CN101528690A

CN101528690A - Isoindoline derivatives for the treatment of arrhythmias

Info

Publication number: CN101528690A
Application number: CNA2007800338641A
Authority: CN
Inventors: A·比约; J·博斯特伦; O·戴维森; H·埃姆特纳斯; U·格兰; T·伊利夫斯基; J·卡贾纽斯; R·奥尔森; L·桑德伯格; G·斯特兰德伦; J·森德尔; Z·-Q·袁
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2006-07-12
Filing date: 2007-07-12
Publication date: 2009-09-09
Also published as: ECSP099090A; ZA200900076B

Abstract

The present invention provides compounds of formula I, wherein R<1> to R<7> have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.

Description

Be used for the treatment of ARR isoindoline derivative

Invention field

The present invention relates to novel medicinal 3-oxo isoindole quinoline (oxoisoindoline)-1-benzamide compound, especially for the ARR compound of treatment.

Background technology

It is undesired that irregular pulse can be defined as speed, the rhythm and pace of moving things or the starting point of heartbeat, perhaps for can cause movable abnormal conducted interference.Irregular pulse can be carried out clinical classification by starting point (be on the chamber, comprise atrium, chamber, irregular pulse ventricular arrhythmia) and/or the through-rate (being bradyarrhythmia (slowly) and tachyarrhythmia (soon)) set.

In the treatment irregular pulse, the negative findings of " tradition " antiarrhythmic drug that employing is worked by the conduction of velocity that slows down (I class antiarrhythmic drug) in clinical (referring to, heart disorder inhibition test (CAST) result of NewEngland Journal of Medicine 321,406 (1998) report for example) prompting should be developed has the compound that selectivity postpones the heart repolarization and therefore prolongs the timed interval of QT.III class antiarrhythmic drug can be defined as to prolong strides the potential cycle of membrane interaction that (it is by outside K ⁺Electric current outflow stop or inwardly the negatively charged ion electric current raise causes) and refractoriness, and do not influence the medicine of cardiac conduction.Activate Delayed Rectifier Potassium Current I fast and slowly _KrAnd I _KsFor being related to the main electric current of the whole processs of repolarization of action potential between plateau, most iii class medicament mainly blocks Ikr respectively, and is hitherto known by retardance I _Kr(III class or other) and a kind of unfavorable factor of the medicine that delayed repolarization works is: known to almost used medicine show that the ventricle arrhythmogenic effect of sole mode is also referred to as the property reversed chamber speed (weight break point), it is fatal sometimes.Consider that from the angle of safety minimizing of this phenomenon (it also shows the result with the non-cardiac drug of administration, as phenothiazine, trinucleated thymoleptic, antihistaminic and microbiotic) is the key issue that solves effective antiarrhythmic drug supply.

In people's atrial muscle cell, α quick active Delayed Rectifier Potassium Current, I _Kur, be also referred to as I _SoOr I _SusBe identified.Confirmed the gene I that encodes most possibly _KurChannel protein, and be called Kv1.5 (people (1993) Circ Res such as Wang, 73:1061-0176, people such as Feng (1997) Circ Res, 80:572-579).Since the slow inactivation of electric current, I _KurDuring plateau, keep and help significantly to act on the current potential repolarization of atrial muscle cell.What is interesting is most that voltage clamp research repolarization electric current does not have I in reference's ventricular muscle cell _KurHave (people such as Amos, J.Physiol, (1996) 491 (I): 31-50).Like this, I _KurSelectivity retardance agent be the compound of retardance Kv1.5, it is not normal for treatment atrium rule to be very important, medicament only postpones the repolarization in the myocardium of atrium since it is so, prevents the generation of the ventricle arrhythmia relevant with postponing ventricular bipolarization (that is the property reversed ventricular tachycardia).

Shown these characteristics of Kv1.5 retarding agent are by record (people such as Peukert, J.MED Chem (2003) 46:486-498; People such as Knobloch, Naunyn-Schmiedeberg ' s ArchPharmacol, (200) 366:482-487).

Some 3-oxo isoindole quinoline-1-carboxamides derivatives have been known.3-oxo isoindole quinoline-1-carboxamides derivatives is for being used for the desirable title of multi-component reaction (MCR).Tetrahedron Letters (1998), 39 (18), 2725-2728 discloses some (N-tertiary butyls-3-oxo-2-propyl group isoindoline-1-methane amide of the 3-oxo isoindole quinoline-1-carboxamides derivatives by so-called Ugi prepared in reaction, the N-tertiary butyl-1 methyl-3-oxo-2-propyl group isoindoline-1-methane amide, N, 1-dimethyl-3-oxo-2-propyl group isoindoline-1-methane amide, N-cyclohexyl-3-oxo-2-propyl group isoindoline-1-methane amide, 2-benzyl-N-the tertiary butyl-3-oxo isoindole quinoline-1-methane amide, 2-benzyl-N, 1-dimethyl-3-oxo isoindole quinoline-1-methane amide, 2-benzyl-N-the tertiary butyl-1-methyl-3-oxo isoindole quinoline-1-methane amide, 2-benzyl-N, 1-dimethyl-3-oxo isoindole quinoline-1-methane amide.

" organic chemistry magazine " (1999), 64 (3), 1074-1076 discloses such compound { 4-[1-(tertiary butyl formyl radical)-3-oxo-1,3-dihydro-2H-isoindole-2-yl] butyl } t-butyl carbamate, 2-benzyl-3-oxo-N-(2-styroyl) isoindoline-1-methane amide; 2-benzyl-N-butyl-3-oxo isoindole quinoline-1-methane amide; 2-benzyl-N-(2-methoxyethyl)-3-oxo isoindole quinoline-1-methane amide, 2-(2-hydroxyethyl)-3-oxo-N-(2-styroyl) isoindoline-1-methane amide, N-butyl-2-(2-hydroxyethyl)-3-oxo-isoindoline-1-methane amide, 2-(2-hydroxyethyl)-N-(2-methoxyethyl)-3-oxo isoindole quinoline-1-methane amide, 2-[3-(1H-imidazoles-1-yl) propyl group]-3-oxo-N-(2-styroyl) isoindoline-1-methane amide, N-butyl-2-[3-(1H-imidazoles-1-yl) propyl group]-3-oxo isoindole quinoline-1-methane amide, 2-[3-(1H-imidazoles-1-yl) propyl group]-N-(2-methoxyethyl) 3-oxo-isoindoline-1-methane amide, 2-cyclohexyl-3-oxo-N-(2-styroyl) isoindoline-1-methane amide, N-butyl-2-cyclohexyl-3-oxindole quinoline-1-methane amide, 2-cyclohexyl-N-(2-methoxyethyl)-3-oxo isoindole quinoline-1-methane amide) with at Bioorganic﹠amp; Medicinal Chemistry Letters (2002); 12 (14); 1813-1816 (2-cyclohexyl-N-hexyl-3-oxo isoindole quinoline-1-methane amide; N; 2-dihexyl-3-oxo isoindole quinoline-1-methane amide; N-hexyl-2-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide; N-hexyl-2-(4-hydroxyl butyl)-3-oxo isoindole quinoline-1-methane amide; N; 2-dicyclohexyl-3-oxo isoindole quinoline-1-methane amide; N-cyclohexyl-2-hexyl-3-oxo isoindole quinoline-1-methane amide; N-cyclohexyl-2-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide; N-cyclohexyl-2-(4-hydroxyl butyl)-3-oxo isoindole quinoline-1-methane amide; the tertiary butyl { 4-[1-(cyclohexyl carbamyl)-3-oxo-1; 3-dihydro-2H-isoindole-2 base] butyl } carbamate; N-diamantane-1-base-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide; N-diamantane-1-base-2-hexyl-3-oxo isoindole quinoline-1-methane amide; N-diamantane-1-base-2-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide; N-diamantane-1-base-2-(2-morpholine-4-base ethyl)-3-oxo isoindole quinoline-1-methane amide; N-(2, the 6-3,5-dimethylphenyl)-2-hexyl-3-oxo isoindole quinoline-1-methane amide).Tetrahedron Letters 53 volumes, the 19th phase, 6653-6679 discloses by so-called Ugi prepared in reaction 3-oxygen isoindoline-1-carboxamides derivatives (6-{[(2-allyl group-1-methyl-3-oxo-2,3-dihydro-1H-isoindole-1-yl) carbonyl] amino } caproic acid.These with reference in do not expect the medicinal application of prepared compound.Tetrahedron Letters (2002), 43 (6), 943-946 discloses some the 3-oxindoles quinolines-1-carboxamides derivatives (N by Diels-Alder type reaction preparation, 2-dibenzyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide, N-benzyl-2-the tertiary butyl-5-hydroxyl-3-oxo-4-benzene isoindoline-1-methane amide, N-benzyl-2-the tertiary butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide, N, 2-dibenzyl-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide, N-benzyl-2-the tertiary butyl-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide)." organic chemistry magazine " (2004), 69 (4), 1207-1214 discloses compound (N, 2-dibenzyl-5-{[(2-nitrophenyl) alkylsulfonyl] amino }-3-oxo isoindole quinoline-1-methane amide.Do not expect the medicinal application of prepared compound." heterocyclic chemistry magazine " (1997), 34 (4), 1371-1374 discloses the 3-oxo isoindole quinoline-1-carboxamides derivatives (N by the asymmetric replacement of the carbonylation cyclization preparation of 2-bromobenzaldehyde and primary amine, 2-dibenzyl-3-oxo isoindole quinoline-1-methane amide, N, 2-diethyl-3-oxo isoindole quinoline-1-methane amide, N, 2-dibutyl-3-oxo isoindole quinoline-1-methane amide, N, 2-docosyl-3-oxo isoindole quinoline-1-methane amide, N, two (4-the methoxy-benzyl)-3-oxo isoindole quinolines of 2--1-methane amide, 3-oxo-N, 2-dipropyl isoindoline-1-methane amide, N, 2-diheptyl-3-oxo isoindole quinoline-1-methane amide, 3-oxo-N, 2-phenylbenzene isoindoline-1-methane amide).Do not expect the medicinal application of prepared compound.Some other 3-oxo isoindole quinoline-1-carboxamides derivatives is disclosed in Zhurnal Obshchei Khimii (1965), 1 (7) 1292-7; YakugakuZasshi (1969), 89 (3), 418-21; Journal of the Chemical Society, PerkinTransactions1:Organic and Bio-Organic Chemistry (1972-1999) (1980), (4) 846-8 (2-(4-nitre phenyl)-3-(tetramethyleneimine-1-base carbonyl) 1-isoindolinone); EP1566378A1 (2-(3-fluorophenyl)-5,6-dimethyl-3-[(4-methylpiperazine 1-yl)-carbonyl] 1-isoindolinone; EP1661898; CHEMCATS (by the online chemical classification that provides of STN) (N-[2-(3, the 4-dimethoxy phenyl) ethyl] 3-oxo-2-(1-styroyl) isoindoline-1-methane amide, N-cyclopentyl-2-(3-methoxybenzyl)-3-oxo isoindole quinoline-1-methane amide; 2-(1,3-benzo dioxolane-5-ylmethyl)-and the N-{[(4-aminomethyl phenyl) alkylsulfonyl] methyl }-3-oxo isoindole quinoline-1-methane amide, N-cyclohexyl-3-oxo-2-(2-thienyl methyl) isoindoline-1-methane amide, 2-benzyl-N-cyclohexyl-3-oxo-isoindoline-1-methane amide, the N-{[(4-aminomethyl phenyl) alkylsulfonyl] methyl }-3-oxo-2-(2-thenyl) isoindoline-1-methane amide, 2-(4-benzyl chloride base)-N-{[(4-aminomethyl phenyl) alkylsulfonyl] methyl }-3-oxo isoindole quinoline-1-methane amide, N-cyclohexyl-2-(furfuryl)-3-oxo isoindole quinoline-1-methane amide, 2-(4-benzyl chloride base)-N-cyclohexyl-3-oxo isoindole quinoline-1-methane amide, WO03/040096 (tertiary butyl 1-benzyl-2-hydroxyl-3-[(2-hydroxyl-3-{[(3-oxygen-2,3 dihydros-1H-isoindole 1-yl) and carbonyl] amino }-the 4-phenyl butyl) ammonia] propyl group } carbamate); US5559256, Chemical﹠amp; Pharmaceutical Bulletin (1998) 36 (1), 190-201; Journal of the Chemical Society (1972-1999), (1972), (6), 835-840; : Justus Liebigs Annalen Der Chemie (1978), volume 2,283-288 (1-hydroxyl-2 methyl-3-oxo-N-(pyridine-2-ylmethyl) isoindoline-1-methane amide, N-[3-(dimethylamino) propyl group]-1-hydroxyl-2-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide, N-(3-azatropylidene-1-base propyl group)-1-hydroxyl-3-oxo-2-phenyl isoindoline-1-methane amide, 1-hydroxyl-2 methyl-3-oxo isoindole quinoline-1-carbohydrazide, 1-hydroxyl-3-oxo-phenyl isoindoline-1-carbohydrazide, Zeitschrift for Naturforschung, B, 1993, volume 48:8,1094-1104 (2-benzoyl-1-hydroxyl-3-oxo-N-phenyl isoindoline-1-methane amide); J.Prakt.Chem, 2,159,1941,241,244,254; " heterocycle " 38, the 8 phases of volume, 1994,1828-1838; " organic chemistry magazine " 17,1952,4,8,1-13; Tetrahedron, English, 53,19,1997,6653-6680; Tetrahedron Letters rolled up for 38 the 3rd phases, 1997,359-362 (6-{[(2-allyl group-1-methyl-3-oxo-2,3-dihydro-1H-isoindole 1-yl) carbonyl] amino } caproic acid and 6-{[(1-methyl-2-octyl group-3-oxo-2,3 dihydros-1H-isoindole-1-yl) carbonyl] amino } caproic acid).EP1566378A1 discloses the isoindoline derivative and has had anaesthetic effect (anestetic effect).EP1661898A1 discloses the isoindoline derivative and has been used for the treatment of cancer, EP1749817A1 isoindoline derivative control neuropathic pain (neturophatic pain).US2007/0099930 discloses the effect that the xylylenimine ketone that replaces has modulators of glucokinase.Further the isoindoline derivative is documented in " synthesizing " 2006, the 23 phases, 4046-4052 page or leaf (methyl [1-(tertiary butyl formamyl)-3-oxygen-1,3-dihydro-2H-isoindole-2-yl] acetic ester); " organic chemistry magazine " 2006,71,9544-9547 (N1-cyclopentyl-N4-(2, the 6-difluorophenyl)-2-(2,4 3,5-dimethylphenyl)-5-methyl-3-oxo isoindole quinoline-2,4-diformamide).

Disclosed compound is by restricted condition b in the above-mentioned file of enumerating) from the application's compound claim, get rid of.Restricted condition c) compound does not prove that in its concentration of testing activity is arranged.

Common pending application US 60/830186 describes restricted condition a).

In addition, following compound is the known compound in the chemical abstracts, but does not provide reference: 3-oxo-N, 2-phenylbenzene isoindoline-1-methane amide.

We are surprised to find one group of new 3-oxo isoindole quinoline-1-benzamide compound and show the electrophysiology activity, the blocking activity of preferred Kv1.5, and therefore expection is used for ARR treatment.

Summary of the invention

According to the invention provides formula I compound or its pharmacy acceptable salt:

Wherein

R ¹Expression C ₁-C ₁₂(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COR ⁹,-SR ¹⁰,-COXR ¹¹,-N (R ^12a) (R ^12b) ,-N (R ^13a) C (O) OR ^13b,-OC (O) N (R ^14a) (R ^14b), SO ₂(R ¹⁵), aryl or Het ¹); R in addition ¹Expression aryl or Het ²

R ⁸～R ¹¹, R ^13a, R ^13b, R ¹⁵When occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁹(C wherein ₁-C ₆Alkyl, aryl and Het ⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ¹⁰);

R ^12aAnd R ^12bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹¹(C wherein ₁-C ₆Alkyl, aryl and Het ¹¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ¹²), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^14aAnd R ^14bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹³(C wherein ₁-C ₆Alkyl, aryl and Het ¹³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ¹⁴), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ²Expression C ₁-C ₁₂Alkyl (wherein alkyl group randomly is selected from following group and replaces by one or more: halogen ,-OR ¹⁶,-COR ¹⁷, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, trialkylsilkl ,-COXR ¹⁸, aryl or Het ³);

R in addition ²Expression-(CH ₂) _kN (R ^19a) (R ^19b) ,-(CH ₂) _kNR ^20aC (O) N (R ^20b) (R ^20c) ,-(CH ₂) _nNR ^21aSO ₂R ^21b,-(CH ₂) _nSO ₂R ²²,-(CH ₂) _kN (R ^23a) C (O) OR ^23b,-OC (O) N (R ^24a) (R ^24b), C ₃-C ₈Cycloalkyl, aryl or Het ⁴

R ¹⁶～R ¹⁸, R ²¹, R ²², R ^23a, R ^23bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹⁵(C wherein ₁-C ₆Alkyl, aryl and Het ¹⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ¹⁶);

R ^19aAnd R ^19bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹⁹(C wherein ₁-C ₆Alkyl, aryl and Het ¹⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²⁰), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^20a, R ^20bAnd R ^20cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²¹(C wherein ₁-C ₆Alkyl, aryl and Het ²¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²²); R ^20bAnd R ^20cCan represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ³Expression hydrogen, C ₁-C ₁₂Alkyl (wherein alkyl group randomly is selected from following group and replaces by one or more: halogen ,-OR ²⁵,-COR ²⁶, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, trialkylsilkl ,-COXR ²⁷, aryl or Het ⁵);

R in addition ³Expression-(CH ₂) _kN (R ^28a) (R ^28b) ,-(CH ₂) _kN (R ^29a) C (O) N (R ^29b) (R ^29c) ,-(CH ₂) _nNR ^30aSO ₂R ^30b,-(CH ₂) _nSO ₂R ³¹,-(CH ₂) _kN (R ^32a) C (O) OR ^32b,-OC (O) N (R ^33a) (R ^33b), C ₃-C ₈Cycloalkyl, aryl or Het ⁶

R ²⁵～R ²⁷, R ³⁰, R ³¹, R ^32a, R ^32bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²³(C wherein ₁-C ₆Alkyl, aryl and Het ²³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²⁴);

R ^28aAnd R ^28bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²⁵(C wherein ₁-C ₆Alkyl, aryl and Het ²⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²⁶), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^33aAnd R ^33bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²⁷(C wherein ₁-C ₆Alkyl, aryl and Het ²⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²⁸), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^29a, R ^29bAnd R ^29cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²⁹(C wherein ₁-C ₆Alkyl, aryl and Het ²⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ³⁰); R ^29bAnd R ^29cCan represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ⁴Expression hydrogen ,-OH, aryl, C ₁-C ₆(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, hydroxyl, C ₂-C ₄Thiazolinyl, trialkylsilkl) ,-OR ³⁴,-(CH ₂) _mR ³⁵

R ³⁴When occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ³¹(C wherein ₁-C ₆Alkyl, aryl and Het ³¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ³²);

R ³⁵Represent aryl or Het independently ³³(wherein aryl and Het ³³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ³⁴);

R ⁵～R ⁷When occurring each time, represent independently hydrogen ,-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl ,-OR ³⁶,-N (R ^37a) (R ^37b) ,-C (O) R ³⁸,-C (O) OR ³⁹,-C (O) N (R ^40a) (R ^40b) ,-NC (O) OR ⁴¹,-OC (O) N (R ^42a) (R ^42b) ,-N (R ^43a) C (O) R ^43b,-N (R ^44a) S (O) ₂R ^44b,-S (O) ₂R ⁴⁵,-OS (O) ₂R ⁴⁶,-(CH ₂) _nN (R ^47a) (R ^47b) ,-(CH ₂) _nNR ^48aC (O) N (R ^48b) (R ^48c) ,-(CH ₂) _nNR ^49aSO ₂R ^49b, trialkylsilkl, aryl or Het ⁷

R ³⁶, R ³⁸, R ³⁹, R ⁴¹, R ⁴³, R ^44a, R ^44b, R ⁴⁵, R ⁴⁶, R ^49aAnd R ^49bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ³⁵(C wherein ₁-C ₆Alkyl, aryl and Het ³⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ³⁶);

R ^37aAnd R ^37bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ³⁷(C wherein ₁-C ₆Alkyl, aryl and Het ³⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ³⁸), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^40aAnd R ^40bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ³⁹(C wherein ₁-C ₆Alkyl, aryl and Het ³⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴⁰), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^42aAnd R ^42bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁴¹(C wherein ₁-C ₆Alkyl, aryl and Het ⁴¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴²), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^47aAnd R ^47bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁴³(C wherein ₁-C ₆Alkyl, aryl and Het ⁴³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴⁴), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^48a, R ^48bAnd R ^48cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁴⁵(C wherein ₁-C ₆Alkyl, aryl and Het ⁴⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴⁶), R ^48bAnd R ^48cCan represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

Aryl is optional when occurring each time to be replaced by following group :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, C ₃-C ₈Cycloalkyl, C ₂-C ₆Thiazolinyl, phenyl, Het ⁸,-OR ⁵⁰,-(CH ₂) _mR ⁵¹,-SR ⁵²,-C (O) R ⁵³,-COXR ⁵⁴,-N (R ^55a) (R ^55b) ,-SO ₂R ⁵⁶,-OS (O) ₂R ⁵⁷,-(CH ₂) _mN (R ^58a) (R ^58b) ,-(CH ₂) _mNR ^59aC (O) N (R ^59b) (R ^59c) ,-C (O) OR ⁶⁰,-C (O) N (R ^61a) (R ^61b) ,-N (R ^62aC (O) R ^62b,-N (R ^63a) C (O) OR ^63b,-OC (O) N (R ^64a) (R ^64b) ,-N (R ^65a) S (O) ₂R ^65bAnd OC (O) R ⁶⁶

R ⁵⁰～R ⁵⁴, R ⁵⁶, R ⁵⁷, R ⁶⁰, R ^62a, R ^62b, R ^63a, R ^63b, R ^65a, R ^65bAnd R ⁶⁶When occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁴⁷(C wherein ₁-C ₆Alkyl, aryl and Het ⁴⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴⁸);

R ⁵¹Represent aryl or Het independently ⁴⁹(wherein aryl and Het ⁴⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵⁰);

R ^55aAnd R ^55bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵¹(C wherein ₁-C ₆Alkyl, aryl and Het ⁵¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵²), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^58aAnd R ^58bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵³(C wherein ₁-C ₆Alkyl, aryl and Het ⁵³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵⁴), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^59aWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵⁵(C wherein ₁-C ₆Alkyl, aryl and Het ⁵⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵⁶); R ^59bAnd R ^59cCan represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^61aAnd R ^61bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵⁷(C wherein ₁-C ₆Alkyl, aryl and Het ⁵⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵⁸); Or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^64aAnd R ^64bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵⁹(C wherein ₁-C ₆Alkyl, aryl and Het ⁵⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁶⁰);

Het ¹～Het ⁶⁰Represent to contain one or more heteroatomic 5-12 unit heterocyclic groups that are selected from oxygen, nitrogen and/or sulphur when occurring each time independently, described group randomly is selected from following substituting group and replaces by one or more :-OH, oxo, halogen, cyano group, nitro, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, aryl, other (further) Het ,-OR ⁶⁷,-(CH ₂) _mR ⁶⁸,-SR ⁶⁹,-COXR ⁷⁰,-N (R ^71a) (R ^71b) ,-SO ₂R ⁷²,-(CH ₂) _mN (R ^73a) (R ^73b) ,-(CH ₂) _mNR ^74aC (O) N (R ^74b) (R ^74c) ,-C (O) R ⁷⁵,-C (O) OR ⁷⁶,-C (O) N (R ^77a) (R ^77b) ,-N (R ^78a) C (O) R ^78b,-N (R ^79a) S (O) ₂R ^79b, OC (O) (R ⁸⁰) ,-NC (O) OR ⁸¹,-OC (O) N (R ^82a) (R ^82b);

R ⁶⁷, R ⁶⁹, R ⁷⁰, R ⁷², R ⁷⁵, R ⁷⁶, R ^78a, R ^78b, R ^79a, R ^79b, R ⁸⁰Or R ⁸¹When occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁶¹(C wherein ₁-C ₆Alkyl, aryl and Het ⁶¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁶²);

R ⁶⁸Expression aryl or Het ⁶³(wherein aryl and Het ⁶³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁶⁴);

R ^71aAnd R ^71bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁶⁵(C wherein ₁-C ₆Alkyl, aryl and Het ⁶⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁶⁶), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^73aAnd R ^73bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁶⁷(C wherein ₁-C ₆Alkyl, aryl and Het ⁶⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁶⁸); Or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^74a, R ^74bAnd R ^74cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁶⁹(C wherein ₁-C ₆Alkyl, aryl and Het ⁶⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁷⁰); R ^74bAnd R ^74cCan represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^77aAnd R ^77bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁷¹(C wherein ₁-C ₆Alkyl, aryl and Het ⁷¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁷²); Or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

R ^82aAnd R ^82bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁷³(C wherein ₁-C ₆Alkyl, aryl and Het ⁷³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁷⁴), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

Het ⁶¹～Het ⁷⁴Represent to contain one or more heteroatomic 5-12 unit heterocyclic groups that are selected from oxygen, nitrogen and/or sulphur when occurring each time independently, described group randomly is selected from following substituting group and replaces by one or more :-OH, oxo, halogen, cyano group, nitro, C ₁-C ₆Alkyl;

X represents nitrogen-atoms or Sauerstoffatom;

M is 0～10 integer;

N is 0～4 integer;

K is 1～5 integer;

Condition is:

A) R ²Or R ³Do not represent the following formula fragment:

Wherein,

R ⁸³And R ⁸⁴When occurring each time, represent halogen, C independently ₁-C ₁₂Alkyl, C ₁-C ₁₂Alkoxyl group, C ₁-C ₁₂Haloalkyl, C ₁-C ₁₂Halogenated alkoxy, cyano group ,-SR ⁸⁶,-N (R ^87a) R ^87b, C ₂-C ₆Alkynyl, aryl or Het ⁷⁵

R ⁸⁵Expression hydrogen, C ₁-C ₁₂Alkyl or C ₁-C ₁₂Alkoxyl group (C wherein ₁-C ₁₂Alkyl and C ₁-C ₁₂Alkoxy base randomly is selected from following group and replaces by one or more: halogen, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, cyano group, oxo, aryl, Het ⁷⁶,-OR ⁸⁸,-SR ⁸⁹,-COXR ⁹⁰,-N (R ^91a) R ^91b,-SO ₂R ⁹²);

Het ⁷⁵～Het ⁷⁶Represent to contain one or more heteroatomic 5-12 unit heterocyclic groups that are selected from oxygen, nitrogen and/or sulphur when occurring each time independently, described group randomly is selected from following substituting group and replaces by one or more :-OH, oxo, halogen, cyano group, nitro, C ₁- ₆Alkyl, C ₁- ₆Alkoxyl group, aryl, aryloxy ,-N (R ^93a) R ^93b,-C (O) R ^93c,-C (O) OR ^93d,-C (O) N (R ^93e) R ^93f,-N (R ^93g) C (O) R ^93hWith-N (R ⁹³ⁱ) S (O) ₂R ^93j, OC (O) R ^93kWith other Het;

R ⁸⁶～R ⁹³When occurring each time, represent hydrogen or C independently ₁- ₆Alkyl;

X represents O or N;

B) described compound is not following compound or its pharmaceutically acceptable derivates:

2-(4-nitrophenyl)-3-(tetramethyleneimine-1-carbonyl) 1-isoindolinone;

N, 2-dibenzyl-3-oxo isoindole quinoline-1-methane amide;

N, 2-diethyl-3-oxo isoindole quinoline-1-methane amide;

N, 2-dibutyl-3-oxo isoindole quinoline-1-methane amide;

N, the two dodecyls of 2--3-oxo isoindole quinoline-1-methane amide;

N, two (4-the methoxy-benzyl)-3-oxo isoindole quinolines of 2--1-methane amide;

3-oxo-N, 2-dipropyl isoindoline-1-methane amide;

N, 2-diheptyl-3-oxo isoindole quinoline-1-methane amide;

3-oxo-N, 2-phenylbenzene isoindoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-propyl group isoindoline-1-methane amide;

N-(tertiary butyl)-1-methyl-3-oxo-2-propyl group-isoindoline-1-methane amide;

N, 1-dimethyl-3-oxo-2 propyl group isoindoline-1-methane amide;

N-cyclohexyl-3-oxo-2-propyl group isoindoline-1-methane amide;

N-(phenyl)-3-oxo-2-propyl group isoindoline-1-methane amide;

2-benzyl-N-the tertiary butyl-3-oxo isoindole quinoline-1-methane amide;

