by one or two low alkyl group; aryl, aromatic heterocycle, halogen and R ^Z

(g) aromatic heterocycle or the non-aromatic heterocyclics that can be respectively replaced by one or more groups that are selected from down group :-OH ,-O-low alkyl group, the amino that can be replaced by one or two low alkyl group; the formamyl that can be replaced by one or two low alkyl group; aryl, aromatic heterocycle, halogen and R ^ZWith

(h) low alkyl group or the low-grade alkenyl that can be replaced to substituting group shown in (g) by one or more (a) respectively.

Can be enumerated as " can substituted low alkyl group " among the B at above-mentioned (a) to the group shown in (g), the substituting group of the permission of " can substituted low-grade alkenyl " and " can substituted low-grade alkynyl ".

In the The compounds of this invention of general formula (I) expression, contain chiral carbon atom sometimes, therefore may have optical isomer according to substituent kind.The present invention includes the mixture and the isolating optical isomer of these optical isomers.In addition, there is tautomer in the The compounds of this invention sometimes, the present invention includes the chorista of these isomer and their mixture.

Compound of the present invention forms salt sometimes, such salt so long as pharmacy acceptable salt all comprise in the present invention.Specifically can exemplify and mineral acids such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid, the acid salt that organic acids such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, aspartic acid or L-glutamic acid form, with the mineral alkali that comprises metals such as sodium, potassium, calcium, magnesium, salt that organic basess such as methylamine, ethamine, thanomin, Methionin, ornithine form and ammonium salt etc.In addition, the present invention also comprises the various hydrates and the solvate of The compounds of this invention and pharmacy acceptable salt thereof and has polymorphous material.And, comprise in the The compounds of this invention that all are converted into the compound of the compound or its salt with above-mentioned general formula (I), promptly so-called prodrug at the body intracellular metabolite.Group as forming prodrug of the present invention can be set forth in Prog.Med., 5; 2157-2161, the group of record in 1985., and the group of wide river bookstore " exploitations of pharmaceuticals " the 7th volume molecular designing 163-198 page or leaf record of publishing nineteen ninety.

(preparation method)

The compounds of this invention and pharmacy acceptable salt thereof can utilize based on it and examine substantially or the feature of substituting group kind, adopt various known synthesis method manufacturings.Below exemplify representational method for making.But sometimes according to the kind of functional group, at raw material to stage of intermediate with this functional group with suitable protecting group, the group that can change into this functional group easily replaces, this also is effective on manufacturing technology.After this, remove protecting group as required, can obtain required compound.Such functional group can exemplify hydroxyl, carboxyl and amino etc., and such protecting group can exemplify the protecting group of record in Greene and the Wuts work " protecting group in the organic synthesis (third edition) ", can suitably use according to reaction conditions.

＜intermediate preparation method 〉

(in the reaction process, R ², a, b, X, the implication of Y and A is as previously mentioned; Lv represents leaving group; B ¹Represent above-mentioned B or hydroxyl, the protecting group of amino or alkylthio (sulfanil group); R ^aExpression carboxyl, low alkyl group oxygen carbonyl (oxy carbonyl) or cyano group.Down together)

This method is to prepare compound (c) by the leaving group Lv with compound (b) substitution compound (a), and as required compound (c) being hydrolyzed then prepares the method for compound (d).

(the first step)

The example of the leaving group Lv of compound (a) comprises: fluoro, chloro, mesyloxy, tolysulfonyl oxygen base and trifluoro-methanesulfonyl oxy, preferred fluoro, chloro and mesyloxy wherein.

This is reflected at room temperature to reflux, uses the compound (a) and the compound (b) of equimolar amount, or one of them is excessive, does not have solvent or carries out in reaction-inert solvent, and described solvent is as aromatic hydrocarbons such as benzene,toluene,xylenes; Diethyl ether, tetrahydrofuran (THF) (ether such as THF) ， diox; Methylene dichloride, 1,2-ethylene dichloride, the halon of chloroform etc.; N, dinethylformamide (DMF); N,N-DIMETHYLACETAMIDE (DMA); N-Methyl pyrrolidone; Dimethyl sulfoxide (DMSO) (DMSO); Ethyl acetate esters such as (EtOAc); Acetonitrile etc., or methyl alcohol (MeOH), ethanol (EtOH), alcohol such as 2-propyl alcohol (iPrOH).According to compound, under some situation should organic bases (better be triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine or 4-(N, N-dimethylamino) pyridine) or the alkali of metal-salt (better salt of wormwood, cesium carbonate, sodium hydroxide or sodium hydride) react under existing.

(second step)

Reaction can be carried out like this: being cooled to heating under backflow, at solvent such as the aromatic hydrocarbons to this reactionlessness, ether, halohydrocarbon, alcoholic solvent, DMF, DMA, DMSO, pyridine is in the water etc., at sulfuric acid, hydrochloric acid, mineral acids such as Hydrogen bromide, formic acid, organic acid or sodium hydroxide such as acetate, potassium hydroxide, salt of wormwood, yellow soda ash, cesium carbonate, alkali such as ammonia exist down, and processing compound (c) reacts.

＜the first kind of preparation method 〉

(in this reaction process, R ¹According to front definition, R ^bThe expression low alkyl group.Down together)

This preparation method makes the compound (d) and compound (1a) condensation prepared compound (1b) that makes in above-mentioned intermediate preparation method, hydrolysis compound (1b), hydrolysate and compound (1d) condensation prepared compound (1c) then, thus make The compounds of this invention (I) (B wherein ¹Be B) or (1e) (B wherein ¹Be hydroxyl, amino or alkylthio) method.

(the first step)

Compound (d) is used for described reaction with free acid, also can use its reactive derivatives.The reactive derivatives of compound (d); can enumerate common esters such as methyl esters, ethyl ester, the tert-butyl ester; carboxylic acid halides such as acyl chlorides, acylbromide; acid azide; with the N-hydroxybenzotriazole, the active ester of p-nitrophenol and N-hydroxy-succinamide etc., symmetric form acid anhydrides; with the mixed acid anhydride of halogeno-acid alkyl ester, pivalyl halogen, Tosyl chloride etc. such as alkyl carbonyl halide, the mixed acid anhydride of the phosphoric acid class mixed acid anhydride that obtains with diphenyl phosphoryl chloride, N-methylmorpholine reaction etc. etc.

When compound (d) when reacting with free acid or active ester do not separate and when reacting, preferably use as dicyclohexylcarbodiimide (DCC), 11 '-carbonyl pair-1H-imidazoles (CDI), diphenylphosphine acylazide (DPPA), diethyl phosphinylidyne nitrile and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride condensing agents such as (EDCIHCl).

Especially in the present invention, the method that chloride method, active esterifying agent and condensing agent coexistence and the method for reaction, common ester are handled with amine can easyly easily make The compounds of this invention, and is comparatively convenient.

Reactive derivatives that uses according to reaction and condensing agent different, can be in the organic solvents to reactionlessness such as halogenated hydrocarbon, aromatic hydrocarbon based, ethers, ester class, acetonitrile, DMF and DMSO, under the cooling, be cooled under the room temperature or room temperature is reacted to heating.

In this connection, use excessive compound (1a) to react, or at alkali such as N-methylmorpholine, Trimethylamine 99, triethylamine, diisopropylethylamine, N, accelerine, pyridine, 4-(N, N-dimethylamino) pyridine, picoline, lutidine (rutidine) etc. exist next successful reaction is carried out more favourable sometimes.In addition, can use pyridine hydrochloride, pyridine tosilate, N, the salt that weak base such as accelerine hydrochloride and strong acid form.Available pyridine is as solvent.

Good especially is in acetonitrile, DMF equal solvent, at pyridine, N, reacts under the existence of salt such as alkali such as accelerine or pyridine hydrochloride.

(second step)

This reaction was carried out according to second step of intermediate preparation method.

(the 3rd step)

This reaction is carried out according to first kind of preparation method's the first step.

Compound (1e) can be removed protecting group or also introduce the side chain that needs according to ordinary method as required according to the following described compound of the present invention (I) of making.Introducing required side chain also can carry out according to following second kind of preparation method's the 3rd step.

＜the second kind of preparation method 〉

(in this reaction process, B ²It is the protecting group of hydroxyl, amino or alkylthio.Down together)

This preparation method makes compound (dd) (wherein, the B that makes in above-mentioned intermediate preparation method ²Be not B) and compound (1a) condensation prepared compound (2a), remove protecting group B ²Make compound (2b), make itself and compound (2c) or (2d) condensation make compound (2f), hydrolysis makes compound (2f), then with compound (1d) thus condensation makes The compounds of this invention (I).

(the first step)

This reaction is carried out according to first preparation method's the first step.

(second step)

As the protecting group of hydroxyl, amino or alkylthio, be set forth in above-mentioned " protecting group in the organic synthesis (third edition) " described protecting group.This reaction is carried out according to the method described in " protecting group in the organic synthesis (third edition) ".

Particularly, when using benzyl, can also adopt benzyl and pentamethylbenzene in strongly acidic solution such as trifluoroacetic acid etc., to react and remove benzyl as the protecting group of hydroxyl.

(the 3rd step)

The leaving group Lv of compound (2c) can enumerate chloro, bromo, iodo, mesyloxy, tolysulfonyl oxygen base and trifluoro-methanesulfonyl oxy, wherein, and preferred bromo, mesyloxy and tolysulfonyl oxygen base.

To using the reaction of compound (2c), can adopt conventional alkylated reaction, preferably, can use compound (2b) and (2c), under the cooling, be cooled under the room temperature or room temperature to heating, excessive with equimolar amount or wherein a kind of compound, as acetonitrile, DMF, DMSO, in the solvent to reactionlessness such as ether, at salt of wormwood, yellow soda ash, cesium carbonate, sodium hydroxide reacts under the existence of alkali such as potassium hydroxide.

The reaction of use compound (2d) can be under the Mitsunobu reaction conditions, in as non-protonic solvents such as ether, DMF, N-Methyl pyrrolidone to this reactionlessness, in the presence of azodicarboxy acid dialkyl esters such as organic phosphines such as triphenylphosphine and diethylazodicarboxylate, azo-2-carboxylic acid's dipropyl, react (Synthesis, 1981, p.1).

(the 4th step)

This reaction was carried out according to first preparation method's second step.

(the 5th step)

In addition; the present invention can be prepared by steps such as the common conventional known alkylation of adopting of optional coupling those skilled in the art, acylations, substitution reaction, oxidation, reduction, hydrolysis by the compound of the present invention that adopts first preparation method or second preparation method to obtain by some compound of formula (I) expression.Can enumerate, oxidized sulfur atom by oxygenants such as metachloroperbenzoic acids, and adopt or according to " Jikken Kagaku Koza (Experimental Chemistry Course) 4th edition " (Maruzen, 1990-1992) described in method carry out this class reaction.In addition, these steps that those skilled in the art adopt usually are not limited to be applied to The compounds of this invention, and these steps can also be applied to prepare intermediate.Illustrate, for example these steps can be applicable to the compound by second kind of preparation method's the 3rd step acquisition, afterwards, carry out next step.

Zhi Bei The compounds of this invention can be used as that free cpds separates and purifying by this way, or carries out salify according to usual manner and handle, and separates and purifying as salt.Separate, the chemical operation of routines such as purifying can adopt extraction, concentrated, evaporation, crystallization, filtration, recrystallization, various chromatographys carries out.

Various isomer can utilize the difference of the physicochemical property between the isomer to separate with ordinary method.For example, racemic mixture can obtain optically pure isomer by the general mesotomy methods such as optical resolution method of the diastereomeric salt that forms with common optical activity acid such as tartrate.Non-enantiomer mixture can separate by fractional crystallization or various chromatograms etc.In addition, optically active compound can be made with suitable optical activity raw material.

Industrial usability

Compound of the present invention is to arginine vasopressin V ₂Acceptor has good hormesis.Therefore, The compounds of this invention has the antidiuretic activity based on these effect characteristics, can effectively prevent and/or treat frequent micturition, the urinary incontinence, the enuresis, central diabetes insipidus, nycturia and nocturnal enuresis.Except that these, because these compounds have based on V ₂The release blood coagulation VIII factor of these effect characteristics of receptor agonist activity and the effect of von willebrand's (von Willebrand) factor, useful to various bleedings, hemorrhage in the time of can diagnosing, prevent and treat hematostaxis, hemophilia, Von Willebrand disease, uremia, congenital or acquired character dysfunction of platelet, traumatic and operation effectively, liver cirrhosis etc.

In addition, The compounds of this invention is minimum to the restraining effect of drug metabolism enzyme CYP3A4 and CYP2C9, thus with produce interactional possibility through CYP3A4 or the metabolic other drug of CYP2C9 and have an arginine vasopressin V than previously known ₂The benzo-aza of receptor agonism Derivative is few, is gratifying on the merging therapy this point that can be used for safely with multiple medicine.

As through the metabolic medicine of CYP3A4, can exemplify Simvastatin, lovastatin, fluvastatin, midazolam, nifedipine, ammonia nitrogen Horizon, nicardipine etc., as through the metabolic medicine of CYP2C9, it is (comprehensively clinical to exemplify diclofenac, Ibuprofen BP/EP, indomethacin, tolbutamide, Glyburide, losartan etc., 48 (6), 1427-1431,1999.).

The pharmacological action of The compounds of this invention is identified by following test method.

(1) V ₂Receptor binding assays

With reference to the method for Tahara etc. (British Journal of Pharmacology, Vol 125, p.1463-1470,1998), preparation expressing human V ₂Chinese hamster ovary celI film sample.With film sample 2 μ g with [ ³H]-arginine vasopressin (hereinafter to be referred as " [ ³H]-vassopressin ", 0.5nM, specific activity=75Ci/mmol) and each test compound (10 ^-10～10 ^-5M) containing 10mM MgCl together ₂, 0.1% bovine serum albumin (BSA) the 50mM Tris-hydrochloride buffer (pH=7.4) of total amount 250 μ l in cultivated 60 minutes in 25 ℃.Use thereafter cell harvestor separated free type [ ³H]-vassopressin and receptors bind type [ ³H]-vassopressin, make the receptors bind type [ ³H]-the vassopressin sorption is on the glass filter of single filter plate GF/B.After the thorough drying, mix with microtest plate flicker mixture, usefulness top counter (top counter) mensuration receptors bind type [ ³H]-amount of vassopressin, calculate inhibiting rate with following formula again.

Inhibiting rate (%)=100-(C ₁-B ₁)/(C ₀-B ₁) * 100

C ₁: under the test compound coexistence of concentration known, handle [ ³H]-when vassopressin and receptor membrane sample, with film sample bonded [ ₃H]-amount of vassopressin.

C ₀: when test compound does not exist, handle [ ³H]-situation of vassopressin and receptor membrane sample under, with film sample bonded [ ³H]-amount of vassopressin.

B ₁: at excessive vassopressin (10 ^-6M) coexistence handle down with [ ₃H]-vassopressin and when handling the receptor membrane sample, with film sample bonded [ ³H]-amount of vassopressin.

Calculate the concentration (IC that inhibiting rate is 50% o'clock each test compound by following formula ₅₀Value), calculate the affinity of test compound to acceptor, i.e. dissociation constant (Ki) with following formula thus.

Dissociation constant (Ki)=IC ₅₀/ (1+[L]/Kd)

[L]: [ ³H]-concentration of vassopressin

Kd: by saturated in conjunction with the experiment try to achieve [ ³H]-vassopressin is to the dissociation constant of acceptor.

(table 1) is to V ₂The affinity of acceptor

Compound	Ki(nM)	Compound	Ki(nm)
Compound	Ki(nM)	Compound	Ki(nm)	Embodiment 3	11	Embodiment 31	10
Embodiment 9	19	Embodiment 54	17	Embodiment 3	11	Embodiment 31	10
Embodiment 9	19	Embodiment 54	17	Embodiment 14	18	Embodiment 55	16
Embodiment 24	4.3	Embodiment 134	12	Embodiment 14	18	Embodiment 55	16
Embodiment 24	4.3	Embodiment 134	12	Embodiment 46	5.8	Embodiment 136	11
Embodiment 98	6.2	Comparative compound	68	Embodiment 46	5.8	Embodiment 136	11

In this connection, comparative compound be meant the embodiment 32 of No. 97/22591, international monopoly publication WO record compound (compound name: 2-[(5R)-1-(2-chloro-4-tetramethyleneimine-1-base benzoyl)-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza

-5-yl]-N-sec.-propyl ethanamide).

As shown in table 1, The compounds of this invention is to V ₂Acceptor has high-affinity.

(2) antidiuresis test (intravenous administration)

It is male rat that the Wistar in 10～12 ages in week is used in experiment, 5 every group.A group intravenously gives the compound of embodiment 3, dosage is 0.3mg/kg, B group intravenously gives the compound of embodiment 9, dosage is 0.3mg/kg, be and be dissolved in solvent (physiological saline that contains DMSO) and give afterwards, the solvent that C group only gives 1ml/kg dosage in contrast, per os is forced to give distilled water 30ml/kg (water load) after 15 minutes.Give the water load and in metabolic cage, gather urine after 2 hours, as 100%, calculate the urine amount as the homaluria rate with the water lifting capacity.In order to estimate the homaluria rate after 1 hour of each group of employing and the mean value of the homaluria rate after 2 hours.It the results are shown in Table 2.

(table 2)

Antidiuretic activity (intravenous administration)

As shown in Table 2, The compounds of this invention has good antidiuretic activity.

(3) antidiuresis test (oral)

It is male rat that the Wistar in 10～12 ages in week is used in experiment.Make its oral each test compound, force oral distilled water 30ml/kg (water load) after 15 minutes.Give the water load and in metabolic cage, gather urine after 4 hours, the water lifting capacity as 100%, is calculated the urine amount as the homaluria rate.Estimating to adopt makes the homaluria rate reduce the dosage (ED of 50% necessary test compound ₅₀).As a result, but The compounds of this invention intravenous administration not only also has good antidiuretic activity when oral.

(4) Cytochrome P450 (3A4) enzyme inhibition test

Method (Analytical Biochemistry, 248,188-190,1997) with reference to Crespi etc. is tested.

With 96 orifice plates with substrate 7-benzyloxy-4-(trifluoromethyl) tonka bean camphor (5 * 10 ^-5M), each test compound (4.9 * 10 ^-8～5 * 10 ^-5M) and enzyme (5 * 10 ^-9M), contain 8.2 μ M NADP+, 0.41mM G-6-P salt, 0.41mM MgCl at total amount 200 μ l ₂And in the 200mM phosphoric acid buffer (pH=7.4) of 0.4 unit/ml glucose-6-phosphate dehydrogenase (G6PD), cultivated 30 minutes in 37 ℃.After this, add the 0.5M 2-amino-2-hydroxymethyl-1 that contains 80% acetonitrile, the ammediol aqueous solution stops reaction, reads the plate device with fluorescence and measures fluorescence intensity (excitation wavelength 409nm, wavelength of fluorescence 530nm).Calculate inhibiting rate with following formula, obtain inhibiting rate and be 50% o'clock test compound concentration (IC ₅₀).It the results are shown in Table 3.

Inhibiting rate (%)=100-(C ₁-B ₁)/(C ₀-B ₁) * 100

C ₁: the fluorescence intensity when having the test compound, enzyme of concentration known and substrate;

C ₀: do not add the test compound, the fluorescence intensity when only having enzyme and substrate;

B ₁: the fluorescence intensity of blank well.

(5) Cytochrome P450 (2C9) enzyme inhibition test

With 96 orifice plates with substrate 7-methoxyl group-4-(trifluoromethyl) tonka bean camphor (7.5 * 10 ^-5M), test compound (4.9 * 10 ^-8～5 * 10 ^-5M) and enzyme (10 ^-8M), at the 8.2 μ M NADP that contain of total amount 200 μ l ⁺, 0.41mM G-6-P salt, 0.41mM MgCl ₂And in the 200mM phosphoric acid buffer (pH=7.4) of 0.4 unit/ml glucose-6-phosphate dehydrogenase (G6PD), cultivated 45 minutes in 37 ℃.After this add the 0.5M 2-amino-2-hydroxymethyl-1 that contains 80% acetonitrile, the ammediol aqueous solution stops reaction, reads the plate device with fluorescence and measures fluorescence intensity (excitation wavelength 409nm, wavelength of fluorescence 530nm).Use the formula identical to calculate inhibiting rate again, obtain inhibiting rate and be 50% o'clock test compound concentration (IC with above-mentioned (4) ₅₀).It the results are shown in Table 3.

(table 3)

Restraining effect to CYP (3A4 and 2C9)

As shown in table 3, The compounds of this invention demonstrates extremely low restraining effect to drug metabolism enzyme CYP3A4 and CYP2C9.Illustrated identical in comparative compound wherein and the table 1.

Pharmaceuticals of the present invention can prepare with ordinary method with carrier, filler and other additives with The compounds of this invention shown in one or more general formulas (I) and the medicament that is commonly used to prepare medicament.Administration can be adopted following any form, and is promptly oral with tablet, pill, capsule, granule, powder, liquor etc., injection such as quiet notes, intramuscular injection or suppository, intranasal, through mucous membrane, through non-oral administrations such as skin etc.

Of the present inventionly be used for oral solids composition and comprise tablet, powder, granule etc.In this class solids composition with active substance more than a kind and at least a inert diluent, as mixing such as lactose, N.F,USP MANNITOL, glucose, hydroxypropylcellulose, Microcrystalline Cellulose, starch, Polyvinylpyrolidone (PVP), silicoaluminate magnesium.According to well-established law, can contain inert diluent additive in addition in the composition, as lubricants such as Magnesium Stearates, disintegrating agents such as glycolic cellulose calcium, solubility promoters such as stablizers such as lactose, L-glutamic acid or aspartic acid etc.Tablet or pill can wrap sugar-coat or gastric solubility or the enteric film with sucrose, gelatin, hydroxypropylcellulose, hypromellose phthalate etc. in case of necessity.

Oral liquid composition comprises pharmaceutically acceptable emulsion, solution, suspension agent, syrup, elixir etc., contains inert diluent commonly used, for example pure water or ethanol.Except that inert solvent, composition also can contain auxiliary agent, sweeting agent, seasonings, perfume compound, sanitass such as wetting agent, suspension agent.

Parenteral injection comprises aseptic water-based or nonaqueous solution, suspension agent and emulsion.The thinner example that uses in aqueous solution agent, the suspension agent has distilled water for injection and physiological saline.The thinner that is used for nonaqueous solution, suspension agent for example has alcohols, Polysorbate 80s etc. such as propylene glycol, polyoxyethylene glycol, olive wet goods vegetables oil, EtOH.This based composition also can contain additive such as sanitas, wetting agent, emulsifying agent, dispersion agent, stablizer such as lactose, and solubility promoters such as L-glutamic acid and aspartic acid etc.They can filter, cooperate methods such as sterilant or irradiation through bacterial filter and asepticize.They also can be made into aseptic solids composition, use with sterilized water or aseptic solvent for injection dissolving back before use.

Common per daily dose when oral is about 0.0001～50mg/kg by body weight, better is about 0.001～10mg/kg, 0.01～1mg/kg more preferably, and they can once a day or divide 2～4 administrations.During intravenously administrable, per daily dose is about 0.0001～1mg/kg by body weight, better is about 0.0001～0.1mg/kg, once a day or divide administration for several times.Dosage should be considered different situations decisions such as symptom, age, sex.But dosage can be with various condition variation, and is hour enough than above-mentioned dosage sometimes.

The best mode that carries out an invention

Below specify the present invention with embodiment, but the present invention is not limited only to these embodiment.In this connection, the starting compound that uses among the embodiment also comprises new compound, and these starting compounds are illustrated as a reference example from the method for known compound preparation.

Reference example 1

5.2g 60% sodium hydride oil dispersion liquid is suspended among the 50ml DMF, ice-cooled following, add the 6.73ml phenylcarbinol.After being warmed to room temperature, add 12.3g 4-fluoro-2-trifluoromethylbenzoic acid, stirred 6 hours under the room temperature.In reaction mixture, add the 1M aqueous hydrochloric acid,, obtain 16.39g 4-(benzyloxy)-2-(trifluoromethyl) phenylformic acid by filtering the crystallization of collecting precipitation.

MS(+)；297

According to the mode identical, use the reference example 2 to 4 shown in the corresponding feedstock production table 4 respectively with reference example 1.

To this, symbol has following implication (down together) in the table.

Rf: the reference example numbering,

Data: physical-chemical data (NMR: use (CH ₃) ₄Si unless otherwise indicated, uses DMSO-d as interior mark ₆As measuring solvent, show ¹The peak δ (ppm) that H-NMR measures,

MS(+)：FAB-MS[M+H] ⁺，MS(-)：FAB-MS[M-H] ⁺，EMS(+)：ESI-MS[M+H] ⁺，EMS(-)：ESI-MS[M-H] ⁺，

R ^A, R ^B: the substituting group in the general formula,

NPr: n-propyl, cPr: cyclopropyl.

To this, to the NMR data, there is such situation, a kind of compound still wherein, is only described one corresponding to the peak that is considered to the main conformer that exists owing to existing two or more conformers to provide complex data.In addition, by measuring when heating, these peaks converge on one type the peak that shows compound.

(table 4)

Rf	R ^A	R ^B	Data
Rf	R ^A	R ^B	Data	2	CF ₃	cPr-CH ₂O-	EMS(-)：259
3	Cl	nPr-S-	MS(+)：231	2	CF ₃	cPr-CH ₂O-	EMS(-)：259
3	Cl	nPr-S-	MS(+)：231	4	CF ₃	nPr-S-	MS(-)：263

Reference example 5

4.44g 4-fluoro-2-methyl thrifluorobenzene is dissolved among the 40ml DMF, adds 3.32g salt of wormwood and 4.10ml N-methyl-N-propylamine, stirred this mixture 14 hours at 80 ℃.After the reaction mixture, by adding entry and EtOAc is separated.Organic layer washs with saturated brine, use anhydrous sodium sulfate drying, the crude product that obtains by evaporating solvent carries out silica gel column chromatography then, with hexane-EtOAc (4: 1) wash-out, decompression concentrates down, obtains 4.79g 4-[methyl (propyl group) amino]-2-(trifluoromethyl) methyl benzoate.

MS(+)：276

Reference example 6

4.78g reference example 5 compound dissolutions in 20ml MeOH, are added 6.94g 5M aqueous sodium hydroxide solution therein, stirred 5 hours at 70 ℃.Cool off this reaction mixture, decompression concentrates down.The resistates that obtains neutralizes with the 1M aqueous hydrochloric acid, filters the crystallization of collecting precipitation, obtains 4.36g 4-[methyl (propyl group) amino]-2-(trifluoromethyl) phenylformic acid.

MS(+)：262

Reference example 7

8.0g reference example 1 compound dissolution is in 80ml THF, ice-cooled following, add 8ml thionyl chloride and 3 DMF therein, at room temperature stirred then 3 hours.By the evaporation reaction solvent, carry out drying then, obtain chloride compounds.With this compound and 6.84g (Z)-(4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit) methyl acetate mixes, and mixes with the 50ml pyridine down ice-cooled, then stirring at room 12 hours.After finishing reaction, evaporating solvent, and carry out layer by adding 1M aqueous hydrochloric acid with EtOAc and separate.Anhydrous sodium sulfate drying is used in organic layer water and saturated brine washing.Evaporating solvent, the resistates of acquisition recrystallization in EtOH, obtain 9.12g (2Z)-1-[4-(benzyloxy)-2-(trifluoromethyl) benzoyl]-4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } methyl acetate.

EMS(+)：532

According to the mode identical, use corresponding raw material respectively, the contrast reference example 8 to 11 shown in the preparation table 5 with reference example 7.

To this, implication (down together) below the symbolic representation in the table.

Me: methyl.

(table 5)

Rf	R ^A	R ^B	Data
Rf	R ^A	R ^B	Data	8	CF ₃	cPr-CH ₂O-	EMS(+)：496
9	Cl	nPr-S-	MS(+)：466	8	CF ₃	cPr-CH ₂O-	EMS(+)：496
9	Cl	nPr-S-	MS(+)：466	10	CF ₃	nPr-S-	MS(+)：500
11	CF ₃	nPr-N(Me)-	MS(+)：497	10	CF ₃	nPr-S-	MS(+)：500

Reference example 12

The compound dissolution of 9.1g reference example 7 in the 100ml trifluoroacetic acid, is added the 5.1g pentamethylbenzene therein, stirred 12 hours under the room temperature.Filter out insolubles, under reduced pressure concentrated filtrate.In the resistates that obtains, add diethyl ether, filter the crystallization of collecting precipitation, obtain 6.22g (2Z)-4,4-two fluoro-1-[4-(benzyloxy)-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } methyl acetate.

EMS(+)：442

Reference example 13

The compound dissolution of 3.89g reference example 12 in 20ml DMSO, is added the 2.06g monobromo-acetic acid tert-butyl ester and 1.46g salt of wormwood therein, stirred 2 hours under the room temperature.After filtering out insolubles, carry out layer with EtOAc and separate by adding entry.Organic layer washs with saturated brine, uses anhydrous sodium sulfate drying.Evaporating solvent, the resistates of acquisition carries out silica gel column chromatography, and chloroform-MeOH (80: 1) is an elutriant; acquisition 3.55g (2Z)-and 1-[4-(2-tert.-butoxy-2-oxo oxyethyl group)-2-(trifluoromethyl) benzoyl]-4,4-two fluoro-1,2; 3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } methyl acetate.EMS(+)：556

Reference example 14

The compound dissolution of 3.75g reference example 13 in the 20ml trifluoroacetic acid, was stirred 30 minutes under the room temperature.By the evaporating solvent that reduces pressure down, obtain 3.25g[4-{[(5Z)-4,4-two fluoro-5-(2-methoxyl group-2-oxo ethylidene)-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza

-1-yl] carbonyl }-3-(trifluoromethyl) phenoxy group] acetate.

MS(+)：450

Reference example 15

The compound dissolution of 1.09g reference example 14 in 10ml DMF, is added 324mg HOBt therein, 460mg WSCD, 1.20ml dimethylamine (2.0M THF solution) and 0.335ml triethylamine at room temperature stirred 6 hours then.In this reaction solution, add sodium bicarbonate aqueous solution; collect the precipitation that forms by filtering; the crude product that obtains washes with water; decompression is dry down; obtain 1.14g (2Z)-1-[4-(2-dimethylamino-2-oxo oxyethyl group)-2-(trifluoromethyl) benzoyl]-4,4-two fluoro-1,2; 3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } methyl acetate.

MS(+)：527

Reference example 16

The compound dissolution of 1.00g reference example 12 in 15ml THF, is added 0.415ml 1-butanols therein, and 1.19g triphenylphosphine and 2.08ml diethylazodicarboxylate at room temperature stirred 17 hours then.In reaction mixture, add entry and EtOAc, carry out layer and separate.Anhydrous magnesium sulfate drying is used in organic layer water and saturated brine washing.Evaporating solvent, the resistates of acquisition carries out silica gel column chromatography, and with chloroform-MeOH (50: 1) wash-out, decompression concentrates down, acquisition 1.41g thick (2Z)-1-[4-butoxy-2-(trifluoromethyl) benzoyl] and-4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } methyl acetate.

The compound dissolution that obtains above in 5ml MeOH-10ml THF, is mixed with the 1M aqueous sodium hydroxide solution, then stirring at room 2 hours.Behind the evaporating solvent, add 1M hydrochloric acid and chloroform-iPrOH (3: 1 mixed solvents), carry out layer and separate.Organic layer washs with saturated brine, uses anhydrous sodium sulfate drying.By evaporating solvent, acquisition 1.01g (2Z)-1-[4-butoxy-2-(trifluoromethyl) benzoyl] and-4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } acetate.

MS(+)：484

According to the mode identical, use corresponding raw material respectively, the reference example 17 to 19 shown in the preparation table 6 with reference example 16.

IBu: isobutyl-.

(table 6)

Rf	R ^A	R ^B	Data
Rf	R ^A	R ^B	Data	17	CF ₃	nPr-O-	MS(+)：470
18	CF ₃	iBu-O-	MS(+)：483	17	CF ₃	nPr-O-	MS(+)：470
18	CF ₃	iBu-O-	MS(+)：483	19	Cl	iBu-O-	MS(+)：450

Reference example 20

The compound dissolution of 1.43g reference example 7 in the mixed solvent of 15ml MeOH-25ml THF, is mixed with the 1M aqueous sodium hydroxide solution, stirred 2 hours under the room temperature.Behind the evaporating solvent, change this liquid for acid by adding 1M hydrochloric acid, then by filtering the white solid of collecting precipitation; decompression is down dry, obtain 1.39g (2Z)-1-[4-(benzyloxy)-2-(trifluoromethyl) benzoyl]-4,4-two fluoro-1; 2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } acetate.

MS(+)：518

According to the mode identical, use corresponding raw material respectively, the reference example 21 to 25 shown in the preparation table 7 with reference example 20.

(table 7)

Rf	R ^A	R ^B	Data
Rf	R ^A	R ^B	Data	21	CF ₃	cPr-CH ₂O-	EMS(+)：482
22	Cl	nPr-S-	MS(+)：452	21	CF ₃	cPr-CH ₂O-	EMS(+)：482
22	Cl	nPr-S-	MS(+)：452	23	CF ₃	nPr-S-	MS(+)：486
24	CF ₃	nPr-N(Me)-	MS(+)：483	23	CF ₃	nPr-S-	MS(+)：486
24	CF ₃	nPr-N(Me)-	MS(+)：483	25	CF ₃	Me ₂NOCCH ₂-O-	MS(+)：513

Reference example 26

Add the vitriol oil in the MeOH solution of reference example 1 compound, heating down 3 days refluxes.This reaction mixture is poured in the frozen water, extracted with ether.Behind the evaporating solvent, the resistates of acquisition is dissolved in EtOH, mixes with 10% palladium carbon, and in nitrogen atmosphere, stirring at room 24 hours obtains 4-hydroxyl-2-(trifluoromethyl) methyl benzoate.

MS(+)：221

Reference example 27

In the acetonitrile solution of the compound of reference example 26, add martonite and salt of wormwood, stirred 1 hour, obtain 4-(2-oxopropoxy)-2-(trifluoromethyl) methyl benzoate at 60 ℃.

ESI-MS(+)：299[M+23] ⁺

Reference example 28

In 78 ℃, fluoridize in the dichloromethane solution that (diethylamino) sulphur adds reference example 27 compounds three, stirred 24 hours under the room temperature, obtain 4-(2,2-difluoro propoxy-)-2-(trifluoromethyl) methyl benzoate.

EI-MS：298[M] ⁺

Reference example 29

The 5M aqueous sodium hydroxide solution is joined in the MeOH solution of reference example 28 compounds, stirred 2.5 hours, obtain 4-(2,2-difluoro propoxy-)-2-(trifluoromethyl) phenylformic acid at 90 ℃.

MS(-)：283

Reference example 30

(2S)-the third-1, add triethylamine in the dichloromethane solution of 2-glycol, at-20 ℃ of dichloromethane solutions that add ptoluene-sulfonyl chlorine, stirred 18 hours under the room temperature then, obtain (2S)-2-hydroxypropyl-4-toluene sulfonic acide ester.

MS(+)：231

Reference example 30A

Add N in the THF solution of reference example 30 compounds, accelerine and diacetyl oxide stirred acquisition (1S)-1-methyl-2-{[(4-aminomethyl phenyl 1 hour in 0 ℃) alkylsulfonyl] oxygen } ethyl acetic acid.