2-benzyl-N, 1-dimethyl-3-oxo isoindole quinoline-1-methane amide;

2-benzyl-N-the tertiary butyl-1-methyl-3-oxo isoindole quinoline-1-methane amide;

2-benzyl-N, 1-dimethyl-3-oxo isoindole quinoline-1-methane amide;

(4-{1-[(tertiary butyl amino) carbonyl]-3-oxo-1,3 dihydro-2H-isoindole-2-yl } butyl) t-butyl carbamate;

2-benzyl-3-oxo-N-(2-styroyl) isoindoline-1-methane amide;

2-benzyl-N-butyl-3-oxo isoindole quinoline-1-methane amide;

2-benzyl-N-(2-methoxy ethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-hydroxyethyl) 3-oxo-N-(2-styroyl) isoindoline-1-methane amide;

N-butyl-2-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-hydroxyethyl)-N-(2-methoxy ethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3-(1H-imidazoles-1-yl) propyl group)-3-oxo-N-(2-styroyl)-isoindoline-1-methane amide;

N-butyl-2-[3-(1H-imidazoles-1-yl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-[3-(1H-imidazoles-1-yl) propyl group]-N-(2-methoxy ethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(cyclohexyl)-3-oxo-N-(2-styroyl)-isoindoline-1-methane amide;

N-butyl-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

2-cyclohexyl-N-(2-methoxy ethyl)-3-oxo isoindole quinoline-1-methane amide;

N, 2-dibenzyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-the tertiary butyl-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide;

N-benzyl-2-the tertiary butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N, 2-dibenzyl-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide;

N-benzyl-2-the tertiary butyl-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

2-cyclohexyl-N-hexyl-3-oxo isoindole quinoline-1-methane amide;

N, 2-dihexyl-3-oxo isoindole quinoline-1-methane amide;

N-hexyl-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide;

N-hexyl-2 (4-hydroxyl butyl)-3-oxo isoindole quinoline-1-methane amide;

N, 2-dicyclohexyl-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-2-hexyl-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-2 (2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-2 (4-hydroxyl butyl)-3-oxo isoindole quinoline-1-methane amide;

(4-{1-[(cyclohexyl amino) carbonyl]-3-oxo-1,3 dihydro-2H-isoindole-2-yl } butyl) t-butyl carbamate;

N-diamantane-1-base-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

N-diamantane-1-base-2-hexyl-3-oxo isoindole quinoline-1-methane amide;

N-diamantane-1-base-2-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide;

N-diamantane-1-base-2-(2-morpholine-4-base ethyl)-3-oxo isoindole quinoline-1-methane amide;

N, 2-dibenzyl-5-{[(2-nitrophenyl) alkylsulfonyl] amino }-3-oxo isoindole quinoline-1-methane amide;

[1-(tertiary butyl formamyl)-3-oxo-1,3 dihydro-2H-isoindole-2 base] ethyl acetate;

N-[2-(3, the 4-Dimethoxyphenyl) ethyl]-3-oxo-2-(1-styroyl) isoindoline-1-methane amide;

N-cyclopentyl-2-(3-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(1,3-benzo dioxole-5 ylmethyl)-N-{[(4-aminomethyl phenyl) alkylsulfonyl] methyl }-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-3-oxo-2-(2-thienyl methyl) isoindoline-1-methane amide;

2-benzyl-N-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

The N-{[(4-aminomethyl phenyl) alkylsulfonyl] methyl }-3-oxo-2-(2-thienyl methyl) isoindoline-1-methane amide;

2-(4-benzyl chloride base)-N-{[(4-aminomethyl phenyl) alkylsulfonyl] methyl }-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-2-(2-furyl methyl)-3-oxo isoindole quinoline-1-methane amide;

2-(4-benzyl chloride base)-N-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

1-benzyl-2-hydroxyl-3-[(2-hydroxyl-3-{[(3-oxo-2,3-dihydro-1H-isoindole-1-yl) and carbonyl] amino }-4 phenyl butyls) amino] propyl group } t-butyl carbamate;

1-hydroxy-2-methyl-3-oxo-N-(pyridine-2-ylmethyl) isoindoline-1-methane amide;

N-[3-(dimethylamino) propyl group]-1-hydroxyl-2-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide;

N-(3-azepan-1-base propyl group)-1-hydroxyl-3-oxo-2-phenyl isoindoline-1-methane amide;

2-benzoyl-1-hydroxyl-3-oxo-N-phenyl isoindoline-1-methane amide;

3-oxo-N, 2-phenylbenzene isoindoline-1-methane amide;

6-{[(1-methyl-2-octyl group-3-oxo-2,3-dihydro-1H-isoindole-1-yl) carbonyl] amino } caproic acid;

N-(methyl)-2-benzoyl-1-hydroxyl-3-oxindole quinoline-1-methane amide;

N-(phenyl)-2-benzoyl-1-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

6-[(2-allyl group-1-methyl-3-oxo isoindole quinoline-1-carbonyl)-amino]-caproic acid;

N-{ (1S, 2R)-1-(3, the 5-difluorobenzyl)-3-[(3-Ethylbenzyl) amino]-the 2-hydroxypropyl }-2-ethyl-3-oxo isoindole quinoline-1-methane amide;

N1-cyclopentyl-N4-(2, the 6-difluorophenyl)-2-(2, the 4-3,5-dimethylphenyl)-5-methyl-3-oxo isoindole quinoline-1, the 4-diformamide;

[1-(tertiary butyl formamyl)-3-oxo-1,3-dihydro-2H-isoindole-2-yl] methyl acetate;

1-hydroxy-2-methyl-3-oxo isoindole quinoline-1-carbohydrazide;

1-hydroxyl-3-oxo-phenyl isoindoline-1-carbohydrazide;

C) described compound is not following compound or its pharmaceutically acceptable derivates:

2-(2-ethoxyethyl group)-N-sec.-propyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-(3-tetramethyleneimine-1-base propyl group) isoindoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-(tetrahydrofuran (THF)-2-ylmethyl) isoindoline-1-methane amide;

2-[1-(hydroxymethyl) butyl]-N-sec.-propyl-3-oxo isoindole quinoline-1-methane amide;

N-sec.-propyl-2-(3-methyl butyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(3-methyl butyl)-3-oxo isoindole quinoline-1-methane amide;

N-{[2-(3-methyl butyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } glycine methyl ester;

N-(2-[1-(methylol) butyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) tert-butyl glycinate;

N-{[2-(3-methyl butyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate;

N-(tertiary butyl)-2-[1-(methoxymethyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(diethylamino) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[1-(methylol) butyl]-3-oxo isoindole quinoline-1-methane amide;

N-{[3-oxo-2-(2-thienyl methyl)-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate;

N-(2-[2-(methylthio group) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) tert-butyl glycinate;

N-{[2-(cyclopropyl methyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } glycine methyl ester; Or

2-(2, the 2-dimethyl propyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide.

Formula I compound is called " The compounds of this invention " hereinafter as defined above.

In one embodiment, R ¹Expression C ₁-C ₇(wherein alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COXR ¹¹, aryl or Het ¹); Further R ¹Expression Het ²

In one embodiment, R ¹Expression C ₁-C ₇(wherein alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COXR ¹¹, phenyl, naphthyl or Het ¹).

In one embodiment, R ¹Expression (1-benzyl-pyrrole alkane-3 base), (1-fluoro-3-phenyl-propane-2-yl), (1-methyl-5-phenyl-pyrazole-3-yl) methyl, (1-methylpyrrole-2 base) methyl, (2, the 3-difluorophenyl) methyl, (2, the 4-difluorophenyl) methyl, (2, the 5-Dimethoxyphenyl) methyl, (2, the 5-3,5-dimethylphenyl) methyl, (2-bromophenyl) methyl, (2-chloro-4-fluoro-phenyl) methyl, (2-chloro-6-phenoxy group-phenyl) methyl, (2-chloro-phenyl-) methyl, (2-dimethylamino-2-phenyl-ethyl), (2-ethoxyl phenenyl) methyl, (2-fluorophenyl) methyl, (2-p-methoxy-phenyl) methyl, (2-methyl-2-phenyl-propyl group), (2-aminomethyl phenyl) methyl, (2-Phenoxyphenyl) methyl, (2-phenyl) methyl, (2-pyridin-3-yl phenyl) methyl, (3, the 4-dichlorophenyl) methyl, (3, the 4-difluorophenyl) methyl, (3, the 5-Dimethoxyphenyl) methyl, (3-chloro-phenyl-) methyl, (3-cyano group-4-fluoro-phenyl) methyl, (3-cyano-phenyl) methyl, (3-fluorophenyl) methyl, (3-hydroxyl-2,2-dimethyl-propyl group), (3-p-methoxy-phenyl) methyl, (3-phenyl 1,2-oxazole-5-yl) methyl, (3-phenyl) methyl, (3-pyrroles-1-base phenyl) methyl, (4-chloro-phenyl-) methyl, (4-dimethylaminophenyl) methyl, (4-fluorophenyl) methyl, (4-hydroxy phenyl) methyl, (4-methoxycarbonyl phenyl) methyl, (4-Phenoxyphenyl) methyl, (4-phenyl) methyl, (5-methyl-2-phenyl-1,3-oxazole-4 base) methyl, (5-methyl-3-phenyl-1,2-oxazole-4 base) methyl, (phenyl-pyridine-2-base-methyl); [(1R)-1-(4-p-methoxy-phenyl) ethyl], [(1S)-the 1-phenylethyl], [(1R)-the 1-phenylethyl], [(1R)-2-(4-chloro-phenyl-)-1-(4,4,4-trifluoro butyl formamyl) ethyl], [(1R)-2-(4-chloro-phenyl-)-1-methoxycarbonyl-ethyl], [(1S)-1-naphthalene-1-base ethyl], [(2R)-2-(4-chloro-phenyl-) propyl group], [(2S)-2-(4-chloro-phenyl-) propyl group], [(4-chloro-phenyl-)-pyridin-4-yl-methyl], [(4-fluorophenyl)-pyridin-3-yl-methyl], [(4-fluorophenyl)-pyridin-3-yl-methyl], [(4-fluorophenyl)-pyridin-3-yl-methyl], [2-(2, the 4-dichlorophenyl) phenyl] methyl, [2-(2, the 4-difluorophenyl) phenyl] methyl, [2-(2, the 5-difluorophenyl) phenyl] methyl, [2-(2-chloro-phenyl-) phenyl] methyl, [2-(3, the 4-dichlorophenyl) phenyl] methyl, [2-(3, the 4-difluorophenyl) phenyl] methyl, [2-(3-chloro-4-fluoro-phenyl) phenyl] methyl, [2-(3-fluorophenyl) phenyl] methyl, [2-(4-chloro-2-methyl-phenyl)-2,2-two fluoro-ethyls], [2-(4-chloro-phenyl-) phenyl] methyl, [2-(4-fluoro-2-methyl-phenyl) phenyl] methyl, [2-(4-fluorophenoxy) phenyl] methyl, [2-(4-fluorophenyl) phenyl] methyl, [2-(4-p-methoxy-phenyl)-2-oxo-ethyl], [2-(4-p-methoxy-phenyl) phenyl] methyl, [2-(4-aminomethyl phenyl) phenyl] methyl, [2-(trifluoromethyl) phenyl] methyl, [2-[4-(trifluoromethyl) phenoxy group] phenyl] methyl, [3-(difluoro-methoxy) phenyl] methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl, [4-(difluoro-methoxy) phenyl] methyl, [4-(trifluoromethyl) phenyl] methyl, 1-(1H-indol-3-yl) propane-2-base, 1-(4-fluorophenyl) ethyl, 1-naphthalene-1-base ethyl, 1-naphthalene-2-base ethyl, the 1-phenylethyl, the 1-phenyl propyl, 2-(1-cyclohexenyl) ethyl, 2-(2-ethoxyl phenenyl) ethyl, 2-(2-p-methoxy-phenyl) ethyl, 2-(2-Phenoxyphenyl) ethyl, 2-(3, the 4-dichlorophenyl) ethyl, 2-(3, the 5-Dimethoxyphenyl) ethyl, 2-(3-bromo-4-p-methoxy-phenyl) ethyl, 2-(3-fluorophenyl) ethyl, 2-(4-bromophenyl) ethyl, 2-(4-chloro-phenyl-) ethyl, 2-(4-chloro-phenyl-) propyl group, 2-(4-fluorophenoxy) propyl group, 2-(4-fluorophenyl) ethyl, 2-(4-fluorophenyl) propyl group, 2-(4-Phenoxyphenyl) ethyl, 2-(4-p-methoxy-phenyl) ethyl, 2-(4-p-methoxy-phenyl) ethyl, 2-(4-phenyl) ethyl, 2-(5-bromo-2-methoxyl group-phenyl) ethyl, 2-(6-chloro-1H-indol-3-yl) ethyl, 2, the 2-dimethyl propyl, 2, the 2-diphenyl-ethyl, 2-[2-(trifluoromethoxy) phenyl] ethyl, 2-[3-(trifluoromethyl) phenyl] ethyl, 2-[4-(diethylamino formyl radical) phenyl] ethyl, 2-[4-(trifluoromethyl) phenyl] ethyl, 2-benzo [1,3] dioxole-5-base ethyl, the 2-methyl butyl, the 2-methyl-propyl, 2-naphthalene-1-base propyl group, the 2-phenoxy propyl, the 2-phenyl propyl, 2-thiophene-2-base ethyl, 3, the 3-dimethylbutyl, the 3-phenyl propyl, 3-tetramethyleneimine-1-base propyl group, 4-phenyl butane-2-base; The 4-phenyl butyl; 9H-fluorenes-9-base, diphenyl-methyl, benzyl, suberyl, cyclohexyl, cyclohexyl methyl, naphthalene-1-ylmethyl, pentane-3-base, styroyl, thiophene-2-ylmethyl, 2-phenyl-propane-2-base, the 1-phenyl propyl, [2-(4-chloro-phenyl-)-2-methyl-propyl group], [4-fluoro-2-(4-fluorophenyl) phenyl] methyl, (4-fluoro-2-phenyl-phenyl) methyl, [5-fluoro-2-(4-fluorophenyl) phenyl] methyl, (5-fluoro-2-phenyl-phenyl) methyl, 1-(4-fluorophenyl) ethyl, 2-(4-chloro-phenyl-) propane-2-base, 2-(4-fluorophenyl) propane-2-base or 1-(4-chloro-phenyl-) ethyl.

(use is named above-mentioned group from the program (the 4th edition) of the Lexichem software package (package) of Openeye.)

In one embodiment, R ²Expression C ₁-C ₆(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl ,-COR ¹⁷, trimethyl silyl ,-COXR ¹⁸, aryl or Het ³); R in addition ²Expression aryl or Het ⁴

In one embodiment, R ²Expression (1-benzyl-pyrrole alkane-3-yl); (1-methylpyrrole-2-yl) methyl; (2; 2-difluoro benzo [1; 3] methyl dioxole-5-yl); (2; the 3-Dimethylcyclohexyl); (2; the 4-difluorophenyl) methyl; (2-chloro-4-methyl sulphonyl-phenyl) methyl; (2-chloro-phenyl-) methyl; (2-fluoro-4-methyl sulphonyl-phenyl) methyl; (2-hydroxy phenyl) methyl; (2-methylpropane-2-yl) oxygen base carbonyl methyl; (3; the 4-dichlorophenyl) methyl; (3; the 4-difluorophenyl) methyl; (3; the 4-Dimethoxyphenyl) methyl; (3-formamyl-4-fluoro-phenyl) methyl; (3-chloro-phenyl-) methyl; (3-cyano group-4-fluoro-phenyl) methyl; (3-cyano-phenyl) methyl; (3-p-methoxy-phenyl); (3-methyl-5-phenyl-1; 2-oxazole-4-yl) methyl; (4-amino-2-methyl-pyrimidine-5-yl) methyl; (4-formamyl phenyl); (4-formamyl phenyl) methyl; (4-cyano group-2; 6-two fluoro-phenyl) methyl; (4-cyano-phenyl); (4-cyano-phenyl) methyl; (4-dimethylamino phenyl) methyl; (4-fluorophenyl) methyl; (4-hydroxy phenyl) methyl; (4-methylcyclohexyl); (4-methyl sulphonyl phenyl) methyl; (5-methyl isophthalic acid; 2-oxazole-3-yl) methyl; (5-methyl-2-furyl) methyl; (5-methyl-2-phenyl-1; 3-oxazole-4-yl) methyl; (5-methylpyrazine-2-yl) methyl; [2-(trifluoromethyl) phenyl] methyl; [3-(amino methyl) 4-fluoro-phenyl] methyl; [3-(difluoro-methoxy) phenyl] methyl; [3-(formyl-dimethylamino) 4-fluoro-phenyl] methyl; [3-(trifluoromethyl) phenyl] methyl; [3; two (trifluoromethyl) phenyl of 5-] methyl; [3-[[(2; 2-difluoro ethanoyl) amino] methyl] 4-fluoro-phenyl] methyl; [4-(acetylamino methyl) phenyl] methyl; [4-(amino methyl) phenyl]; [4-(difluoro-methoxy) phenyl] methyl; [4-(trifluoromethyl) phenyl] methyl; [4-[[(2; 2-difluoro ethanoyl) amino] methyl] phenyl]; [4-[[(2-acetyl fluoride base) amino] methyl] phenyl] methyl; [5-(2-furyl)-1; 2-oxazole-3-yl) methyl; [6-(trifluoromethyl) pyridin-3-yl) methyl; 1H-indol-3-yl methyl; 1-pyridin-4-yl ethyl; 2-(1H-indol-3-yl) ethyl; 2-(2; the 4-dichlorophenyl) ethyl; 2-(2; the 6-dichlorophenyl) ethyl; 2-(2-chloro-phenyl-) ethyl; 2-(3; the 4-dichlorophenyl) ethyl; 2-(3; the 4-Dimethoxyphenyl) ethyl; 2-(3-chloro-phenyl-) ethyl; 2-(3-fluorophenyl) ethyl; 2-(4-benzoyl-piperazine-1-yl) ethyl; 2-(4-chloro-phenyl-) ethyl; 2-(4-fluorophenyl) ethyl; 2-(4-p-methoxy-phenyl) ethyl; 2-[3-(trifluoromethyl) phenyl] ethyl; 2-benzo [1; 3] dioxole-5-base ethyl; 2-ethoxy carbonyl ethyl; the 2-furyl methyl; the 2-methoxy ethyl; 2-pyridine-2-base ethyl; 2-pyridin-4-yl ethyl; 2-thiophene-2-base ethyl; 3-imidazoles-1-base propyl group; the 3-methoxycarbonyl propyl; 4; 4; 4-trifluoro butyl; 4; 4-difluoro butyl; benzo [1,3] dioxole-5-ylmethyl; benzotriazole-1-ylmethyl; benzyl; butyl; cyclohexyl; ethyl; the methoxycarbonyl methyl; styroyl; propane-2-base; propyl group; the pyridin-3-yl methyl; the pyridin-4-yl methyl; the tertiary butyl; the trimethyl silyl methyl; (5-oxo-1-propane-2-base-tetramethyleneimine-3-yl) methyl; propane-2-base carbamyl ylmethyl; (2-fluorophenyl) methyl; (3-fluorophenyl) methyl; the 1-phenylethyl; 2-phenyl-propane-2-base or 5-cyano group amyl group.

(use is named above-mentioned group from the program (the 4th edition) of the Lexichem software package of Openeye.)

In one embodiment, R ¹Expression C ₁-C ₇(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COXR ¹¹, aryl or Het ¹); R in addition ¹Expression Het ²And

R ²Expression C ₁-C ₆(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₇Cycloalkyl ,-COR ¹⁷, trimethyl silyl ,-COXR ¹⁸, aryl or Het ³); R in addition ²Expression aryl or Het ⁴

In one embodiment, R ¹Expression C ₃-C ₈(described group of naphthene base randomly is selected from following group and replaces by one or more cycloalkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COXR ¹¹, aryl or Het ¹); And

R ²Expression C ₁-C ₆(wherein alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₇Cycloalkyl, COR ¹⁷, trimethyl silyl ,-COXR ¹⁸, aryl or Het ³); Further R ²Expression aryl or Het ⁴

In one embodiment, R ³Expression hydrogen, C ₁-C ₄(wherein alkyl group randomly is selected from following group and replaces by one or more alkyl: fluorine, C ₂-C ₆Thiazolinyl, trialkylsilkl ,-COXR ²⁷, aryl or Het ⁵).

In one embodiment, R ³Expression hydrogen.

In one embodiment, R ⁴Expression hydrogen.

In one embodiment, R ⁵～R ⁷When occurring each time, represent independently hydrogen ,-OH, halogen, cyano group, C ₁- ₆Alkyl ,-OR ³⁶,-C (O) N (R ^40a) (R ^40b) ,-N (R ^44a) S (O) ₂R ^44b

In one embodiment, aryl when occurring each time independently randomly by-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl ,-OR ⁵⁰, C ₂-C ₆Thiazolinyl, phenyl, Het ⁸Replace; R wherein ⁵⁰Expression C ₁-C ₆Alkyl or aryl.

In one embodiment, aryl is phenyl when occurring each time.

In one embodiment of the present invention, formula I compound is:

Wherein, R ^aBe hydrogen or fluorine;

R ^bBe hydrogen or fluorine;

R ^cBe hydrogen or fluorine;

R ³Be the C that is randomly replaced by 1,2 or 3 fluorine end _1-4Alkyl;

R ⁵Be hydrogen or C _1-4Alkyl;

R ⁶Be hydrogen, OH, halogen or C _1-4Alkoxyl group;

R ⁷Be hydrogen or halogen.

In one embodiment of the present invention, formula I compound is:

Wherein, R ^dBe hydrogen or C _1-4Alkyl;

R ^eBe hydrogen or C _1-4Alkyl;

R ^fBe hydrogen or C _1-4Alkyl;

R ^gBe hydrogen or halogen;

R ^hBe hydrogen or halogen;

R ^jBe hydrogen or halogen;

R ⁵Be hydrogen or halogen.

In one embodiment of the present invention, formula I compound is:

Wherein, R ^kBe hydrogen or C _1-4Alkyl;

R ^lBe hydrogen or C _1-4Alkyl;

R ^mBe hydrogen or halogen;

R ²Be C _3-6Alkyl;

R ⁵Be hydrogen or halogen;

R ⁶Be hydrogen or halogen.

In one embodiment of the present invention, formula I compound is:

Wherein, R ⁿBe hydrogen or halogen;

R ^pBe hydrogen or halogen;

R ²Be C _3-6Alkyl or choose the benzyl that in phenyl ring, is replaced wantonly by halogen;

R ⁵Be hydrogen or halogen.

In one embodiment of the present invention, R ¹Be (2-phenyl) methyl (Biphenylmethyl), randomly replaced by 1-3 fluorine;

R ²Be selected from ethyl, propyl group, normal-butyl, the tertiary butyl, 4,4,4-trifluoro butyl, 4,4-difluoro butyl, 4-fluorine butyl, benzo [1,3] dioxole-5-base-methyl, (2,2-difluoro benzo [1,3] dioxole-5-yl)-methyl, benzyl, (2-chloro-phenyl-) methyl, (4-fluorophenyl) methyl, (2-trifluoromethyl) methyl, (3-cyano-phenyl) methyl, (4-cyano-phenyl) methyl, (3-cyano group-4-fluorophenyl) methyl, (4-formamyl phenyl) methyl, (5-methylpyrazine-2-yl) methyl, the pyridin-3-yl methyl, (4-amino-2-methyl-pyrimidine-5-yl) methyl, [6-(trifluoromethyl) pyridin-3-yl] methyl, the pyridin-3-yl methyl, [6-(trifluoromethyl) pyridin-3-yl] methyl, the pyridin-4-yl methyl, [4-[[(2,2-difluoro ethanoyl) amino] methyl] phenyl] methyl, [4-(acetylamino methyl) phenyl] methyl, [4-[[(2-acetyl fluoride base) amino] methyl] phenyl] methyl, 2-phenylethyl or 2-(4-fluorophenyl) ethyl;

R ⁵～R ⁷Be independently selected from-OH, methyl, methoxyl group, chlorine, fluorine, cyano group, sulfonyloxy methyl amino, fluoro methoxyl group, difluoro-methoxy, trifluoromethanesulfonic acid base;

R ³Be hydrogen;

R ⁵Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, methyl, methoxyl group, fluorine or chlorine;

Or its enantiomer.

In embodiments of the invention, R ¹Be diphenyl-methyl (diphenyl methyl), randomly replaced by one or more substituting groups that are selected from fluorine or chlorine;

R ²Be selected from ethyl, propyl group, butyl, the tertiary butyl, 4,4-difluoro butyl, 4,4,4-trifluoro butyl, benzyl, (2-chloro-4-methyl sulphonyl-phenyl) methyl, (4-methyl sulphonyl-phenyl) methyl, (2-fluoro-4-methyl sulphonyl-phenyl) methyl, (4-methyl sulphonyl-phenyl) methyl, (2-hydroxy phenyl) methyl, [2-(trifluoromethyl) phenyl] methyl, (2,4 difluorobenzene base) methyl, (2-chloro-phenyl-) methyl, 2-(4-fluorophenyl) ethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In embodiments of the invention, R ¹Be 4-phenyl butane-2-base, randomly replaced by one or more substituting groups that are selected from fluorine or chlorine;

R ²Be selected from (2-chloro-phenyl-) methyl, [2-(trifluoromethyl) phenyl] methyl, benzyl, 2-phenylethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be 3, the 3-dimethylbutyl;

R ²Be selected from [3-(difluoro-methoxy) phenyl] methyl, [3-(trifluoromethoxy) phenyl] methyl, 2-(1H-indol-3-yl) ethyl, 1H-indol-3-yl methyl, (3-chloro-phenyl-) methyl, (3, the 4-dichlorophenyl) methyl, [4-(difluoro-methoxy) phenyl] methyl, 2-(3-fluorophenyl) ethyl, 2-benzo [1,3] dioxole-5-base ethyl, 2-[3-(trifluoromethyl) phenyl] ethyl, 2-(3, the 4-dichlorophenyl) ethyl, 2-(2, the 4-dichlorophenyl) ethyl, 2-(2, the 6-dichlorophenyl) ethyl, 2-(4-chloro-phenyl-) ethyl, 2-(3-chloro-phenyl-) ethyl or 2-(2-chloro-phenyl-) ethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be benzyl (phenyl methyl), randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group;

R ²Be selected from ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, benzo [1,3] dioxole-5-base-methyl, benzyl, 1-phenylethyl, 2-phenylethyl, cyclopentyl, described group is randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group, trifluoromethyl;

R in addition ²Expression pyridin-3-yl methyl, pyridin-4-yl methyl, [3-[[(2,2-difluoro ethanoyl) amino] methyl]-4-fluoro-phenyl] methyl, [4-(difluoro-methoxy) phenyl] methyl, (4-dimethylaminophenyl) methyl, [5-(2-furyl) 1,2-oxazole-3-yl] methyl, [5-(2-furyl) 1,2-oxazole-3-yl] methyl, 2-(3, the 4-Dimethoxyphenyl) ethyl, butane-2-base, cyclopentyl, (2, the 3-Dimethylcyclohexyl), (4-hydroxy phenyl) methyl, [2-(trifluoromethyl) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, methyl, methoxyl group, bromine, chlorine, fluorine, trimethyl silyl;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be (2-cyclopentyl phenyl) methyl;

R ²Be selected from 4,4-difluoro butyl, methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from bromine, fluorine, chlorine or cyano group;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be the 1-phenylethyl, randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group, methoxyl group;

R ²Be selected from ethyl, propyl group, the tertiary butyl, 4,4-difluoro butyl, 4,4,4-trifluoro butyl, 4-methyl sulphonyl, benzyl, wherein benzyl is randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group;

R in addition ²Expression picolyl, ((2,2-difluoro ethanoyl) amino) methyl, difluoro-methoxy, dimethylamino, 5-(2-furyl) 1,2-oxazole-3-base-methyl, cyclopentyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be 3-hydroxyl-2, the 2-dimethyl propyl;

R ²Be selected from [3-(difluoro-methoxy) phenyl] methyl, (3, the 4-dichlorophenyl) methyl, (3-chloro-phenyl-) methyl, [3-(trifluoromethyl) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, fluorine, chlorine;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be 2-(4-chloro-phenyl-) propyl group;

R ²Be selected from methyl, ethyl, n-propyl, propane-2-base, butyl, (4-amino-2-methyl-pyrimidine-5-yl) methyl, (5-methylpyrazine-2-yl) methyl, the pyridin-3-yl methyl, [6-(trifluoromethyl) pyridin-3-yl] methyl, (4-amino-2-methyl-pyrimidine-5-yl) methyl, [6-(trifluoromethyl) pyridin-3-yl] methyl, (5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl, 4,4,4-trifluoro butyl, (4-methyl sulphonyl phenyl) methyl, benzyl, (2,2-difluoro benzo [1,3] methyl dioxole-5-yl), (4-methyl sulphonyl phenyl) methyl, butyl, 2-(1H-indol-3-yl) ethyl, (4-formamyl phenyl) methyl, (4-cyano-phenyl) methyl, [3-(formyl-dimethylamino)-4-fluoro-phenyl] methyl, [3-(formyl-dimethylamino)-4-fluoro-phenyl] methyl, [4-(amino methyl) phenyl], [4-[[(2,2-difluoro ethanoyl) amino] methyl] phenyl], (4-formamyl phenyl), the pyridin-4-yl methyl, the 3-methoxy-propyl, (3-cyano group-4-fluoro-phenyl) methyl, [3-[[(2,2-difluoro ethanoyl) amino] methyl]-4-fluoro-phenyl] methyl, [3-(amino methyl)-4-fluoro-phenyl] methyl, [3-formamyl-4-fluoro-phenyl] methyl, 2-pyridin-4-yl ethyl, (1-methylpyrrole-2-yl) methyl, [4-(difluoro-methoxy) phenyl] methyl, (1-benzyl-pyrrole alkane-3-yl), 3-imidazoles-1-base propyl group, (4-dimethylaminophenyl) methyl, (4-methyl sulphonyl phenyl) methyl, the 3-dimethylaminopropyl, 1-pyridin-3-yl ethyl, (3-p-methoxy-phenyl), 1-pyridin-4-yl ethyl, (4-cyano-phenyl), the 3-methoxy-propyl, benzo [1,3] dioxole-5-ylmethyl, (3, the 4-dimethoxy phenyl) methyl, (3-methyl-5-phenyl-1,2-oxazole-4-yl) methyl, (5-methyl isophthalic acid, 2-oxazole-3-yl) methyl, [2-(trifluoromethyl) phenyl] methyl, (2-chloro-phenyl-) methyl, 2-(3, the 4-Dimethoxyphenyl) ethyl, 2-thiophene-2-base ethyl, 2-(4-p-methoxy-phenyl) ethyl, the 2-phenylethyl, the 2-methoxy ethyl, (4-fluorophenyl) methyl, methoxycarbonyl methyl or benzotriazole-1-ylmethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine, chlorine;

Or its enantiomer.

R ²The expression tertiary butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, bromine, fluorine, chlorine, methyl ,-OCH ₃,-OCH ₂F, trimethyl silyl;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be 2-(4-fluorophenyl) propyl group;

R ²Expression 4,4,4-trifluoro butyl, benzyl, the tertiary butyl, butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, bromine, fluorine, chlorine, methoxyl group;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be 2, the 2-dimethyl propyl;

R ²Expression [3-(trifluoromethoxy) phenyl] methyl, [3-(difluoro-methoxy) phenyl] methyl, (3, the 4-dichlorophenyl) methyl, 2-[3-(trifluoromethyl) phenyl] ethyl, 2-(1H-indol-3-yl) ethyl, (3-chloro-phenyl-) methyl, [4-(difluoro-methoxy) phenyl] methyl, [3-(trifluoromethyl) phenyl] methyl, 2-(3-fluorophenyl) ethyl, 2-(2-chloro-phenyl-) ethyl, 2-(3-chloro-phenyl-) ethyl, 2-(2, the 4-dichlorophenyl) ethyl, 2-(4-chloro-phenyl-) ethyl, 2-(2, the 6-dichlorophenyl) ethyl, benzo [1,3] dioxole-5-ylmethyl or benzyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be 2-phenyl-propane-2-base;

R ²Expression benzyl, 1-phenylethyl, (4-fluorophenyl) methyl, 4,4,4-trifluoro butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be the 1-phenyl propyl;

R ²Be benzyl, (2-chloro-phenyl-) methyl, [2-(trifluoromethyl) phenyl] methyl or (4-dimethylaminophenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ¹Be [2-(4-chloro-phenyl-)-2-methyl-propyl group];

R ²The expression normal-butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine or chlorine;

Or its enantiomer.

In one embodiment of the present invention, R ²Be (2-chloro-phenyl-) methyl;

R ¹Expression diphenyl-methyl, (2-pyridin-3-yl phenyl) methyl, (3, the 4-difluorophenyl) methyl, 1-(1H-indol-3-yl) propane-2-base, 2-(4-chloro-phenyl-) propyl group, (2, the 5-3,5-dimethylphenyl) methyl, [(1R)-1-(4-p-methoxy-phenyl) ethyl], 2-(1H-indol-3-yl) propyl group, [(1R)-1-(3-p-methoxy-phenyl) ethyl], [(1S)-1-naphthalene-1-base ethyl], 1-phenyl propyl, 2-phenyl propyl, 3-phenyl propyl, 2-styroyl, 4-phenyl butane-2-base, (2-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine and chlorine;

Or its enantiomer.

In one embodiment of the present invention, R ²Be (3, the 4-dichlorophenyl) methyl;

R ¹Be (3-hydroxyl-2,2-dimethyl-propyl group), 2,2-dimethyl propyl, 2-methyl-propyl or 3,3-dimethylbutyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be (3-chloro-phenyl-) methyl;

R ¹Expression (3-hydroxyl-2,2-dimethyl-propyl group), 2-methyl-propyl, 2,2-dimethyl propyl, 3,3-dimethylbutyl, (4-hydroxy phenyl) methyl or (3-cyano-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be (3-cyano group-4-fluoro-phenyl) methyl;

R ¹Be (2-chloro-4-fluoro-phenyl) methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl, (3-cyano group-4-fluoro-phenyl) methyl, 2-phenylethyl, benzyl, (3, the 4-difluorophenyl) methyl, (2-phenyl) methyl or 2-(4-chloro-phenyl-) propyl group;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be (3-cyano-phenyl) methyl;

R ¹Be (2-phenyl) methyl, (3-chloro-phenyl-) methyl, (3, the 4-difluorophenyl) methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl or [4-(trifluoromethyl) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be (4-fluorophenyl) methyl;

R ¹Be [(4-chloro-phenyl-)-pyridin-4-yl-methyl], [(4-fluorophenyl)-pyridin-3-yl-methyl], (phenyl-pyridine-2-base-methyl), 2-(4-p-methoxy-phenyl) ethyl, (4-chloro-phenyl-) methyl, (2-phenyl) methyl, diphenyl-methyl, (2-pyridin-3-yl phenyl) methyl, (3, the 4-difluorophenyl) methyl, (1-fluoro-3-phenyl-propane-2 base), (1-methylpyrrole-2-yl) methyl, (2-phenyl) methyl, 2-(4-chloro-phenyl-) propyl group, 1-(4-chloro-phenyl-) ethyl, 2-(4-chloro-phenyl-) propane-2-base, 2-(4-fluorophenyl) propane-2-base, 2-phenyl-propane-2-base;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be (4-hydroxy phenyl) methyl;

R ¹Be (3, the 4-difluorophenyl) methyl, (3-chloro-phenyl-) methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl or [4-(trifluoromethyl) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be [2-(trifluoromethyl) phenyl] methyl;

R ¹Be (2-p-methoxy-phenyl) methyl, (2-fluorophenyl) methyl, diphenyl-methyl, 2-(4-chloro-phenyl-) ethyl, [4-(piperidines-1-carbonyl) phenyl] methyl, 2-(4-chloro-phenyl-) propyl group, (2-phenyl) methyl, 1-phenyl propyl, 2-phenyl propyl, 4-phenyl butane-2-base, 2-phenylethyl, 3-phenyl propyl, 2-methyl butyl, cyclohexyl methyl, (3-fluorophenyl) methyl, (2-ethoxyl phenenyl) methyl, [4-(trifluoromethoxy) phenyl] methyl or (3, the 4-difluorophenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine, chlorine, methoxyl group or methyl;

Or its enantiomer.

In one embodiment of the present invention, R ²Be [3-(difluoro-methoxy) phenyl] methyl;

R ¹Be 1-phenylethyl, (3-hydroxyl-2,2-dimethyl-propyl group), 3,3-dimethylbutyl or 2,2-dimethyl propyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be [3-(trifluoromethoxy) phenyl] methyl;

R ¹Expression 3,3-dimethylbutyl or 2,2 dimethyl propyls;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be [3-(trifluoromethyl) phenyl] methyl;

R ¹Be (3-hydroxyl-2,2-dimethyl-propyl group), 2-dimethyl propyl, 3,3-dimethylbutyl, 2,2 dimethyl propyls or (1-methylpyrrole-2-yl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be [4-(difluoro-methoxy) phenyl] methyl;

R ¹Be 2-methyl-propyl, 3,3-dimethylbutyl, 2,2-dimethyl propyl, (2-chloro-4-fluoro-phenyl) methyl, 2-(4-chloro-phenyl-) propyl group or [3, two (trifluoromethyl) phenyl of 5-] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be [6-(trifluoromethyl) pyridin-3-yl] methyl;

R ¹Be 2-(4-chloro-phenyl-) propyl group or (2-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be 2-(1H-indol-3-yl) ethyl;

R ¹Be 2-(4-chloro-phenyl-) propyl group, 2-(2-Phenoxyphenyl) ethyl, 2-[4-(diethylamino formyl radical) phenyl] ethyl, 2-(3-fluorophenyl) ethyl, 2-[2-(trifluoromethoxy) phenyl] ethyl, 2-(4-fluorophenyl) ethyl, 2-(3, the 5-Dimethoxyphenyl) ethyl, 2-(4-phenyl) ethyl, 2-(4-Phenoxyphenyl) ethyl, 2-(2-ethoxyl phenenyl) ethyl or 2-benzo [1,3] dioxole-5-base ethyl, 2,2-dimethyl propyl, 3, the 3-dimethylbutyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be 2-(2,4 dichloro benzene base) ethyl;

R ¹Be 2-methyl-propyl, 3,3-dimethylbutyl or 2,2 dimethyl propyls;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be 2-(2, the 6-dichlorophenyl) ethyl;

R ¹Be 2-methyl-propyl, 3,3-dimethylbutyl or 2,2 dimethyl propyls;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be 4,4,4-trifluoro butyl;

R ¹Be [2-(trifluoromethyl) phenyl] methyl, [(1R)-1-phenylethyl], diphenyl-methyl, 2-(4-chloro-phenyl-) propyl group, (2-phenyl) methyl, (2-phenoxy phenyl) methyl, (2-phenyl) methyl, 2-(4-chloro-phenyl-) ethyl, 2-(4-fluorophenyl) ethyl, 2-(4-fluorophenyl) propyl group, 2-(4-chloro-phenyl-) propane-2-base, 2-(4-fluorophenyl) propane-2-base or 2-phenyl-propane-2-base;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, methyl, bromine, fluorine and chlorine;

Or its enantiomer.

In one embodiment of the present invention, R ²Be 4,4-difluoro butyl;

R ¹Be (2-cyclopentyl phenyl) methyl, [2-(trifluoromethyl) phenyl] methyl, [(1R)-1-phenylethyl], (2-phenyl) methyl, diphenyl-methyl, 2-(4-chloro-phenyl-) propyl group or (2-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be benzyl;

R ¹The expression benzyl, diphenyl-methyl, [2-(trifluoromethyl) phenyl] methyl, (2-pyridin-3-yl phenyl) methyl, (4-Phenoxyphenyl) methyl, (2, the 4-difluorophenyl) methyl, [4-(difluoro-methoxy) phenyl] methyl, [3-(difluoro-methoxy) phenyl] methyl, (3-pyrroles-1-base phenyl) methyl, (3-fluorophenyl) methyl, (4-cyano-phenyl) methyl, (3, the 5-Dimethoxyphenyl) methyl, (2-p-methoxy-phenyl) methyl, (2-ethoxyl phenenyl) methyl, [4-(trifluoromethyl) phenyl] methyl, (3, the 4-difluorophenyl) methyl, (2, the 5-3,5-dimethylphenyl) methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl, (2-aminomethyl phenyl) methyl, (2, the 3-difluorophenyl) methyl, (2-bromophenyl) methyl, [(4-fluorophenyl)-pyridin-3-yl-methyl], [(4-chloro-phenyl-)-pyridin-4-yl-methyl], (phenyl-pyridine-2-base-methyl), (1-methyl-5-phenyl-pyrazole-3-yl) methyl, (5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl, (5-methyl-3-phenyl-1,2-oxazole-4-yl) methyl, (3-phenyl 1,2-oxazole-5-yl) methyl, 2-(4-chloro-phenyl-) ethyl, 2-(4-fluorophenyl) ethyl, 2-[4-(trifluoromethyl) phenyl] ethyl, 2-(5-bromo-2-methoxyl group-phenyl) ethyl, 2-(3-bromo-4-methoxyl group-phenyl) ethyl, 2-(4-fluorophenyl) propyl group, 2-(4-chloro-phenyl-) propyl group, 4-phenyl butane-2-base, [2-(4-chloro-2-methyl-phenyl)-2,2-two fluoro ethyls], 2-naphthalene-1-base propyl group, (2-methyl-2-phenyl-propyl group), the 2-phenoxy propyl, 2-(4-fluorophenoxy) propyl group, 2-phenyl-propane-2-base, suberyl, 2-(2-p-methoxy-phenyl) ethyl, 1-naphthalene-1-base ethyl, 2-[3-(trifluoromethyl) phenyl] ethyl, 2-(6-chloro-1H-indol-3-yl) ethyl, 2-(4-chloro-phenyl-) propyl group, [(1R)-1-(4-p-methoxy-phenyl) ethyl], [(1R)-1-(3-p-methoxy-phenyl) ethyl], 4-phenyl butane-2-base, the 1-phenylethyl, the 2-phenylethyl, 1-naphthalene-2-base ethyl, 2-(1-cyclohexenyl) ethyl, 1-(4-fluorophenyl) ethyl, 2-(4-fluorophenyl) propane-2-base, 2-phenyl-propane-2-base, 1-phenyl propyl or (2-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine and chlorine ,-OH, methyl or methoxy;

Or its enantiomer.

In one embodiment of the present invention, R ²Be normal-butyl;

R ¹Be (2-phenyl) methyl, (2-Phenoxyphenyl) methyl, [2-(4-fluorophenoxy) phenyl] methyl, 2-(3-fluorophenyl) ethyl, 2-(4-fluorophenyl) ethyl, 2-(4-chloro-phenyl-) ethyl, 2-[4-(trifluoromethyl) phenyl] ethyl, 2-(4-chloro-phenyl-) propyl group, 2-(4-fluorophenyl) propyl group, (2-phenyl) methyl, 2-(4-phenyl) ethyl, 2-naphthalene-1-base propyl group, 2-(2-ethoxyl phenenyl) ethyl, 2-(2-phenoxy phenyl) ethyl, 2-(4-Phenoxyphenyl) ethyl, 2-[2-(trifluoromethoxy) phenyl] ethyl, 2-(3, the 5-Dimethoxyphenyl) ethyl, 2-benzo [1,3] dioxole-5-base ethyl, (1-fluoro-3-phenyl-propane-2 base), 2-(4-chloro-phenyl-) propyl group, naphthalene-1-ylmethyl, 1-naphthalene-2-base ethyl, (2-phenyl) methyl, [2-(4-chloro-phenyl-)-2-methyl-propyl group];

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine, chlorine ,-OH, methyl, methoxyl group;

Or its enantiomer.

In one embodiment of the present invention, R ²Be ethyl;

R ¹Be diphenyl-methyl, (2-phenyl) methyl or 2-(4-chloro-phenyl-) propyl group;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be the 2-phenylethyl;

R ¹Be (2-phenyl) methyl, 2-(4-p-methoxy-phenyl) ethyl, (4-chloro-phenyl-) methyl, 2-(4-chloro-phenyl-) ethyl, 2-(3, the 4-dichlorophenyl) ethyl, (3, the 4-difluorophenyl) methyl, 2-(4-chloro-phenyl-) propyl group, (2-chloro-4-fluoro-phenyl) methyl or 4-phenyl butane-2-base;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be propyl group;

R ¹Be (2-phenyl) methyl, diphenyl-methyl or 2-(4-chloro-phenyl-) propyl group;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, R ²Be pyridin-3-yl methyl or pyridin-4-yl methyl;

R ¹Be (2-phenyl) methyl, 2-(4-chloro-phenyl-) propyl group, (3, the 4-difluorophenyl) methyl, (2-chloro-4-fluoro-phenyl) methyl or 1-(4-fluorophenyl) ethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine, chlorine ,-OH;

Or its enantiomer.

In one embodiment of the present invention, R ²Be the tertiary butyl;

R ¹Be (2-phenyl) methyl, [2-(trifluoromethyl) phenyl] methyl, [4-(difluoro-methoxy) phenyl] methyl, (2-chloro-phenyl-) methyl, (2-p-methoxy-phenyl) methyl, (3, the 4-difluorophenyl) methyl, (3, the 4-difluorophenyl) methyl, (4-Phenoxyphenyl) methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl, (4-fluoro-2-phenyl-phenyl) methyl, (5-fluoro-2-phenyl-phenyl) methyl, the 1-phenylethyl, 2-(4-chloro-phenyl-) ethyl, 2-(2-Phenoxyphenyl) ethyl, 2-[2-(trifluoromethoxy) phenyl] ethyl, 2, the 2-diphenyl-ethyl, 2-(4-fluorophenyl) propyl group, 2-(4-chloro-phenyl-) propyl group, (2-phenyl) methyl, 2-(4-phenyl) ethyl, [2-(3-fluorophenyl) phenyl] methyl, [2-(4-fluorophenyl) phenyl] methyl, [2-(3, the 4-difluorophenyl) phenyl] methyl, [2-(2, the 4-difluorophenyl) phenyl] methyl, [2-(2, the 5-difluorophenyl) phenyl] methyl, [2-(2, the 4-dichlorophenyl) phenyl] methyl, [2-(3, the 4-dichlorophenyl) phenyl] methyl, [2-(2-chloro-phenyl-) phenyl] methyl, [2-(4-chloro-phenyl-) phenyl] methyl, [2-(4-aminomethyl phenyl) phenyl] methyl, [2-(4-fluoro-2-methyl-phenyl) phenyl] methyl, [2-(4-p-methoxy-phenyl) phenyl] methyl, [4-fluoro-2-(4-fluorophenyl) phenyl] methyl, [2-(3-chloro-4-fluorophenyl) phenyl] methyl, [2-(4-fluoro-2-methyl-phenyl) phenyl] methyl, [5-fluoro-2-(4-fluorophenyl) phenyl] methyl, diphenyl-methyl, [(1R)-2-(4-chloro-phenyl-)-1-(4,4,4-trifluoro butyl formamyl) ethyl], [3, two (trifluoromethyl) phenyl of 5-] methyl, 9H-fluorenes-9-base, [2-[4-(trifluoromethyl) phenoxy group] phenyl] methyl, 2-naphthalene-1-base propyl group, [(1R)-2-(4-chloro-phenyl-)-1-methoxycarbonyl-ethyl], (1-methyl-5-phenyl-pyrazole-3-yl) methyl or [2-(4-chloro-2-methyl-phenyl)-2,2-two fluoro-ethyls], (3-phenyl) methyl, (4-fluorophenyl) methyl, (4-phenyl) methyl, [(4-chloro-phenyl-)-pyridin-4-yl-methyl], 2-(4-fluorophenyl) propyl group or 2-(4-Phenoxyphenyl) ethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from-OH, bromine, chlorine, fluorine, methyl, methoxyl group, sulfonyloxy methyl amino, trimethyl silyl, cyano group ,-OCHF ₂,-OCH ₂F ,-OSO ₂CF ₃

Or its enantiomer.

In one embodiment of the present invention, R ²Be the trimethyl silyl methyl;

R ¹Be [3-(difluoro-methoxy) phenyl] methyl, [4-(difluoro-methoxy) phenyl] methyl, naphthalene-1-ylmethyl, 1-naphthalene-1-base ethyl, 2-(4-bromophenyl) ethyl, (2-chloro-6-phenoxy group-phenyl) methyl or (3, the 4-dichlorophenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

Or its enantiomer.

In one embodiment of the present invention, The compounds of this invention is formula I as defined above, but except restricted condition a), b) and c), but also comprise restricted condition d): R ²Expression-(CH ₂) _kN (R ^19a) (R ^19b), wherein k represents 2; R ^19aAnd R ^19bThe expression methyl;

Perhaps R ²Expression is selected from the Het of thiazolyl or pyridyl ⁴

Perhaps R ²The phenyl that expression is replaced by dimethylamino;

And R ⁵～R ⁷Be selected from C ₁-C ₃Alkyl ,-OR ³⁶, R wherein ³⁶Be selected from C ₁-C ₃Alkyl;

R then ¹Do not represent phenyl, benzyl, pyridyl, pyridylmethyl, pyrimidyl, cyclohexyl, methylpiperazine base, indanyl or naphthyl, randomly be selected from 1～3 following substituting group and replace: halogen (as fluorine, chlorine, bromine, iodine), hydroxyl, C ₁-C ₄Alkyl (as methyl, ethyl, propyl group, sec.-propyl, butyl), C ₁-C ₄Alkoxyl group (as methoxyl group, oxyethyl group, propoxy-, isopropoxy and butoxy), trifluoromethyl, the C that is replaced by at least one fluorine atom ₁-C ₃Alkyl (as trifluoromethoxy, trifluoro ethoxy and trifluoro propoxy-), acid amides, carboxyl, cyano group, C ₁-C ₄Alkylthio (as methylthio group, ethylmercapto group, rosickyite base and butylthio), nitro, amino, methylamino, dimethylamino, dimethylaminomethyl, dipropyl amino methyl, methylene radical dioxy base (methylenedioxy), phenoxy group, benzyloxy, C ₂-C ₅Alkanoyloxy (as acetoxyl group, propionyloxy and butyryl acyloxy), C ₁-C ₃ω-hydroxyalkyl (as methylol, hydroxyethyl), C ₂-C ₅Alkanoyloxy-C ₁-C ₃Alkyl (as acetoxy-methyl, ethanoyl oxygen base ethyl and propionyloxy methyl), C ₂-C ₅Alkyl amido (as kharophen and propionamido), carbalkoxy (as methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, different third oxygen carbonyl and the butoxy carbonyl), carbobenzoxy and benzene methoxycarbonyl.

Except as otherwise noted, what the alkyl of this paper definition and alkoxyl group can be for straight chains, perhaps when the carbon atom of sufficient amount (that is, minimum three), can be side chain or cyclic.In addition, when the carbon atom of sufficient amount (that is, minimum four), this type of alkyl and alkoxyl group can also be part ring-type or acyclic.Except as otherwise noted, alkyl and alkoxyl group can also be replaced by one or more halogen atoms (especially fluorine atom).Except as otherwise noted, cyclic alkyl, for example C ₃-C ₈Cycloalkyl can be randomly by one or more being selected from-OH, oxo, halogen, cyano group, nitro, amino, alkylamino, C ₁- ₆Alkyl, C ₁- ₆The substituting group of alkoxyl group, aryl, aryloxy or Het group replaces.

The alkylidene group (alkylene group) of this paper definition be divalence and can be for straight chain, perhaps be side chain when the carbon atom of sufficient amount (minimum 3).Except as otherwise noted, alkylidene group can also be replaced by one or more halogen atoms (especially fluorine atom).

Term used herein " aryl " comprises C ₆- ₁₀Aromatic yl group is as phenyl, naphthyl etc.Term used herein " aryloxy " comprises C ₆- ₁₀Aryloxy group is as phenoxy group, naphthyloxy etc.For fear of doubt, aryloxy group as referred to herein is connected with the rest part of molecule by the Sauerstoffatom of oxygen groups.Except as otherwise noted, aryl and aryloxy can be replaced by one or more substituting groups, and described substituting group comprises-OH, halogen, cyano group, nitro, C ₁- ₆Alkyl, C ₁- ₆Alkoxyl group, sulphonamide, methyl sulphonyl, aryl, anilino and methylsulfinyl.When being substituted, aryl and aryloxy are preferably replaced by 1-3 substituting group.

Term used herein " halogen " and " halogen " comprise fluorine, chlorine, bromine and iodine.

Het (the Het that can mention ¹～Het ⁷⁶) group comprises and contain 1-4 heteroatoms (being selected from oxygen, nitrogen and/or sulphur), and wherein the total atom number in the loop systems is those groups of 5-12.The Het group can be fully saturated on characteristic, all (the wholly aromatic) of aromaticity, part aromaticity and/or dicyclo.The heterocyclic group that can mention comprises the benzodioxan base, benzo dioxane heptyl (benzodioxepanyl), the benzo dioxolyl, benzofuryl, benzimidazolyl-, the benzo morpholinyl, benzotriazole base benzoxazinyl, the benzo thiophenyl, chromanyl, cinnolines base alkyl dioxin, dioxy thia pentyl (dioxothiolanyl), furyl, imidazolyl, imidazo [1,2-α] pyridyl, indyl, isoquinolyl isoxazolyl, morpholinyl, the oxo-pyrrolidine base, oxo-piperidine base oxazolyl, the 2 base, piperazinyl, piperidyl, purine radicals, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidone-base, pyrrolidyl, pyrrolinyl, pyrryl, quinazolyl, quinolyl, THP trtrahydropyranyl, tetrahydrofuran base, tetrazolium, thiazolyl, thienyl, the thiochroman base, triazolyl etc.Substituting group in the time of suitably on the Het group can be arranged on any atom (comprising heteroatoms) of loop systems.The binding site of Het group can be by any atom in the loop systems that comprises heteroatoms (if suitable), or can be used as a loop systems part appoint and the condensed carbocyclic ring on atom.The Het group can be N-or S-oxidised form.

Except as otherwise noted, the Het group can be randomly by one or more being selected from-OH, oxo, halogen, cyano group, nitro, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, aryl, aryloxy or other Het group replace.

Further term " hydrocarbon " refers to only comprise any structure of carbon atom and hydrogen atom.

Term " alkyl (hydrocarbon radical) " or " alkyl (hydrocarbyl) " refer to that removing appointing of one or more hydrogen from hydrocarbon closes structure.

Term " thiazolinyl " refers to have the monovalent straight or branched hydrocarbyl group of at least one carbon-carbon double bond.Two keys of thiazolinyl can be non-conjugated or conjugation be incorporated into unsaturated group.Except as otherwise noted, thiazolinyl defined herein can be straight chain or be side chain when the carbon atom of enough numbers (minimum 3) or cyclic.In addition, when the carbon atom of enough numbers (minimum 4), this type of thiazolinyl can also be a part ring-type/acyclic.Except as otherwise noted, thiazolinyl can also be replaced by one or more halogen atoms (especially fluorine atom).

Term " assorted alkyl " refers to be replaced the group that forms by the heteroatoms of one or more N of being selected from, O and S owing to one or more carbon atoms of alkyl.

The compounds of this invention can show tautomerism, and all tautomeric forms and composition thereof all comprise within the scope of the present invention.

The compounds of this invention can also contain one or more unsymmetrical carbons, and can therefore show optically-active and/or diastereo-isomerism.Diastereomer can separate by routine techniques (as chromatogram or fractional crystallization).Can separate various steric isomers by racemoid or other mixture that uses routine techniques (for example fractional crystallization or HPLC technology) separating compound.Perhaps, required optically active isomer can prepare by the following method: make suitable opticity raw material not cause that racemization or difference react under the mutually isomerized condition, or pass through derivatization method, for example use homochiral acid, (as HPLC, in the enterprising circumstances in which people get things ready for a trip spectrum of silicon-dioxide) separates non-mapping ester then by conventional methods.All steric isomers include within the scope of the present invention.All enantiomers and composition thereof include within the scope of the invention.

Shortenings is listed in the end of this specification sheets.

The illustrative example of any part of any substituting group, R group or this type of group includes but not limited to:

C ₁-C ₆Alkyl: methyl, ethyl, propyl group, sec.-propyl, 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group, 2-methyl-1-butene base, 3-methyl isophthalic acid-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl group, 2-methyl-1-pentene base, 3-methyl-1-pentene base, 4-methyl-1-pentene base, 2-methyl-2-amyl group, 3-methyl-2-amyl group, 4-methyl-2-amyl group, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, neo-pentyl and hexyl;

C ₂-C ₆Thiazolinyl: vinyl, allyl group, butenyl, pentenyl, hexenyl, cyclohexenyl, butadienyl, pentadienyl and hexadienyl;

C ₃-C ₈Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and ring octyl group;

The illustrative example of substituting group Het is benzodioxan base, benzotriazole base, furyl, imidazolyl, indyl, oxazolyl, piperazinyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidyl, pyrryl and thienyl.