MS(+)：273

Reference example 30B

Reference example 26 compounds and salt of wormwood are joined in the DMF solution of reference example 30A compound, stirred 17 hours, obtain 4-{[(2S at 70 ℃)-2-(acetoxyl group) propyl group] oxygen }-2-(trifluoromethyl) methyl benzoate.

MS(+)：321

Reference example 31

At 0 ℃, 1M potassium hydroxide-MeOH solution is added in the MeOH solution of compound of reference example 30B, stirred 1 hour under the room temperature, obtain 4-{[(2S)-the 2-hydroxypropyl] oxygen }-2-(trifluoromethyl) methyl benzoate.

MS(+)：279

Reference example 32

In-78 ℃, fluoridize (diethylamino) sulphur with three and join in the dichloromethane solution of reference example 31 compounds, stirred 15 hours under the room temperature, obtain 4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) methyl benzoate.

FAB-MS(+)：280[M] ⁺

Reference example 33

The 5M aqueous sodium hydroxide solution is added in the MeOH solution of reference example 32 compounds, stirred 6 hours, obtain 4-{[(2R at 70 ℃)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) phenylformic acid.

MS(+)：267

Reference example 34

In 0 ℃, sodium borohydride is joined in the EtOH solution of reference example 27 compounds, stirred 1 hour under the room temperature, obtain 4-(2-hydroxyl propoxy-)-2-(trifluoromethyl) methyl benzoate.

ESI-MS(+)：301[M+23] ⁺

Reference example 35

According to the mode identical, use (2R)-the third-1,2-glycol, preparation (2R)-2-hydroxypropyl-4-toluene sulfonic acide ester with reference example 30.

MS(+)：231

Reference example 35A

According to the mode identical, use the compound of reference example 35, preparation (1R)-1-methyl-2-{[(4-aminomethyl phenyl with reference example 30A) alkylsulfonyl] oxygen } ethyl acetic acid.

MS(+)：273

Reference example 35B

According to the mode identical, use the compound of reference example 35A, preparation 4-{[(2R with reference example 30B)-2-(acetoxyl group) propyl group] oxygen }-2-(trifluoromethyl) methyl benzoate.

MS(+)：321

Reference example 36

According to the mode identical, use the compound 4-{[(2R of reference example 35B with reference example 31)-the 2-hydroxypropyl] oxygen }-2-(trifluoromethyl) methyl benzoate.

MS(+)：279

Reference example 37

According to the mode identical, use the compound of reference example 36, preparation 4-{[(2S with reference example 32)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) methyl benzoate.

MS(+)：281

Reference example 38

According to the mode identical, use the compound of reference example 37, preparation 4-{[(2S with reference example 33)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) phenylformic acid.

MS(+)：267

According to the mode identical, use corresponding raw material respectively, the reference example 39 to 41 shown in the preparation table 8 with reference example 7.

(table 8)

Rf	R ^B	R ^D	Data
Rf	R ^B	R ^D	Data	39	(S)-O-CH ₂CHFCH ₃	H	EMS(+)：502
40	(R)-O-CH ₂CHFCH ₃	H	EMS(+)：502	39	(S)-O-CH ₂CHFCH ₃	H	EMS(+)：502
40	(R)-O-CH ₂CHFCH ₃	H	EMS(+)：502	41	(S)-O-CH ₂CHFCH ₃	F	MS(+)：520
42	(R)-O-CH ₂CHFCH ₃	F	MS(+)：520	41	(S)-O-CH ₂CHFCH ₃	F	MS(+)：520
42	(R)-O-CH ₂CHFCH ₃	F	MS(+)：520	41	-O-CH ₂CF ₂CH ₃	H	MS(+)：520

According to the mode identical, use corresponding raw material respectively, the reference example 42 to 46 shown in the preparation table 9 with reference example 20.

(table 9)

Rf	R ^B	R ^D	Data
Rf	R ^B	R ^D	Data	42	(S)-O-CH ₂CHFCH ₃	H	MS(+)：488
43	(R)-O-CH ₂CHFCH ₃	H	MS(+)：488	42	(S)-O-CH ₂CHFCH ₃	H	MS(+)：488
43	(R)-O-CH ₂CHFCH ₃	H	MS(+)：488	44	(S)-O-CH ₂CHFCH ₃	F	MS(+)：506
45	(R)-O-CH ₂CHFCH ₃	F	MS(+)：506	44	(S)-O-CH ₂CHFCH ₃	F	MS(+)：506
45	(R)-O-CH ₂CHFCH ₃	F	MS(+)：506	46	-O-CH ₂CF ₂CH ₃	H	MS(+)：506

Embodiment 1

In 5ml DMF, with 43mg HOBt, 61mgWSCD, 35mg hydrochloric acid G-NH2 and 0.045ml triethylamine mix with the compound dissolution of 150mg reference example 20, then stirring at room 4 hours.In this reaction mixture, add saturated sodium bicarbonate aqueous solution and EtOAc, carry out layer and separate.Anhydrous magnesium sulfate drying is used in organic layer water and saturated brine washing.Evaporating solvent, the resistates of acquisition recrystallization in EtOH obtains 139mg (2Z)-N-(2-amino-2-oxoethyl)-2-{1-[4-(benzyloxy)-2-(trifluoromethyl) benzoyl]-4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide.

According to the mode identical, use corresponding raw material respectively, the embodiment 2 to 16 shown in the preparation table 10 with embodiment 1.

Embodiment 17

The compound dissolution of 150mg embodiment 20 in 3.5ml THF, is dripped DMF with 0.3ml thionyl chloride and 2-3 and mixes, stirred 1 hour under the room temperature.Decompression is evaporating solvent down, and uses toluene to carry out component distillation and further remove thionyl chloride.The resistates that obtains is dissolved in THF, this drips of solution is added in the ammoniacal liquor.In this reaction mixture, add EtOAc, carry out layer and separate.Organic layer washs with saturated brine, uses anhydrous magnesium sulfate drying.The crude product recrystallization in iPrOH-diisopropyl ether mixed solvent that obtains obtains 126mg

(2Z)-and 2-{1-[4-(benzyloxy)-2-(trifluoromethyl) benzoyl]-4,4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza -5-subunit } ethanamide.

According to the mode identical, use corresponding raw material, the embodiment 18 shown in the preparation table 11 with embodiment 17.In addition,, use corresponding raw material respectively, the embodiment 19 and 20 shown in the preparation table 10 according to the mode 2 identical with reference example 12.

Embodiment 21

The compound dissolution of 325mg embodiment 6 in 5ml 1, in the 2-ethylene dichloride, is mixed with the 148mg m-chlorobenzoic acid down ice-cooled, and stirring is 4 hours under the room temperature.This reaction mixture and 10% (w/v) Na ₂S ₂O ₃5H ₂The O aqueous solution, water and chloroform mix, and carry out layer and separate.Organic layer washs with saturated sodium bicarbonate aqueous solution; use anhydrous sodium sulfate drying; evaporating solvent, the crude product of acquisition carries out silica gel column chromatography, with chloroform-MeOH (23: 2) wash-out; decompression concentrates down; obtain 121mg (2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-two fluoro-1-[4-(propyl group sulfinyl) benzoyl]-1,2; 3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide.

According to the mode identical, use the embodiment 22 shown in the corresponding feedstock production table 10 with embodiment 21.In addition, adopt method described in method noted earlier or the embodiment, or well known to a person skilled in the art that method or its improve, and use corresponding feedstock production table 11 to the embodiment shown in 18 23 to 147 respectively.

To this, implication below the symbolic representation in the table (down with).

Ex: embodiment numbering,

R ^C: substituting group in the general formula,

Et: ethyl, nBu: normal-butyl, Ph: phenyl, Py: pyridyl, Bn: benzyl, Gly: formamyl methylamino-(NHCH ₂CONH ₂), Etha:2-hydroxyethylamino (NHCH ₂CH ₂OH), Car: amino (NH ₂).To this, the position that the numeral of each substituting group front replaces.Illustrate ,-NHPh (2-OH) refers to 2-hydroxy phenyl amino, and-NHCH ₂(2-Py) refer to pyridine-2-base methylamino-.

(table 10)

Ex	R ^A	R ^B	R ^C	MS(+)
Ex	R ^A	R ^B	R ^C	MS(+)	1	-CF ₃	Bn-O-	-CH ₂-CONH ₂	574
2	-CF ₃	Bn-O-	-(CH ₂) ₂-OH	561	1	-CF ₃	Bn-O-	-CH ₂-CONH ₂	574
2	-CF ₃	Bn-O-	-(CH ₂) ₂-OH	561	3	-CF ₃	cPr-CH ₂O-	-CH ₂-CONH ₂	538
4	-CF ₃	cPr-CH ₂O-	-(CH ₂) ₂-OH	525	3	-CF ₃	cPr-CH ₂O-	-CH ₂-CONH ₂	538
4	-CF ₃	cPr-CH ₂O-	-(CH ₂) ₂-OH	525	5	-Cl	nPr-S-	-CH ₂-CONH ₂	508
6	-CF ₃	nPr-S-	-CH ₂-CONH ₂	542	5	-Cl	nPr-S-	-CH ₂-CONH ₂	508
6	-CF ₃	nPr-S-	-CH ₂-CONH ₂	542	7	-CF ₃	nPr-O-	-CH ₂-CONH ₂	526
8	-CF ₃	nPr-O-	-(CH ₂) ₂-OH	513	7	-CF ₃	nPr-O-	-CH ₂-CONH ₂	526
8	-CF ₃	nPr-O-	-(CH ₂) ₂-OH	513	9	-CF ₃	nBu-O-	-CH ₂-CONH ₂	540
10	-CF ₃	nBu-O-	-(CH ₂) ₂-OH	527	9	-CF ₃	nBu-O-	-CH ₂-CONH ₂	540
10	-CF ₃	nBu-O-	-(CH ₂) ₂-OH	527	11	-CF ₃	iBu-O-	-CH ₂-CONH ₂	540
12	-CF ₃	iBu-O-	-(CH ₂) ₂-OH	527	11	-CF ₃	iBu-O-	-CH ₂-CONH ₂	540
12	-CF ₃	iBu-O-	-(CH ₂) ₂-OH	527	13	-Cl	iBu-O-	-CH ₂-CONH ₂	506
14	-CF ₃	nPr-N(Me)-	-CH ₂-CONH ₂	539	13	-Cl	iBu-O-	-CH ₂-CONH ₂	506
14	-CF ₃	nPr-N(Me)-	-CH ₂-CONH ₂	539	15	-CF ₃	Me ₂NOCCH ₂-O-	-CH ₂-CONH ₂	569
16	-CF ₃	nPr-O-	-H	469	15	-CF ₃	Me ₂NOCCH ₂-O-	-CH ₂-CONH ₂	569
16	-CF ₃	nPr-O-	-H	469	17	-CF ₃	Bn-O-	-H	517
18	-CF ₃	nPr-N(Me)-	-H	482	17	-CF ₃	Bn-O-	-H	517
18	-CF ₃	nPr-N(Me)-	-H	482	19	-CF ₃	HO-	-CH ₂-CONH ₂	484
20	-CF ₃	HO-	-H	427	19	-CF ₃	HO-	-CH ₂-CONH ₂	484
20	-CF ₃	HO-	-H	427	21	-CF ₃	nPr-S(＝O)-	-CH ₂-CONH ₂	558
22	-CF ₃	nPr-S(＝O) ₂-	-CH ₂-CONH ₂	574	21	-CF ₃	nPr-S(＝O)-	-CH ₂-CONH ₂	558

(table 11)

Ex	R ^B	R ^D	MS(+)
Ex	R ^B	R ^D	MS(+)	23	-OnPr	F	544
24	-OnPr	Cl	560	23	-OnPr	F	544
24	-OnPr	Cl	560	25	-OnPr	Br	604，606
26	-O-CH ₂C(CH ₃)＝CH ₂	H	538	25	-OnPr	Br	604，606
26	-O-CH ₂C(CH ₃)＝CH ₂	H	538	27	-O-(CH ₂) ₂CH ₂F	H	544
28	(S)-O-CH ₂CHFCH ₃	H	544	27	-O-(CH ₂) ₂CH ₂F	H	544
28	(S)-O-CH ₂CHFCH ₃	H	544	29	(R)-O-CH ₂CHFCH ₃	H	544
30	(S)-O-CH ₂CHFCH ₃	F	562	29	(R)-O-CH ₂CHFCH ₃	H	544
30	(S)-O-CH ₂CHFCH ₃	F	562	31	(R)-O-CH ₂CHFCH ₃	F	562
32	-O-CH ₂CHFCH ₃	H	544	31	(R)-O-CH ₂CHFCH ₃	F	562
32	-O-CH ₂CHFCH ₃	H	544	33	-O-CH ₂CF ₂CH ₃	H	562
34	-O-CH ₂CF ₂CH ₃	F	580	33	-O-CH ₂CF ₂CH ₃	H	562
34	-O-CH ₂CF ₂CH ₃	F	580	35	-N(Me)Et	H	525
36	-N(Et)nPr	H	553	35	-N(Me)Et	H	525
36	-N(Et)nPr	H	553	37	-N(Me)nBu	H	553
38	-N(Me)iBu	H	553	37	-N(Me)nBu	H	553
38	-N(Me)iBu	H	553	39	-NnPr ₂	H	567
40	-SEt	H	528	39	-NnPr ₂	H	567
40	-SEt	H	528	41	-SiBu	H	556
42	-SCH＝CH ₂	H	526	41	-SiBu	H	556
42	-SCH＝CH ₂	H	526	43	-SCH ₂CH ₂F	H	546
44	-S(CH ₂) ₂CH ₂F	H	560	43	-SCH ₂CH ₂F	H	546
44	-S(CH ₂) ₂CH ₂F	H	560	45	-SCH ₂CHFCH ₃	H	560

(table 12)

Ex	R ^B	R ^D	MS(+)
Ex	R ^B	R ^D	MS(+)	46	-OnPr	F	531
47	-OnPr	Cl	547	46	-OnPr	F	531
47	-OnPr	Cl	547	48	-O-CH ₂cPr	H	525
49	-O-(CH ₂) ₂CH ₂F	H	531	48	-O-CH ₂cPr	H	525
49	-O-(CH ₂) ₂CH ₂F	H	531	50	-O-CH ₂CHFCH ₃	H	531
51	-O-CH ₂CF ₂CH ₃	H	549	50	-O-CH ₂CHFCH ₃	H	531
51	-O-CH ₂CF ₂CH ₃	H	549	52	(S)-O-CH ₂CHFCH ₃	H	531
53	(R)-O-CH ₂CHFCH ₃	H	531	52	(S)-O-CH ₂CHFCH ₃	H	531
53	(R)-O-CH ₂CHFCH ₃	H	531	54	(S)-O-CH ₂CHFCH ₃	F	549
55	(R)-O-CH ₂CHFCH ₃	F	549	54	(S)-O-CH ₂CHFCH ₃	F	549
55	(R)-O-CH ₂CHFCH ₃	F	549	56	-O-CH ₂CF ₂CH ₃	F	567
57	-N(Me)(CH ₂) ₂CH ₂F	H	544	56	-O-CH ₂CF ₂CH ₃	F	567
57	-N(Me)(CH ₂) ₂CH ₂F	H	544	58	-N(Et)nPr	H	540
59	-SCH＝CH ₂	H	513	58	-N(Et)nPr	H	540
59	-SCH＝CH ₂	H	513	60	-SCH ₂CH ₂F	H	533
61	-S(CH ₂) ₂CH ₂F	H	547	60	-SCH ₂CH ₂F	H	533

(table 13)

Ex	R ^B	R ^D	MS(+)
Ex	R ^B	R ^D	MS(+)	62	-OnPr	F	487
63	-OnPr	Cl	503	62	-OnPr	F	487
63	-OnPr	Cl	503	64	-OnPr	Br	547，549
65	-O-(CH ₂) ₂CH ₂F	H	487	64	-OnPr	Br	547，549
65	-O-(CH ₂) ₂CH ₂F	H	487	66	-O-CH ₂CHFCH ₃	H	487
67	-O-CH ₂CF ₂CH ₃	H	505	66	-O-CH ₂CHFCH ₃	H	487
67	-O-CH ₂CF ₂CH ₃	H	505	68	-O-CH ₂CF ₂CH ₃	F	523
69	(S)-O-CH ₂CHFCH ₃	H	487	68	-O-CH ₂CF ₂CH ₃	F	523
69	(S)-O-CH ₂CHFCH ₃	H	487	70	(R)-O-CH ₂CHFCH ₃	H	487
71	(S)-O-CH ₂CHFCH ₃	F	505	70	(R)-O-CH ₂CHFCH ₃	H	487
71	(S)-O-CH ₂CHFCH ₃	F	505	72	(R)-O-CH ₂CHFCH ₃	F	505
73	-N(Me)(CH ₂) ₂CH ₂F	H	500	72	(R)-O-CH ₂CHFCH ₃	F	505
73	-N(Me)(CH ₂) ₂CH ₂F	H	500	74	-N(Me)CH ₂CF ₂CH ₃	H	518
75	-N(Et)nPr	H	496	74	-N(Me)CH ₂CF ₂CH ₃	H	518
75	-N(Et)nPr	H	496	76	-N(Et)(CH ₂) ₂CH ₂F	H	514
77	-NnPr ₂	H	510	76	-N(Et)(CH ₂) ₂CH ₂F	H	514

(table 14)

Ex	R ^C	R ^D	MS(+)
Ex	R ^C	R ^D	MS(+)	78	-NH(CH ₂) ₂OMe	H	527
79	-NHC(Me) ₂CH ₂OH	H	541	78	-NH(CH ₂) ₂OMe	H	527
79	-NHC(Me) ₂CH ₂OH	H	541	80	-NH(CH ₂) ₂F	H	515
81	-NH(CH ₂) ₃OH	H	527	80	-NH(CH ₂) ₂F	H	515
81	-NH(CH ₂) ₃OH	H	527	82	-NH(CH ₂) ₃F	H	529
83	-NHCH ₂CH(OH)CH ₂OH	H	543	82	-NH(CH ₂) ₃F	H	529
83	-NHCH ₂CH(OH)CH ₂OH	H	543	84	-NHCH ₂CH(R-OH)CH ₂OH	H	543
85	-NHCH ₂CH(S-OH)CH ₂OH	H	543	84	-NHCH ₂CH(R-OH)CH ₂OH	H	543
85	-NHCH ₂CH(S-OH)CH ₂OH	H	543	86	-NHCH ₂CH(R-OH)CH ₂OH	F	561
87	-NH(CH ₂) ₂O(CH ₂) ₂OH	H	557	86	-NHCH ₂CH(R-OH)CH ₂OH	F	561
87	-NH(CH ₂) ₂O(CH ₂) ₂OH	H	557	88	-NH(CH ₂) ₂NMe ₂	H	540
89	-NH(CH ₂) ₂CONH ₂	H	540	88	-NH(CH ₂) ₂NMe ₂	H	540
89	-NH(CH ₂) ₂CONH ₂	H	540	90	-NHCH(CONH ₂) ₂	H	569
91	-NHCH ₂CONHMe	H	540	90	-NHCH(CONH ₂) ₂	H	569
91	-NHCH ₂CONHMe	H	540	92	-NHCH ₂CONMe ₂	H	554
93	-NH(CH ₂) ₂NHCOCH ₃	H	554	92	-NHCH ₂CONMe ₂	H	554
93	-NH(CH ₂) ₂NHCOCH ₃	H	554	94	-N(CH ₂CH ₂OH) ₂	H	557
95	-N(CH ₂CONH ₂) ₂	H	583	94	-N(CH ₂CH ₂OH) ₂	H	557
95	-N(CH ₂CONH ₂) ₂	H	583	96	-NHPh	H	545
97	-NHPh(2-OH)	H	561	96	-NHPh	H	545
97	-NHPh(2-OH)	H	561	98	-NHPh(3-OH)	H	561
99	-NHPh(4-OH)	H	561	98	-NHPh(3-OH)	H	561
99	-NHPh(4-OH)	H	561	100	-NHPh(2-CONH ₂)	H	588
101	-NHPh(3-CONH ₂)	H	588	100	-NHPh(2-CONH ₂)	H	588
101	-NHPh(3-CONH ₂)	H	588	102	-NHPh(4-CONH ₂)	H	588
103	-NHPh(3-SO ₂NH ₂)	H	624	102	-NHPh(4-CONH ₂)	H	588
103	-NHPh(3-SO ₂NH ₂)	H	624	104	-NHPh(4-SO ₂NH ₂)	H	624
105	-NHPh(3-NHCOMe)	H	602	104	-NHPh(4-SO ₂NH ₂)	H	624

(table 15)

(table 16)

(table 17)

(table 18)

Ex	R ^1A	MS(+)
Ex	R ^1A	MS(+)	146	Gly	493
147	Car	436	146	Gly	493

Below, list the NMR data of some embodiment compounds at table 19.

(table 19)

Ex	NMR
Ex	NMR	1	2.35-2.55(1H，br)，2.60-2.80(1H，br)，3.00-3.15(1H，br)，3.76(2H，s)，4.75-4.90 (1H，br)，5.09(2H，s)，6.45(1H，s)，6.73(1H，d，J＝7.8Hz)，6.87(1H，d，J＝7.8Hz)，7.03 (1H，dd，J＝7.8，2.4Hz)，7.10-7.19(2H，m)，7.24-7.40(9H，m)，8.68(1H，t，J＝5.7Hz).
2	2.25-2.55(1H，br)，2.60-2.80(1H，br)，3.05-3.20(1H，br)，3.20-3.25(2H，m)，3.42- 3.50(2H，m)，4.72(1H，t，J＝5.4Hz)，4.75-4.90(1H，br)，5.09(2H，s)，6.39(1H，s)，6.72 (1H，d，J＝7.8Hz)，6.87(1H，d，J＝7.3Hz)，7.04(1H，dd，J＝2.0，8.3Hz)，7.16(1H，t，J＝ 7.6Hz)，7.22-7.42(8H，m)，8.46(1H，t，J＝5.4Hz).	1
2		3	0.24-0.30(2H，m)，0.49-0.58(2H，m)，1.08-1.20(1H，m)，2.33-2.45(1H，br)，2.60-2.97 (1H，br)，3.02-3.29(1H，br)，3.68-3.88(4H，m)，4.60-5.05(1H，br)，6.44(1H，s)，6.71 (1H，d，J＝8.8Hz)，6.85(1H，d，J＝8.8Hz)，6.93(1H，dd，J＝2.0，8.8Hz)，7.11-7.38(6H，m)， 8.48(1H，t，J＝5.4Hz).
4	0.24-0.31(2H，m)，0.48-0.56(2H，m)，1.09-1.21(1H，m)，2.27-2.46(1H，br)，2.65-2.90 (1H，br)，3.00-3.26(3H，m)，3.43-3.52(2H，m)，3.80(2H，d，J＝6.8Hz)，4.73(1H，d，J＝5.3 Hz)，4.75-4.92(1H，br)，6.39(1H，s)，6.71(1H，d，J＝7.3Hz)，6.84(1H，d，J＝8.8Hz)，6.93 (1H，dd，J＝2.5，8.8Hz)，7.13-7.18(2H，m)，7.24(1H，t，J＝7.3Hz)7.30-7.34(1H，m)，8.48 (1H，t，J＝5.3Hz).	3
4		5	0.92(3H，t，J＝7.6Hz)，1.46-1.55(2H，m)，2.24-2.50(1H，br)，2.65-2.84(1H，br)，2.89- 2.93(2H，m)，3.04-3.22(1H，br)，3.75(2H，s)，4.70-4.92(1H，br)，6.37(1H，s)，6.87 (1H，s)，6.94(1H，d，J＝7.6Hz)，7.01(1H，d，J＝8.0Hz)，7.14-7.53(6H，m)，8.62(1H，s).
6	0.93(3H，t，J＝7.2Hz)，1.48-1.57(2H，m)，2.28-2.52(1H，br)，2.63-2.87(1H，br)，2.94- 2.97(2H，m)，3.08-3.20(1H，br)，3.73-3.76(2H，m)，4.73-4.88(1H，br)，6.48(1H，s)， 6.73(1H，d，J＝8.0Hz)，6.84(1H，d，J＝8.0Hz)，7.14-7.76(7H，m)，8.69(1H，t，J＝5.2Hz).	5
6		7	0.92(3H，t，J＝7.3Hz)，1.62-1.72(2H，m)，2.30-2.50(1H，br)，2.60-2.80(1H，br)，3.00- 3.10(1H，br)，3.76(2H，s)，3.90(2H，t，J＝6.6Hz)，4.70-4.90(1H，br)，6.45(1H，s)，6.72 (1H，d，J＝7.8Hz)，6.85(1H，d，J＝7.8Hz)，6.94(1H，dd，J＝2.1，7.6Hz)，7.10-7.38(6H，m)， 8.68(1H，t，J＝5.4Hz).
8	0.92(3H，t，J＝7.3Hz)，1.62-1.72(2H，m)，2.30-2.50(1H，br)，2.60-2.80(1H，br)，3.00- 3.20(1H，br)，3.23(2H，t，J＝5.9Hz)，3.44-3.50(2H，m)，3.90(2H，t，J＝6.6Hz)，4.72(1H， t，J＝5.4Hz)，4.75-4.86(1H，br)，6.40(1H，s)，6.71(1H，d，J＝7.8Hz)，6.85(1H，d， J＝8.3Hz)，6.95(1H，dd，J＝2.5，8.8Hz)，7.10-7.18(2H，m)，7.25(1H，t，J＝7.1Hz)，7.30- 7.34(1H，m)，8.46(1H，t，J＝5.6Hz).	7
8		9	0.89(3H，t，J＝7.3Hz)，1.31-1.42(2H，m)，1.57-1.67(2H，m)，2.30-2.50(1H，br)，2.70-2 .85(1H，br)，3.00-3.20(1H，br)，3.76(2H，s)，3.94(2H，t，J＝6.6Hz)，4.65-4.95(1H，br) ，6.45(1H，s)，6.72(1H，d，J＝7.8Hz)，6.85(1H，d，J＝8.8Hz)，6.94(1H，dd，J＝2.4，8.8Hz)， 7.10-7.20(3H，m)，7.22-7.32(2H，m)，7.33-7.37(1H，m)，8.68(1H，t，J＝5.3Hz).
10	0.89(3H，t，J＝7.4Hz)，1.32-1.42(2H，m)，1.58-1.67(2H，m)，2.25-2.45(1H，br)，2.60- 2.80(1H，br)，3.00-3.15(1H，br)，3.20-3.30(2H，m)，3.44-3.50(2H，m)，3.94(2H，t， J＝6.4Hz)，4.73(1H，t，J＝5.2Hz)，4.75-4.87(1H，br)，6.39(1H，s)，6.71(1H，d，J＝7.8Hz) ，6.84(1H，d，J＝8.8Hz)，6.95(1H，dd，J＝2.5，8.8Hz)，7.12-7.18(2H，m)，7.21-7.26(1H， m)，7.30-7.33(1H，m)，8.46(1H，t，J＝5.6Hz).	9
10		11	0.92(6H，d，J＝6.8Hz)，1.89-2.00(1H，m)，2.30-2.50(1H，br)，2.60-2.80(1H，br)，3.00- 3.20(1H，br)，3.70-3.82(4H，m)，4.75-4.85(1H，br)，6.45(1H，s)，6.72(1H，d，J＝7.9Hz) ，6.86(1H，d，J＝8.8Hz)，6.95(1H，dd，J＝2.4，8.3Hz)，7.12-7.19(3H，m)，7.23-7.30(2H， m)，7.36(1H，dd，J＝7.8Hz，1.5Hz)，8.68(1H，t，J＝5.6Hz).

(table 19, continuous)

Ex	NMR
Ex	NMR	12	0.92(6H，d，J＝6.4Hz)，1.89-2.00(1H，m)，2.30-2.50(1H，br)，2.60-2.80(1H，br)， 3.00-3.15(1H，br)，3.19-3.25(2H，m)，3.44-3.50(2H，m)，3.72(2H，d，J＝6.3Hz)， 4.73(1H，t，J＝5.1Hz)，4.76-4.88(1H，br)，6.40(1H，s)，6.71(1H，d，J＝7.3Hz)，6.85 (1H，d，J＝8.8Hz)，6.96(1H，dd，J＝2.5，8.3Hz)，7.13-7.18(2H，m)，7.22-7.27(1H，m) ，7.32(1H，dd，J＝7.8Hz，1.5Hz)，8.46(1H，t，J＝5.6Hz).
13	0.91(6H，d，J＝6.8Hz)，1.86-1.98(1H，m)，2.25-2.50(1H，br)，2.60-2.80(1H，br)， 3.00-3.15(1H，br)，3.67(2H，d，J＝6.3Hz)，3.70-3.78(2H，br)，4.73-4.90(1H，br)， 6.35(1H，s)，6.63-6.69(1H，m)，6.89-6.96(3H，m)，7.11-7.20(2H，m)，7.22-7.33 (3H，m)，8.62(1H，s).	12
13		14	0.80(3H，t，J＝7.2Hz)，1.40-1.45(2H，m)，2.27-2.53(1H，br)，2.55-2.77(1H，br)， 2.86(3H，s)，2.92-3.15(1H，br)，3.24(2H，s)，3.75(2H，s)，4.71-5.05(1H，br)， 6.44(1H，s)，6.58(1H，d，J＝8.4Hz)，6.67(1H，d，J＝8.4Hz)，6.71(1H，d，J＝7.6Hz)， 6.77(1H，s)，7.14-7.36(5H，m)，8.64(1H，s).
15	2.30-2.50(1H，br)，2.65-2.85(1H，br)，2.80(3H，s)，2.92(3H，s)，3.00-3.20(1H，b r)，3.70-3.82(2H，m)，4.75-4.90(1H，br)，4.86(2H，s)，6.44(1H，s)，6.73(1H，d，J＝ 7.8Hz)，6.83(1H，d，J＝8.3Hz)，6.90(1H，dd，J＝2.4，8.3Hz)，7.11-7.20(3H，m)，7.24 -7.30(2H，m)，7.36(1H，dd，J＝7.3Hz，1.4Hz)，8.68(1H，t，J＝5.7Hz).	14
15		16	0.92(3H，t，J＝7.8Hz)，1.61-1.71(2H，m)，2.35-2.55(1H，br)，2.60-2.80(1H，br)， 3.00-3.20(1H，br)，3.90(2H，t，J＝6.4Hz)，4.70-4.90(1H，br)，6.38(1H，s)，6.72 (1H，d，J＝7.8Hz)，6.84(1H，d，J＝8.7Hz)，6.96(1H，dd，J＝2.5，8.6Hz)，7.10-7.18 (2H，m)，7.22-7.27(1H，m)，7.28-7.31(1H，m)，7.35(1H，s)，7.87(1H，s).
17	2.30-2.55(1H，br)，2.60-2.80(1H，br).3.05-3.25(1H，br)，4.75-4.95(1H，br)， 5.09(2H，s)，6.38(1H，s)，6.73(1H，d，J＝7.8Hz)，6.86(1H，d，J＝8.7Hz)，7.05(1H， dd，J＝2.4，8.4Hz)，7.13-7.18(1H，m)，7.22-7.42(9H，m)，7.88(1H，s).	16
17		18	0.81(3H，t，J＝7.2Hz)，1.40-1.46(2H，m)，2.24-2.52(1H，br)，2.57-2.78(1H，br)，2 .85(3H，s)，2.95-3.17(1H，br)，3.23(2H，s)，4.70-5.02(1H，br)，6.36(1H，s)，6.62 -6.76(4H，m)，7.16-7.34(4H，m)，7.84(1H，s).
19	2.30-2.50(1H，br)，2.55-2.80(1H，br)，3.00-3.20(1H，br)，3.75(2H，s)，4.70- 4.90(1H，br)，6.47(1H，s)，6.66-6.76(3H，m)，7.00(1H，d，J＝1.5Hz)，7.10-7.19(2H ，m)，7.22-7.30(2H，m)，7.35(1H，d，J＝7.8Hz)，8.65(1H，t，J＝5.6Hz)，10.3(1H，s).	18
19		20	2.30-2.50(1H，br)，2.55-2.80(1H，br)，3.00-3.20(1H，br)，4.70-4.90(1H，br)， 6.41(1H，s)，6.67-6.74(3H，m)，7.00(1H，s)，7.15(1H，tdJ＝1.4，7.8Hz)，7.24(1H， t，J＝7.6Hz)，7.27-7.32(1H，m)，7.34(1H，s)，7.85(1H，s)，10.3(1H，s).
21	0.87(3H，t，J＝7.2Hz)，1.19-1.27(1H，m)，1.45-1.58(1H，m)，2.18-2.52(1H，br)， 2.65-2.78(1H，br)，2.93-3.00(2H，m)，3.06-3.25(1H，br)，3.74-3.76(2H，m)，4.75 -4.92(1H，br)，6.55(1H，s)，6.73(1H，d，J＝7.6Hz)，7.12-7.15(3H，m)，7.24-7.33 (2H，m)，7.36(1H，dd，J＝1.6，7.2Hz)，7.71(1H，d，J＝8.0Hz)，7.98(1H，s)，8.70(1H， s).	20
21		22	0.84(3H，t，J＝7.6Hz)，1.38-1.47(2H，m)，2.15-2.54(1H，br)，2.67-2.90(1H，br)， 3.15-3.30(1H，br)，3.34-3.52(2H，m)，3.75-3.77(2H，m)，4.75-4.90(1H，br)，6.61 (1H，s)，6.74(1H，d，J＝8.0Hz)，7.13-7.17(3H，m)，7.26-7.39(2H，m)，7.37-7.39(1H ，m)，7.97(1H，d，J＝8.4Hz)，8.16(1H，s)，8.71(1H，s).
30	1.32(3H，dd，J＝6.4，29.2Hz)，2.31-2.43(1H，br)，2.60-2.80(1H，br)，3.18-3.27 (1H，br)，3.20-3.34(2H，m)，4.00-4.37(2H，m)，4.64-5.10(2H，m)，6.56(1H，s)， 6.73-6.80(1H，m)，6.87(1H，d，J＝8.8Hz)，7.02-7.08(2H，m)，7.14(1H，s)，7.24- 7.26(2H，m)，7.32(1H，s)，8.60-8.64(1H，br).	22

(table 19, continuous)