The The compounds of this invention that can mention is those wherein R ₁Expression (2-phenyl) methyl, (4-Phenoxyphenyl) methyl, 2-Phenoxyphenyl methyl, 2-(4-chloro-phenyl-) propyl group, 2-(trifluoromethyl) phenyl methyl, 2, the 2-dimethyl propyl, diphenyl-methyl, 1-phenylethyl or 2, the 2-dimethyl propyl, [2-(3, the 4-difluorophenyl) phenyl] methyl, [2-(4-chloro-phenyl-)-2-methyl-propyl group], [4-fluoro-2-(4-fluorophenyl) phenyl] methyl, (4-fluoro-2-phenyl) methyl, [5-fluoro-2-(4-fluorophenyl) phenyl] methyl, (5-fluoro-2-phenyl-phenyl) methyl, 1-(4-fluorophenyl) ethyl, 2-(4-chloro-phenyl-) propane-2-base, 2-(4-fluorophenyl) propane-2-base or 1-(4-chloro-phenyl-) ethyl.

The The compounds of this invention that can mention is those wherein R ₂Be ethyl, propyl group, butyl, the tertiary butyl, 4; 4-difluoro butyl, 4; 4; 4-trifluoro butyl, methoxycarbonyl methyl, benzyl, 3,4-dichlorophenylmethyl, (4-fluorophenyl) methyl, [3-(difluoro-methoxy) phenyl] methyl, (5-oxo-1-propane-2-base-tetramethyleneimine-3-yl) methyl, propane-2-base carbamyl methyl, (2-fluorophenyl) methyl, (3-fluorophenyl) methyl, 1-phenylethyl, 2-phenyl-propane-2-base or 5-cyanogen amyl group.

The The compounds of this invention that can mention comprise those wherein aryl be the optional phenyl that is replaced by one or more fluorine, chlorine, hydroxyl, methoxyl group, cyano group, carbamyl, dialkyl amido, methyl sulphonyl, trifluoromethyl, aminoalkyl group, difluoro-methoxy.

The The compounds of this invention that can mention be those wherein at least a among substituent R 1 and the R2 be aryl.

The The compounds of this invention that can mention is those wherein R ₁Be selected from huge (bulky) with side chain side chain, for example biphenyl, diphenyl-methyl (diphenyl methyl), side chain styroyl and the tertiary butyl; And R ₂Be selected from benzyl and lipophilic group.Lipophilic group is selected from for example tertiary butyl, 4,4-difluoro butyl, 4,4,4-trifluoro butyl and normal-butyl.

In one embodiment, The compounds of this invention is the compound of formula I, wherein,

R ¹Expression C ₁-C ₁₂(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, cyano group, oxo ,-OR ⁸,-SR ¹⁰,-COXR ¹¹,-N (R ^12a) (R ^12b) ,-N (R ^13a) C (O) OR ^13b,-OC (O) N (R ^14a) (R ^14b) ,-SO ₂R ¹⁵, aryl or Het ¹); R in addition ¹Expression aryl or Het ²

R ⁸, R ¹⁰, R ¹¹, R ^13a, R ^13b, R ¹⁵When occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁹(C wherein ₁-C ₆Alkyl, aryl and Het ⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ¹⁰);

R ^12aAnd R ^12bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹¹(C wherein ₁-C ₆Alkyl, aryl and Het ¹¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ¹²);

R ^14aAnd R ^14bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹³(C wherein ₁-C ₆Alkyl, aryl and Het ¹³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl or Het ¹⁴);

R ²Expression C ₁-C ₁₂(wherein alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, trialkylsilkl ,-COXR ¹⁸, aryl or Het ³);

In addition, R ²Expression-(CH ₂) _kN (R ^19a) (R ^19b) ,-(CH ₂) _kNR ^20aC (O) N (R ^20b) (R ^20c) ,-(CH ₂) _nNR ^21aSO ₂R ^21b,-(CH ₂) _nSO ₂R ²²,-OC (O) N (R ^24a) (R ^24b), aryl or Het ⁴

R ¹⁸, R ²¹, R ²²When occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹⁵(C wherein ₁-C ₆Alkyl, aryl and Het ¹⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ¹⁶);

R ^19aAnd R ^19bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹⁹(C wherein ₁-C ₆Alkyl, aryl and Het ¹⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²⁰);

R ^20a, R ^20bAnd R ^20cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²¹(C wherein ₁-C ₆Alkyl, aryl and Het ²¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²²);

R ³Expression hydrogen, C ₁-C ₁₂(wherein alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, trialkylsilkl ,-COXR ²⁷, aryl or Het ⁵);

In addition, R ³Expression-(CH ₂) _kN (R ^28a) (R ^28b) ,-(CH ₂) _kN (R ^29a) C (O) N (R ^29b) (R ^29c) ,-(CH ₂) _nNR ^30aSO ₂R ^30b,-(CH ₂) _nSO ₂R ³¹,-OC (O) N (R ^33a) (R ^33b), aryl or Het ⁶

R ²⁷, R ^30a, R ^30b, R ³¹When occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²³(C wherein ₁-C ₆Alkyl, aryl and Het ²³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²⁴);

R ^28aAnd R ^28bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²⁵(C wherein ₁-C ₆Alkyl, aryl and Het ²⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²⁶);

R ^33aAnd R ^33bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²⁷(C wherein ₁-C ₆Alkyl, aryl and Het ²⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ²⁸);

R ^29a, R ^29bAnd R ^29cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²⁹(C wherein ₁-C ₆Alkyl, aryl and Het ²⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ³⁰);

R ⁴Expression hydrogen ,-OH, aryl, C ₁-C ₆(wherein alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, hydroxyl, C ₂-C ₄Thiazolinyl, trialkylsilkl) ,-OR ³⁴,-(CH ₂) _mR ³⁵

R ^37aAnd R ^37bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ³⁷(C wherein ₁-C ₆Alkyl, aryl and Het ³⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ³⁸);

R ^40aAnd R ^40bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ³⁹(C wherein ₁-C ₆Alkyl, aryl and Het ³⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴⁰);

R ^42aAnd R ^42bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁴¹(C wherein ₁-C ₆Alkyl, aryl and Het ⁴¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴²);

R ^47aAnd R ^47bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁴³(C wherein ₁-C ₆Alkyl, aryl and Het ⁴³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴⁴);

R ^48a, R ^48bAnd R ^48cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁴⁵(C wherein ₁-C ₆Alkyl, aryl and Het ⁴⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁴⁶);

R ^55aAnd R ^55bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵¹(C wherein ₁-C ₆Alkyl, aryl and Het ⁵¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵²);

R ^58aAnd R ^58bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵³(C wherein ₁-C ₆Alkyl, aryl and Het ⁵³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵⁴);

R ^59aWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵⁵(C wherein ₁-C ₆Alkyl, aryl and Het ⁵⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵⁶);

R ^61aAnd R ^61bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁵⁷(C wherein ₁-C ₆Alkyl, aryl and Het ⁵⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁵⁸);

Het ¹～Het ⁶⁰Represent to contain one or more heteroatomic 5-12 unit heterocyclic groups that are selected from oxygen, nitrogen and/or sulphur when occurring each time independently, described group randomly is selected from following substituting group and replaces by one or more :-OH, oxo, halogen, cyano group, nitro, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, aryl, other Het ,-OR ⁶⁷,-(CH ₂) _mR ⁶⁸,-SR ⁶⁹,-COXR ⁷⁰,-N (R ^71a) (R ^71b) ,-SO ₂R ⁷²,-(CH ₂) _mN (R ^73a) (R ^73b) ,-(CH ₂) _mNR ^74aC (O) N (R ^74b) (R ^74c) ,-C (O) R ⁷⁵,-C (O) OR ⁷⁶,-C (O) N (R ^77a) (R ^77b) ,-N (R ^78a) C (O) R ^78b,-N (R ^79a) S (O) ₂R ^79b, OC (O) (R ⁸⁰) ,-NC (O) OR ⁸¹,-OC (O) N (R ^82a) (R ^82b);

R ^71aAnd R ^71bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁶⁵(C wherein ₁-C ₆Alkyl, aryl and Het ⁶⁵Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁶⁶);

R ^73aAnd R ^73bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁶⁷(C wherein ₁-C ₆Alkyl, aryl and Het ⁶⁷Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁶⁸);

R ^74a, R ^74bAnd R ^74cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁶⁹(C wherein ₁-C ₆Alkyl, aryl and Het ⁶⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁷⁰);

R ^77aAnd R ^77bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁷¹(C wherein ₁-C ₆Alkyl, aryl and Het ⁷¹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁷²);

R ^82aAnd R ^82bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁷³(C wherein ₁-C ₆Alkyl, aryl and Het ⁷³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ⁷⁴);

X represents nitrogen-atoms or Sauerstoffatom;

M is 0～10 integer;

N is 0～4 integer;

K is 1～5 integer;

And restricted condition is: a), b) and c) as defined above.

In one embodiment, The compounds of this invention is the compound of formula I, wherein

R ⁴Expression-OH, aryl, C ₁-C ₆(wherein alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, hydroxyl, C ₂-C ₄Thiazolinyl, trialkylsilkl) ,-OR ³⁴,-(CH ₂) _mR ³⁵

Preparation

According to the present invention, also be provided for the method for preparation I compound, described method comprises: make formula II compound (R wherein ³～R ⁵As hereinbefore defined) with amine R ¹-NH ₂And isonitrile R ²-NC reacts under standard Ugi reaction conditions, obtains formula I compound, wherein R ¹～R ⁵As hereinbefore defined.

According to the present invention, also be provided for the method for preparation I compound, described method comprises reacts formula III compound and amine under standard amide coupled reaction condition, wherein R ¹～R ⁷As hereinbefore defined.

According to the present invention, also be provided for the method for preparation I compound, described method comprises that the four component UGI reaction of amine, acid, aldehyde and isonitrile obtains intermediate compound (IV):

According to literature method, make compound (IV) experience intramolecularly Diels-Alder reaction then, obtain formula I compound.

Described synthetic order is derived from the method for having announced: D.L.Wright, C.V.Robotham and K.Abound, Tetrahedron Lett.2002,43,943-946.

According to the present invention, also be provided for the method for preparation I compound, described method comprises that the four component UGI reaction of amine, acid, aldehyde and isonitrile obtains intermediate compound (V):

According to literature method, make compound (V) experience intramolecularly Diels-Alder reaction then, obtain formula I compound.

Similarly reaction is recorded in J.Org.Chem.2004, and 69,1207-1214.

For fear of doubt, should understand in this manual, group by " above defining ", " definition as mentioned " or " as defined above " limit, described group comprises first and to occur and generalized definition and each and all specific definitions that is used for this group.

Prefix n-, s-, i-, t-, tert-have its common implication: just, secondary, different and uncle.

The technician also will understand, and change in some formula I compound of various standard substituting groups or functional group and conversion will obtain other formula I compound.For example, carbonyl reduction can be become hydroxyl or alkylidene group, can convert hydroxyl to halogen, and iodine, bromine and chlorine can convert cyano group to.

Can adopt routine techniques that The compounds of this invention is separated from its reaction mixture.

It will be understood by those skilled in the art that in aforesaid method the functional group of midbody compound can maybe may need protected base protection.

The functional group that wishes protection comprises hydroxyl, amino and carboxylic acid.The appropriate protection base that is used for hydroxyl comprise trialkylsilkl and alkyl diaryl silyl (as; t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), tetrahydrochysene pyrrole south base and alkyl-carbonyl (as, methyl carbonyl and ethyl carbonyl).Be used for amino appropriate protection base and comprise benzyl, sulfoamido (as benzene sulfonamido), tert-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl or benzene methoxycarbonyl.The appropriate protection base that is used for amidino groups and guanidine radicals comprises the benzyloxy carbonyl.The appropriate protection base that is used for carboxylic acid comprises C _1-6Alkyl ester or benzyl ester.

The protection of functional group and go the protection can occur in before or after any reactions steps mentioned above.

Remove protecting group according to technology well known to those skilled in the art or technology hereinafter described.

The use of protecting group is at " Protective Groups in Organic Chemistry ", and J.W.F.McOmie edits, Plenum Press (1973) and " Protective Groups in OrganicSynthesis " the 3rd edition, T.W.Greene﹠amp; P.G.M.Wutz, Wiley-Interscience has carried out sufficient description in (1999).

It will be appreciated by those skilled in the art that, for to replace, and convenient in some cases mode obtains The compounds of this invention, each mentioned processing step of this paper can be different order carry out, and/or single reaction can be carried out (that is, can add substituting group and/or it is carried out chemical conversion the relevant different intermediate of above-mentioned and specific reaction) in the different steps of whole route.This will depend on some factors especially, for example be present in other functional group in the specific substrates character, key intermediate operability and with the protecting group strategy of taking (if desired).Obviously, related chemical type will influence the demand property and the type thereof of the selection of the reagent that uses in the described synthesis step, employed protecting group, and finish the synthetic order.

Those skilled in the art also will understand; though the shielded derivative of some of formula I compound (can make before the protection stage in last going) itself may not have pharmacologically active; but they can carry out parenteral or oral administration, and metabolism forms the The compounds of this invention with pharmacologically active in vivo then.Therefore such derivative is described as " prodrug ".In addition, some formula I compound can serve as the prodrug of other formula I compound.

All prodrugs of formula I compound all comprise within the scope of the present invention.

Medicinal use

Because The compounds of this invention has pharmacologically active, so they are useful.Therefore they can be used as medicine.

Therefore, the present invention provides The compounds of this invention on the other hand, and it is as medicine.

Especially, The compounds of this invention shows that potassium channel suppresses active, and particularly the Kv1.5 blocking-up is active, for example proves in the experiment below.

Therefore expect that The compounds of this invention is useful on prevention and treatment suppresses influence or promoted disease, particularly irregular pulse by Kv1.5, as atrium fibrillation, auricular flutter, atrial arrhythmia, atrial tachycardia.

Therefore The compounds of this invention is instructed to be used for the treatment of or prevents wherein to think and comprise ischemic heart disease, sudden cardiac onste, myocardial infarction, heart failure, heart operation and thromboembolic states incident by heart disease or the indication relevant with heart disease that irregular pulse (as atrium fibrillation, auricular flutter, atrial arrhythmia, atrial tachycardia) plays a major role.

The present invention provides treatment ARR method on the other hand, and described method comprises the The compounds of this invention of the people who suffers from or easily suffer from this type of illness being treated significant quantity.

Pharmaceutical preparation

Usually will be with in oral, subcutaneous, intravenously, intra-arterial, transdermal, the nose, by sucking, or close other parenteral approach by appointing, to comprise the pharmaceutical dosage forms of activeconstituents, in pharmaceutically acceptable formulation, give The compounds of this invention.According to illness to be treated and patient, and route of administration, can give described composition by different dosage.

The compounds of this invention can be united with any other medicines that are used for the treatment of irregular pulse and/or other cardiovascular disorder.

Therefore, another aspect of the present invention provides pharmaceutical preparation, and it comprises and pharmaceutically acceptable adjuvant, diluent or carrier blended The compounds of this invention.

The compounds of this invention to the suitable per daily dose in people's the therapeutic treatment is being the about 0.005-25.0mg/kg body weight of oral administration, the about 0.005-10mg/kg body weight of parenteral admin.The compounds of this invention is being the about 0.005-10.0mg/kg body weight of oral administration to the per daily dose example in people's the therapeutic treatment, the about 0.005-5.0mg/kg body weight of parenteral admin.

The compounds of this invention has the ARR advantage of effective opposing.

The compounds of this invention can use separately or combine with one another and use and/or unite use with other the suitable therapeutical agent that is used for the treatment of aforementioned diseases or other disease, described other suitable therapeutical agent comprises: other anti-arrhythmic, as I class medicament (as, Propafenone), II class medicament (for example carvedilol (carvadiol) and propranolol), III class medicament (as, sotalol, P162a, amiodarone, Azimilide, ibutilide), IV class medicament is (as, diltiazem

And verapamil), the 5-HT antagonist (as, sulamserod (sulamserol), serraline and trosetron), Dronedarone, atrium alternative cpd (as RSD1235), cardiac glycoside (comprising purple foxglove and Strophanthin G); Calcium channel blocker (L type and T type), for example diltiazem , verapamil, nifedipine, amlodipine and mybefradi.

In another aspect of the present invention, the solvate of formula (I) compound or its pharmacy acceptable salt or solvate or this type of salt can with the antithrombotic agent Combined Preparation, for example, anagrelide hydrochloride, Bivalirudin, Cilostazole, dalteparin sodium, Danaparoid sodium, dazoxiben hydrochloride, efegatran sulfate, Enoxaparin Sodium, fluretofen, Ifetroban, ifetroban sodium, Lamifiban, hydrochloric acid lotrafiban (lotrafiban), Napsagatran, the acetate Orbofiban, acetate roxifiban (roxifiban), SIBRAFIBAN, Tinzaparin sodium, trifenagrel, ReoPro, zolimomab aritox or its pharmaceutically acceptable derivates.

In another aspect of the present invention, the solvate of formula (I) compound or its pharmacy acceptable salt or solvate or this type of salt can with other medicament Combined Preparation that serves as or send the factor IIa agonist, described other medicament for example is 3DP-4815, AZD-0837, Mei Jiala group, Xi Meijia group, ART-123, Lepirudin, AVE-5026, bivaluridin, dabigatran ester (dabigatranetexilate), E-4444, odiparcil, Ardeparin Sodium, pegmusirudin, LB-30870, dermatan sulfate (dermatan), argatroban, MCC-977, desirudin, deligoparin sodium, PGX-100, hydroxyzine pentasaccharide (idraparinux) sodium, SR-123781, SSR-182289A, SCH-530348, TRIB50, TGN-167, TGN-255 and WO94/29336, compound described in WO97/23499 and the WO02/44145 (they incorporate this paper by reference into).

In another aspect of the present invention, the solvate of formula (I) compound or its pharmacy acceptable salt or solvate or this type of salt can with the fibrinogen deceptor antagonists Combined Preparation, described fibrinogen deceptor antagonists for example is acetate roxifiban, Fradafiban, Orbofiban, lotrafiban hydrochloride, Tirofiban, xemilofiban, monoclonal antibody 7E3 and SIBRAFIBAN or their pharmaceutically acceptable derivates.

In another aspect of the present invention, the solvate of formula (I) compound or its pharmacy acceptable salt or solvate or this type of salt can with the platelet suppressant drug Combined Preparation, described platelet suppressant drug for example is a Cilostazole (cilostezol), SR-25990C, prostaglin X, U-53217A, the ticlopidine hydrochloride, acetylsalicylic acid, Ibuprofen BP/EP, Naproxen Base, sulindac (sulindae), indomethacin, mefenamic acid ester Droxicam, diclofenac, sulfinpyrazone and piroxicam, Dipyridamole or their pharmaceutically acceptable derivates.

In another aspect of the present invention, the solvate of formula (I) compound or its pharmacy acceptable salt or solvate or this type of salt can with the platelet aggregation inhibitor Combined Preparation, described platelet aggregation inhibitor for example is Acadesine, Beraprost, beraprost sodium, U 61431F, U 53059 (itezigrel), lifarizine, lotrafiban hydrochloride, Orbofiban acetate, oxagrelate, Fradafiban, Orbofiban, Tirofiban and Xemilofiban or their pharmaceutically acceptable derivates.

In another aspect of the present invention, formula (I) compound or its pharmaceutically acceptable derivates can with hemorheologic agent (for example pentoxifylline or its pharmaceutically acceptable derivates) Combined Preparation.

In another aspect of the present invention, formula (I) compound or its pharmaceutically acceptable derivates can relevant blood coagulation inhibitor with lipoprotein or its pharmaceutically acceptable derivates Combined Preparation.

In another aspect of the present invention, the solvate of formula (I) compound or its pharmacy acceptable salt or solvate or this type of salt can with factor VIIa inhibitors or its pharmaceutically acceptable derivates Combined Preparation.

Cyclooxygenase inhibitors (that is, COX-1 and/or cox 2 inhibitor) is general as acetylsalicylic acid, indomethacin, Ibuprofen BP/EP, piroxicam, naphthalene

Happy luxuriant growth of former times

And NSAID; Diuretic(s) such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, Hydrex, methyl chlorothiazide, trichlormethiazide, many thiazines, benzthiazide, Ethacrynic Acid tricrynafen, chlorthalidone, Furosemide, musolimine, bumetanide, triamterene, guanamprazine and spironolactone; Hypotensive agent such as alpha-adrenergic blocking agent, beta-adrenergic blocking agent, calcium channel blocker, diuretic(s), renin inhibitor, ACE inhibitor is (as captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, Ramipril, lisinopril), A II antagonist (losartan for example, irbesartan, valsartan), ET antagonist (sitaxentan for example, atrsentan and U.S. Patent number 5,612,359 and 6,043265 disclosed compounds), dual ET/AII antagonist (for example disclosed compound of WO00/01389), neutral endopeptidase (NEP) inhibitor, vasopeptidase inhibitors (dual NEP-ACE inhibitor) (drawing and gemopatrilat) as handkerchief song difficult to understand, the combination of nitrate and this class antihypertensive drug; The HMG-CoA reductase inhibitor, (but also be called as Pravastatin, lovastatin, atorvastatin, Simvastatin, NK-104 (be called itavastatin not only or the Buddhist nun cuts down Ta Ting or nisbastatin) and ZD-4522, superstatin or atavastatin or visastatin), other decreasing cholesterol/fat medicine as, the LDL medicine falls, as, the combination of combination, Simvastatin and the ezetimide of torcetrapid (Pfizer), exetimibe, atorvastatin and torcetrapid, inhibitor for squalene synthetic enzyme, the special class of shellfish and bile acid chelating agent (for example QUESTRAN).

Among the present invention on the other hand, the solvate of formula (I) compound or its pharmacy acceptable salt or solvate or this type of salt can with anti-obesity compound or its pharmaceutically acceptable derivates Combined Preparation, described anti-obesity compound is pancreatic lipase inhibitor for example, as orlistat (EP129,748), ATL-962, GT-389255 or appetite (satiety) controlled substance, for example sibutramine (

GB 2,184,122 and US 4,929,629), PYY 3-36 (amylin), APD-356,1426, Axokine, T-71, cannaboid 1 (CB1) antagonist or inverse agonist, or their pharmacy acceptable salt, solvate, the solvate of this type of salt, or its prodrug, rimonabant (EP656354) for example, AVE-1625, CP945598, SR-147778, SLV-319, with described as WO01/70700, or synthetic (FAS) inhibitor of lipid acid or its pharmacy acceptable salt, solvate, the solvate of this type of salt, or its prodrug or melanin concentration hormone (MCH) antagonist, or its pharmacy acceptable salt, solvate, the solvate of this type of salt or, its prodrug, for example 856464 and as described in the WO04/004726, antidiabetic drug is as biguanides (as N1,N1-Dimethylbiguanide), alpha-glucosidase inhibitors (as acarbose), Regular Insulin, MAG's row naphthalene class (for example Rui Gelie naphthalene), sulfonylurea is (as glimepiride, Glyburide and Glipizide), biguanides/Glyburide composition (being glucovance), thiazolidinediones is (as troglitazone, rosiglitazone and pioglitazone), the PPAR-gamma agonist, aP2 inhibitor and DP4 inhibitor, Tiroidina simulant (mimetics) (comprising the thryoid receptor antagonist) (thyrotropin for example, many Tiroidina (polythyroid), KB-130015 and Dronedarone).

The compounds of this invention can also be used or co-administered with pacemaker or defibrillation equipment with independent activeconstituents.

Among the present invention on the other hand, the solvate of formula (I) compound or its pharmacy acceptable salt or solvate or this type of salt can be selected from following anticoagulant Combined Preparation: argatroban, Bivalirudin, dalteparin sodium, desirudin, temparin, Lyapolate Sodium, nafamostat mesilate, phenprocoumon, Tinzaparin sodium and Warnerin or its pharmaceutically acceptable derivates.

The present invention provides a kind of combined prod on the other hand, and it comprises:

(A) The compounds of this invention as hereinbefore defined or pharmaceutically acceptable derivates and

(B) anti-coagulant,

Wherein component (A) and (B) in each and pharmaceutically acceptable adjuvant, diluent or carrier compounding close.Component (B) can also be any therapeutical agent noted earlier.

This type of composition product provides the Combined Preparation of The compounds of this invention and other treatment agent, therefore preparation that can be independent exists, at least a The compounds of this invention that comprises in those preparations wherein, and at least aly comprise other therapeutical agent or can be used as (promptly being mixed with) combined preparation (that is, existing) with the unitary agent that comprises The compounds of this invention and other therapeutical agent.

This sample is sent out further and is provided:

(1) pharmaceutical preparation, its comprise with pharmaceutically acceptable adjuvant, diluent or carrier blended as with above defined The compounds of this invention or its pharmaceutically acceptable derivates;

(2) kit, it comprises following component:

(a) pharmaceutical preparation, its comprise with pharmaceutically acceptable adjuvant, diluent or carrier blended as with above defined The compounds of this invention or its pharmaceutically acceptable derivates; With

(b) pharmaceutical preparation, it comprises anti-coagulant and pharmaceutically acceptable adjuvant, diluent or carrier,

Component (a) and (b) provide with the co-administered form of other medicaments being suitable for separately wherein.

When this paper uses, term " anti-coagulant " comprises and is selected from following material: acetylsalicylic acid, warfarin, enoxaparin, heparin, low molecular weight heparin, Cilostazole, clopidogrel, ticlopidine, Tirofiban, ReoPro, Dipyridamole, the plasma proteins fraction, human albumin, the lower molecular weight dextran, hydroxyethylamyle, reteplase, alteplase, streptokinase, urokinase, reach heparin, filgrastin (filgrastin), immunoglobulin (Ig), Ginkgolide B, r-hirudin, Foropafant, traxaprone, than cutting down Lu Ding, dermatan sulfate mediolanum, eptilibatide, Tirofiban, thrombomodulin, ReoPro, lower molecular weight dermatan sulfate-opocrin, Eptacog alfa, argatroban, fondaparinux sodium, tifacogin, Lepirudin, desirudin, OP2000, roxifiban, Parnaparin Sodium, people's hemochrome (Hemosol), ox blood pigment (Biopure), people's hemochrome (Northfield), anticoagulant enzyme III, RSR 13, heparin-oral (Emisphere) transgenosis anticoagulant enzyme III, H37695, Enoxaparin Sodium, mesoglycan, CTC 111, Bivalirudin and their any derivative and/or combination.

The special anti-coagulant that can mention comprises acetylsalicylic acid and warfarin.

Term " anticoagulant " also comprises thrombin inhibitors.The thrombin inhibitors that can mention comprises low molecular weight thrombin inhibitor.Term " low molecular weight thrombin inhibitor " is understood by those skilled in the art, but and comprise any inhibition hemocoagulase to the experiment detection level (by in the body and/or experiment in vitro determine), and it has and is lower than approximately 2000, preferably is lower than the composition of the material (for example compound) of about 1000 molecular weight.

Preferred low molecular weight thrombin inhibitor comprise based on low molecular weight peptide, based on amino acid whose and/or based on thrombin inhibitors and its derivative of peptide analogs.

Term " based on low molecular weight peptide; based on amino acid whose and/or based on the thrombin inhibitors of peptide analogs " fully understood by those skilled in the art, comprise the low molecular weight thrombin inhibitor that has 1-4 peptide bond, and comprise that Claesson is at Blood Coagul.Fibrin.5, described in 411 (1994) summaries those, and U.S. Patent number 4,346,078, International Patent Application WO 93/11152, WO 93/18060, WO 93/05069, WO 94/20467, WO 94/29336, WO 95/35309, WO 95/23609, WO 96/03374, WO 96/06832, WO 96/06849, WO 96/25426, WO 96/32110, WO 97/01338, WO 97/02284, WO 97/15190, WO 97/30708, WO 97/40024, WO 97/46577, WO 98/06740, WO 97/49404, WO 97/11693, WO 97/24135, WO 97/47299, WO 98/01422, WO 98/57932, WO 99/29664, WO 98/06741, WO 99/37668, WO 99/37611, WO 98/37075, WO 99/00371, WO 99/28297, WO 99/29670, WO 99/40072, WO 99/54313, WO 96/31504, WO 00/01704 and WO 00/08014; With european patent application 648780,468231,559046,641779,185390,526877,542525,195212,362002,364344,530167,293881,686642,669317,601459 and 623596 disclosed those.The disclosure of all these documents is incorporated this paper by reference into.

Among the application, the derivative of thrombin inhibitors comprises any pharmacy acceptable salt of chemical modification thing (if any ester, prodrug and the metabolite of activity or non-activity) and these compounds and the solvate of solvate (as hydrate) and any this type of salt.

Preferably the thrombin inhibitors based on low molecular weight peptide comprises those that are generically and collectively referred to as " adding group (gatrans) ".The group that specifically adds that can mention comprises HOOC-CH ₂-(R) Cha-Pic-Nag-H (being called Inogatran) and HOOC-CH ₂-(R) Cgl-Aze-Pab-H (being called Melagatran) (respectively referring to International Patent Application WO 93/11152 and WO94/29336, and wherein acronym lists).

International Patent Application WO 97/23499 discloses many compounds of having found the useful as thrombin inhibitor prodrugs, and described prodrug has general formula

R ^aOOCH-CH ₂-(R)Cgl-Aze-Pab-R ^b

R wherein ^aExpression H, benzyl or C _1-10Alkyl, R ^b(hydrogen atom in the amidino groups unit of its displacement Pab-H) expression OH, OC (O) R ^cOr OC (O) R ^d, R ^cExpression C _1-17Alkyl, phenyl or 2-naphthyl, and R ^dExpression C _1-12Alkyl, phenyl, C _1-3Alkyl phenyl or 2-naphthyl.Preferred compound comprises R ^aOOCH-CH ₂-(R) Cgl-Aze-Pab-OH, wherein, R ^aExpression benzyl or C _1-10Alkyl, as ethyl or sec.-propyl, be in particular EtOOCH-CH ₂-(R) Cgl-Aze-Pab-OH.Active blood coagulation is coagulated enzyme inhibitors itself and is disclosed among the WO94/29336.

Other low molecular weight thrombin inhibitor that can mention comprise among the WO02/44145 disclosed those, as compound or its pharmaceutically acceptable derivates of following general formula:

Wherein,

R ^cExpression-OH or-CH ₂OH;

R ¹Represent the halogenic substituent that at least one is optional;

R ²Represent one or two C _1-3Alkoxy substituent, it (is R that described substituent moieties itself is replaced by one or more fluoro substituents ²Represent one or two fluoroalkyl (C _1-3) group);

Y represents-CH ₂-or-(CH ₂) ₂-; With

R ³Expression I (i) or I structure fragment (ii):

R wherein ⁴Expression H or one or more fluoro substituents;

R ⁵Expression H, OR ⁶Or C (O) OR ⁷

R ⁶Expression H, C _1-10Alkyl, C _1-3Alkylaryl or C _1-3(moieties of the two kinds of groups in back is randomly interrupted by one or more Sauerstoffatoms alkoxy aryl, the aryl moiety of next two kinds of groups is randomly replaced by one or more substituting groups that are selected from halogen, phenyl, methyl or methoxy, and wherein the three kinds of groups in back are also randomly replaced by one or more halogenic substituent);

R ⁷Expression C _1-10Alkyl (wherein the two kinds of groups in back are randomly interrupted by one or more Sauerstoffatoms) or C _1-3Alkylaryl or C _1-3(moieties of the two kinds of groups in back is randomly interrupted by one or more Sauerstoffatoms alkoxy aryl, the aryl moiety of next two kinds of groups is randomly replaced by one or more substituting groups that are selected from halogen, phenyl, methyl or methoxy, and wherein the three kinds of groups in back are also randomly replaced by one or more halogenic substituent); With

X ₁, X ₂, X ₃, X ₄In one or two expression-N-, other expression-CH-.

Find wherein R ⁵For the above-mentioned general formula compound of H can (wherein thrombin inhibitors comprises accordingly wherein R as the prodrug of thrombin inhibitors ⁵Above-mentioned general formula compound for H).

Disclosed specilization compound comprises those compounds of following general formula among the WO02/44145 that can mention:

Wherein

R ²Expression-OCHF ₂,-OCF ₃,-OCH ₂CH ₂F or-OCH ₂CHF ₂

R ⁵Expression H or OR ⁶And

R ⁶Expression methyl, ethyl, n-propyl, sec.-propyl or cyclobutyl.

In this respect, disclosed specilization compound comprises following thrombin inhibitors among the WO02/44145 that can mention

Ph(3-Cl)(5-OCHF ₂)-(R)CH(OH)C(O)-Aze-Pab；

With its methoxyl group amidino groups prodrug

Ph(3-Cl)(5-OCHF ₂)-(R)CH(OH)C(O)-Aze-Pab(OMe)。

The compounds of this invention has the ARR advantage of effective opposing.

Compare with the compound of prior art, The compounds of this invention improve to be renderd a service, is being improved selectivity and/or reduce and have advantage aspect total removing especially.These advantages can provide corresponding useful properties in practice.For example, can be used as pharmaceutical preparation, The compounds of this invention can have lower clinical dosage every day, longer action period and/or the side effect situation of improvement.

Compare with the prior art compound known, The compounds of this invention also have more effective, lower toxicity, more wide spectrum activity, higher usefulness, longer effect, side effect still less (comprising lower generation irregular pulse such as ventricular arrhythmia), be easier to absorb or have the advantage of other useful pharmacological property.

Biological experiment

Test A

Rb ⁺The outflow test

This test uses flame atomic absorption spectrometry to pass through Rb ⁺Ion outflows and identifies the compound of the people Kv1.5 passage potassium channel of heterogenous expression in retardance Chinese hamster ovary (CHO) cell.For experimental study, the Chinese hamster ovary celI of the cDNA stable transfection that people Kv1.5 uses is grown in Falcon converges layer, described Falcon is the tissue culture treated plate of the black wall clear bottom in 384 holes, described plate is 37 ℃ of overnight incubation in the cell cultures couveuse.

After the overnight incubation, the washed cell plate also will contain Rb ⁺The ionic damping fluid is added on the cell plate.Then with described plate at CO ₂Hatched in (37 ℃) other 3-4 hour in the couveuse.Wash plate after this incubation period adds compound, adds the K that contains rising then ⁺The damping fluid of concentration is so that activate the Kv1.5 passage.After the hatching of short period of time, the aliquots containig of supernatant liquor is transferred in the supernatant liquor plate, for carry out subsequently with atomic absorption spectrum (ICR8000, Aurora Biomed company) to Rb ⁺Concentration determination.With basic Rb ⁺Outflow (only accepting the concentration mg/L in the hole of lavation buffer solution) is defined as 100% and suppresses, with the Rb that stimulates ⁺Outflow (only accepts to contain the K of rising ⁺Concentration mg/L in the hole of the lavation buffer solution of concentration) being defined as 0% suppresses.

Test B

Electrophysiology by the potassium current in the cell of stably express people Kv1.5 potassium channel writes down and confirms activity, and the functional measure renderd a service of the compound that provides specificity to influence the Kv1.5 passage.Use the test of high-throughput planar diaphragm pincers (people such as Schroeder, J.Biomol.Screen (2003) 8 (1) 50-64; Willumsen, Am Biotech Lab (2006) 24 (4); 20-21) or the full cell structure patch clamp technique of standard (people such as Hamill, Pflugers Archiv (1981) 391:85) carry out electrophysiologic studies.The Chinese hamster ovary celI of the cDNA stable transfection that will use through people Kv1.5 is exposed in the medicine then, and activates the Kv1.5 passage.

41.7N-the testing program of benzyl-2-(1-methyl isophthalic acid-styroyl)-3-oxo isoindole quinoline-1-methane amide by revising according to people's such as Pelsson method (Cardiavasc Pharmacol (2005) 46:7-17).Carry out the off-line data analysis, use before the administration and the paired comparisons after the administration to measure the inhibition effect of every kind of compound.

In test A and test B, the title compound of above embodiment is tested.When testing in test A, most compounds of the present invention have activity, find that the overwhelming majority in them shows IC ₅₀＜30 μ M, preferred IC ₅₀＜10 μ M, or under the concentration of 30 μ M, inhibiting rate＞20%, or active IC ₅₀＜10 μ M.

In test A:

The compounds of this invention	IC50 tests A	Embodiment
The compounds of this invention	IC50 tests A	Embodiment	N-benzyl-2-(1-methyl isophthalic acid-phenylethyl)-3-oxo isoindole quinoline-1-methane amide	1.7
N-benzyl-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide	0.4			1.7
	0.4		N-[3-(difluoro-methoxy) benzyl]-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide	2.4
N, 2-dibenzyl-6-bromo-3-oxo isoindole quinoline-1-methane amide	0.84			2.4
	0.84		(1R or 1S)-N-benzyl-3-oxo-2-[(1S or 1R)-and the 1-phenylethyl] isoindoline-1-methane amide (E4)	1.5	25
6-bromo-2-(2-cyclopentyl benzyl)-N-methyl-3-oxo isoindole quinoline-1-methane amide	2.7			1.5	25
	2.7		6-chloro-2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide	1.3
N-benzyl-6-chloro-3-oxo-2-[(1S)-the 1-phenylethyl] isoindoline-1-methane amide	2.2			1.3
	2.2		N-benzyl-5-bromo-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide	2.1
N-benzyl-6-bromo-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide	0.21			2.1
	0.21		N-[3-(difluoro-methoxy) benzyl]-6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide	1.4
N-(3-benzyl chloride base)-6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide	0.34			1.4
	0.34		6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide	1.7

6-chloro-N-[3-(difluoro-methoxy) benzyl]-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide	0.41
	0.41		6-chloro-N-(3-benzyl chloride base)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide	2.1
N-(tertiary butyl)-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide	1.9			2.1
	1.9		N-(tertiary butyl)-6-chloro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide	1.1
6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl)-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide	2.5			1.1
	2.5		6-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl]-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide	2
2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-cyano group-3-oxo isoindole quinoline-1-methane amide	2.4	36		2
	2.4	36	The 2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide	2.1
2-(biphenyl-2-ylmethyl)-6-chloro-N-ethyl-3-oxo isoindole quinoline-1-methane amide	1			2.1
	1		2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-propyl group isoindoline-1-methane amide	1.1
2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide	2.8			1.1
	2.8		6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide	0.68
6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide	0.42			0.68
	0.42		2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide	1.5
2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide	0.78			1.5
	0.78		2-(biphenyl-2-ylmethyl)-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide	0.94
N-benzyl-6-chloro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide	0.55	9		0.94
	0.55	9	N-benzyl-6-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline	1.3

-1-methane amide
-1-methane amide			N-benzyl-6-fluoro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide	1.4
2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide	2.3			1.4
	2.3		2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-propyl group isoindoline-1-methane amide	1.3
2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide	1.8			1.3
	1.8		2-(biphenyl-2-ylmethyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide	1.5
N-(tertiary butyl)-2-[(1-methyl-5-phenyl-1H-pyrazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide	2.5	28		1.5
	2.5	28	2-(biphenyl-2-ylmethyl)-6-bromo-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide	2.4	29
N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide	2			2.4	29
	2		N-(tertiary butyl)-2-[(3 ', 4 '-DCBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide	0.72
N-[3-(difluoro-methoxy) benzyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide	1.8			0.72
	1.8		N-[3-(difluoro-methoxy) benzyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide	1.3
N-(tertiary butyl)-6-chloro-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide	2.8			1.3
	2.8		2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide	0.61
N-benzyl-2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo isoindole quinoline-1-methane amide	0.42			0.61
	0.42		2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-chloro-3-oxo isoindole quinoline-1-methane amide	1.6
6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide	0.46			1.6
	0.46		6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide	2.8

N-(tertiary butyl)-6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide	0.91
	0.91		N-benzyl-6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide	0.15
N-(4,4-difluoro butyl)-2-(diphenyl-methyl)-3-oxo isoindole quinoline-1-methane amide	8	22		0.15
	8	22	2-[2-(4-chloro-phenyl-) propyl group]-N-[(2,2-two fluoro-1,3-benzo dioxole-5-yl) methyl]-3-oxo isoindole quinoline-1-methane amide	0.58
N-(3, the 4-dichloro benzyl)-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide	2.5			0.58
	2.5		(R or S) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (E1)	1.1	3
(S or R) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (E2)	17	3		1.1	3
	17	3	2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide	2.7	19
2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-fluoro-3-oxo isoindole quinoline-1-methane amide	6.7			2.7	19
	6.7		N-benzyl-2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo isoindole quinoline-1-methane amide	1
2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-(fluorine methoxyl group)-4-methyl-3-oxo isoindole quinoline-1-methane amide	1.7	14		1
	1.7	14	2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-methoxyl group-4-methyl-3-oxo isoindole quinoline-1-methane amide	2.2
N-(3-benzyl chloride base)-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide	2.9			2.2
	2.9		N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-N-ethyl-3-oxo isoindole quinoline-1-methane amide	0.93
N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo isoindole quinoline-1-methane amide	0.89			0.93
	0.89		N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo-2-{2-[4-(trifluoromethyl) phenoxy group] benzyl } isoindoline-1-methane amide	2
N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-formyl	0.56			2
	0.56		2-(diphenyl methyl)-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-	2.5

Methane amide
Methane amide			N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide	0.71
N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide	0.74			0.71
	0.74		N-benzyl-N-butyl-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide	0.34
N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide	2.2	46		0.34
	2.2	46	N-(tertiary butyl)-2-[(4 '-fluorine biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide	7.3
2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide	0.62			7.3
	0.62		2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-7-hydroxyl-3-oxo isoindole quinoline-1-methane amide	3	42
2-(biphenyl-2-ylmethyl)-N-(4-{[(difluoro ethanoyl)-amino] methyl } benzyl)-3-oxo isoindole quinoline-1-methane amide	2.4	17		3	42
	2.4	17	2-(3-benzyl chloride base)-N-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide	2
2-[2-(4-chloro-phenyl-) propyl group]-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide	1.2			2
	1.2		2-(biphenyl-2-ylmethyl)-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide	2.8	7
N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-(fluorine methoxyl group)-4-methyl-3-oxo isoindole quinoline-1-methane amide	3			2.8	7
	3		2-[3, two (trifluoromethyl) benzyls of 5-]-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide	1.8
2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide	1.8			1.8
	1.8		N-(1,3-benzo dioxole-5-ylmethyl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide	0.62
(1S or 1R)-N-butyl-2-[(2R or 2S)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E2)	0.73	13		0.62
	0.73	13	(1R or 1S)-N-butyl-2-[(2S or 2R)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E4)	1.7	13

(1R or 1S)-N-butyl-2-[(2R or 2S)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E3)	0.5	13
	0.5	13	(1S or 1R)-N-butyl-2-[(2S or 2R)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E1)	15	13
N-benzyl-3-oxo-2-[(3-phenyl-isoxazole azoles-5-yl) methyl] isoindoline-1-methane amide	1			15	13
	1		N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide	1.3	12
N-(tertiary butyl)-5,6-two chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide	1.8			1.3	12
	1.8		2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide	0.7
N-(2-benzyl chloride base)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide	0.75			0.7
	0.75		(R or S) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide	3.4	34
2-[2-(4-chloro-phenyl-) propyl group]-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide	1.9			3.4	34
	1.9		N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-4,5-dimethoxy-3-oxo isoindole quinoline-1-methane amide	0.61
N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide	0.51			0.61
	0.51		N-benzyl-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide	6	24
N-benzyl-2-(2-bromobenzyl)-3-oxo isoindole quinoline-1-methane amide	2.5			6	24
	2.5		2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide	3.3	33
N-benzyl-2-(2-hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide	1.8			3.3	33
	1.8		N-benzyl-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide	1
N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide	0.73			1
	0.73		N-butyl-2-[2-(4-chloro-phenyl-)-2-methyl-propyl]-3-oxo isoindole quinoline-1-methane amide	0.53	49
N-(tertiary butyl)-2-[(4 ', 5 DfBPs-2-yl) methyl]-the 3-oxo	9.3			0.53	49

Isoindoline-1-methane amide
Isoindoline-1-methane amide			N-(tertiary butyl)-2-[(5-fluorine biphenyl-2-yl)-methyl]-3-oxo isoindole quinoline-1-methane amide	13
N-(tertiary butyl)-2-[(4,4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide	5.6	48		13
	5.6	48	N-(tertiary butyl)-2-[(4-fluorine biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide	5.2
(1R or 1S)-N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide	13	47		5.2
	13	47	(1S or 1R)-N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide	5.5	47

The present invention will be described by following examples.

Embodiment

Use is named compound in the present patent application from the program (9.0 editions, Batch by name or labs) of ACD Labs.

Embodiment

Abbreviation

AIBN:2,2 '-azo two (2-methyl propionitrile);

C: degree centigrade;

BOC-acid anhydride: tert-Butyl dicarbonate;

Dai Si-Martin's reagent: 1,1,1-triacetyl Oxy-1,1-dihydro-1,2-benzenesulfonyl-3 (1H)-ketone;

DCM: methylene dichloride;

DMF:N, N '-dimethyl formamide;

DME: glycol dimethyl ether;

DMAP: dimethyl aminopyridine;

DMSO: dimethyl sulfoxide (DMSO);

ES: electron spray(ES);

ESI: electro-spray ionization;

EtOAc: ethyl acetate;

EtOH: ethanol;

DME: glycol dimethyl ether;

HPLC: high performance liquid chromatography;

HRMS: high resolution mass spec;

LAH: lithium aluminum hydride;

MeCN: acetonitrile;

MeOH: methyl alcohol;

MTBE: methyl tertiary butyl ether;

K ₂CO ₃: salt of wormwood;

MS: mass spectrum;

NMR: nucleus magnetic resonance;

TEA: triethylamine;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran (THF);

UV: ultraviolet;

Atm: atmosphere (pressure);

Rt: room temperature;

H: hour;

Mins: minute;

Br: broad peak;

Brs: wide unimodal;

S: unimodal;

D: bimodal;

T: triplet;

Q: quartet;

M: multiplet;

sep： septett；

Dd: doublet of doublet;

Dm: dual multimodal;

Td: triple bimodal;

General experimental arrangement

Except as otherwise noted, (0.040-0.063mm is Merck) or from Biotage to use purification on normal-phase silica gel 60 ^TMSP1 ^TMPurification system (uses silicon-dioxide FLASH+ ^TMTubing string) carries out flash column chromatography.

At BRUKER ACP 300 or Varian Unity Plus400, on 500 or 600 spectrographs, respectively 300,400,500,600MHz ¹Under the H frequency and 75,100,125,150MHz ¹³Operation is carried out under the C frequency ¹H NMR and ¹³C NMR measures.Perhaps, can on the BRUKERACE200 spectrograph, carry out at the frequency place in 50.3MHz ¹³C NMR measures.

Can or can in spectrum, not represent rotational isomer, this depends on the easness of spectrum resolution.

Except as otherwise noted, solvent is as interior mark, and (ppm) provides chemical shift with the δ value.

* solution is taken from and is dissolved in (CH ₃) ₂Concentrating sample among the SO, and with (CD ₃) ₂The SO dilution.Because a large amount of (CH ₃) ₂SO is present in sample, at first carries out prescan, and analyzes and suppress (CH automatically ₃) ₂SO (2.54ppm) and H ₂The peak of O (3.3ppm).This means that the peak intensity that is present in these 3.3ppm and 2.54ppm peripheral region is lowered in this so-called wet 1D test.See impurity in this external spectrum, triplet appears in described spectrum at the 1.12ppm place, it is unimodal to occur at 2.96 places, occur two multiplets between 2.76-2.70 and 2.61-2.55.These impurity most probables are dimethyl sulfone and diethyl sulfoxide.

In Smith Creator or Emrys Optimizer (available from Personal Chemistry, Uppasla, Sweden), adopt the mode of single node heating to carry out microwave heating.

Use ZQ (available from four utmost point devices of Waters) to obtain mass spectrum (MS) data, in the time of suitably, collect positively charged ion data or negatively charged ion data.

Use TOF-MS LCT, Q-TOF micro or the LCTP system on (from Waters) obtain accurate mass spectrum (HRMS) data.

Injection filter is from Adantec MFS company.Used aperture is 0.5 μ m.Used cationic exchange coloum from

Synthesizing of intermediate

Preparation A

2-(4-fluoro-phenyl)-propylamine

(i) 1-fluoro-4-pseudoallyl-benzene

Under ice-cooled condition, (52.9g, (190g is in THF 0.47mol) (400ml) suspension 0.47mol) to join methyl triphenyl phosphonium iodide with potassium tert.-butoxide.After stirring 1 hour under the ice-cooled condition, drip THF (100ml) solution of 4-fluoro acetophenone (30g 0.199mol).Stirred reaction mixture is two hours under room temperature, and uses the saturated ammonium chloride solution quencher.Under reduced pressure remove THF, and sherwood oil (petether) extraction, water, salt water washing, and use anhydrous sodium sulfate drying, obtain the inferior title compound (30g, 100%) of light yellow liquid shape by inspissated oil ether layer.

(ii) 2-(4-fluoro-phenyl)-propylamine

At 0 ℃, with the borine among the THF (96ml, 0.096mol, 1M solution) be added drop-wise to 1-fluoro-4-pseudoallyl-benzene from above-mentioned steps (i) (30g, in THF 0.24mol) (350ml) solution, with reaction mixture stirring at room 3 hours.Reaction mixture to 0 ℃, add in batches hydroxylamine-o-sulfonic acid (27.72g, 0.24mol).Reaction mixture refluxed is spent the night.Water quencher reaction mixture and concentrated carries out acidifying with 1.5N hydrochloric acid then.The reaction mixture ethyl acetate extraction, water layer neutralizes with 10% sodium hydroxide solution, uses dichloromethane extraction.Dichloromethane layer water, salt water washing and evaporation.Obtain title compound (8.5g, 23%).

Preparation B

[2-(4-chloro-phenyl-) propyl group] amine

(i) 1-chloro-4-isopropenylbenzene

Under ice-cooled condition, (72.4g, (261g is in THF 0.646mol) (500ml) suspension 0.646mol) to join methyl triphenyl phosphonium iodide with potassium tert.-butoxide.After stirring 1 hour under the ice-cooled condition, drip THF (100ml) solution of 4-chloro-acetophenone (50g 0.323mol).Stirred reaction mixture is 1 hour under room temperature, and reaction mixture is with the sherwood oil dilution and filter concentrated filtrate.By column chromatography (petroleum ether solution that uses 6% ethyl acetate is as eluent) purifying crude product, obtain the inferior title compound of light yellow liquid shape, output (42g, 86%).

(ii) [2-(4-chloro-phenyl-) propyl group] amine

At 0 ℃, the THF solution (124ml, 1M solution) of borine is added drop-wise to 1-chloro-4-isopropenylbenzene from above-mentioned steps (i), and (41.5g is in THF 0.272mol) (500ml) solution, stirring at room reaction mixture 3 hours.Reaction mixture is cooled to 0 ℃, add in batches hydroxylamine-o-sulfonic acid (30.76g, 0.272mol).Reaction mixture refluxed is spent the night.The quencher of reaction mixture water is also used ethyl acetate extraction, and ethyl acetate layer water, salt water washing are dry in anhydrous sodium sulphate, and concentrate.Enriched material is dissolved in the anhydrous diethyl ether (20ml), stirred 0.5 hour with saturated hydrochloric acid in the diethyl ether.Solids removed by filtration salt with the sodium hydrogen carbonate solution neutralization, extracts unhindered amina with diethyl ether.The salt water washing of diethyl ether layer, through anhydrous sodium sulfate drying, and the concentrated title compound (18g, 39%) that obtains.

Preparation C

1-(4 '-fluorine biphenyl-2-yl) methylamine

(i) N-[[2-(4-fluorophenyl) phenyl] methyl] t-butyl carbamate

In the bottle that is suitable in microwave oven, using, with N-(tertbutyloxycarbonyl)-2-bretylium (1.74mmol, 0.5g) and tetrakis triphenylphosphine palladium (0.087mmol, 0.101g) (2.096mmol 0.293g) is dissolved among the DME (10ml) with the 4-fluorobenzoic boric acid.(3.49mmol 1.14g) is dissolved in the 2ml water, joins in the mixture then with cesium carbonate.Make the argon gas bubbling pass through mixture 5 minutes.(10min, 130 ℃) react in microwave oven.(0.5g 1.65mmol) is used for next step to inferior title compound crude product without being further purified.

(ii) [2-(4-fluorophenyl) phenyl] methylamine

Will be from N-[[2-(4-fluorophenyl) phenyl of step (i)] methyl] (1.6591mmol 0.5g) is dissolved in the saturated ethyl acetate of hydrochloric acid t-butyl carbamate, and stirring at room 2 hours.Evaporation removes and desolvates, and (begin with equivalent heptane/DCM 50/50, the concentration with DCM is elevated to 100% then, uses 10%MeOH (to use NH afterwards by the purification by flash chromatography hydrochloride ₃Saturated) eluted product, (silica gel 600.004-0.063mm).Merge the fraction that contains product, evaporation removes and desolvates, and obtains the title compound of 320mg (1.59mmol).

Preparation D

Prepare following amine according to above-mentioned preparation C

1-(4 '-methyl diphenyl-2-yl) methylamine;

1-(4 '-methoxyl biphenyl-2-yl) methylamine;

1-(4 '-fluoro-2 '-methyl diphenyl-2-yl) methylamine.

Preparation E

(2-cyclopentyl benzyl) amine hydrochlorate

(i) three second acetic acid 2-cyclopentyl phenylesters

To 2-cyclopentyl phenol (10g, add in anhydrous DCM (150ml) solution 0.09mmol) pyridine (8ml 0.14mol), and is cooled to 0 ℃, drip then trifluoroacetic anhydride (15.6ml, 0.14mol).Spend the night in the stirring at room reaction mixture.The quencher of reaction mixture water is with DCM (200ml) extraction.Organic layer water (2x 50ml) and salt brine solution (1x 50ml) washing concentrate step 1 product (18g, 99.4%) that obtains the brown liquid shape.Crude product is directly used in next step.

(ii) 2-cyclopentyl cyanobenzene

(18g successively adds Zn (CN) in dry DMF 0.06mol) (150ml) solution to three second acetic acid 2-cyclopentyl phenylesters ₂(7.2g, 0.06moD and Pd (PPh ₃) ₄(5.6g 0.005mol), under nitrogen atmosphere, spends the night in 130 ℃ of backflows.With the reaction mixture cool to room temperature, water (200ml) quencher is also used EtOAc (200ml) dilution, filters then.Filtrate water (3x 50ml) and salt brine solution (1x 50ml) thorough washing.Concentrate organic layer,, obtain the product (10.4g, 99.3%) of the step 2 of light yellow solid shape by silica gel column chromatography (using the petroleum ether solution of 5%EtOAc) purifying crude product.

(iii) (2-cyclopentyl benzyl) amine

At 0 ℃, to lithium aluminum hydride (5.7g, drip in anhydrous THF (50ml) suspension 0.15mol) the 2-cyclopentyl cyanobenzene be dissolved among the anhydrous THF (100ml) (10.4g, 0.06mol).Spend the night in the stirring at room reaction solution.Reactant is cooled to 0 ℃ also with 6M KOH quencher, dilutes with THF.Pass through diatomite filtration, concentrated filtrate then.In diethyl ether (100ml) solution of crude product, add saturated hydrochloric acidic diethyl ether (50ml) solution, stir 10min.Filter then, the throw out petroleum ether obtains the title compound (10.3g, 98.1%) of white solid.

Preparation F

(2-cyclohexyl benzyl) amine hydrochlorate

(i) 2-phenylcyclohexane formonitrile HCN

(12g successively adds Zn (CN) in dry DMF 0.05mol) (100ml) solution to the cyclohexyl bromobenzene ₂(5.9g, 0.05mol) and Pd (PPh ₃) ₄(5.8g 0.005mol), spends the night 130 ℃ of backflows.With the reactant cool to room temperature, water (200ml) quencher is also used EtOAc (200ml) dilution, filters then.Filtrate water (3x 50ml) and salt brine solution (1x 50ml) thorough washing.Concentrate organic layer, obtain the product (10g) of the step 1 of yellow viscous liquid shape.Described crude product is used for next step.

(ii) (2-cyclohexyl benzyl) amine

At 0 ℃, to lithium aluminum hydride (5.1g, drip in anhydrous THF (60ml) suspension 0.13mol) the 2-phenylcyclohexane formonitrile HCN be dissolved among the anhydrous THF (140ml) from above-mentioned steps (i) (10g, 0.054mmol).After the stirring at room reaction mixture spends the night, it is cooled to 0 ℃ also with 6M KOH quencher.Further dilute with THF, pass through diatomite filtration then.Vacuum concentrated filtrate.In diethyl ether (100ml) solution of crude product, add the saturated hydrochloric acid in the diethyl ether (20ml), stir 10min.Filter then, the throw out petroleum ether obtains the title compound (8g, 78.4%) of white solid.

Preparation G

4-(fluorine butyl) amine hydrochlorate

(i) (the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } butyl) amine

At 0 ℃, (20g adds triethylamine in methylene dichloride 0.224mol) (200ml) solution to the 4-amino butanol.Under identical temperature, add TERT-BUTYL DIMETHYL CHLORO SILANE (33.8g, 0.224mol), in stirring at room 4 hours.The reaction mixture dilute with water.Organic layer water, salt water washing are through anhydrous sodium sulfate drying and concentrated.Crude product (42g, 92%) is purified and be used for next step.