Ex	NMR
Ex	NMR	31	1.33(3H，ddJ＝6.3，29.3Hz)，2.33-2.47(1H，br)，2.59-2.83(1H，br)，3.03-3.25(1H， br)，3.72-3.85(2H，m)，4.02-4.24(2H，m)，4.72-4.84(1H，br)，4.86-5.07(1H，m)， 6.56(1H，s)，6.74-6.80(1H，m)，6.88(1H，d，J＝8.8Hz)，7.00-7.08(2H，m)，7.14(1H，s) ，7.21-7.26(2H，m)，7.32(1H，s)，8.65(1H，t，J＝5.4Hz).
51	1.67(3H，t，J＝19.5Hz)，2.30-2.48(1H，br)，2.46-2.90(1H，br)，3.08-3.34(3H，m)， 3.39-4.00(2H，m)，4.32(2H，t，J＝12.7Hz)，4.70-4.78(2H，m)，6.38(1H，s)，6.72(1H，d ，J＝7.8Hz)，6.89(1H，d，J＝8.8Hz)，7.04(1H，dd，J＝2.4，8.8Hz)，7.15(1H，dt，J＝1.5， 7.8Hz)，7.22-7.34(3H，m)，8.47(1H，t，J＝5.3Hz).	31
51		52	1.32(3H，dd，J＝6.4，23.5Hz)，2.36-2.47(1H，br)，2.65-2.76(1H，br)，3.18-3.30(3H， m)，3.43-3.49(2H，m)，4.00-4.20(2H，m)，4.68-5.06(3H，m)，6.39(1H，s)，6.72(1H，d， J＝8.8Hz)，6.87(1H，d，J＝8.8Hz)，6.98(1H，dd，J＝2.4，8.8Hz)，7.15(1H，dt，J＝1.4， 8.8Hz)，7.21-7.27(2H，m)，7.32(1H，dd，J＝1.4，8.8Hz)，8.46(1H，t，J＝5.8Hz).
53	1.32(3H，dd，J＝6.8，23.9Hz)，2.37-2.46(1H，br)，2.65-2.83(1H，br)，3.19-3.28(3H， m)，3.44-3.50(2H，m)，4.00-4.20(2H，m)，4.69-5.05(3H，m)，6.39(1H，s)，6.73(1H，d， J＝8.8Hz)，6.87(1H，d，J＝8.8Hz)，6.99(1H，dd，J＝2.4，8.8Hz)，7.15(1H，dt，J＝1.4， 8.8Hz)，7.21-7.27(2H，m)，7.32(1H，dd，J＝1.4，8.8Hz)，8.46(1H，t，J＝5.4Hz).	52
53		54	1.33(3H，dd，J＝5.9，29.8Hz)，2.31-2.46(1H，br)，2.61-2.84(1H，br)，3.18-3.26(2H， m)，3.44-3.50(2H，m)4.01-4.22(2H，m)，4.74(1H，t，J＝5.3Hz)，4.76-4.85(1H，br)， 4.96-5.06(1H，m)，6.51(1H，s)，6.70-6.77(1H，m)，6.86(1H，d，J＝8.8Hz)，7.01-7.08 (1H，m)，7.19(2H，dd，J＝2.9，8.8Hz)，7.25(1H，d，J＝2.9Hz)，7.66(1H，d，J＝8.8Hz)， 8.46(1H，t，J＝5.9Hz).
55	1.32(3H，dd，J＝5.9，29.8Hz)，2.32-2.46(1H，br)，2.61-2.84(1H，br)，3.03-3.27(2H， m)，3.44-3.51(2H，m)，4.02-4.22(2H，m)，4.74(1H，t，J＝5.3Hz)，4.76-4.85(1H，br)， 4.87-5.06(1H，m)，6.52(1H，s)，6.70-6.78(1H，m)，6.87(1H，d，J＝8.8Hz)，7.00-7.08 (1H，m)，7.19(2H，dd，J＝2.9，8.8Hz)，7.24(1H，d，J＝2.9Hz)，7.67(1H，d，J＝8.8Hz)， 8.47(1H，t，J＝5.4Hz).	54
55		56	1.69(3H，t，J＝19.6Hz)，2.31-2.46(1H，br)，2.61-2.83(1H，br)，3.05-3.27(3H，m)， 3.43-3.50(2H，m)，4.34(2H，t，J＝12.7Hz)，4.68-4.86(2H，m)，6.50(1H，s)，6.73-6.78 (1H，m)，6.89(1H，d，J＝8.8Hz)，7.01-7.13(2H，m)，7.20(1H，dd，J＝2.9，8.8Hz)，7.31 (1H，d，J＝2.9Hz)，8.43(1H，t，J＝5.4Hz).
84	0.97(3H，t，J＝7.3Hz)，1.61-1.72(2H，m)，2.31-2.47(1H，br)，2.65-2.81(1H，br)， 2.99-3.17(3H，m)，3.32-3.40(2H，m)，3.52-3.61(1H，m)，3.90(2H，t，J＝7.3Hz)，4.54 (1H，t，J＝5.9Hz)，4.75-4.87(2H，m)，6.40(1H，s)，6.71(1H，d，J＝8.8Hz)，6.85(1H，d，J ＝8.8Hz)，6.95(1H，dd，J＝2.5，8.8Hz)，7.12-7.19(2H，m)，7.24(1H，t，J＝8.8Hz)，7.34 (1H，dd，J＝1.4，8.8Hz)，8.45(1H，t，J＝5.4Hz).	56
84		85	0.98(3H，t，J＝7.3Hz)，1.61-1.71(2H，m)，2.30-2.46(1H，br)，2.65-2.80(1H，br)， 2.99-3.20(3H，m)，3.32-3.39(2H，m)，3.51-3.62(1H，m)，3.90(2H，t，J＝7.3Hz)，4.54 (1H，t，J＝5.9Hz)，4.76-4.90(2H，m)，6.40(1H，s)，6.71(1H，d，J＝8.8Hz)，6.86(1H，d，J ＝8.8Hz)，6.94(1H，dd，J＝2.5，8.8Hz)，7.12-7.19(2H，m)，7.24(1H，t，J＝8.8Hz)，7.34 (1H，dd，J＝1.4，8.8Hz)，8.45(1H，t，J＝5.4Hz).
86	0.93(3H，t，J＝6.8Hz)，1.61-1.72(2H，m)，2.31-2.46(1H，br)，2.61-2.83(1H，br)， 3.00-3.21(3H，m)，3.31-3.39(2H，m)，3.52-3.63(1H，m)，3.92(2H，t，J＝6.8Hz)，4.56 (1H，t，J＝5.9Hz)，4.52-4.86(2H，m)，6.53(1H，s)，6.71-6.77(1H，m)，6.85(1H，d，J＝ 8.8Hz)，6.99(1H，dd，J＝2.0，8.8Hz)，7.04(1H，dt，J＝2.0，8.8Hz)，7.17(1H，d，J＝2.0Hz )，7.21(1H，dd，J＝2.0，8.8Hz)，8.42(1H，t，J＝5.3Hz).	85

(table 19, continuous)

Ex	NMR
Ex	NMR	129	1.32(3H，dd，J＝6.3，23.4Hz)，2.34-2.46(1H，br)，2.55-2.83(1H，br)，3.20-3.32 (3H，m)，3.35-3.40(2H，m)，3.52-3.60(1H，m)，4.00-4.20(2H，m)，4.50-4.59(1H，m )，4.73-5.05(3H，m)，6.39(1H，s)，6.72(1H，d，J＝8.8Hz)，6.87(1H，d，J＝8.8Hz)， 6.98(1H，dd，J＝2.5，8.8Hz)，7.15(1H，dt，J＝2.5，8.8Hz)，7.19-7.27(2H，m)，7.34 (1H，dd，J＝1.4，8.8Hz)，8.47(1H，t，J＝5.4Hz).
130	1.31(3H，dd，J＝6.3，23.4Hz)，2.26-2.47(1H，br)，2.62-2.84(1H，br)，3.00-3.23 (3H，m)，3.32-3.38(2H，m)，3.53-3.62(1H，m)，4.00-4.20(2H，m)，4.45(1H，t，J＝ 5.4Hz)，4.76-5.05(3H，m)，6.40(1H，s)，6.72(1H，d，J＝7.8Hz)，6.88(1H，d，J＝8.8H z)，6.99(1H，dd，J＝2.5，8.8Hz)，7.15(1H，dt，J＝1.4，7.8Hz)，7.20-7.28(2H，m)， 7.34(1H，dd，J＝1.4，7.8Hz)，8.47(1H，t，J＝5.9Hz).	129
130		132	1.31(3H，dd，J＝6.4，23.4Hz)，2.30-2.46(1H，br)，2.54-2.80(1H，br)，3.00-3.32 (3H，m)，3.34-3.40(2H，m)，3.52-3.61(1H，m)，4.00-4.20(2H，m)，4.51-4.60(1H，m )，4.72-5.05(3H，m)，6.40(1H，s)，6.72(1H，d，J＝8.8Hz)，6.87(1H，d，J＝8.8Hz)， 6.99(1H，dd，J＝2.5，8.8Hz)，7.15(1H，dd，J＝2.5，8.8Hz)，7.19-7.29(2H，m)，7.31- 7.36(1H，m)，8.46(1H，t，J＝5.4Hz).
133	1.33(3H，dd，J＝6.3，23.9Hz)，2.27-2.46(3H，m)，2.60-2.84(1H，br)，3.22-3.34 (1H，br)，3.34-3.40(2H，m)，4.00-4.22(2H，m)，4.70-5.06(2H，m)，6.44(1H，s)，6. 71-6.76(1H，m)，6.81-6.89(2H，m)，7.01-7.07(2H，m)，7.19(1H，dd，J＝2.9，8.8Hz) ，7.24(1H，d，J＝2.9Hz)，7.33-7.38(1H，br)，8.45-8.52(1H，br).	132
133		134	1.33(3H，dd，J＝6.4，29.8Hz)，2.26-2.46(3H，m)，2.64-2.87(1H，br)，3.00-3.23 (1H，br)，3.27-3.42(2H，m)，4.01-4.22(2H，m)，4.66-5.07(2H，m)，6.49(1H，s)， 6.71-6.78(1H，m)，6.87(2H，d，J＝8.8Hz)，7.00-7.08(2H，m)，7.19(1H，dd，J＝2.9， 8.8Hz)，7.24(1H，d，J＝2.9Hz)，7.33-7.39(1H，br)，8.50(1H，t，J＝5.4Hz).
135	1.32(3H，dd，J＝6.3，23.9Hz)，2.32-2.46(1H，br)，2.63-2.84(1H，br)，3.00-3.24 (3H，m)，3.33-3.40(2H，m)，3.52-3.61(1H，m)，4.01-4.21(2H，m)，4.57(1H，t，J＝ 5.3Hz)，4.73-5.06(3H，m)，6.52(1H，s)，6.72-6.78(1H，m)，6.87(1H，d，J＝8.8Hz)， 7.00-7.08(2H，m)，7.18-7.26(2H，m)，8.38-8.48(1H，m).	134
135		136	1.33(3H，dd，J＝6.3，13.4Hz)，2.34-2.47(1H，br)，2.56-2.82(1H，br)，3.01-3.32 (3H，m)，3.33-3.39(2H，m)，3.52-3.61(1H，m)，4.02-4.22(2H，m)，4.57(1H，t，J＝ 5.4Hz)，4.75-4.85(2H，m)，4.87-5.07(1H，m)，6.51(1H，s)，6.71-6.77(1H，m)， 6.87(1H，d，J＝8.3Hz)，7.01-7.08(2H，m)，7.19-7.25(2H，m)，8.43(1H，t，J＝5.4Hz)
140	1.69(3H，t，J＝19.3Hz)，2.26-2.47(3H，m)，2.62-2.83(1H，br)，3.05-3.22(1H，br) ，3.25-3.44(2H，m)，4.34(2H，t，J＝12.4Hz)，4.68-4.92(1H，br)，6.48(1H，s)，6.72 -6.77(1H，m)，6.83-6.95(2H，m)，7.01-7.13(2H，m)，7.19(1H，dd，J＝2.9，8.8Hz)， 7.30(1H，d，J＝2.9Hz)，7.34-7.40(1H，br)，8.50(1H，t，J＝5.3Hz).	136

Below, at table 20 to 36 structures of listing other compounds of the present invention.Adopt method described in method noted earlier or the embodiment, or well known to a person skilled in the art method or its improvement, synthetic these compounds.

To this, implication below the symbolic representation in the table.

No: compound number.

R ^1A,-A ^A-B ^A, X, Y: the substituting group in each general formula,

IPr: sec.-propyl, tBu: the tertiary butyl, cBu: cyclobutyl; nPen: n-pentyl, cPen: cyclopentyl, iAm: isopentyl; nHex: n-hexyl; pyrr: tetramethyleneimine-1-base, pipe: piperidines-1-base, pipa: piperazine-1-base; mor: morpholine-4-base; Ac: ethanoyl, Ms: methylsulfonyl, cynao: cyano group.

(table 20)

No	R ^1A	-A ^A-B ^A	No	R ^1A	-A ^A-B ^A
No	R ^1A	-A ^A-B ^A	No	R ^1A	-A ^A-B ^A	A1	Gly	-O-Me	A30	Car	-O-(CH ₂) ₂-cyano group
A2	Gly	-O-Et	A31	Etha	-O-CH ₂CH(Me)OMe	A1	Gly	-O-Me	A30	Car	-O-(CH ₂) ₂-cyano group
A2	Gly	-O-Et	A31	Etha	-O-CH ₂CH(Me)OMe	A3	Etha	-O-Et	A32	Etha	-O-CH ₂CH(Me)OMe
A4	Car	-O-Et	A33	Car	-O-CH ₂CH(Me)OMe	A3	Etha	-O-Et	A32	Etha	-O-CH ₂CH(Me)OMe
A4	Car	-O-Et	A33	Car	-O-CH ₂CH(Me)OMe	A5	Etha	-O-iPr	A34	Etha	-O-CH ₂CF ₂CF ₃
A6	Car	-O-nBu	A35	Car	-O-CH ₂CF ₂CF ₃	A5	Etha	-O-iPr	A34	Etha	-O-CH ₂CF ₂CF ₃
A6	Car	-O-nBu	A35	Car	-O-CH ₂CF ₂CF ₃	A7	Car	-O-iBu	A36	Etha	-O-CH ₂CF ₂CHF ₂
A8	Gly	-O-tBu	A37	Car	-O-CH ₂CF ₂CHF ₂	A7	Car	-O-iBu	A36	Etha	-O-CH ₂CF ₂CHF ₂
A8	Gly	-O-tBu	A37	Car	-O-CH ₂CF ₂CHF ₂	A9	Gly	-O-iAm	A38	Gly	-O-(CH ₂) ₂OH
A10	Gly	-O-nPen	A39	Etha	-O-(CH ₂) ₂OH	A9	Gly	-O-iAm	A38	Gly	-O-(CH ₂) ₂OH
A10	Gly	-O-nPen	A39	Etha	-O-(CH ₂) ₂OH	A11	Etha	-O-nHex	A40	Car	-O-(CH ₂) ₂OH
A12	Gly	-O-cPen	A41	Gly	-O-CH ₂CO ₂H	A11	Etha	-O-nHex	A40	Car	-O-(CH ₂) ₂OH
A12	Gly	-O-cPen	A41	Gly	-O-CH ₂CO ₂H	A13	Gly	-O-Ph	A42	Etha	-O-CH ₂CO ₂H
A14	Car	-O-Ph	A43	Car	-O-CH ₂CO ₂H	A13	Gly	-O-Ph	A42	Etha	-O-CH ₂CO ₂H
A14	Car	-O-Ph	A43	Car	-O-CH ₂CO ₂H	A15	Gly	-O-CH ₂CF ₃	A44	Etha	-N(Me)-iBu
A16	Gly	-O-CH ₂CHF ₂	A45	Car	-N(Me)-iBu	A15	Gly	-O-CH ₂CF ₃	A44	Etha	-N(Me)-iBu
A16	Gly	-O-CH ₂CHF ₂	A45	Car	-N(Me)-iBu	A17	Gly	-O-CH ₂CH≡CH	A46	Etha	-S-Et
A18	Gly	-O-(CH ₂) ₂CH≡CH	A47	Car	-S-Et	A17	Gly	-O-CH ₂CH≡CH	A46	Etha	-S-Et
A18	Gly	-O-(CH ₂) ₂CH≡CH	A47	Car	-S-Et	A19	Gly	-O-(CH ₂) ₂OMe	A48	Gly	-S-iPr
A20	Car	-O-CH ₂cPr	A49	Etha	-S-iPr	A19	Gly	-O-(CH ₂) ₂OMe	A48	Gly	-S-iPr
A20	Car	-O-CH ₂cPr	A49	Etha	-S-iPr	A21	Gly	-O-CH ₂cBu	A50	Car	-S-iPr
A22	Car	-O-CH ₂cBu	A51	Gly	-N(Me)-CH ₂CH ₂OMe	A21	Gly	-O-CH ₂cBu	A50	Car	-S-iPr
A22	Car	-O-CH ₂cBu	A51	Gly	-N(Me)-CH ₂CH ₂OMe	A23	Gly	-O-CH ₂tBu	A52	Etha	-N(Me)-CH ₂CH ₂OMe
A24	Etha	-O-CH ₂tBu	A53	Car	-N(Me)-CH ₂CH ₂OMe	A23	Gly	-O-CH ₂tBu	A52	Etha	-N(Me)-CH ₂CH ₂OMe
A24	Etha	-O-CH ₂tBu	A53	Car	-N(Me)-CH ₂CH ₂OMe	A25	Gly	-O-CH ₂CONH ₂	A55	Gly	-N(Me)-nBu
A27	Gly	-O-CH ₂CONHMe	A56	Etha	-N(Me)-nBu	A25	Gly	-O-CH ₂CONH ₂	A55	Gly	-N(Me)-nBu
A27	Gly	-O-CH ₂CONHMe	A56	Etha	-N(Me)-nBu	A28	Gly	-O-(CH ₂) ₂-cyano group	A57	Car	-N(Me)-nBu
A29	Etha	-O-(CH ₂) ₂-cyano group	A58	Etha	-N(nPr)-nPr	A28	Gly	-O-(CH ₂) ₂-cyano group	A57	Car	-N(Me)-nBu

(table 21)

No	R ^1A	-A ^A-B ^A
No	R ^1A	-A ^A-B ^A	A59	-NHCH ₂CH(S-OH)CH ₂OH	(S)-O-CH ₂CHFCH ₃
A60	-NHCH ₂CH(S-OH)CH ₂OH	(R)-O-CH ₂CHFCH ₃	A59	-NHCH ₂CH(S-OH)CH ₂OH	(S)-O-CH ₂CHFCH ₃

(table 22)

No	R ^1A	-A ^A-B ^A
No	R ^1A	-A ^A-B ^A	A61	Gly	-O-Et
A62	Car	-O-nPr	A61	Gly	-O-Et
A62	Car	-O-nPr	A63	Gly	-O-iPr
A64	Etha	-O-nBu	A63	Gly	-O-iPr

(table 23)