(ii) (the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } butyl) t-butyl carbamate

Under nitrogen atmosphere, in 0 ℃ to (the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } butyl) amine (42g, add in methylene dichloride 0.20mol) (400ml) solution triethylamine (58ml, 0.413mol), the BOC-acid anhydride (54.12g, 0.248mol).In stirring at room reaction mixture 1 hour.Reaction mixture dilutes with ice cold water.Organic layer water and salt water washing.Organic layer also concentrates with anhydrous sodium sulfate drying then.By silica gel chromatography (using the EtOAc/ sherwood oil) purifying resistates, obtain the inferior title compound (60g, 95%) of colorless oil.

(iii) (the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base } butyl) the imino-tert-Butyl dicarbonate

In anhydrous acetonitrile (600ml) solution of (the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } butyl) t-butyl carbamate (from above step (ii) (60g, 95%)), add DMAP (36.23g, 0.29mol).Adding BOC-acid anhydride (64.7g, 0.29mol).With reaction mixture in stirring at room 24 hours.And then once add DMAP (36.23g, 0.29mol) and the BOC-acid anhydride (64.7g, 0.29mol).In the stirring at room reaction mixture other 4 days.Concentrated reaction mixture by silica gel chromatography (using the EtOAc/ sherwood oil) purifying resistates, obtains the inferior title compound (62g, 77%) of colorless oil.

(iv) (3-hydroxypropyl) imino-tert-Butyl dicarbonate

Under nitrogen atmosphere, in 0 ℃ to (the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } butyl) imino-tert-Butyl dicarbonate (from (iii) (60g of step, 0.148)) anhydrous THF (600ml) solution in add tetrabutyl ammonium fluoride (150ml, 1M THF solution).Spend the night in the stirring at room reaction mixture.Reaction mixture is concentrated, enriched material is dissolved in the ethyl acetate.Ethyl acetate layer is water, 10% citric acid, 10% sodium bicarbonate and salt brine solution washing successively.Concentrated reaction mixture by silica gel chromatography (using the EtOAc/ sherwood oil) purifying resistates, obtains the inferior title compound (37g, 86%) of light yellow liquid shape.

(v) (3-fluoropropyl) imino-tert-Butyl dicarbonate

Under nitrogen atmosphere, in-40 ℃ to from (iv) (3-hydroxypropyl) imino-tert-Butyl dicarbonate (35g of step, 0.121mol) anhydrous THF (400ml) solution in add triethylamine (84.9mol, 0.60ml) and (diethylin) sulfur trifluoride (102g, 0.60mol).Reaction mixture slowly is warmed to room temperature, in stirring at room 3 days.By adding methyl alcohol quencher reaction at 0 ℃.Concentrated reaction mixture by silica gel chromatography (using the EtOAc/ sherwood oil) purifying resistates, obtains the inferior title compound (11.8g, 33%) of light yellow liquid shape.

(vi) 4-(fluorine butyl) amine hydrochlorate

((v), 11.8g adds the saturated hydrochloric acid in the ether (200ml) in anhydrous diethyl ether 0.040mol) (30ml) solution from above step to (3-fluoropropyl) imino-tert-Butyl dicarbonate at 0 ℃.With reaction mixture in stirring at room 24 hours.Concentrated reaction mixture by using acetone/diethyl ether recrystallization, obtains the title compound (4.1g, 80%) of light yellow solid shape.

Preparation H

(4,4-difluoro butyl) amine hydrochlorate

(i) (3-oxopropyl) imino-tert-Butyl dicarbonate

Under nitrogen atmosphere, (66g adds (3-hydroxypropyl) imino-tert-Butyl dicarbonate (30g, dichloromethane solution 0.103mol) in methylene dichloride 0.155mol) (300ml) solution to Dai Si-Martin's reagent in-78 ℃.Reaction mixture is warmed to room temperature, under uniform temp, stirs and spend the night.Reaction mixture passes through diatomite filtration.Concentrated filtrate stirs enriched material and diethyl ether, separates and concentrated diethyl ether layer.By column chromatography (using the EtOAc/ sherwood oil) the spissated crude product of purifying, obtain the required intermediate (23g, 77%) of light yellow liquid shape.

(ii) (4,4-difluoro butyl) imino-tert-Butyl dicarbonate

Under nitrogen atmosphere, in-40 ℃ of intermediates to step (i) (23g, add in anhydrous methylene chloride 0.080mol) (200ml) solution (diethylin) sulfur trifluoride (38.7g, 0.24mol).Make reaction mixture slowly be warmed to room temperature, stirring at room 2 hours.In the slow impouring cold water of reaction mixture.Isolating organic layer water, salt water washing also concentrate.By silica gel chromatography (using the EtOAc/ sherwood oil) purifying resistates, obtain the inferior title compound (11.12g, 45%) of light yellow liquid shape.

(iii) (4,4-difluoro butyl) amine hydrochlorate

(11.2g adds the saturated hydrochloric acid in the ether (150ml) in anhydrous diethyl ether 0.035mol) (30ml) solution to step intermediate (ii) at 0 ℃.In stirring at room reaction mixture 24 hours.Concentrated reaction mixture by using acetone/diethyl ether with the crude product recrystallization, obtains the title compound (4.5g, 86%) of light yellow solid shape.

Preparation I

(4,4-difluoro butyl) methane amide

With (4,4-difluoro butyl) amine (above-mentioned preparation H) (6g, 0.041mol) and triethylamine (14.46ml 0.103mol) refluxes in ethyl formate (150ml) and spends the night.With the reaction mixture cool to room temperature, filter.Concentrated filtrate by column chromatography (using the EtOAc/ sherwood oil) purifying crude product, obtains the title compound (4.2g, 74%) of light yellow liquid shape.

Preparation J

(4,4,4-trifluoro butyl) methane amide

(i) (4,4,4-trifluoro butyl) amine hydrochlorate

In room temperature with diazo diethyl dicarboxylate (31.1ml, 0.195mol) toluene (150ml) solution slowly add 4,4,4-three fluoro butanol (25g, 0.195ml), triphenylphosphine (51g, 0.195mol) and the iminodicarboxylic acid di tert butyl carbonate (38g is 0.175mol) in the solution in toluene (300ml).In stirring at room reaction mixture 24 hours.Under ice-cold condition, in reaction mixture, add trifluoroacetic acid (30ml), other 24 hours in stirring at room.Reaction mixture water (500ml) dilution.Isolating water layer washs with diethyl ether, makes alkalescence with the 5N sodium hydroxide solution then.Basic solution extracts with diethyl ether.Diethyl ether layer anhydrous magnesium sulfate drying.Then saturated hydrochloric acid diethyl ether solution is joined also to stir in the above-mentioned ethereal solution and spend the night.Ether is removed in decompression, and gained material and methylbenzene azeotropic obtain title compound (11.8g, 37%).

(ii) (4,4,4-trifluoro butyl) methane amide

Will (14.6ml, mixture 0.14mol) reflux 24 hours in ethyl formate (250ml) from (4,4, the 4-trifluoro butyl) amine (8.7g) of step (i) and triethylamine.With the reaction mixture cool to room temperature, filter.Concentrated filtrate, by column chromatography (using 50% ethyl acetate/petroleum ether) purifying crude product as eluent, obtain the colourless liquid shape title compound (5.5g, 67%, 3.84g).

Preparation K

(4-fluorine butyl) methane amide

With (4-fluorine butyl) amine hydrochlorate (above-mentioned preparation G) (4.12g, 0.032mol) and triethylamine (14.6ml, 0.14mol) (13.6ml refluxed 24 hours in 0.097mol) at ethyl formate.With the reaction mixture cool to room temperature, filter then.Concentrated filtrate by column chromatography (using 50% ethyl acetate/petroleum ether as eluent) purifying crude product, obtains the title compound (3.12g, 80%) of light yellow liquid shape.

Preparation L

3-isocyano-methyl-5-methyl-isoxazoles

(i) N-(5-methyl-isoxazoles-3 ylmethyl)-methane amide

In the bottle that is suitable in microwave oven, using, add N-(5-methyl-isoxazoles-3 base) methylamine (1g, 8.9mmol) and ethyl formate (17ml, solution 212mmol).Under nitrogen atmosphere in 150 ℃ of heated mixt 15min.After the irradiation, with the mixture cool to room temperature, and evaporation.Obtain the 1.378g crude product, N-(5-methyl-isoxazole-3-base methyl)-methane amide (99% yield) uses without being further purified.

[M+1](ES)141.0；

¹H NMR(500MHz，CDCl ₃)δ8.57(br s，1H)；8.12(s，1H)；6.11(s，1H)；4.29(d，2H)；2.37(s，3H)。

(ii) 3-isocyano-methyl-5-methyl-isoxazoles

(4.2g 17.7mmol) joins in acetonitrile (15ml) solution of N-(5-methyl-isoxazoles-3 ylmethyl)-methane amide (1.378g, 8.8mmol is from above step (i)) with (methoxycarbonyl sulphonamide) triethyl ammonium hydroxide (inner salt).Described mixture stirred 3 hours in 50 ℃ under nitrogen atmosphere, then cool to room temperature.

The solution of 3-isocyano-methyl-5-methyl-isoxazoles is used for preparing the compound of embodiment without being further purified.

Preparation M

(isocyano-methyl) benzene

(i) N-benzyl methane amide

(2.07mL 19mmol) is dissolved in the ethyl formate (24mL), and reaction solution was stirred 20 hours at 45 ℃ with benzene methanamine.Evaporating solvent, the described product of concentrating under reduced pressure obtains title compound (2.44g, 95.2%). ¹H-NMR(500MHz，CDCl ₃)δ8.36-8.25(s，1H)，7.5-7.2(m，5H)，6.02-5.57(s，1H)，4.56-4.46(d，2H)。

(ii) (isocyano-methyl) benzene

Will from the N-benzyl methane amide of step (i) (2.44g, 18.1mmol) and (methoxycarbonyl sulphonamide) triethyl ammonium hydroxide inner salt (burgess (Burgess) reagent) (4.31g 18.1mmol) adds in the flask, adds anhydrous MeCN (25ml).Reaction mixture was stirred 3 hours at 50 ℃.Thick title compound is used for next step without being further purified.

Preparation N

1-chloro-3-(isocyano-methyl) benzene

(i) N-(3-benzyl chloride base) methane amide

(0.283g 2.0mmol) was dissolved in the ethyl formate (8mL), 45 ℃ of stirring reaction liquid 16 hours with 1-(3-chloro-phenyl-) methylamine.Evaporating solvent with the product concentrating under reduced pressure, obtains title compound (0.350g, 103%). ¹H-NMR(500MHz，CDCl ₃)δ8.23-8.09(m，1H)，7.38-7.18(m，3H)，4.8-4.34(s，2H)。

(ii) 1-chloro-3-(isocyano-methyl) benzene

(0.128g, 0.755mmol) (0.182g 0.764mmol) adds in the flask, adds MeCN (6mL) with (methoxycarbonyl sulphonamide) triethyl ammonium hydroxide inner salt (burgess reagent) with N-(3-benzyl chloride base) methane amide.Reaction mixture was stirred 3 hours at 50 ℃.Crude product (the crude) is used for next step without being further purified.

Preparation O

4-(isocyano-methyl)-5-methyl-2-phenyl-1, the 3-oxazole

(i) N-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl] methane amide

(0.512g 2.72mmol) is dissolved in the ethyl formate (8mL), and reaction solution was stirred 22 hours at 45 ℃ with 1-(5-methyl-2-phenyl-1,3-oxazole-4-yl) methylamine.Evaporating solvent carries out concentrating under reduced pressure to product, obtains inferior title compound (0.559g, 95%). ¹H-NMR(500MHz，CDCl ₃)δ8.3-8.18(m，1H)，8.07-7.99(m，2H)，7.62-7.34(m，3H)，6.51-5.91(m，1H)，4.46-4.32(d，2H)，2.62-2.38(m，2H)；MS(ESI)m/z 217([M+H] ⁺)。

(ii) 4-(isocyano-methyl)-5-methyl-2-phenyl-1, the 3-oxazole

Will be from the N-[(5-methyl-2-phenyl-1 of above step (i), 3-oxazole-4-yl) methyl] methane amide (0.259g, 1.2mmol) and (methoxycarbonyl sulphonamide) triethyl ammonium hydroxide inner salt (burgess reagent) (0.288g, 1.21mmol) in the adding flask, adding MeCN (6mL).Reaction mixture was stirred 3 hours at 50 ℃.Crude product is used for next step without being further purified.

Preparation P

1,1-two fluoro-4-butyl isocyanides

With N-[(4,4-difluoro butyl) (0.076g, 0.554mmol) (0.132g 0.554mmol) adds in the flask methane amide (from above-mentioned preparation I), adds MeCN (2mL) with (methoxycarbonyl sulphonamide) triethyl ammonium hydroxide inner salt (burgess reagent).Reaction mixture was stirred 3 hours at 50 ℃.Crude product is used for preparing the compound of following embodiment without being further purified.

Preparation Q

[(2,2-two fluoro-1,3-benzo dioxole-5 base) methyl] amine hydrochlorate

(i) 2,2-two fluoro-1,3-benzo dioxole-5-formoxime

At room temperature, with 2,2-two fluoro-1,3-benzo dioxole-5-formaldehyde (8g, 0.0429mol) methyl alcohol (50ml) drips of solution be added to well-beaten oxammonium hydrochloride (4.18g be 0.060mol) and in methyl alcohol (100ml) solution of sodium acetate (4.9g0.060mol).With reaction mixture stirring at room 6 hours.Then reaction mixture is carried out concentrating under reduced pressure, enriched material dilute with water, dichloromethane extraction.Dichloromethane layer water, salt water washing through anhydrous sodium sulfate drying, and concentrate and to obtain thick intermediate.With the crystallization from the dichloromethane/hexane solvent of thick intermediate, obtain title compound (6.2g, 72%).

(ii) 1-(2,2-two fluoro-1,3-benzo dioxole-5 base) methylamine hydrochloride

Under nitrogen atmosphere, in 0 ℃ will be from 2 of above-mentioned steps (i), 2-two fluoro-1, (6.2g, THF 0.030mol) (25ml) solution slowly are added to LAH, and (2.9g is in THF 0.077mol) (100ml) suspension for 3-benzo dioxole-5-formoxime.Then with reaction mixture stirring at room 8 hours.Afterwards reaction mixture is cooled to 0 ℃ of KOH solution (3ml) quencher of also using 6M.Reaction mixture is through diatomite filtration, and solid residue with the ethyl acetate washing for several times.Concentrate the filtrate that merges, obtain crude product.Crude product is dissolved in the ether, and stirred 2 hours with saturated HCl in the ether (20ml).Filtering solution then, dried residue, white powder title compound (4.8g, 83.3%).

Preparation R

(2,2-two fluoro-1,3-benzo dioxole-5 base) methyl-isocyanide (methyl isocyanide)

(i) 1-(2,2-two fluoro-1,3-benzo dioxole-5 base) methylamine

(2.0g 8.94mmol) adds in the flask, adds K with 1-(2,2-two fluoro-1,3-benzo dioxole-5 base) methylamine hydrochloride ₂CO ₃(30ml) and the 2M solution of DCM (30ml).With reaction mixture stirring at room 2 hours.Separate this two-phase, water is used DCM (20ml) extraction again.Collect organic phase and use MgSO ₄Drying filters out salt.The evaporation organic phase, under reduced pressure enriched product obtains title compound (1.53g, 91.4%). ¹H-NMR(500MHz，CDCl ₃)δ7.15-6.95(m，3H)，4.07-3.78(s，2H)；MS(ESI)m/z 188([M+H] ⁺)。

(ii) N-[(2,2-two fluoro-1,3-benzene dioxole-5-yl) methyl] methane amide

1-(2,2-two fluoro-1,3-benzo dioxole-5 base) methylamine (is dissolved in the ethyl formate (40mL) from above-mentioned steps (i) (1.53g, 8.18mmol)), reaction solution was stirred 20 hours at 45 ℃.Evaporating solvent carries out concentrating under reduced pressure to product, obtains inferior title compound (1.72g, 97.6%). ¹H-NMR(500MHz，CDCl ₃)δ8.35-8.25，7.09-6.95(m，3H)，6.01-5.61(m 1H)，4.53-4.45(d，2H)；MS(ESI)m/z 214([M+H] ⁺)。

(iii) (2,2-two fluoro-1,3-benzo dioxole-5 base) methyl-isocyanide

With N-[(2,2-two fluoro-1,3-benzene dioxole-5-yl) methyl] methane amide is (from (ii) (0.320g of above-mentioned steps, 1.49mmol)) and (methoxycarbonyl sulphonamide) triethyl ammonium hydroxide inner salt (burgess reagent) (0.359g, 1.51mmol) add in the flask, add anhydrous MeCN (8mL).Reaction mixture was stirred 3 hours at 50 ℃.Crude product is used for next step (AZ12609901) without being further purified.

Preparation S

1,2-two chloro-4-(isocyano-methyl) benzene

(i) N-(3, the 4-dichloro benzyl) methane amide

To 1-(3, the 4-dichlorophenyl) methylamine (352g, add in 2.00mmol) ethyl formate (8.0mL 99.4mmol), spends the night mixture (16h) 45 ℃ of stirrings, then vacuum concentration, obtain the crude product of 433mg.Crude product is used for next step without being further purified. ¹H-NMR(500MHz，CD ₃OD)δ8.18(s，1H)，7.51-7.47(m，2H)，7.27-7.23(m，1H)，4.40(s，2H)。

(ii) 1,2-two chloro-4-(isocyano-methyl) benzene

N-in being dissolved in MeCN (6ml) (3, the 4-dichloro benzyl) methane amide (from add in the above-mentioned steps (i) (245mg, 1.20mmol)) (methoxycarbonyl sulphonamide) triethyl ammonium hydroxide inner salt (burgess reagent) (286mg, 1.20mmol).Reaction mixture was stirred 3 hours at 50 ℃.After the cool to room temperature, this mixture is directly transferred to next reactions steps, need not any aftertreatment.

Preparation T

Methane amide via similar above-mentioned preparation L, M, N, O, P, Q, R prepares the isonitrile that can not be purchased from corresponding amine, and is used for preparing the compound of following embodiment.

Preparation U

4-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone

(i) 3-fluoro-N-(2-hydroxyl-1,1-dimethyl ethyl) benzamide

In 0 ℃, under nitrogen atmosphere, (20g, (14.6ml 0.171mol), adds a DMF then to add oxalyl chloride in methylene dichloride 0.142mol) (200ml) solution to the 3-fluorobenzoic acid.With reaction mixture stirring at room 2 hours.Concentrated reaction mixture then, and under 0 ℃, nitrogen atmosphere, drip 2-amino-2-methyl propyl alcohol (28g, methylene dichloride 0.314mol) (100ml) solution.Gained solution was at room temperature stirred other 2 hours.Filter reaction mixture, concentrated filtrate.Not purified and be used for next step through spissated white solid (30g).

(ii) 2-(3-fluorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

Under room temperature, stirring, thionyl chloride (60g) in 3-fluoro-N-(2-hydroxyl-1,1-diformazan ethyl) benzamide ((30g)) from above-mentioned steps (i), and stirred other 15 minutes.In yellow solution impouring anhydrous diethyl ether (200ml), reaction mixture neutralizes with 20% cold sodium hydroxide solution.Diethyl ether layer water, salt water washing through anhydrous sodium sulfate drying, and concentrate.By silica gel chromatography (using the EtOAc/ sherwood oil) purifying resistates, obtain the inferior title compound (18.5g, 67.3%) of brown liquid shape.

(iii) 4-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone

Under-78 ℃, nitrogen atmosphere, to 2-(3-fluorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (18.5g, 0.958mol) drip s-butyl lithium (103ml, 1.4M cyclohexane solution) in diethyl ether (200ml) solution of ((ii)) from above-mentioned steps, under uniform temp, stirred other 30 minutes.Add dry DMF (20ml) then.With reaction mixture other 2 hours in stirring at room.Reaction solution 6N hydrochloric acid quencher, and concentrate.Enriched material and 6N hydrochloric acid (400ml) reflux and spend the night.Stir with the reaction mixture cool to room temperature and with diethyl ether (200ml).Separate organic layer, and water, salt water washing, through anhydrous sodium sulfate drying, concentrate and obtain thick cyclic products.By recrystallization (diethyl ether/sherwood oil) purifying crude product, obtain title compound (8g, 49.6%), be white solid.

Preparation V

5-chloro-3-hydroxyl-2-cumarone-1 (3H)-ketone

(i) 4-chloro-N-(2-hydroxyl-1,1-diformazan ethyl) benzamide

Under 0 ℃, nitrogen atmosphere, (50g, (34ml 0.383mol), adds a DMF then to add oxalyl chloride in methylene dichloride 0.319mol) (400ml) solution to the 4-chloro-benzoic acid.With reaction mixture stirring at room 2 hours.Concentrated reaction mixture then, and under 0 ℃, nitrogen atmosphere, drip 2-amino-2-methyl propyl alcohol (62.8g, methylene dichloride 0.702mol) (200ml) solution.Gained solution other 2 hours in stirring at room.Filter reaction mixture, concentrated filtrate.(use MeOH/CHCl by silica gel chromatography ₃) the purifying resistates, obtain required intermediate (68g, 93.5%), be brown liquid.

(ii) 2-(4-chloro-phenyl-)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

Under stirring at room, (, and stirred other 15 minutes from thionyl chloride (120.8g 1.05mol) in the above-mentioned steps (i) (68g, 0.30mol)) to 4-chloro-N-(2-hydroxyl-1,1-dimethyl ethyl) benzamide.In yellow solution impouring anhydrous diethyl ether (500ml), reaction mixture neutralizes with 20% cold sodium hydroxide solution.Diethyl ether layer water, salt water washing through anhydrous sodium sulfate drying, and concentrate.By silica gel chromatography (using the MeOH/ sherwood oil) purifying resistates, obtain the inferior title compound (53g, 84.6%) of brown liquid shape.

(iii) 5-chloro-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2 base) phenyl aldehyde

Under-78 ℃, nitrogen atmosphere, to 2-(4-chloro-phenyl-)-4,4-dimethyl-4,5-dihydro-1, (19g 0.906mol) is added dropwise to s-butyl lithium (110ml, 1.4M cyclohexane solution) to the 3-oxazole in the diethyl ether of (from above-mentioned steps (ii)) (400ml) solution, make reaction mixture be warming up to 0 ℃, stirred other 1 hour down at 0 ℃.Reaction mixture is cooled to once more-78 ℃, adds dry DMF (10ml) then and be warmed to ambient temperature overnight.Quencher of reaction solution water and dilution.Isolating organic layer water and salt water washing, organic layer anhydrous sodium sulfate drying then, vacuum concentration obtains thick inferior title compound (20g), is yellow liquid.

(iv) 5-chloro-3-hydroxyl-2-cumarone-1 (3H)-ketone

Spend the night with aqueous hydrochloric acid (300ml water, the dense HCl of 150ml) in 80 ℃ of heating 5-chloro-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2 base) phenyl aldehydes (20g) ((iii)) from above-mentioned steps.Stir with the reaction mixture cool to room temperature and with diethyl ether (500ml).Diethyl ether layer water and salt water washing, organic layer anhydrous sodium sulfate drying, and vacuum concentration.Thick material recrystallization from the ethyl acetate/petroleum ether solvent systems obtains title compound (4.9g, 31.6%), is light brown solid.

Preparation W

5-bromo-3-hydroxyl-2-cumarone-1 (3H)-ketone

(i) 4-bromo-N-(2-methylol) phenylformic acid

(9g 0.042mol) refluxes in methyl alcohol (150ml) and spends the night with 2N aqueous sodium hydroxide solution (100ml) with the 5-bromo phthalide.The reaction mixture decompression is concentrated down.The enriched material dilute with water, and with rare HCl acidifying.Filter solid precipitation, resistates washs with cold water and cold ethyl acetate, and drying obtains inferior title compound (9.7g, 100%), is white solid.

(ii) 5-bromo-3-hydroxyl-2-cumarone-1 (3H)-ketone

Under-0 ℃, nitrogen atmosphere, to from 4-bromo-N-(2-methylol) phenylformic acid of above-mentioned steps (i) (9.7g, add in acetonitrile 0.042mol) (300ml) solution Dai Si-Martin cross iodine alkane (26.8g, 0.0633mol).With reaction mixture in stirring at room 14 hours.Filter reaction mixture is used the washed with dichloromethane throw out.Concentrated filtrate.Enriched material and 200ml concentrated hydrochloric acid were in 70 ℃ of heating 6 hours.Reaction mixture dilutes with big water gaging, and uses ethyl acetate extraction.Organic layer salt water washing through anhydrous sodium sulfate drying, and concentrates.By recrystallization enriched material from ethyl acetate/petroleum ether, obtain title compound (4.9g, 51%), be white solid.

Preparation X

5-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone

(i) 4-fluoro-N-(2-hydroxyl-1,1-dimethyl ethyl) benzamide

In 0 ℃, under nitrogen atmosphere, (50g, (34ml 0.393mol), adds a DMF then to add oxalyl chloride in methylene dichloride 0.357mol) (400ml) solution to the 4-fluorobenzoic acid.Stirring at room reaction mixture 2 hours.Concentrated reaction mixture then, and (70g is in methylene dichloride 0.785mol) (200ml) solution to be added drop-wise to 2-amino-2-methyl propyl alcohol in 0 ℃ under nitrogen atmosphere.Gained solution at room temperature stirred other 2 hours.Filter reaction mixture, concentrated filtrate.The not purified next step that is used for of spissated liquid substance (75g).

(ii) 2-(4-fluorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole

In room temperature, stir under, to 4-fluoro-N-(2-hydroxyl-1,1-dimethyl ethyl) benzamide (from above-mentioned steps (i) (75g) in thionyl chloride (144g), stirred other 15 minutes.With in the yellow solution impouring anhydrous diethyl ether (500ml), reaction mixture neutralizes with 20% cold sodium hydroxide solution then.Diethyl ether layer water, salt water washing through anhydrous sodium sulfate drying, and concentrate.By silica gel chromatography (using the EtOAc/ sherwood oil) purifying resistates, obtain the inferior title compound (65g, 95%) of brown liquid shape.

(iii) 2-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl)-5-fluorobenzaldehyde

At-78 ℃, under nitrogen atmosphere, to 2-(4-fluorophenyl)-4,4-dimethyl-4,5-dihydro-1, (40g 0.206mol) is added dropwise to s-butyl lithium (192ml in the diethyl ether of (from above-mentioned steps (ii)) (800ml) solution to the 3-oxazole, 1.4M cyclohexane solution), under uniform temp, stirred other 3 hours.Add dry DMF (40ml) then and be warming up to ambient temperature overnight.Quencher of reaction solution water and dilution.Isolating organic layer water and salt water washing, organic layer anhydrous sodium sulfate drying then, vacuum concentration obtains thick intermediate (36g), is yellow liquid.

(iv) 5-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone

With 2-(4,4-dimethyl-4,5-dihydro-1,3-oxazole-2-yl)-5-fluorobenzaldehyde (36g) ((iii)) and aqueous hydrochloric acid (400ml water, the dense HCl of 200ml) from above-mentioned steps 80 ℃ of heated overnight.Stir with the reaction mixture cool to room temperature and with diethyl ether (500ml).Diethyl ether layer water and salt water washing, organic layer anhydrous sodium sulfate drying, and vacuum concentration.Thick material recrystallization from the ethyl acetate/petroleum ether solvent systems obtains title compound (7g, 26%), is pale solid.

Preparation Y

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole woods-1-carboxylic acid

(i) 2-(2-oxyethyl group-2-oxoethyl) ethyl benzoate

2-carboxymethyl phenylformic acid (25g) is dissolved in the dehydrated alcohol (250ml), adds the vitriol oil (1ml).Gained solution is at Di An ﹠amp; Stark (Dean﹠amp; Stark) refluxed 2 days in the device, and replace replacement solvent 3 times with dehydrated alcohol.Ethanol is removed in decompression, and enriched material is dissolved in the ethyl acetate.Ethyl acetate layer, concentrates and obtains inferior title compound (30g) through anhydrous sodium sulfate drying with saturated sodium bicarbonate solution, water and salt water washing, is yellow oily.

(ii) 2-(1-bromo-2-oxyethyl group-2-oxoethyl) ethyl benzoate

Will (30g be 0.127mol) with N-bromosuccinamide (22.5g, 0.127mol) mixing in tetracol phenixin (300ml) from 2-(2-oxyethyl group-2-oxoethyl) ethyl benzoate of step (i).Add AIBN, refluxed 2 days.Wash reaction mixture then with water, through anhydrous sodium sulfate drying and concentrate, use 2% ethyl acetate/petroleum ether by column purification with thick purification of intermediate, obtain inferior title compound (26g, 65%), be brown liquid.

(iii) 2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole woods-1-carboxylic acid, ethyl ester

In 0 ℃ under nitrogen atmosphere, (20g 0.118mol) is added drop-wise to that (18.6g is in acetonitrile 0.059mol) (150ml) solution from step intermediate (ii) with [2-(4-chloro-phenyl-) propyl group] amine.Spend the night in the stirring at room reaction mixture then.Filter reaction mixture, the resistates washed with dichloromethane concentrates the filtrate that merges.10% ethyl acetate obtains inferior title compound (23g, 100%) as the thick intermediate of eluent purifying in the use sherwood oil, is white solid.

(iv) 2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole woods-1-carboxylic acid

Under 0 ℃, with aqueous sodium hydroxide solution (3g in the 50ml water, 0.0075mol) joins well-beaten 2-[2-(4-chloro-phenyl-) propyl group]-(13g is in ethanol 0.036mol) (100ml) solution for 3-oxo isoindole woods-1-carboxylic acid, ethyl ester.Then in stirring at room reaction mixture 2 hours.Concentrating under reduced pressure reaction mixture and dilute with water are used ethyl acetate extraction, and water layer is used ethyl acetate extraction with 2M HCl acidifying.Ethyl acetate layer salt water washing through anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains title compound (11.5g, 95.8%).

Preparation Z

2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole woods-1-carboxylic acid, ethyl ester

In 0 ℃ under nitrogen atmosphere, (25g, (25g is in acetonitrile 0.0793mol) (150ml) solution 0.16mol) to be added drop-wise to 2-(1-bromo-2-oxyethyl group-2-oxoethyl) ethyl benzoate with 2-(4-chloro-phenyl-) ethamine.Then with reaction mixture in stirred overnight at room temperature.Filter reaction mixture, the resistates washed with dichloromethane concentrates the filtrate that merges.The petroleum ether solution that uses 15% ethyl acetate obtains title compound (22g, 80.8%) as eluent purifying crude product, is white solid.

Preparation AA

2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole woods-1-carboxylic acid

Under 0 ℃, with aqueous sodium hydroxide solution (3g in the 50ml water, 0.075mol) joins well-beaten 2-[2-(4-chloro-phenyl-) ethyl]-(15g is in ethanol 0.043mol) (100ml) solution for 3-oxo isoindole woods-1-carboxylic acid, ethyl ester (above-mentioned preparation Z).Then with reaction mixture in stirring at room 2 hours.With reaction mixture concentrating under reduced pressure and dilute with water, use ethyl acetate extraction, water layer is used ethyl acetate extraction with 2N HCl acidifying.Ethyl acetate layer salt water washing, through anhydrous sodium sulfate drying, concentrating under reduced pressure obtains title compound (13g, 94.8%).

Preparation AB

Hydrochloric acid (2-phenoxy benzyl) amine

(i) 1-bromo-2-phenoxy group benzene

(9.2g, 0.135mol) water (20ml) drips of solution is added to the 2-phenoxybenzamine (25g 0.135mol) in the solution in 40% Hydrogen bromide (50ml), and stirred other 10 minutes with Sodium Nitrite under 0 ℃.(21.3,0.149mol) in the boiling mixture in 40% Hydrogen bromide (50ml), adding refluxed other 30 minutes afterwards then reaction mixture to be joined cuprous bromide.Reaction mixture, dilute with water also extracts with diethyl ether.The diethyl ether layer is with 5% hydrochloric acid, 10% potassium hydroxide, water, salt water washing, through anhydrous sodium sulfate drying, concentrate and obtain thick intermediate.Use sherwood oil to obtain inferior title compound (14.8g, 45%) by the thick intermediate of column purification as eluent.

(ii) 2-phenoxy group cyanobenzene

Under nitrogen atmosphere, with 1-bromo-2-phenoxy group benzene (from above-mentioned steps (i), 14.8g, 0.0594mol), Zn (CN) ₂(6.9g, 0.0594mol) and Pd (PPh ₃) ₄(6.8g, 0.00594mol) solution in dimethyl formamide (100ml) is in 130 ℃ of heated overnight.With the reaction mixture cool to room temperature, water (200ml) dilution.Reaction mixture and ethyl acetate (200ml) stirred 15 minutes, passed through diatomite filtration.Isolate ethyl acetate layer, and water and salt water washing, through anhydrous sodium sulfate drying, also concentrated, thick intermediate obtains inferior title compound (10.1g, 87.8%) by column chromatography (using the petroleum ether solution of 4%EtOAc) purifying, is colourless liquid.

(iii) hydrochloric acid (2-phenoxy benzyl) amine

At 0 ℃ under nitrogen atmosphere, with 2-phenoxy group cyanobenzene ((ii)) (10.1g from above-mentioned steps, 0.0517mol) THF (50ml) drips of solution be added to well-beaten LAH (4.9g be in THF 0.129mol) (50ml) suspension, then in stirred overnight at room temperature.Reaction mixture stirred 30 minutes with THF (50ml) in addition with 0 ℃ 6N KOH (5ml) quencher.Filter reaction mixture, resistates washs with ethyl acetate.Concentrated filtrate obtains thick amine.Saturated HCl diethyl ether (20ml) solution is joined in diethyl ether (20ml) solution of thick amine, and stir 2h.Filter reaction mixture, dried residue obtain title compound (10g, 97.08%).

Preparation AC

Hydrochloric acid (two pyridin-3-yl methyl) amine

(i) two pyridin-3-yl ketones

((15g in anhydrous diethyl ether 0.095mol) (200ml) solution, and stirred 15 minutes 0.114mol) to be added drop-wise to the 3-bromopyridine for 71.3ml, 1.6M with n-BuLi at-78 ℃.(13g, anhydrous diethyl ether 0.095mol) (50ml) drips of solution is added in the reaction mixture, stirs other 2 hours under uniform temp with Nikithan at-78 ℃.Reaction solution is with the saturated ammonium chloride quencher and use ethyl acetate extraction then.Organic layer washs with saturated brine, and through anhydrous sodium sulfate drying and concentrated, crude product is gone up purifying at NEUTRAL ALUMINUM post (use ethanol/methylene), obtains inferior title compound (8.5g, 49%), is brown liquid.

(ii) two pyridin-3-yl ketoximes

With two pyridin-3-yl ketones (from above-mentioned steps (i)) (8.5g, 0.046mol) anhydrous methanol (50ml) solution join well-beaten sodium acetate (9.6g, 0.117mol) and oxammonium hydrochloride (8.12g is in anhydrous methanol 0.117mol) (50ml) solution.Reaction mixture was refluxed 2 hours under nitrogen atmosphere.Reaction mixture is concentrated, dilute with water, use dichloromethane extraction.Organic layer water, salt water washing through anhydrous sodium sulfate drying, concentrate and obtain inferior title compound (9.5g, 100%).

(iii) hydrochloric acid (two pyridin-3-yl methyl) amine

With two pyridin-3-yl ketoximes (above-mentioned steps (ii) (9.5g, 0.0477mmol)) and ammonium acetate (5.5g 0.0716mmol) is dissolved in ethanol (00ml), water (80ml) and 40%NH ₃(aqueous solution) (100ml) in.With mixture heating up to 80 ℃, through one hour time add zinc powder (15.5g, 0.23mmol).Spend the night at 80 ℃ of stirred reaction mixtures then, cool to room temperature filters vacuum concentrated filtrate afterwards.Remaining aqueous solution is used dichloromethane extraction with 10MNaOH (aqueous solution) alkalization.The organic phase that merges, through anhydrous sodium sulfate drying and concentrates with salt solution (40ml) washing.Spissated yellow viscous substance is dissolved in the ethyl acetate, and drips, stirred 1 hour with the saturated diethyl ether (50ml) of hydrogen chloride gas.Filter reaction mixture, the drying solid resistates obtains title compound (9.2g, 65%), is pale solid.

Preparation AD

3-(2-amino-ethyl) cyanobenzene trifluoroacetate

(i) [2-(3-bromophenyl) ethyl] t-butyl carbamate

With the BOC acid anhydride (12ml, 0.054mol) join ice-cold 3-Bretylium Tosylate (10g, 0.049mol) and triethylamine (10.4ml is in methylene dichloride 0.10mol) (100ml) solution.After stirring 1h under the room temperature, the quencher of reaction mixture water, and use dichloromethane extraction.Organic layer water and salt water washing through anhydrous sodium sulfate drying and concentrated, obtain inferior title compound (15g, 100%).

(ii) [2-(3-cyano-phenyl) ethyl] t-butyl carbamate

With the tertiary butyl tertiary butyl [2-(3-bromophenyl) ethyl] carbamate (15g, 0.05mol), Zn (CN) 2 (5.87g, 0.05mol) and tetra-triphenylphosphine palladium (0) (5.7g, 0.05mol) mixture in dry DMF (150ml) under nitrogen atmosphere in 140 ℃ the heating 5h.With the reaction mixture cool to room temperature, the water quencher is filtered and is passed through Celite pad then.Reaction mixture ethyl acetate extraction, ethyl acetate layer be water, salt water washing successively, through anhydrous sodium sulfate drying and concentrated.By the thick material of column chromatography (petroleum ether solution of 20% ethyl acetate is as eluent in the use) purifying, obtain required inferior title compound (7g, 57%) then, be white solid.

(iii) 3-(2-amino-ethyl) cyanobenzene trifluoroacetate

Trifluoroacetic acid (5ml) is joined in methylene dichloride (20ml) solution of [2-(3-cyano-phenyl) ethyl] t-butyl carbamate (10g) and at room temperature stir and spend the night.Removal of solvent under reduced pressure and excessive trifluoroacetic acid obtain viscous oil.Develop viscous oil with diethyl ether, white solid occurs.Decantation diethyl ether, dry white solid obtain title compound (6g).

Preparation AE

[2-fluoro-4-(sulfonyloxy methyl) benzyl] amine

(i) thiocarbamate O-(4-cyano group-3-fluorophenyl) dimethyl esters

Stir 2-fluoro-4-hydroxy benzonitrile (10g, 0.0729), DMAP (900mg, 0.00729mol), triethylamine (30ml, 0.218mol) and dimethyl sulphide for urea chloride (11g, 0.0875mol) mixture in anhydrous methylene chloride (200ml), and flow through night next time in nitrogen atmosphere.The quencher of reaction mixture water is also used dichloromethane extraction.Organic layer water, salt water washing are through dried over sodium sulfate.Solvent evaporated under reduced pressure, resistates is developed with sherwood oil.Filtration product, vacuum-drying obtain inferior title compound (14g, 85.8%), are yellow solid.

(ii) thiocarbamate S-(4-cyano group-3-fluorophenyl) dimethyl esters

To mix from thiocarbamate O-(4-cyano group-3-fluorophenyl) dimethyl esters (14g) and the diphenyl ether (200ml) of above-mentioned steps (i), stirred 6 hours at 210 ℃.Diphenyl ether is removed in underpressure distillation, and thick material and petroleum ether and stirring are also filtered.Resistates with petroleum ether for several times, the air-dry inferior title compound (13.4g, 95.7%) that obtains is the light brown solid.

(iii) 2-fluoro-4-sulfydryl cyanobenzene

Will (13.4g 0.059mol) be dissolved among the THF (150ml), adds KOH (6.7g, methyl alcohol 0.11mol) (200L) solution therein from above-mentioned steps thiocarbamate S-(4-cyano group-3-fluorophenyl) dimethyl esters (ii).Reaction mixture in stirring at room 3h, is concentrated then.Thick material is dissolved in the ethyl acetate.Ethyl acetate layer uses the 3N hcl acidifying to pH=2.Ethyl acetate layer water and salt water washing are through anhydrous sodium sulfate drying and concentrated.The thick intermediate (9g) of gained is directly used in next step without being further purified.

(iv) 2-fluoro-4-(methylthio group) cyanobenzene

With methyl-iodide (12.5g, 0.058mol) be added dropwise to from above-mentioned steps 2-fluoro-4-sulfydryl cyanobenzene (9g (iii), 0.058mol) and salt of wormwood (12.1g, 0.088mol) in the solution in anhydrous acetonitrile (150ml), under nitrogen atmosphere in stirring at room 3 hours.Filter reaction mixture, concentrated filtrate obtain inferior title compound (9.6g, 100%).

(v) 2-fluoro-4-(sulfonyloxy methyl) cyanobenzene

To join in Glacial acetic acid/water/alcoholic acid mixture (140ml, 2: 2: 3) from above-mentioned steps 2-fluoro-4-(methylthio group) cyanobenzene (9.6g, 0.0524) (iv), and stir 10min.Reaction mixture is cooled to 0 ℃, and add in batches oxone (40.4g, 0.065mol).Stirring at room reaction mixture 2 hours, and dilute with methylene dichloride.Leach inorganic layer, mother liquor distributes between water and methylene dichloride.Organic layer water and salt water washing are through dried over sodium sulfate.Solvent evaporated under reduced pressure uses ethyl acetate/petroleum ether to obtain required sulfone (9g, 80%) by recrystallization then.

(vi) 2-fluoro-4-(sulfonyloxy methyl) benzonitrile

In methyl alcohol (150ml) solution of 2-fluoro-4-(methylthio group) cyanobenzene (9g), add Raney's nickel (2g), use ammonia saturated then.Reaction mixture under the 3kg hydrogen pressure in Pa Er jolting device hydrogenation spend the night.Filter reaction mixture, concentrated filtrate.Enriched material is dissolved in the ethyl acetate, and under nitrogen atmosphere with ether in saturated HCl stir and spend the night.Filter solid sediment,, obtain title compound (1.3g, 14.3%), be light yellow solid with diethyl ether washing and dry.

Preparation AF

Hydrochloric acid [2-chloro-4-(methyl sulphonyl) benzyl] amine

(i) thiocarbamate O-(3-chloro-4-cyano-phenyl) dimethyl ester

With 2-chloro-4-hydroxy-phenylformonitrile (25g, 0.162mol), DMAP (1.9g, 0.162mol), triethylamine (68ml, 0.483mol) and dimethyl sulphide for urea chloride (24g, the 0.195mol) stirring that under nitrogen atmosphere, refluxes of the mixture in anhydrous methylene chloride (500ml).Dichloromethane extraction is used in the quencher of reaction mixture water.Organic layer water, salt water washing and through dried over sodium sulfate.Solvent evaporated under reduced pressure, resistates is developed with sherwood oil (pet ether).Product is filtered and vacuum-drying, obtain required intermediate (38g, 97%), be yellow solid.

(ii) thiocarbamate S-(3-chloro-4-cyano-phenyl) dimethyl ester

Thiocarbamate O-(3-chloro-4-cyano-phenyl) dimethyl ester (38g) and diphenyl ether (500ml) are mixed, stirred 6 hours at 210 ℃.Diphenyl ether is removed in underpressure distillation then, with thick material and petroleum ether and stirring and filtration.Resistates with petroleum ether for several times, the air-dry required intermediate (37.8g, 99.5%) that obtains is the light brown solid.

(iii) 2-chloro-4-sulfydryl cyanobenzene

(35g 0.145mol) is dissolved among the THF (400ml), and (163g is in methyl alcohol 0.30mol) (200L) solution to wherein adding potassium hydroxide with thiocarbamate S-(3-chloro-4-cyano-phenyl) dimethyl ester.Reaction mixture stirring at room 3 hours, is concentrated then.Thick material is dissolved in the ethyl acetate.Ethyl acetate layer is acidified to pH=2 with 3N HCl.Ethyl acetate layer water and salt water washing are through anhydrous sodium sulfate drying and concentrated.Resulting thick intermediate is directly used in next step without being further purified (25g).

(iv) 2-chloro-4-(methylthio group) cyanobenzene

With methyl iodide (31.4g, 0.22mol) be added drop-wise to 2-chloro-4-sulfydryl cyanobenzene (25g, 0.147mol) and salt of wormwood (20.4g, 0.22mol) in the solution in anhydrous acetonitrile (300ml), under nitrogen atmosphere in stirring at room 3h.Filter reaction mixture then, concentrated filtrate obtains required intermediate (26g, 96.2%).

(v) 2-chloro-4-(methyl sulphonyl) cyanobenzene

(26g 0.145mol) joins in Glacial acetic acid/water/alcoholic acid mixture (900ml, 2: 2: 3), and stirs 10min with 2-chloro-4-(methylthio group) cyanobenzene.Reaction mixture is cooled to 0 ℃, and add in batches oxone (217g, 0.353mol).Reaction mixture in stirred overnight at room temperature, is diluted with methylene dichloride.Leach organic layer, mother liquor distributes between water and methylene dichloride.Organic layer water and salt water washing are through dried over sodium sulfate.Solvent evaporated under reduced pressure uses ethyl acetate/petroleum ether to obtain inferior title compound (18g, 59%) by recrystallization then, is white solid.

(vi) hydrochloric acid [2-chloro-4-(methyl sulphonyl) benzyl] amine

In the solution of intermediate (8g) in methyl alcohol (200ml) of step 5, add Raney's nickel (2.5g), use ammonia saturated then.Reaction mixture under the 3kg hydrogen pressure in Pa Er jolting device hydrogenation spend the night.Filter reaction mixture, concentrated filtrate.Enriched material is dissolved in the ethyl acetate, and under nitrogen atmosphere with ether in saturated HCl stir and spend the night.Filter solid sediment,, obtain title compound (7g, 86.4%), be solid with diethyl ether washing and dry.

Preparation AG

Hydrochloric acid 2-(4-chloro-phenyl-)-2-methyl-third-1-amine

(i) 2-(4-chloro-phenyl-)-2-methyl propionitrile

0 ℃ to 2-(4-chloro-phenyl-)-2-acetonitrile (10g, add in DMF stirred solution 0.066mol) in batches sodium hydride (3.95g, 0.1649mol).Made the reaction mixture stirring at room 1 hour.And then be cooled to 0 ℃ and drip methyl iodide (28.0g, 0.198mol).Reaction mixture was stirred 4 hours in 40 ℃.Use the cold water diluted reaction mixture, use the ethyl acetate extraction product.Organic layer water and salt water washing.Organic layer is through anhydrous sodium sulfate drying, vacuum concentration.Resistates carries out purifying by the silica gel chromatography that uses (ethyl acetate/petroleum ether), obtains inferior title compound (7.7g, 65%), is colourless liquid.

(ii) hydrochloric acid 2-(4-chloro-phenyl-)-2-methyl-third-1-amine

At 0 ℃ of LiAlH in THF ₄(4.06g, 0.107mol) drip in the mixture step 1 intermediate (7.7g, 0.043mol).Make reaction mixture in stirred overnight at room temperature.Reaction mixture is cooled to 0 ℃ of 6M KOH solution quencher of also using 10ml.Reaction mixture dilutes with THF, stirs 30min under the room temperature.Reaction mixture is filtered concentrated filtrate.Resistates dilutes with diethyl ether, at 0 ℃ of HCl that adds in the ether.Filter and collect white solid,, obtain required product title compound (6g, 77%) with anhydrous diethyl ether washing and vacuum-drying.

Preparation AH

7-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone

(i) 1-(dimethoxy-methyl)-3-fluorobenzene

To the 3-fluorobenzaldehyde (17.5g, add in methyl alcohol 0.141mol) (175ml) stirred solution trimethyl orthoformate (17.5ml, 0.159mol) and PTSA (175mg).Stirred reaction mixture spends the night under the room temperature.Reaction mixture is with 1% the methyl alcohol KOH solution quencher of 30ml.Concentration response material, and dilute with water, the product ethyl acetate extraction.Organic layer water and salt water washing.Organic layer is through anhydrous sodium sulfate drying, and vacuum concentration.The fractionation crude product is colourless liquid to obtain required intermediate (20g, 83.6%).

(ii) 7-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone

Under nitrogen atmosphere, (20g, the dropping in THF 0.11mol) (200ml) solution derives from the s-butyl lithium (220ml, 1.4M cyclohexane solution) of step (i), stirs other 3 hours under uniform temp to 1-(dimethoxy methyl)-3-fluorobenzene in-78 ℃.Remove CO then ₂Up to the red solution flavescence, and slowly be raised to room temperature.Reaction mixture was stirred other 1 hour, use the 20mlHCl quencher then.Concentrated reaction mixture afterwards.With the crude reaction material that so obtains and the hydrochloric acid in the water (300ml concentrated hydrochloric acid, 200ml water) 80 ℃ of heated overnight.Stir with the reaction mixture cool to room temperature and with diethyl ether (100ml) then.Diethyl ether layer water and salt water washing.Organic layer is through anhydrous sodium sulfate drying, vacuum concentration.Thick material is prepared HPLC obtains title compound (2.3g, 11.7%), be white solid.

Preparation AI

1-(3 ', 4 '-DfBP-2-yl) methylamine

(i) [(3 ', 4 '-DfBP-2-yl) methyl] t-butyl carbamate

In miniature bottle, with (2-bromobenzyl) t-butyl carbamate (1.74mmol, 0.50g), (0.087mmol, 0.10g) (2.10mmol 0.33g) is dissolved among the DME (10ml) tetrakis triphenylphosphine palladium with (3, the 4-difluorophenyl) boric acid.(3.49mmol 1.14g) is dissolved in the 2ml water, joins then in this mixture with cesium carbonate.Make the argon gas bubbling pass through mixture 5 minutes.(, then EtOAc concentration is brought up to 70%, (silica gel 600.004-0.063mm) by the purification by flash chromatography crude product with heptane/EtOAc 90/10 beginning of degree such as grade.Merge the fraction that contains product, remove by evaporation and desolvate, obtain title compound (3.00g, 89.6%).1H-NMR(500MHz，CDCl ₃)：δ7.46-7.42(m，1H)；7.41-7.36(m，1H)；7.36-7.30(m，1H)；7.25-7.18(m，2H)；7.17-7.11(m，1H)；7.06-7.01(m，1H)；4.75(bs，1H)；4.31-4.17(m，2H)；1.45(s，9H)。

(ii) 1-(3 ', 4 '-DfBP-2-yl) methylamine

(9.39mmol 3.00g) is dissolved among the saturated EtOAc of HCl and in stirring at room 2 hours with [(3 ', 4 '-DfBP-2-yl) methyl] t-butyl carbamate.By the evaporative removal solvent, (heptane/DCM 50/50 beginning with the degree such as grade is elevated to 100% with DCM concentration then, uses 10%MeOH (to use NH afterwards by the purification by flash chromatography hydrochloride ₃Saturated) eluted product (silica gel 600.004-0.063mm)).Merge the fraction that contains product, remove by evaporation and desolvate, obtain title compound (2.00g, 97.1%).IH-NMR(500MHz，CDCl ₃)：δ7.55-7.50(m，1H)；7.42-7.35(m，1H)；7.32-7.15(m，4H)；7.14-7.06(m，1H)；4.82-4.79(m，2H)；3.78-3.73(m，2H)。

Preparation AJ

1-(4,4 '-DfBP-2-yl) methylamine

(i) [(4,4 '-DfBP-2-yl) methyl] t-butyl carbamate

In miniature bottle, with 1-bromo-4-fluorobenzene (11.15mmol, 1.95g), tetrakis triphenylphosphine palladium (0.41mmol, 0.47g) and (2-{[(tertbutyloxycarbonyl) amino] methyl-the 4-fluorophenyl) (9.29mmol 2.50g) is dissolved among the DME (10ml) boric acid.(18.58mmol 6.05g) is dissolved in the 2ml water, joins then in this mixture with cesium carbonate.Make N ₂(g) bubbling passed through mixture 5 minutes.(20min reacts in 130deg) at microwave oven.(, then EtOAc concentration is brought up to 60%, (silica gel 600.004-0.063mm) by the purification by flash chromatography crude product with heptane/EtOAc 95/5 beginning of degree such as grade.Merge the fraction that contains product, remove by evaporation and desolvate, obtain title compound (2.54g, 85.6%).1H-NMR(500MHz，CDCl ₃)：δ7.30-7.21(m，2H)，7.21-7.08(m，4H)；7.03-6.97(m，1H)，4.79(bs，1H)，4.29-4.13(m，2H)；1.45(s，9H)。

(ii) 1-(4,4 '-DfBP-2-yl) methylamine

(7.95mmol 2.54g) is dissolved among the saturated EtOAc of HCl and in stirring at room 2 hours with [(4,4 '-DfBP-2-yl) methyl] t-butyl carbamate.By the evaporative removal solvent, (heptane/EtOAc 50/50 beginning with the degree such as grade is elevated to 100% with EtOAc concentration to the hydrochloride by the purification by flash chromatography product then, uses 10%MeOH (to use NH afterwards ₃Saturated) eluted product (silica gel 600.004-0.063mm)).Merge the fraction that contains product, remove by evaporation and desolvate, obtain title compound (1.64g, 94.1%).1H-NMR(500MHz，CD ₃OD)：δ7.34-7.27(m，3H)；7.22-7.13(m，3H)，7.05-7.0(m，1H)；4.81(s，2H)，3.72(s，2H)。

Preparation AK

Prepare following amine according to above-mentioned preparation AI and AJ.

[(4-fluorine biphenyl-2-yl) methyl] amine

[(5-fluorine biphenyl-2-yl) methyl] amine

[(4 ', 5-DfBP-2-yl) methyl] amine

Embodiment

Embodiment 1

2-[2-(4-chloro-phenyl-) propyl group]-N-[(5-methyl-isoxazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide

With hydrochloric acid 2-(4-chloro-phenyl)-propylamine (16.9g, 8.2mmol) and triethylamine (1.14ml) handle 2-carbamoyl benzoate (1.23g, methyl alcohol 8.2mmol) (15ml) solution.With mixture in stirring at room 30 minutes.Add the 3-isocyano-methyl-5-methyl-isoxazole solution derive from preparation L, in stirring at room mixture 16 hours.Enriched mixture is dissolved in the 50ml methylene dichloride, with the saturated NaHCO of 100ml ₃Solution washing.Separate organic phase, through dried over mgso and evaporation.Use preparation HPLC purifying surplus oil, obtain title compound (0.903g, 26% yield).

[M+1](ES)424.10

¹H NMR(500MHz，CDCl ₃)δ7.46-7.61(m，3H)；7.35-7.44(m，1H)；7.07-7.27(m，5H)；5.81(s，1H)；4.78(s，1H)；4.46-4.56(m，1H)；4.31-4.39(m，1H)；4.12-4.27(m，1H)；3.15-3.40(m，2H)；2.35(s，3H)；1.23(d，3H)。

Embodiment 2

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole woods-1-methane amide

(i) N-(biphenyl-2-ylmethyl)-N-[2-(tertiary butyl amino)-1-(2-furyl)-2-oxoethyl] fourth-2-alkynyl amide

With (biphenyl-2-ylmethyl) amine (23.78mmol 4.36g) is dissolved in the methyl alcohol, add the 2-furfural (23.78mmol, 2.29g) and fourth-2-acetylenic acid (23.78mmol, 2.00g).In stirring at room mixture 30 minutes.Adding isocyano-uncle butane (23.78,1.98g), in the stirring at room mixture overnight.Evaporation removes and desolvates.Product is used for next step and is not further purified.

(ii) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole woods-1-methane amide

Will be from N-(biphenyl-2-ylmethyl)-N-[2-(tertiary butyl amino)-1-(2-furyl)-2-oxoethyl of above step (i)] fourth-2-alkynyl amide (23.0mmol, 9.87g) be dissolved in the dimethylbenzene (200ml), adding Ytterbiumtriflate (III) (2.30mmol, 1.43g).Make mixture backflow 1.5h, do not stay raw material.Desolvate by evaporating to remove.Crude product is by purification by flash chromatography (begin the heptane/EtOAc80/20 with the degree such as grade, then EtOAc concentration is elevated to 100% (silica gel 600.004-0.063mm)).Product precipitates on post, must carry out wash-out with 50%MeOH, then with product recrystallization from methyl alcohol, obtains title compound (4.52g, 45.9%).

¹H-NMR (500MHz, DMSO-d ₆): δ 7.96 (s, 1H), 7.45-7.28 (m, 7H), 7.26-7.20 (m, 1H), 7.20-7.14 (m, 1H), 7.06-7.01 (m, 1H), 6.97-6.92 (m, 1H), 5.07 (d, 1H), 4.63 (s, 1H), 3.90 (d, 1H), 2.45 (s, 3H), 1.11 (s, 9H); To (C ₂₇H ₂₈N ₂O ₃+ H)+the HRMS calculated value: 429.5436; Measured value (ES[M+H]+): 429.5454.

Described synthetic order comes from the processing step of delivering: D.L.Wright, C.V.Robotham and K.Aboud, Tetrahedron Lett.2002,43,943-946.