No	R ^1A	-X-	Y	-A ^A-B ^A
No	R ^1A	-X-	Y	-A ^A-B ^A	B1	Gly	-N＝C-	N	-O-nPr
B2	Etha	-N＝C-	N	-O-nPr	B1	Gly	-N＝C-	N	-O-nPr
B2	Etha	-N＝C-	N	-O-nPr	B3	Car	-N＝C-	N	-O-nPr
B4	Gly	-N＝C-	N	-O-iBu	B3	Car	-N＝C-	N	-O-nPr
B4	Gly	-N＝C-	N	-O-iBu	B5	Etha	-N＝C-	N	-O-iBu
B6	Car	-N＝C-	N	-O-iBu	B5	Etha	-N＝C-	N	-O-iBu
B6	Car	-N＝C-	N	-O-iBu	B7	Gly	-N＝C-	N	-S-nPr
B8	Etha	-N＝C-	N	-S-nPr	B7	Gly	-N＝C-	N	-S-nPr
B8	Etha	-N＝C-	N	-S-nPr	B9	Car	-N＝C-	N	-S-nPr
B10	Gly	-N＝C-	N	-N(Me)-nPr	B9	Car	-N＝C-	N	-S-nPr
B10	Gly	-N＝C-	N	-N(Me)-nPr	B11	Etha	-N＝C-	N	-N(Me)-nPr
B12	Car	-N＝C-	N	-N(Me)-nPr	B11	Etha	-N＝C-	N	-N(Me)-nPr
B12	Car	-N＝C-	N	-N(Me)-nPr	B13	Gly	-N＝N-	CH	-O-nPr
B14	Etha	-N＝N-	CH	-O-nPr	B13	Gly	-N＝N-	CH	-O-nPr
B14	Etha	-N＝N-	CH	-O-nPr	B15	Car	-N＝N-	CH	-O-nPr
B16	Gly	-N＝N-	CH	-O-iBu	B15	Car	-N＝N-	CH	-O-nPr
B16	Gly	-N＝N-	CH	-O-iBu	B17	Etha	-N＝N-	CH	-O-iBu
B18	Car	-N＝N-	CH	-O-iBu	B17	Etha	-N＝N-	CH	-O-iBu
B18	Car	-N＝N-	CH	-O-iBu	B19	Gly	-N＝N-	CH	-S-nPr
B20	Etha	-N＝N-	CH	-S-nPr	B19	Gly	-N＝N-	CH	-S-nPr
B20	Etha	-N＝N-	CH	-S-nPr	B21	Car	-N＝N-	CH	-S-nPr
B22	Gly	-N＝N-	CH	-N(Me)-nPr	B21	Car	-N＝N-	CH	-S-nPr
B22	Gly	-N＝N-	CH	-N(Me)-nPr	B23	Etha	-N＝N-	CH	-N(Me)-nPr
B24	Car	-N＝N-	CH	-N(Me)-nPr	B23	Etha	-N＝N-	CH	-N(Me)-nPr
B24	Car	-N＝N-	CH	-N(Me)-nPr	B25	Gly	-S-	N	-O-nPr
B26	Etha	-S-	N	-O-nPr	B25	Gly	-S-	N	-O-nPr
B26	Etha	-S-	N	-O-nPr	B27	Car	-S-	N	-O-nPr
B28	Gly	-S-	N	-O-iBu	B27	Car	-S-	N	-O-nPr
B28	Gly	-S-	N	-O-iBu	B29	Etha	-S-	N	-O-iBu
B30	Car	-S-	N	-O-iBu	B29	Etha	-S-	N	-O-iBu
B30	Car	-S-	N	-O-iBu	B31	Gly	-S-	N	-S-nPr
B32	Etha	-S-	N	-S-nPr	B31	Gly	-S-	N	-S-nPr
B32	Etha	-S-	N	-S-nPr	B33	Car	-S-	N	-S-nPr
B34	Gly	-S-	N	-N(Me)-nPr	B33	Car	-S-	N	-S-nPr
B34	Gly	-S-	N	-N(Me)-nPr	B35	Etha	-S-	N	-N(Me)-nPr

(table 24)

No	R ^1A	-X-	Y	-A ^A-B ^A
No	R ^1A	-X-	Y	-A ^A-B ^A	B36	Car	-S-	N	-N(Me)-nPr
B37	Gly	-N＝C-	CH	-O-nPr	B36	Car	-S-	N	-N(Me)-nPr
B37	Gly	-N＝C-	CH	-O-nPr	B38	Etha	-N＝C-	CH	-O-nPr
B39	Car	-N＝C-	CH	-O-nPr	B38	Etha	-N＝C-	CH	-O-nPr
B39	Car	-N＝C-	CH	-O-nPr	B40	Gly	-N＝C-	CH	-O-iBu
B41	Etha	-N＝C-	CH	-O-iBu	B40	Gly	-N＝C-	CH	-O-iBu
B41	Etha	-N＝C-	CH	-O-iBu	B42	Car	-N＝C-	CH	-O-iBu
B43	Gly	-N＝C-	CH	-S-nPr	B42	Car	-N＝C-	CH	-O-iBu
B43	Gly	-N＝C-	CH	-S-nPr	B44	Etha	-N＝C-	CH	-S-nPr
B45	Car	-N＝C-	CH	-S-nPr	B44	Etha	-N＝C-	CH	-S-nPr
B45	Car	-N＝C-	CH	-S-nPr	B46	Gly	-N＝C-	CH	-N(Me)-nPr
B47	Etha	-N＝C-	CH	-N(Me)-nPr	B46	Gly	-N＝C-	CH	-N(Me)-nPr
B47	Etha	-N＝C-	CH	-N(Me)-nPr	B48	Car	-N＝C-	CH	-N(Me)-nPr

(table 25)

No	R ^1A	-X-	Y	-A ^A-B ^A
No	R ^1A	-X-	Y	-A ^A-B ^A	B49	Etha	-C＝C-	N	-O-nPr
B50	Gly	-C＝C-	N	-O-iBu	B49	Etha	-C＝C-	N	-O-nPr
B50	Gly	-C＝C-	N	-O-iBu	B51	Etha	-C＝C-	N	-O-iBu
B52	Car	-C＝C-	N	-O-iBu	B51	Etha	-C＝C-	N	-O-iBu
B52	Car	-C＝C-	N	-O-iBu	B53	Gly	-C＝C-	N	-S-nPr
B54	Etha	-C＝C-	N	-S-nPr	B53	Gly	-C＝C-	N	-S-nPr
B54	Etha	-C＝C-	N	-S-nPr	B55	Car	-C＝C-	N	-S-nPr
B56	Gly	-C＝C-	N	-N(Me)-nPr	B55	Car	-C＝C-	N	-S-nPr
B56	Gly	-C＝C-	N	-N(Me)-nPr	B57	Etha	-C＝C-	N	-N(Me)-nPr
B58	Car	-C＝C-	N	-N(Me)-nPr	B57	Etha	-C＝C-	N	-N(Me)-nPr
B58	Car	-C＝C-	N	-N(Me)-nPr	B59	Gly	-S-	CH	-O-nPr
B60	Etha	-S-	CH	-O-nPr	B59	Gly	-S-	CH	-O-nPr
B60	Etha	-S-	CH	-O-nPr	B61	Car	-S-	CH	-O-nPr
B62	Gly	-S-	CH	-O-iBu	B61	Car	-S-	CH	-O-nPr
B62	Gly	-S-	CH	-O-iBu	B63	Etha	-S-	CH	-O-iBu
B64	Car	-S-	CH	-O-iBu	B63	Etha	-S-	CH	-O-iBu
B64	Car	-S-	CH	-O-iBu	B65	Gly	-S-	CH	-S-nPr
B66	Etha	-S-	CH	-S-nPr	B65	Gly	-S-	CH	-S-nPr
B66	Etha	-S-	CH	-S-nPr	B67	Car	-S-	CH	-S-nPr

(table 26)

No	R ^1A	X	Y	-A ^A-B ^A
No	R ^1A	X	Y	-A ^A-B ^A	B68	Gly	N	S	-N(Me)-nPr
B69	Etha	N	S	-N(Me)-nPr	B68	Gly	N	S	-N(Me)-nPr
B69	Etha	N	S	-N(Me)-nPr	B70	Car	N	S	-N(Me)-nPr

(table 27)

No	R ^1A	-A ^A-B ^A	No	R ^1A	-A ^A-B ^A
No	R ^1A	-A ^A-B ^A	No	R ^1A	-A ^A-B ^A	C1	Gly	-O-iBu	C10	Gly	-S-iPr
C2	Etha	-O-iBu	C11	Etha	-S-iPr	C1	Gly	-O-iBu	C10	Gly	-S-iPr
C2	Etha	-O-iBu	C11	Etha	-S-iPr	C3	Car	-O-iBu	C12	Car	-S-iPr
C4	Gly	-O-nBu	C13	Gly	-S-Et	C3	Car	-O-iBu	C12	Car	-S-iPr
C4	Gly	-O-nBu	C13	Gly	-S-Et	C5	Etha	-O-nBu	C14	Etha	-S-Et
C6	Car	-O-nBu	C15	Car	-S-Et	C5	Etha	-O-nBu	C14	Etha	-S-Et
C6	Car	-O-nBu	C15	Car	-S-Et	C7	Gly	-S-nPr	C16	Gly	-N(Me)-nPr
C8	Etha	-S-nPr	C17	Etha	-N(Me)-nPr	C7	Gly	-S-nPr	C16	Gly	-N(Me)-nPr
C8	Etha	-S-nPr	C17	Etha	-N(Me)-nPr	C9	Car	-S-nPr	C18	Car	-N(Me)-nPr

(table 28)

(table 29)

No	R ^1A	-A ^A-B ^A	No	R ^1A	-A ^A-B ^A
No	R ^1A	-A ^A-B ^A	No	R ^1A	-A ^A-B ^A	C40	Gly	-O-iBu	C49	Gly	-S-iPr
C41	Etha	-O-iBu	C50	Etha	-S-iPr	C40	Gly	-O-iBu	C49	Gly	-S-iPr
C41	Etha	-O-iBu	C50	Etha	-S-iPr	C42	Car	-O-iBu	C51	Car	-S-iPr
C43	Gly	-O-nBu	C54	Gly	-S-Et	C42	Car	-O-iBu	C51	Car	-S-iPr
C43	Gly	-O-nBu	C54	Gly	-S-Et	C44	Etha	-O-nBu	C55	Etha	-S-Et
C45	Car	-O-nBu	C56	Car	-S-Et	C44	Etha	-O-nBu	C55	Etha	-S-Et
C45	Car	-O-nBu	C56	Car	-S-Et	C46	Gly	-S-nPr	C57	Gly	-N(Me)-nPr
C47	Etha	-S-nPr	C58	Etha	-N(Me)-nPr	C46	Gly	-S-nPr	C57	Gly	-N(Me)-nPr
C47	Etha	-S-nPr	C58	Etha	-N(Me)-nPr	C48	Car	-S-nPr	C59	Car	-N(Me)-nPr

(table 30)

(table 31)

No	R ^1A	No	R ^1A
No	R ^1A	No	R ^1A	D1	NHCH ₂-(2-Py)	D33	4-H ₂NOC-pipe
D2	NHPh	D34	NHCH ₂CO-pyrr	D1	NHCH ₂-(2-Py)	D33	4-H ₂NOC-pipe
D2	NHPh	D34	NHCH ₂CO-pyrr	D3	NHCH ₂Ph	D35	NHCH ₂CO-(3-HO-pyrr)
D4	NHCH ₂-(2-HO-Ph)	D36	NHCH ₂CO-(3-HO-pipe)	D3	NHCH ₂Ph	D35	NHCH ₂CO-(3-HO-pyrr)
D4	NHCH ₂-(2-HO-Ph)	D36	NHCH ₂CO-(3-HO-pipe)	D5	NHCH ₂-(3-HO-Ph)	D37	NHCH ₂CO-(4-HO-pipe)
D6	NHCH ₂-(4-HO-Ph)	D38	NH-(3-Ac-Ph)	D5	NHCH ₂-(3-HO-Ph)	D37	NHCH ₂CO-(4-HO-pipe)
D6	NHCH ₂-(4-HO-Ph)	D38	NH-(3-Ac-Ph)	D7	NHCH ₂-(2-H ₂NOC-Ph)	D39	NH-(3-MeHNOC-Ph)
D8	NHCH ₂-(3-H ₂NOC-Ph)	D40	NHCH ₂-(4-H ₂NO ₂S-Ph)	D7	NHCH ₂-(2-H ₂NOC-Ph)	D39	NH-(3-MeHNOC-Ph)
D8	NHCH ₂-(3-H ₂NOC-Ph)	D40	NHCH ₂-(4-H ₂NO ₂S-Ph)	D9	NHCH ₂-(4-H ₂NOC-Ph)	D41	NH-(3-Ms-Ph)
D10	NH-(2-HO-Ph)	D42	NHCH ₂CO-mor	D9	NHCH ₂-(4-H ₂NOC-Ph)	D41	NH-(3-Ms-Ph)
D10	NH-(2-HO-Ph)	D42	NHCH ₂CO-mor	D11	NH-(3-HO-Ph)	D43	NHCH ₂-(6-HO-2-Py)
D12	NH-(4-HO-Ph)	D44	NHCH ₂-(6-MeO-2-Py)	D11	NH-(3-HO-Ph)	D43	NHCH ₂-(6-HO-2-Py)
D12	NH-(4-HO-Ph)	D44	NHCH ₂-(6-MeO-2-Py)	D13	NH-(2-H ₂NOC-Ph)	D45	NHCH ₂-(6-H ₂NOC-2-Py)
D14	NH-(3-H ₂NOC-Ph)	D46	NHCH ₂-(6-cynao-2-Py)	D13	NH-(2-H ₂NOC-Ph)	D45	NHCH ₂-(6-H ₂NOC-2-Py)
D14	NH-(3-H ₂NOC-Ph)	D46	NHCH ₂-(6-cynao-2-Py)	D15	NH-(4-H ₂NOC-Ph)	D47	NHCH ₂-(6-Me ₂NOC-2-Py)
D16	NH-(CH ₂) ₂OMe	D48	NHCH ₂-(6-H ₂N-2-Py)	D15	NH-(4-H ₂NOC-Ph)	D47	NHCH ₂-(6-Me ₂NOC-2-Py)
D16	NH-(CH ₂) ₂OMe	D48	NHCH ₂-(6-H ₂N-2-Py)	D17	NH-(CH ₂) ₃OH	D49	NHCH ₂-(6-Me ₂N-2-Py)
D18	N(CH ₂CH ₂OH) ₂	D50	NHCH ₂-(6-F-2-Py)	D17	NH-(CH ₂) ₃OH	D49	NHCH ₂-(6-Me ₂N-2-Py)
D18	N(CH ₂CH ₂OH) ₂	D50	NHCH ₂-(6-F-2-Py)	D19	NHCH ₂CH(CH ₂OH)OH	D51	NHCH ₂-(6-Cl-2-Py)
D20	N(Me)CH ₂CH ₂OH	D52	NHCH ₂-(6-Me-2-Py)	D19	NHCH ₂CH(CH ₂OH)OH	D51	NHCH ₂-(6-Cl-2-Py)
D20	N(Me)CH ₂CH ₂OH	D52	NHCH ₂-(6-Me-2-Py)	D21	3-HO-pyrr	D53	NHCH ₂-(pyrazoles-2-yl)
D22	3-HO-pipe	D54	NHCH ₂-(pyridazine-2-yl)	D21	3-HO-pyrr	D53	NHCH ₂-(pyrazoles-2-yl)
D22	3-HO-pipe	D54	NHCH ₂-(pyridazine-2-yl)	D23	4-HO-pipe	D55	NHCH ₂-(pyrimidine-2-base)
D24	NHCH ₂CONHMe	D56	N(CH ₂CONH ₂)((CH ₂) ₂OH)	D23	4-HO-pipe	D55	NHCH ₂-(pyrimidine-2-base)
D24	NHCH ₂CONHMe	D56	N(CH ₂CONH ₂)((CH ₂) ₂OH)	D25	NHCH ₂CONMe ₂	D57	NHCH(Me)CH ₂OH
D26	N(Me)CH ₂CONH ₂	D58	NHCH ₂CH(Me)OH	D25	NHCH ₂CONMe ₂	D57	NHCH(Me)CH ₂OH
D26	N(Me)CH ₂CONH ₂	D58	NHCH ₂CH(Me)OH	D27	N(Me)CH ₂CONHMe	D59	NHC(Me) ₂CH ₂OH
D28	N(Me)CH ₂CONMe ₂	D60	NHCH ₂C(Me) ₂OH	D27	N(Me)CH ₂CONHMe	D59	NHC(Me) ₂CH ₂OH
D28	N(Me)CH ₂CONMe ₂	D60	NHCH ₂C(Me) ₂OH	D29	NH(CH ₂) ₂CONH ₂	D61	3-oxo-pipa
D30	N(CH ₂CONH ₂) ₂	D62	NHCH ₂CO-(3-H ₂NOC-pipe)	D29	NH(CH ₂) ₂CONH ₂	D61	3-oxo-pipa
D30	N(CH ₂CONH ₂) ₂	D62	NHCH ₂CO-(3-H ₂NOC-pipe)	D31	NHCH(CONH ₂)CH ₂OH	D63	NHCH ₂CO-(4-H ₂NOC-pipe)
D32	3-H ₂NOC-pipe	D64	NHCH(CH ₂OH) ₂	D31	NHCH(CONH ₂)CH ₂OH	D63	NHCH ₂CO-(4-H ₂NOC-pipe)

(table 32)

(table 33)

No	R ^1A	No	R ^1A
No	R ^1A	No	R ^1A	F1	NHCH ₂-(2-Py)	F33	4-H ₂NOC-pipe
F2	NHPh	F34	NHCH ₂CO-pyrr	F1	NHCH ₂-(2-Py)	F33	4-H ₂NOC-pipe
F2	NHPh	F34	NHCH ₂CO-pyrr	F3	NHCH ₂Ph	F35	NHCH ₂CO-(3-HO-pyrr)
F4	NHCH ₂-(2-HO-Ph)	F36	NHCH ₂CO-(3-HO-pipe)	F3	NHCH ₂Ph	F35	NHCH ₂CO-(3-HO-pyrr)
F4	NHCH ₂-(2-HO-Ph)	F36	NHCH ₂CO-(3-HO-pipe)	F5	NHCH ₂-(3-HO-Ph)	F37	NHCH ₂CO-(4-HO-pipe)
F6	NHCH ₂-(4-HO-Ph)	F38	NH-(3-Ac-Ph)	F5	NHCH ₂-(3-HO-Ph)	F37	NHCH ₂CO-(4-HO-pipe)
F6	NHCH ₂-(4-HO-Ph)	F38	NH-(3-Ac-Ph)	F7	NHCH ₂-(2-H ₂NOC-Ph)	F39	NH-(3-MeHNOC-Ph)
F8	NHCH ₂-(3-H ₂NOC-Ph)	F40	NHCH ₂-(4-H ₂NO ₂S-Ph)	F7	NHCH ₂-(2-H ₂NOC-Ph)	F39	NH-(3-MeHNOC-Ph)
F8	NHCH ₂-(3-H ₂NOC-Ph)	F40	NHCH ₂-(4-H ₂NO ₂S-Ph)	F9	NHCH ₂-(4-H ₂NOC-Ph)	F41	NH-(3-Ms-Ph)
F10	NH-(2-HO-Ph)	F42	NHCH ₂CO-mor	F9	NHCH ₂-(4-H ₂NOC-Ph)	F41	NH-(3-Ms-Ph)
F10	NH-(2-HO-Ph)	F42	NHCH ₂CO-mor	F11	NH-(3-HO-Ph)	F43	NHCH ₂-(6-HO-2-Py)
F12	NH-(4-HO-Ph)	F44	NHCH ₂-(6-MeO-2-Py)	F11	NH-(3-HO-Ph)	F43	NHCH ₂-(6-HO-2-Py)
F12	NH-(4-HO-Ph)	F44	NHCH ₂-(6-MeO-2-Py)	F13	NH-(2-H ₂NOC-Ph)	F45	NHCH ₂-(6-H ₂NOC-2-Py)
F14	NH-(3-H ₂NOC-Ph)	F46	NHCH ₂-(6-cyano group-2-Py)	F13	NH-(2-H ₂NOC-Ph)	F45	NHCH ₂-(6-H ₂NOC-2-Py)
F14	NH-(3-H ₂NOC-Ph)	F46	NHCH ₂-(6-cyano group-2-Py)	F15	NH-(4-H ₂NOC-Ph)	F47	NHCH ₂-(6-Me ₂NOC-2-Py)
F16	NH-(CH ₂) ₂OMe	F48	NHCH ₂-(6-H ₂N-2-Py)	F15	NH-(4-H ₂NOC-Ph)	F47	NHCH ₂-(6-Me ₂NOC-2-Py)
F16	NH-(CH ₂) ₂OMe	F48	NHCH ₂-(6-H ₂N-2-Py)	F17	NH-(CH ₂) ₃OH	F49	NHCH ₂-(6-Me ₂N-2-Py)
F18	N(CH ₂CH ₂OH) ₂	F50	NHCH ₂-(6-F-2-Py)	F17	NH-(CH ₂) ₃OH	F49	NHCH ₂-(6-Me ₂N-2-Py)
F18	N(CH ₂CH ₂OH) ₂	F50	NHCH ₂-(6-F-2-Py)	F19	NHCH ₂CH(CH ₂OH)OH	F51	NHCH ₂-(6-Cl-2-Py)
F20	N(Me)CH ₂CH ₂OH	F52	NHCH ₂-(6-Me-2-Py)	F19	NHCH ₂CH(CH ₂OH)OH	F51	NHCH ₂-(6-Cl-2-Py)
F20	N(Me)CH ₂CH ₂OH	F52	NHCH ₂-(6-Me-2-Py)	F21	3-HO-pyrr	F53	NHCH ₂-(pyrazoles-2-yl)
F22	3-HO-pipe	F54	NHCH ₂-(pyridazine-2-yl)	F21	3-HO-pyrr	F53	NHCH ₂-(pyrazoles-2-yl)
F22	3-HO-pipe	F54	NHCH ₂-(pyridazine-2-yl)	F23	4-HO-pipe	F55	NHCH ₂-(pyrimidine-2-base)
F24	NHCH ₂CONHMe	F56	N(CH ₂CONH ₂)((CH ₂) ₂OH)	F23	4-HO-pipe	F55	NHCH ₂-(pyrimidine-2-base)
F24	NHCH ₂CONHMe	F56	N(CH ₂CONH ₂)((CH ₂) ₂OH)	F25	NHCH ₂CONMe ₂	F57	NHCH(Me)CH ₂OH
F26	N(Me)CH ₂CONH ₂	F58	NHCH ₂CH(Me)OH	F25	NHCH ₂CONMe ₂	F57	NHCH(Me)CH ₂OH
F26	N(Me)CH ₂CONH ₂	F58	NHCH ₂CH(Me)OH	F27	N(Me)CH ₂CONHMe	F59	NHC(Me) ₂CH ₂OH
F28	N(Me)CH ₂CONMe ₂	F60	NHCH ₂C(Me) ₂OH	F27	N(Me)CH ₂CONHMe	F59	NHC(Me) ₂CH ₂OH
F28	N(Me)CH ₂CONMe ₂	F60	NHCH ₂C(Me) ₂OH	F29	NH(CH ₂) ₂CONH ₂	F61	3-oxo-pipa
F30	N(CH ₂CONH ₂) ₂	F62	NHCH ₂CO-(3-H ₂NOC-pipe)	F29	NH(CH ₂) ₂CONH ₂	F61	3-oxo-pipa
F30	N(CH ₂CONH ₂) ₂	F62	NHCH ₂CO-(3-H ₂NOC-pipe)	F31	NHCH(CONH ₂)CH ₂OH	F63	NHCH ₂CO-(4-H ₂NOC-pipe)
F32	3-H ₂NOC-pipe	F64	NHCH(CH ₂OH) ₂	F31	NHCH(CONH ₂)CH ₂OH	F63	NHCH ₂CO-(4-H ₂NOC-pipe)

(table 34)

No	R ^1A	No	R ^1A
No	R ^1A	No	R ^1A	G1	NHCH ₂-(2-Py)	G32	NHCH ₂CO-pyrr
G2	NHPh	G33	NHCH ₂CO-(3-HO-pyrr)	G1	NHCH ₂-(2-Py)	G32	NHCH ₂CO-pyrr
G2	NHPh	G33	NHCH ₂CO-(3-HO-pyrr)	G3	NHCH ₂Ph	G34	NHCH ₂CO-(3-HO-pipe)
G4	NHCH ₂-(2-HO-Ph)	G35	NHCH ₂CO-(4-HO-pipe)	G3	NHCH ₂Ph	G34	NHCH ₂CO-(3-HO-pipe)
G4	NHCH ₂-(2-HO-Ph)	G35	NHCH ₂CO-(4-HO-pipe)	G5	NHCH ₂-(3-HO-Ph)	G36	NH-(3-Ac-Ph)
G6	NHCH ₂-(4-HO-Ph)	G37	NH-(3-MeHNOC-Ph)	G5	NHCH ₂-(3-HO-Ph)	G36	NH-(3-Ac-Ph)
G6	NHCH ₂-(4-HO-Ph)	G37	NH-(3-MeHNOC-Ph)	G7	NHCH ₂-(2-H ₂NOC-Ph)	G38	NHCH ₂-(4-H ₂NO ₂S-Ph)
G8	NHCH ₂-(3-H ₂NOC-Ph)	G39	NH-(3-Ms-Ph)	G7	NHCH ₂-(2-H ₂NOC-Ph)	G38	NHCH ₂-(4-H ₂NO ₂S-Ph)
G8	NHCH ₂-(3-H ₂NOC-Ph)	G39	NH-(3-Ms-Ph)	G9	NHCH ₂-(4-H ₂NOC-Ph)	G40	NHCH ₂CO-mor
G10	NH-(2-HO-Ph)	G41	NHCH ₂-(6-HO-2-Py)	G9	NHCH ₂-(4-H ₂NOC-Ph)	G40	NHCH ₂CO-mor
G10	NH-(2-HO-Ph)	G41	NHCH ₂-(6-HO-2-Py)	G11	NH-(3-HO-Ph)	G42	NHCH ₂-(6-MeO-2-Py)
G12	NH-(4-HO-Ph)	G43	NHCH ₂-(6-H ₂NOC-2-Py)	G11	NH-(3-HO-Ph)	G42	NHCH ₂-(6-MeO-2-Py)
G12	NH-(4-HO-Ph)	G43	NHCH ₂-(6-H ₂NOC-2-Py)	G13	NH-(2-H ₂NOC-Ph)	G44	NHCH ₂-(6-cyano group-2-Py)
G14	NH-(4-H ₂NOC-Ph)	G45	NHCH ₂-(6-Me ₂NOC-2-Py)	G13	NH-(2-H ₂NOC-Ph)	G44	NHCH ₂-(6-cyano group-2-Py)
G14	NH-(4-H ₂NOC-Ph)	G45	NHCH ₂-(6-Me ₂NOC-2-Py)	G15	NH-(CH ₂) ₂OMe	G46	NHCH ₂-(6-H ₂N-2-Py)
G16	NH-(CH ₂) ₃OH	G47	NHCH ₂-(6-Me ₂N-2-Py)	G15	NH-(CH ₂) ₂OMe	G46	NHCH ₂-(6-H ₂N-2-Py)
G16	NH-(CH ₂) ₃OH	G47	NHCH ₂-(6-Me ₂N-2-Py)	G17	N(CH ₂CH ₂OH) ₂	G48	NHCH ₂-(6-F-2-Py)
G18	NHCH ₂CH(CH ₂OH)OH	G49	NHCH ₂-(6-Cl-2-Py)	G17	N(CH ₂CH ₂OH) ₂	G48	NHCH ₂-(6-F-2-Py)
G18	NHCH ₂CH(CH ₂OH)OH	G49	NHCH ₂-(6-Cl-2-Py)	G19	N(Me)CH ₂CH ₂OH	G50	NHCH ₂-(6-Me-2-Py)
G20	3-HO-pyrr	G51	NHCH ₂-(pyrazoles-2-yl)	G19	N(Me)CH ₂CH ₂OH	G50	NHCH ₂-(6-Me-2-Py)
G20	3-HO-pyrr	G51	NHCH ₂-(pyrazoles-2-yl)	G21	3-HO-pipe	G52	NHCH ₂-(pyridazine-2-yl)
G22	4-HO-pipe	G53	NHCH ₂-(pyrimidine-2-base)	G21	3-HO-pipe	G52	NHCH ₂-(pyridazine-2-yl)
G22	4-HO-pipe	G53	NHCH ₂-(pyrimidine-2-base)	G23	NHCH ₂CONHMe	G54	N(CH ₂CONH ₂)((CH ₂) ₂OH)
G24	NHCH ₂CONMe ₂	G55	NHCH(Me)CH ₂OH	G23	NHCH ₂CONHMe	G54	N(CH ₂CONH ₂)((CH ₂) ₂OH)
G24	NHCH ₂CONMe ₂	G55	NHCH(Me)CH ₂OH	G25	N(Me)CH ₂CONH ₂	G56	NHCH ₂CH(Me)OH
G26	N(Me)CH ₂CONHMe	G57	NHC(Me) ₂CH ₂OH	G25	N(Me)CH ₂CONH ₂	G56	NHCH ₂CH(Me)OH
G26	N(Me)CH ₂CONHMe	G57	NHC(Me) ₂CH ₂OH	G27	N(Me)CH ₂CONMe ₂	G58	NHCH ₂C(Me) ₂OH
G28	N(CH ₂CONH ₂) ₂	G59	3-oxo-pipa	G27	N(Me)CH ₂CONMe ₂	G58	NHCH ₂C(Me) ₂OH
G28	N(CH ₂CONH ₂) ₂	G59	3-oxo-pipa	G29	NHCH(CONH ₂)CH ₂OH	G60	NHCH ₂CO-(3-H ₂NOC-pipe)
G30	3-H ₂NOC-pipe	G61	NHCH ₂CO-(4-H ₂NOC-pipe)	G29	NHCH(CONH ₂)CH ₂OH	G60	NHCH ₂CO-(3-H ₂NOC-pipe)
G30	3-H ₂NOC-pipe	G61	NHCH ₂CO-(4-H ₂NOC-pipe)	G31	4-H ₂NOC-pipe	G62	NHCH(CH ₂OH) ₂

(table 35)

No	R ^1A	No	R ^1A
No	R ^1A	No	R ^1A	H1	NHCH ₂-(2-Py)	H33	4-H ₂NOC-pipe
H2	NHPh	H34	NHCH ₂CO-pyrr	H1	NHCH ₂-(2-Py)	H33	4-H ₂NOC-pipe
H2	NHPh	H34	NHCH ₂CO-pyrr	H3	NHCH ₂Ph	H35	NHCH ₂CO-(3-HO-pyrr)
H4	NHCH ₂-(2-HO-Ph)	H36	NHCH ₂CO-(3-HO-pipe)	H3	NHCH ₂Ph	H35	NHCH ₂CO-(3-HO-pyrr)
H4	NHCH ₂-(2-HO-Ph)	H36	NHCH ₂CO-(3-HO-pipe)	H5	NHCH ₂-(3-HO-Ph)	H37	NHCH ₂CO-(4-HO-pipe)
H6	NHCH ₂-(4-HO-Ph)	H38	NH-(3-Ac-Ph)	H5	NHCH ₂-(3-HO-Ph)	H37	NHCH ₂CO-(4-HO-pipe)
H6	NHCH ₂-(4-HO-Ph)	H38	NH-(3-Ac-Ph)	H7	NHCH ₂-(2-H ₂NOC-Ph)	H39	NH-(3-MeHNOC-Ph)
H8	NHCH ₂-(3-H ₂NOC-Ph)	H40	NHCH ₂-(4-H ₂NO ₂S-Ph)	H7	NHCH ₂-(2-H ₂NOC-Ph)	H39	NH-(3-MeHNOC-Ph)
H8	NHCH ₂-(3-H ₂NOC-Ph)	H40	NHCH ₂-(4-H ₂NO ₂S-Ph)	H9	NHCH ₂-(4-H ₂NOC-Ph)	H41	NH-(3-Ms-Ph)
H10	NH-(2-HO-Ph)	H42	NHCH ₂CO-mor	H9	NHCH ₂-(4-H ₂NOC-Ph)	H41	NH-(3-Ms-Ph)
H10	NH-(2-HO-Ph)	H42	NHCH ₂CO-mor	H11	NH-(3-HO-Ph)	H43	NHCH ₂-(6-HO-2-Py)
H12	NH-(4-HO-Ph)	H44	NHCH ₂-(6-MeO-2-Py)	H11	NH-(3-HO-Ph)	H43	NHCH ₂-(6-HO-2-Py)
H12	NH-(4-HO-Ph)	H44	NHCH ₂-(6-MeO-2-Py)	H13	NH-(2-H ₂NOC-Ph)	H45	NHCH ₂-(6-H ₂NOC-2-Py)
H14	NH-(3-H ₂NOC-Ph)	H46	NHCH ₂-(6-cyano group-2-Py)	H13	NH-(2-H ₂NOC-Ph)	H45	NHCH ₂-(6-H ₂NOC-2-Py)
H14	NH-(3-H ₂NOC-Ph)	H46	NHCH ₂-(6-cyano group-2-Py)	H15	NH-(4-H ₂NOC-Ph)	H47	NHCH ₂-(6-Me ₂NOC-2-Py)
H16	NH-(CH ₂) ₂OMe	H48	NHCH ₂-(6-H ₂N-2-Py)	H15	NH-(4-H ₂NOC-Ph)	H47	NHCH ₂-(6-Me ₂NOC-2-Py)
H16	NH-(CH ₂) ₂OMe	H48	NHCH ₂-(6-H ₂N-2-Py)	H17	NH-(CH ₂) ₃OH	H49	NHCH ₂-(6-Me ₂N-2-Py)
H18	N(CH ₂CH ₂OH) ₂	H50	NHCH ₂-(6-F-2-Py)	H17	NH-(CH ₂) ₃OH	H49	NHCH ₂-(6-Me ₂N-2-Py)
H18	N(CH ₂CH ₂OH) ₂	H50	NHCH ₂-(6-F-2-Py)	H19	NHCH ₂CH(CH ₂OH)OH	H51	NHCH ₂-(6-Cl-2-Py)
H20	N(Me)CH ₂CH ₂OH	H52	NHCH ₂-(6-Me-2-Py)	H19	NHCH ₂CH(CH ₂OH)OH	H51	NHCH ₂-(6-Cl-2-Py)
H20	N(Me)CH ₂CH ₂OH	H52	NHCH ₂-(6-Me-2-Py)	H21	3-HO-pyrr	H53	NHCH ₂-(pyrazoles-2-yl)
H22	3-HO-pipe	H54	NHCH ₂-(pyridazine-2-yl)	H21	3-HO-pyrr	H53	NHCH ₂-(pyrazoles-2-yl)
H22	3-HO-pipe	H54	NHCH ₂-(pyridazine-2-yl)	H23	4-HO-pipe	H55	NHCH ₂-(pyrimidine-2-base)
H24	NHCH ₂CONHMe	H56	N(CH ₂CONH ₂)((CH ₂) ₂OH)	H23	4-HO-pipe	H55	NHCH ₂-(pyrimidine-2-base)
H24	NHCH ₂CONHMe	H56	N(CH ₂CONH ₂)((CH ₂) ₂OH)	H25	NHCH ₂CONMe ₂	H57	NHCH(Me)CH ₂OH
H26	N(Me)CH ₂CONH ₂	H58	NHCH ₂CH(Me)OH	H25	NHCH ₂CONMe ₂	H57	NHCH(Me)CH ₂OH
H26	N(Me)CH ₂CONH ₂	H58	NHCH ₂CH(Me)OH	H27	N(Me)CH ₂CONHMe	H59	NHC(Me) ₂CH ₂OH
H28	N(Me)CH ₂CONMe ₂	H60	NHCH ₂C(Me) ₂OH	H27	N(Me)CH ₂CONHMe	H59	NHC(Me) ₂CH ₂OH
H28	N(Me)CH ₂CONMe ₂	H60	NHCH ₂C(Me) ₂OH	H29	NH(CH ₂) ₂CONH ₂	H61	3-oxo-pipa
H30	N(CH ₂CONH ₂) ₂	H62	NHCH ₂CO-(3-H ₂NOC-pipe)	H29	NH(CH ₂) ₂CONH ₂	H61	3-oxo-pipa
H30	N(CH ₂CONH ₂) ₂	H62	NHCH ₂CO-(3-H ₂NOC-pipe)	H31	NHCH(CONH ₂)CH ₂OH	H63	NHCH ₂CO-(4-H ₂NOC-pipe)
H32	3-H ₂NOC-pipe	H64	NHCH(CH ₂OH) ₂	H31	NHCH(CONH ₂)CH ₂OH	H63	NHCH ₂CO-(4-H ₂NOC-pipe)

(table 36)

No	R ^1A	No	R ^1A
No	R ^1A	No	R ^1A	I1	NHCH ₂-(2-Py)	I33	4-H ₂NOC-pipe
I2	NHPh	I34	NHCH ₂CO-pyrr	I1	NHCH ₂-(2-Py)	I33	4-H ₂NOC-pipe
I2	NHPh	I34	NHCH ₂CO-pyrr	I3	NHCH ₂Ph	I35	NHCH ₂CO-(3-HO-pyrr)
I4	NHCH ₂-(2-HO-Ph)	I36	NHCH ₂CO-(3-HO-pipe)	I3	NHCH ₂Ph	I35	NHCH ₂CO-(3-HO-pyrr)
I4	NHCH ₂-(2-HO-Ph)	I36	NHCH ₂CO-(3-HO-pipe)	I5	NHCH ₂-(3-HO-Ph)	I37	NHCH ₂CO-(4-HO-pipe)
I6	NHCH ₂-(4-HO-Ph)	I38	NH-(3-Ac-Ph)	I5	NHCH ₂-(3-HO-Ph)	I37	NHCH ₂CO-(4-HO-pipe)
I6	NHCH ₂-(4-HO-Ph)	I38	NH-(3-Ac-Ph)	I7	NHCH ₂-(2-H ₂NOC-Ph)	I39	NH-(3-MeHNOC-Ph)
I8	NHCH ₂-(3-H ₂NOC-Ph)	I40	NHCH ₂-(4-H ₂NO ₂S-Ph)	I7	NHCH ₂-(2-H ₂NOC-Ph)	I39	NH-(3-MeHNOC-Ph)
I8	NHCH ₂-(3-H ₂NOC-Ph)	I40	NHCH ₂-(4-H ₂NO ₂S-Ph)	I9	NHCH ₂-(4-H ₂NOC-Ph)	I41	NH-(3-Ms-Ph)
I10	NH-(2-HO-Ph)	I42	NHCH ₂CO-mor	I9	NHCH ₂-(4-H ₂NOC-Ph)	I41	NH-(3-Ms-Ph)
I10	NH-(2-HO-Ph)	I42	NHCH ₂CO-mor	I11	NH-(3-HO-Ph)	I43	NHCH ₂-(6-HO-2-Py)
I12	NH-(4-HO-Ph)	I44	NHCH ₂-(6-MeO-2-Py)	I11	NH-(3-HO-Ph)	I43	NHCH ₂-(6-HO-2-Py)
I12	NH-(4-HO-Ph)	I44	NHCH ₂-(6-MeO-2-Py)	I13	NH-(2-H ₂NOC-Ph)	I45	NHCH ₂-(6-H ₂NOC-2-Py)
I14	NH-(3-H ₂NOC-Ph)	I46	NHCH ₂-(6-cyano group-2-Py)	I13	NH-(2-H ₂NOC-Ph)	I45	NHCH ₂-(6-H ₂NOC-2-Py)
I14	NH-(3-H ₂NOC-Ph)	I46	NHCH ₂-(6-cyano group-2-Py)	I15	NH-(4-H ₂NOC-Ph)	I47	NHCH ₂-(6-Me ₂NOC-2-Py)
I16	NH-(CH ₂) ₂OMe	I48	NHCH ₂-(6-H ₂N-2-Py)	I15	NH-(4-H ₂NOC-Ph)	I47	NHCH ₂-(6-Me ₂NOC-2-Py)
I16	NH-(CH ₂) ₂OMe	I48	NHCH ₂-(6-H ₂N-2-Py)	I17	NH-(CH ₂) ₃OH	I49	NHCH ₂-(6-Me ₂N-2-Py)
I18	N(CH ₂CH ₂OH) ₂	I50	NHCH ₂-(6-F-2-Py)	I17	NH-(CH ₂) ₃OH	I49	NHCH ₂-(6-Me ₂N-2-Py)
I18	N(CH ₂CH ₂OH) ₂	I50	NHCH ₂-(6-F-2-Py)	I19	NHCH ₂CH(CH ₂OH)OH	I51	NHCH ₂-(6-Cl-2-Py)
I20	N(Me)CH ₂CH ₂OH	I52	NHCH ₂-(6-Me-2-Py)	I19	NHCH ₂CH(CH ₂OH)OH	I51	NHCH ₂-(6-Cl-2-Py)
I20	N(Me)CH ₂CH ₂OH	I52	NHCH ₂-(6-Me-2-Py)	I21	3-HO-pyrr	I53	NHCH ₂-(pyrazoles-2-yl)
I22	3-HO-pipe	I54	NHCH ₂-(pyridazine-2-yl)	I21	3-HO-pyrr	I53	NHCH ₂-(pyrazoles-2-yl)
I22	3-HO-pipe	I54	NHCH ₂-(pyridazine-2-yl)	I23	4-HO-pipe	I55	NHCH ₂-(pyrimidine-2-base)
I24	NHCH ₂CONHMe	I56	N(CH ₂CONH ₂)((CH ₂) ₂OH)	I23	4-HO-pipe	I55	NHCH ₂-(pyrimidine-2-base)
I24	NHCH ₂CONHMe	I56	N(CH ₂CONH ₂)((CH ₂) ₂OH)	I25	NHCH ₂CONMe ₂	I57	NHCH(Me)CH ₂OH
I26	N(Me)CH ₂CONH ₂	I58	NHCH ₂CH(Me)OH	I25	NHCH ₂CONMe ₂	I57	NHCH(Me)CH ₂OH
I26	N(Me)CH ₂CONH ₂	I58	NHCH ₂CH(Me)OH	I27	N(Me)CH ₂CONHMe	I59	NHC(Me) ₂CH ₂OH
I28	N(Me)CH ₂CONMe ₂	I60	NHCH ₂C(Me) ₂OH	I27	N(Me)CH ₂CONHMe	I59	NHC(Me) ₂CH ₂OH
I28	N(Me)CH ₂CONMe ₂	I60	NHCH ₂C(Me) ₂OH	I29	NH(CH ₂) ₂CONH ₂	I61	3-oxo-pipa
I30	N(CH ₂CONH ₂)	I62	NHCH ₂CO-(3-H ₂NOC-pipe)	I29	NH(CH ₂) ₂CONH ₂	I61	3-oxo-pipa
I30	N(CH ₂CONH ₂)	I62	NHCH ₂CO-(3-H ₂NOC-pipe)	I31	NHCH(CONH ₂)CH ₂OH	I63	NHCH ₂CO-(4-H ₂NOC-pipe)
I32	3-H ₂NOC-pipe	I64	NHCH(CH ₂OH) ₂	I31	NHCH(CONH ₂)CH ₂OH	I63	NHCH ₂CO-(4-H ₂NOC-pipe)

Claims

1. 4 of a formula (I) expression, 4-two fluoro-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza Derivative, or its pharmacy acceptable salt,

Symbol in the formula has following implication

R ¹: the group of formula (II) or formula (III) expression,

Symbol in the formula has following implication

Z ¹: singly-bound, C _1-6Alkylidene group or-C _1-6Alkylidene group-C (=O)-,

R ¹¹:-H or do not replace or be selected from down the C that group replaced that organizes _1-6Alkyl :-OH ,-O-C _1-6Alkyl ,-CO ₂H ,-CO ₂-C _1-6Alkyl, do not replace or by one or two C _1-6The formamyl that alkyl replaces,

R ¹²：

(1) works as Z ¹Expression singly-bound or C _1-6During alkylidene group,

R ¹²For-H ,-OH ,-O-C _1-6Alkyl ,-CO ₂H ,-CO ₂-C _1-6Alkyl, do not replace or by one or two C _1-6Formamyl, replacement or unsubstituted monocycle that alkyl replaces are to trinucleated C _6-14The aromatic hydrocarbon ring, the part have or do not have the replacement of unsaturated link(age) or do not replace C _3-8Non-aromatic hydrocarbon ring, replacement or unsubstituted monocycle, oxygen nitrogenous to trinucleated or 5 to 7 yuan of non-aromatic heterocyclics of the aromatic heterocycle of sulfur heteroatom or replacement or unsubstituted nitrogenous, oxygen or sulfur heteroatom,

(2) work as Z ¹Expression-C _1-6Alkylidene group-C (=O)-time,

R ¹²Be group by formula (III) or formula (IV) expression,

Symbol in the formula has following implication

Z ²: singly-bound or C _1-6Alkylidene group,

R ¹⁵:-H ,-OH ,-O-C _1-6Alkyl ,-CO ₂H ,-CO ₂-C _1-6Alkyl, do not replace or by one or two C _1-6Formamyl, replacement or unsubstituted monocycle that alkyl replaces are to trinucleated C _6-14Aromatic hydrocarbon ring, part have or do not have the replacement or the unsubstituted C of unsaturated link(age) _3-8Non-aromatic hydrocarbon ring, replacement or unsubstituted monocycle are nitrogenous to trinucleated, the aromatic heterocycle of oxygen or sulfur heteroatom or replacement or unsubstituted nitrogenous, oxygen or heteroatomic 5 to 7 yuan of non-aromatic heterocyclics,

R ¹³, R ¹⁴: form replacement or unsubstituted 3 to 10 yuan non-aromatics cyclammonium with adjacent nitrogen atom,

R ²: CF ₃Or halogen,

R ³: H or halogen,

A, b: represent singly-bound or two key separately, one of them is that singly-bound and another are two keys ,-X-:

(1) when a be singly-bound and b when being two key ,-X-is-CH=CH-,-N=CH-,-N=N-or-S-,

(2) when a be two keys and b when being singly-bound ,-X-is-N-Y:

(1) when a be singly-bound and b when being two key, Y is CH or N,

(2) when a be two keys and b when being singly-bound, Y is S,

-A-:-O-,-S-,-NH-or-N (C _1-6Alkyl)-and

B: be substituted separately or unsubstituted C _1-6Alkyl, C _2-6Thiazolinyl, part have or do not have the C of unsaturated link(age) _3-8Non-aromatic hydrocarbon ring or monocycle are to trinucleated C _6-14The aromatic hydrocarbon ring,

Wherein,

The substituting group of following group is selected from (a)-(h): the monocycle that replaces among the B is to trinucleated C _6-14Aromatic hydrocarbon ring, part have or do not have the C of the replacement of unsaturated link(age) _3-8Non-aromatic hydrocarbon ring; R ¹²And R ¹⁵The middle monocycle that replaces is to trinucleated C _6-14Aromatic hydrocarbon ring, part have or do not have the C of the replacement of unsaturated link(age) _3-8The monocycle of non-aromatic hydrocarbon ring, replacement, oxygen nitrogenous to trinucleated or 5 to 7 yuan of non-aromatic heterocyclics of the aromatic heterocycle of sulfur heteroatom or nitrogenous, oxygen that replaces or sulfur heteroatom; And R ¹³And R ¹⁴Middle 3 to 10 yuan the non-aromatics cyclammonium that replaces,

The substituting group of following group is selected from (a)-(g): the C that replaces among the B _1-6Alkyl, C _2-6Thiazolinyl,

Wherein (a)-(h) represents following substituting group:

(a) halogen;

(b)-and OH ,-O-R ^Z,-O-monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring ,-OCO-R ^Z, oxo;

(c)-and SH ,-S-R ^Z,-S-monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring ,-SO-R ^Z,-SO-monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring ,-SO ₂-R ^Z,-SO ₂-monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring, do not replace or by one or two R ^ZThe sulfamyl that replaces;

(d) do not replace or by one or two R ^ZThe amino that replaces ,-NHCO-R ^Z,-NHCO-monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring ,-NHSO ₂-R ^Z,-NHSO ₂-monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring, nitro;

(e)-and CHO ,-CO-R ^Z,-CO ₂H ,-CO ₂-R ^Z, do not replace or by one or two R ^ZThe formamyl that replaces, cyano group;

(f) do not replace or respectively by the monocycles of one or more groups replacements that are selected from down group to trinucleated C _6-14Aromatic hydrocarbon ring or part have or do not have the C of unsaturated link(age) _3-8Non-aromatic hydrocarbon ring :-OH ,-O-C _1-6Alkyl does not replace or by one or two C _1-6The amino that alkyl replaces does not replace or by one or two C _1-6The formamyl that alkyl replaces, monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring, monocycle is nitrogenous to trinucleated, the aromatic heterocycle of oxygen or sulfur heteroatom, halogen and R ^Z

(g) do not replace or 5 to 7 yuan of non-aromatic heterocyclic :-OH of the aromatic heterocycle of nitrogenous by the monocycle of one or more groups replacements that are selected from down group respectively, oxygen or sulfur heteroatom or nitrogenous, oxygen or sulfur heteroatom-O-C to trinucleated _1-6Alkyl does not replace or by one or two C _1-6The amino that alkyl replaces does not replace or by one or two C _1-6The formamyl that alkyl replaces, monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring, monocycle is nitrogenous to trinucleated, the aromatic heterocycle of oxygen or sulfur heteroatom, halogen and R ^ZWith

(h) C that does not replace or replaced to substituting group shown in (g) by one or more (a) respectively _1-6Alkyl or C _2-6Thiazolinyl,

R wherein ^ZThe C that represent not replacement or replaced by one or more substituting groups that are selected from down group _1-6Alkyl :-OH ,-O-C _1-6Alkyl does not replace or by one or two C _1-6The amino that alkyl replaces does not replace or by one or two C _1-6The formamyl that alkyl replaces, monocycle is to trinucleated C _6-14The aromatic hydrocarbon ring, monocycle is nitrogenous to trinucleated, the aromatic nucleus and the halogen of oxygen or sulfur heteroatom.

2. compound as claimed in claim 1 is characterized in that a is a singly-bound, and b is two keys, and-X-is-CH=CH-, and-Y-is-CH-.

3. compound as claimed in claim 2 is characterized in that R ¹Be by the represented group of formula (II).

4. compound as claimed in claim 3 is characterized in that-A-is-O-.

5. compound as claimed in claim 4 is characterized in that ,-B does not replace or substituted C _1-6Alkyl, wherein C _1-6Substituting group on the alkyl as defined in claim 1.

6. compound as claimed in claim 5 is characterized in that R ²Be trifluoromethyl, and R ³Be-H or-F.

7. compound as claimed in claim 1 is characterized in that, described compound is following listed compound or its pharmacy acceptable salt:

-5-subunit } ethanamide;

(2Z)-and N-(2-hydroxyethyl)-2-{4,4,7-three fluoro-1-[4-{[(2S)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza -5-subunit } ethanamide;

-5-subunit } ethanamide;

(2Z)-and 2-{4,4-two fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza -5-subunit }-N-[(2S)-2, and the 3-dihydroxypropyl] ethanamide;

-5-subunit } ethanoyl) amino] propionic acid amide;

(2Z)-N-[(2R)-2, the 3-dihydroxypropyl]-2-{4,4,7-three fluoro-1-[4-{[(2R)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza

-5-subunit } ethanamide;

-5-subunit } ethanamide;

-5-subunit }-N-(2-hydroxyethyl) ethanamide;

(2Z)-and 2-{4,4-two fluoro-1-[4-{[(2S)-the 2-fluoropropyl] oxygen }-2-(trifluoromethyl) benzoyl]-1,2,3,4-tetrahydrochysene-5H-1-benzo-aza -5-subunit }-N-(2-hydroxyethyl) ethanamide;

-5-subunit }-N-(2-hydroxyethyl) ethanamide;

-5-subunit }-N-(2-hydroxyethyl) ethanamide;

-5-subunit } ethanamide;

-5-subunit }-N-[(2S)-2, and the 3-dihydroxypropyl] ethanamide;

-5-subunit }-N-[(2R)-2, and the 3-dihydroxypropyl] ethanamide;

-5-subunit } ethanoyl) amino] propionic acid amide;

-5-subunit } ethanamide;

-5-subunit } ethanoyl) amino] propionic acid amide;

-5-subunit }-N-[(2R)-2, and the 3-dihydroxypropyl] ethanamide; Or

-5-subunit }-N-[(2S)-2, and the 3-dihydroxypropyl] ethanamide.

8. pharmaceutical composition, described pharmaceutical composition comprises the described compound of claim 1 as activeconstituents.

9. pharmaceutical composition as claimed in claim 8, described pharmaceutical composition are arginine vasopressin V ₂Receptor stimulant.

10. pharmaceutical composition as claimed in claim 8, described pharmaceutical composition are frequent micturition therapeutical agents or central diabetes insipidus therapeutical agent at night.