Embodiment 3

(R or S) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide

(S or R) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide

By using Reprosil 20 * 250mm chiral column, with preparation HPLC separation 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole woods-1-methane amide (the embodiment 2) (0.20g of 40% Virahol n-heptane solution as moving phase, 0.47mmol) enantiomer, (+) enantiomer (0.10g) that obtains title compound (E1) and (-) enantiomer (0.10g) (E2).

(+) enantiomer:

HRMS: to (C ₂₇H ₂₈N ₂O ₃+ H) ⁺Calculated value: 429.2178; Measured value (ES[M+H]+): 429.2166.

(-) enantiomer:

HRMS: to (C ₂₇H ₂₈N ₂O ₃+ H) ⁺Calculated value: 429.2178; Measured value (ES [M+H]+): 429.2147.

Embodiment 4

(2R)-and 2-{1-[(tertiary butyl amino) carbonyl]-3-oxo-1,3-dihydro-2H-isoindole-2 base }-3-(4-chloro-phenyl-) methyl propionate

With the 2-carbamoyl benzoate (030g, 2mmol), 4-chloro-D-phenyl methyl lactamine hydrochloride (0.5g, 2mmol) and NEt ₃(0.28ml 2mmol) is dissolved in (5ml) in the methyl alcohol, at room temperature stirs 30 minutes.Add isocyano-uncle butane (0.23ml, 2mmol), with the gained mixture in stirring at room 3 days.The concentrating under reduced pressure mixture, resistates is with preparing the HPLC purifying, and described preparation HPLC uses the WatersHPLC system, is equipped with Kromasil C850.8x 300mm post, uses MeCN/0.1M NH ₄The OAc Laemmli buffer system Laemmli is with from 100%A (5%MeCN+95%0.1M NH ₄OAc) to 100%B (100%0.1M NH ₄OAc) gradient is as moving phase.Concentrating under reduced pressure product fraction and lyophilize obtain title compound (0.22g, 25%).

¹H-NMR(500MHz，CDCl ₃)δ7.87-7.83(m，1H)，7.60-7.49(m，3H)，7.17-7.13(m，2H)，7.02-6.98(m，2H)，4.17-4.12(m，1H)，3.96(s，1H)，3.94(s，3H)，3.80-3.40(m，2H)，1.22(s，9H)。

¹³C-NMR(125MHz，CDCl ₃)δ170.9，169.5，166.7，142.1，135.6，133.4，133.0，130.5，130.0，129.4，129.1，123.8，123.3，67.4，59.5，53.6，51.8，34.0，28.6。

HRMS: to (C ₂₃H ₂₅ClN ₂O ₄+ H)+calculated value: 429.1581; Measured value (ES[M+H]+): 429.1583.

Embodiment 5

N-(tertiary butyl)-2-{ (1R)-1-(4-benzyl chloride base)-2-oxo-2-[(4,4,4-trifluoro butyl) amino] ethyl }-3-oxo isoindole quinoline-1-methane amide.

Under nitrogen atmosphere, with 4,4, (0.087g 0.53mmol) mixes with methylene dichloride (2ml) 4-trifluoro fourth-1-amine, adds Me ₃Al (2M n-heptane solution).At room temperature stirred the gained mixture 1.5 hours, and add (2R)-2-{1-[(tertiary butyl amino) carbonyl]-3-oxo-1,3-dihydro-2H-isoindole-2 base }-3-(4-chloro-phenyl-) methyl propionate (the foregoing description 4) (0.11g, 0.26mmol).At room temperature stirred the gained mixture 20 hours.By adding methyl alcohol quencher reaction, remove by filter formed salt.By silicon-dioxide flash chromatography (use) purifying filtrate with the Biotage Horizon equipment of ethyl acetate/heptane as moving phase.Decompression is the enriched product fraction down, obtains title compound (0.075g, 54%).

HRM: to (C ₂₆H ₂₉ClF ₃N ₃O ₃+ H) ⁺Calculated value: 524.1927; Measured value (ES[M+H] ⁺) 524.1893.

Embodiment 6

N-butyl-2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo isoindole quinoline-1-methane amide

With 2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-carboxylic acid (0.4mmol) (preparation AA) is dissolved among the DCM (2ml), adds solid (3-dimethylamino-propyl group)-ethyl-carbodiimide hydrochloride (0.4mmol).Add N-methyl fourth-1-amine (0.4mmol) after 15 minutes, make then to be reflected at 30 ℃ and to continue 2 days.By silicon-dioxide flash chromatography (use) purification reaction mixture with the Biotage Horizon equipment of ethyl acetate/heptane as moving phase.Decompression is the enriched product fraction down, obtains title compound (0.007g, 5%).

¹H-NMR(500MHz，CDCl ₃)δ7.91-7.87(m，1H)，7.58-7.48(m，2H)，7.40-7.32(m，1H)，7.30-7.24(m，3H)，7.21-7.13(m，2H)，5.26-5.15(m，1H)，4.40-4.24(m，1H)，3.45-3.21(m，3H)，3.10-2.89(m，4H)，1.57-1.45(m，2H)，1.35-1.26(m，2H)，0.94(t，3H)。

HRMS: to (C ₂₂H ₂₅ClN ₂O ₂+ H) ⁺Calculated value: 385.1683; Measured value (ES[M+H] ⁺) 385.1670.

Embodiment 7

2-(biphenyl-2-ylmethyl)-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide

With the 2-carbamoyl benzoate (9.09mmol 1.36g) is dissolved in the methyl alcohol (20ml), add 1-biphenyl-2-base methylamine (9.09mmol, 1.66g), in stirring at room mixture 30 minutes.(9.09mmol 1.29g) joins in the mixture will to be dissolved in 4-(isocyano-methyl) cyanobenzene in the acetonitrile (5ml) then.Spend the night in the stirring at room reactant.By flash chromatography (begin toluene/EtOAc100/0, then EtOAc concentration is elevated to 50%, (silica gel 600.004-0.063mm)) purifying crude product with the degree such as grade.Merge the fraction that contains product, the evaporative removal solvent obtains title compound (2.32g, 55.8%).

¹H-NMR(500MHz，CDCl ₃)：δ7.63-7.56(m，3H)，7.50-7.45(m，2H)；7.45-7.39(m，3H)；7.37-7.24(m，4H)；7.22-7.16(m，3H)；7.00(d，2H)；6.59-6.54(m，1H)；5.24(d，1H)，4.77(s，1H)；4.31(d，1H)；4.29-4.18(m，2H)。

Embodiment 8

N-[4-(amino methyl) benzyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide

To 2-(biphenyl-2-ylmethyl)-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (embodiment 7) (0.43mmol, (2M NH of MeOH 200mg) ₃) (100ml) add Raney's nickel (with anhydrous EtOH prewashing) in the solution.The hydrogenation 16 hours under 1.3 crust of gained mixture.The evaporative removal solvent.By flash chromatography (toluene/MeOH 90/10 beginning with the degree such as grade is elevated to 50% with MeOH concentration, (silica gel 600.004-0.063mm) then) purifying crude product, merge the fraction that contains product, the evaporative removal solvent obtains title compound (0.172g, 85.2%).

¹H-NMR(300MHz，CDCl ₃)：δ7.69(d，1H)，7.55-7.35(m，3H)；7.35-7.13(m，11H)；7.08(d，2H)；4.72(s，1H)；4.19(s，2H)；3.74(s，2H)。

Embodiment 9

N-benzyl-6-chloro-3-oxo-2[(1R)-the 1-phenylethyl] isoindoline-1-methane amide

(3.25mmol 0.6g) is dissolved in the methyl alcohol (10ml), and (3.25mmol 0.38g), and stirred 20 minutes amine to add [(1R)-1-phenylethyl] with 5-chloro-3-hydroxyl-2-cumarone-1 (3H)-ketone (preparation V).(3.25mmol 0.39g) joins in the mixture with (isocyano-methyl) benzene then.Reaction stirred is spent the night under the room temperature, removes by evaporation and desolvates.(begin heptane/EtOAc 90/10 by flash chromatography with the degree such as grade, then EtOAc concentration is elevated to 50%, (silica gel 600.004-0.063mm)) the purifying crude product, merge the fraction that contains product, the evaporative removal solvent, the gained material does not have enough purity, therefore by preparing HPLC to its purifying, described preparation HPLC is with acetonitrile/buffer reagent 20/80 beginning of degree such as grade, then acetonitrile concentration is brought up to 95%, buffer reagent is the mixture of acetonitrile/water (10/90) and ammonium acetate (0.1M), post: KR-100-7-C8,50mm x 250mm flow velocity: 40ml/min.Merge the fraction that contains product, the evaporative removal acetonitrile.Make the free dried overnight of product, obtain title compound (mixture of diastereomer) (0.345g, 26.2%).

¹H-NMR(500MHz，CDCl ₃)：δ7.59-6.9(m，12H)，6.88-6.8(m，1H)，5.68-5.44(m，1H)，5.16-4.33(t，2H)，4.22-3.46(m，1H)，1.78-159(m，3H)；

To (C ₂₄H ₂₁ClN ₂O ₂+ H) ⁺The HRMS calculated value: 405.1368; Measured value (ES[M+H] ⁺): 405.1370.

Embodiment 10

N-butyl-2-[2-(4-fluorophenoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide

With the 2-carbamoyl benzoate (0.33mmol 50mg) is dissolved in the methyl alcohol (1ml), add [2-(4-fluorophenoxy) benzyl] amine hydrochlorate (0.33mmol, 84mg) and TEA (0.66mmol, 64mg).(0.33mmol 28mg) is dissolved in the acetonitrile and joins in the mixture with the 1-butyl isocyanide then.Reaction stirred is spent the night under the room temperature.Evaporation removes and desolvates.By flash chromatography (heptane/EtOAc 90/10 beginning with the degree such as grade is elevated to 100% with EtOAc concentration, (silica gel 600.004-0.063mm) then) purifying crude product, merge the fraction that contains product, evaporative removal EtOAc obtains title compound (47mg, 32.6%).

¹H-NMR(500MHz，CDCl ₃)：δ7,68-7,64(d，1H)，7,62-7,56(d，1H)，7,56-7,5(t，1H)，7,42-7,36(t，1H)，7,36-7,31(d，1H)，7,27-7,20(t，1H)，7,10-6,93(m，5h)，6,85-6,80(d，1h)，6,77-6,71(m，1H)，5,33-5,21(d，1H)，4,98(s，1H)，4,59-4,51(d，1H)，3,33-3,22(m，1H)，3,16-3,05(m，1H)，1,44-1,14(m，5H)，0,94-0,75，(m 3H)；

HRMS: to (C ₂₆H ₂₅FN ₂O ₃+ H)+and calculated value: 433.5069; Measured value (ES [M+H]+): 433.5061.

Embodiment 11

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-(difluoro-methoxy)-4-methyl-3-oxo isoindole quinoline-1-methane amide

In the bottle of 2ml, with 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (embodiment 2) (0.252mmol, 108mg) be dissolved among the DCM (2ml), add 4-butyl ammonium hydrogen sulfate (0.262mmol, 89mg) and sodium hydroxide (0.831mmol, 33mg), and seal this test tube.Make N ₂(gas) bubbling passed through mixture 5 minutes.Make chlorodifluoromethane (gas) bubbling pass through mixture 30 seconds.Stirred the mixture under the room temperature 2 hours.The evaporative removal solvent, (heptane/EtOAc 95/5 beginning with the degree such as grade is elevated to 50% with EtOAc concentration then by flash chromatography, (silica gel 600.004-0.063mm)) the purification reaction mixture, merge the fraction that contains product, the evaporative removal solvent, obtain title compound (44mg, 36.5%). ¹H-NMR(500MHz，CDCl ₃)：δ7,45-7,32(m，7H)，7,32-7,25(m，4H)，6,53(t，1H，)，5,42(s，1H)，5,17(d，1H)，4,47(s，1H)，4,44(d，1H)，2,64(s，3H)，1,09(s，9H)；

To (C ₂₈H ₂₈F ₂N ₂O ₃+ H)+the HRMS calculated value: 479.5515; Measured value (ES[M+H]+): 479.5485.

Embodiment 12

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide

(11.89mmol 2.0g) is dissolved in the methyl alcohol (10ml), adds [2-(4-chloro-phenyl-) propyl group] amine hydrochlorate (11.89mmol with 4-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone (preparation U), 2.452g) and TEA (13.08mmol, 1,324g), stirred 20 minutes.(11.89mmol 0.98g) joins in the mixture with the 1-butyl isocyanide then.Spend the night at the stirring at room reactant.The evaporative removal solvent, (heptane/EtOAc 90/10 with the degree such as grade begins by flash chromatography, then EtOAc concentration is elevated to 50%, (silica gel 600.004-0.063mm)) the purifying crude product, merge the fraction that contains product, the evaporative removal solvent, during evaporation, the product precipitation filters out solid and dry, obtain title compound (1.05g, 21.9%). ¹H-NMR(500MHz，CDCl ₃)：δ7,42-6,90(m，7H)，4,95-4,43(d，1H，230，16Hz)，4,28-4,14(m，1H，)，3,38-3,11(m，4H)，1,45-1,34(m，2H)，1,34-1,18(m，5H)，0,92-0,82(m，3H)；

To (C ₂₂H ₂₄ClFN ₂O ₂+ H)+the MS calculated value: 403.90; Measured value (ES[M+H]+): 403.12.

Embodiment 13

(1S or 1R)-N-butyl-2-[(2S or 2R)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (isomer E1)

(1S or 1R)-N-butyl-2-[(2R or 2S)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (isomer E2)

(1R or 1S)-N-butyl-2-[(2R or 2S)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E3)

(1R or 1S)-N-butyl-2-[(2S or 2R)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E4);

By preparing the HPLC system with N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (the foregoing description 12) (2.60mmol, 1.05g) four kinds of steric isomers separate, described HPLC system disposition has Chirapak IA, 5 μ, 250mm x 20mm post, use MTBE/MeOH (95/5) as moving phase, obtain containing isomer E1 fraction 1, contain the fraction 2 of isomer E2 and contain isomer E3 and the fraction 3 of isomer E4.

Vacuum concentration fraction 1 obtains isomer E1 (0.219g, 20.9%): [α] _D ²⁰=30 (c 1.0, MeCN), and (ee=98.5%);

Vacuum concentration fraction 2 obtains isomer E2 (0.232g, 22.1%): [α] _D ²⁰=156 (c 1.0, MeCN), and (ee=99.3%);

Concentrate fraction 3, and by preparation HPLC separating isomerism body E3 of system and isomer E4, described HPLC system disposition there are (R, R) Whelk-O1,5 μ, 250mm x 20mm post.Use heptane/IPA (50/50) as moving phase, the fraction 4 that obtains containing the fraction 3 of isomer E3 and contain isomer E4.

Vacuum concentration fraction 3 obtains isomer E3 (0.204g, 19.4%): [α] _D ²⁰=36 (c 1.0, MeCN), and (ee=97.7%);

Vacuum concentration fraction 4 obtains isomer E4 (0.160g, 15.2%): [α] _D ²⁰=-177 (c 1.0, MeCN), and (ee=96.0%).

Embodiment 14

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-(fluorine methoxyl group)-4-methyl-3-oxo isoindole quinoline-1-methane amide

In the bottle of 2ml, (0.233mmol 100mg) is dissolved in the acetonitrile (2ml), and adds K with 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (embodiment 2) ₂CO ₃(0.256mmol, 0.25mg), the sealing test tube.Make N ₂(g) bubbling passed through mixture 5 minutes.Make Bromofluoromethane (g) bubbling pass through mixture 30 seconds.In microwave oven, react (20min, 140 ℃).The evaporative removal solvent, (heptane/EtOAc 95/5 beginning with the degree such as grade is elevated to 50% with EtOAc concentration then by flash chromatography, (silica gel 600.004-0.063mm)) the purification reaction mixture, merge the fraction that contains product, the evaporative removal solvent, obtain title compound (68mg, 63.3%). ¹H-NMR (500MHz, CDCl ₃): δ 7,45-7,25 (m, 11H), 5,82-5,79 (m, 1H), 5,71-5,69 (m, 1H), 5,47 (s, 1H), 5,16 (d, 1H), 4,47 (s, 1H), 4,43 (d, 1H), 2,59 (s, 3H), 1,08 (s, 9H); To (C ₂₈H ₂₉FN ₂O ₃+ H)+the HRMS calculated value: 461.5611; Measured value (ES[M+H]+): 461.5596.

Embodiment 15

2-(biphenyl-2-methyl)-1-[(tertiary butyl amino) carbonyl]-4-methyl-3-oxo-2,3-dihydro-1H-isoindole-5-base methanesulfonates

With 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-oxo isoindole quinoline-1-methane amide (embodiment 2) (0.24mmol, 104mg) be dissolved among the DCM, and the adding methylsulfonyl chloride (0.36mmol, 42mg), mixture is cooled to 0 ℃, and drips TEA.Solution is heated to room temperature, stirs 2 hours up to surplus stock (LCMS) not.The evaporative removal solvent, (heptane/EtOAc 95/5 beginning with the degree such as grade is elevated to 50% with EtOAc concentration then by flash chromatography, (silica gel 600.004-0.063mm)) the purification reaction mixture, merge the fraction that contains product, the evaporative removal solvent, obtain title compound (62mg, 50.4%).

¹H-NMR (500MHz, CDCl ₃): δ 7,47-7,42 (m, 8H), 7,30-7,25 (m, 3H), 5,39 (s, 1H), 5,16 (d, 1H), 4,47 (s, 1H), 4,43 (d, 1H), 2,36 (s, 3H), 2,70 (s, 3H), 1,08 (s, 9H); To (C ₂₈H ₃₀N ₂O ₅S+H)+HRMS calculated value: 507.6335; Measured value (ES[M+H]+), 507.6326.

Embodiment 16

The N-{4-[(kharophen) methyl] benzyl }-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide.

With acetate (0.19mmol, 12mg) and o-(benzotriazole-1-yl) n, n, n ', (0.26mmol 0.83mg) in mixed at room temperature, and stirred 20 minutes n '-tetramethyl-urea Tetrafluoroboric acid ester.Add the n-methylmorpholine (0.26mmol, 0.26mg) and N-[4-(amino methyl) benzyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide (embodiment 8) (0.13mmol, 60mg).Stirred reaction mixture spends the night under the room temperature.The evaporative removal solvent, by preparation HPLC purifying crude product, described preparation HPLC is with acetonitrile/buffer reagent 20/80 beginning of degree such as grade, then acetonitrile concentration is brought up to 95%, buffer reagent is the mixture of acetonitrile/water (10/90) and ammonium acetate (0.1M), post: KR-100-7-C8,50mm x 250mm flow velocity: 40ml/min.Merge the fraction that contains product,, obtain title compound (10mg, 15.3%) the product lyophilized overnight. ¹H-NMR (500MHz, CDCl ₃): δ 7,75-7,71 (m, 1H), 7,64-7,65 (m, 2H), 7,52-7,47 (m, 1H), 7,46-7,37 (m, 6H), 7,37-7,22 (m, 3H), 7,13 (d, 2H), 6,86 (d, 2H), 6,04-5,99 (m, 1H), 5,67 (brs, 1H), 5,27 (d, 1H), 4,74 (s, 1H), 4,39 (d, 2H), 4,31 (d, 1H), 4,22-4,09 (m, 2H), 2,03 (s, 3H); To (C ₃₂H ₂₉N ₃O ₃+ H)+the HRMS calculated value: 504.6140; Measured value (ES[M+H]+): 504.6145.

Embodiment 17

2-(biphenyl-2-ylmethyl)-N-(4-{[(two acetyl fluorides) amino] methyl } benzyl)-3-oxo isoindole quinoline-1-methane amide

With difluoroacetic acid (0.19mmol, 19mg) and o-(benzotriazole-1-yl) n, n, n ', (0.26mmol 0.83mg) in mixed at room temperature, and stirred 20 minutes n '-tetramethyl-urea Tetrafluoroboric acid ester.Add the n-methylmorpholine (0.26mmol, 0.26mg) and N-[4-(amino methyl) benzyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide (embodiment 8) (0.13mmol, 60mg).Stirred reaction mixture spends the night under the room temperature.The evaporative removal solvent, by preparation HPLC purifying crude product, described preparation HPLC is with acetonitrile/buffer reagent 20/80 beginning of degree such as grade, then acetonitrile concentration is brought up to 95%, buffer reagent is the mixture of acetonitrile/water (10/90) and ammonium acetate (0.1M), post: KR-100-7-C8,50mm x 250mm flow velocity: 40ml/min.Merge the fraction that contains product,, obtain title compound (12mg, 17.0%) the product lyophilized overnight. ¹H-NMR (500MHz, CDCl ₃): δ 7,61-7,47 (m, 3H), 7,45-7,18 (m, 10H), 7,18-7,12 (m, 1H), 7,07 (d, 2H), 6,85 (d, 2H), 6,49 (brs, 1H), 6,27 (m, 1H), 5,90 (t, 1H), 5,20 (d, 1H), 4,69 (s, 1H), 4,41 (d, 2H), 4,29-4,21 (d, 1H), 4,21-4,05 (m, 2H); To (C ₃₂H ₂₇F ₂N ₃O ₃+ H)+the HRMS calculated value: 540.5948; Measured value (ES[M+H]+): 540.5895.

Embodiment 18

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-4,7-two fluoro-1-methyl-3-oxo isoindole quinoline-1-methane amide

With 2-ethanoyl-3, the 6-difluoro-benzoic acid (0.24mmol 50mg) is dissolved in the methyl alcohol (1ml), and adding (biphenyl-2-ylmethyl) amine (0.24mmol, 46mg).Stir the mixture in 50 ℃ and to spend the night to form imines.(0.24mmol 21mg) is dissolved in the acetonitrile and joins in the mixture with isocyano-uncle butane then.In 50 ℃ of reaction stirred 170h.The product precipitation is also filtered, and washs solid with EtOAc, obtains title compound (23mg, 20.5%). ¹H-NMR (500MHz, CDCl ₃): δ 7,64-7,56 (m, 1H), 7,52-7,43 (m, 2H), 7,42-7,08 (m, 8H), 5,08 (s, 1H), 4,65 (dd, 2H), 1,37 (s, 3H), 0,94 (s, 9H); To (C ₂₇H ₂₆F ₂N ₂O ₂+ H)+the HRMS calculated value: 449.5250; Measured value (ES[M+H]+): 449.5248.

Embodiment 19

2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide

With 4-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone (preparation X) (0.87mmol 147mg) is dissolved in the methyl alcohol (10ml), add (biphenyl-2-ylmethyl) amine (0.87mmol, 160mg) and stir 20min.With 1,1, (0.87mmol 120mg) adds in the mixture 1-three fluoro-4-butyl isocyanides then.Reaction stirred is spent the night under the room temperature.The evaporative removal solvent.By flash chromatography (heptane/acetone 90/10 beginning with the degree such as grade is elevated to 50% with acetone concentration, (silica gel 600.004-0.063mm) then) purifying crude product, merge the fraction that contains product, the evaporative removal solvent obtains title compound (66mg, 16%). ¹H-NMR (500MHz, CDCl ₃): δ 7.50-7.02 (m, 12H), 7.02-6.92 (m, 1H), 5.18-5.08 (D, 1H), 4.62 (s, 1H), 4.28 (d, 1H), 3.25-2.93 (m, 2H), 2.00-1.82 (m, 2H), 1.62-1.44 (m, 2H); To (C ₂₆H ₂₂F ₄N ₂O ₂+ H)+the HRMS calculated value: 471.4788; Measured value (ES[M+H]+): 471.4789.

Embodiment 20

2-(biphenyl-2-ylmethyl)-1-[(tertiary butyl amino) carbonyl]-4-methyl-3-oxo-2,3-dihydro-1H-isoindole-5-base triflate

(1.40mmol 0.6g) is dissolved among the THF (10ml), adds K with 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-carbamyl amine (embodiment 2) ₂CO ₃(4.20mmol, 0.58g) and n-phenyl trifluoromethanesulfonate methylsulfonyl imines (1.54mmol, 0.55g).In microwave oven, react (10min, 120 ℃).The evaporative removal solvent, (begin heptane/DCM 50/50 by flash chromatography with the degree such as grade, then DCM concentration is elevated to 100%, adds EtOAc afterwards, the concentration of EtOAc is elevated to 30% (silica gel 600.004-0.063mm) as eluent) the purifying crude product.Merge the fraction that contains product, the evaporative removal solvent obtains title compound (0.655g, 83.4%). ¹H-NMR (500MHz, CDCl ₃): δ 7.521 (d, 1H), 7.42-7.31 (m, 7H), 7.30-7.24 (m, 2H), 6.08 (s, 1H), 5.26 (d, 1H), 4.53 (s, 1H), 4.44 (d, 1H), 2,52 (s, 3H), 1.16 (s, 9H); To (C ₂₈H ₂₇F ₃N ₂O ₅S+H)+HRMS calculated value: 561.6048; Measured value (ES[M+H]+): 561.6019.

Embodiment 21

2-(biphenyl-2-ylmethyl)-N-(4-{[(acetyl fluoride base) amino] methyl } benzyl)-3-oxo isoindole quinoline-1-methane amide

With gifblaar poison (0.19mmol, 15mg) and o-(benzotriazole-1-yl) n, n, n ', (0.26mmol 0.83mg) in mixed at room temperature, and stirred 20 minutes n '-tetramethyl-urea Tetrafluoroboric acid ester.Add the n-methylmorpholine (0.26mmol, 0.26mg) and N-[4-(amino methyl) benzyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide (embodiment 8) (0.13mmol, 60mg).Stirred reaction mixture spends the night under the room temperature.The evaporative removal solvent, by preparation HPLC purifying crude product, described preparation HPLC is with acetonitrile/buffer reagent 20/80 beginning of degree such as grade, then acetonitrile concentration is brought up to 95%, buffer reagent is the mixture of acetonitrile/water (10/90) and ammonium acetate (0.1M), post: KR-100-7-C8,50mm x 250mm flow velocity: 40ml/min.Merge the fraction that contains product,, obtain title compound (35mg, 51.6%) the product lyophilized overnight. ¹H-NMR (500MHz, CDCl ₃): δ 7.63-7.58 (m, 1H), 7.57-7.48 (m, 2H), 7.44-7.35 (m, 4H), 7.35-7.21 (m, 6H), 7.19-7.15 (m, 1H), 7.11 (d, 2H), 6.91 (d, 2H), 6.63-6.58 (m, 1H), 6.55 (bs, 1H), 5.22 (d, 1H), 4.88 (s, 1H), 4.79 (s, 1H), 4.73 (s, 1H), 4.44 (d, 2H), 4.28 (d, 1H), 4.25-4.13 (m, 2H); To (C ₃₂H ₂₈FN ₃O ₃+ H)+the HRMS calculated value: 522.6044; Measured value (ES[M+H]+), 522.6043.

Embodiment 22

N-(4,4-difluoro butyl)-2-(diphenyl-methyl)-3-oxo isoindole quinoline-1-methane amide

(6.66mmol 1.00g) is dissolved in the methyl alcohol (10ml), and (6.66mmol 1.22g), stirred 20 minutes to add (diphenyl methyl) amine with the 2-carbamoyl benzoate.With 1, (6.66mmol 0.79g) adds in the mixture 1-two fluoro-4-butyl isocyanides then.Reaction stirred is spent the night under the room temperature.The evaporative removal solvent.(begin heptane/EtOAc 90/10 by flash chromatography with the degree such as grade, then EtOAc concentration is elevated to 50%, (silica gel 600.004-0.063mm)) the purifying crude product, merge the fraction that contains product, the evaporative removal solvent, the gained material does not have enough purity, therefore by preparing HPLC to its purifying, described preparation HPLC is with acetonitrile/buffer reagent 20/80 beginning of degree such as grade, then acetonitrile concentration is brought up to 95%, buffer reagent is the mixture of acetonitrile/water (10/90) and ammonium acetate (0.1M), post: KR-100-7-C8,50mm x 250mm flow velocity: 40ml/min.Merge the fraction that contains product, the evaporative removal acetonitrile.Make the product lyophilized overnight, obtain title compound (140mg, 32.3%). ¹H-NMR (500MHz, CDCl ₃): δ 7.68-7.49 (m, 3H), 7.49-7.18 (m, 9H), 7.06-6.93 (m, 2H), 6.78 (s, 1H), 6.25-6.12 (m, 1H), 7.78-5.30 (m, 1H), 5.24 (s, 1H), 2.89-2.70 (m, 1H), 2.63-2.43 (m, 1H), 1.54-1.30 (m, 2H), and 1.25-1.05 (m, 2H); To (C ₂₆H ₂₄F ₂N ₂O ₂+ H) ⁺The HRMS calculated value: 435.1884; Measured value (ES[M+H] ⁺): 435.1882.

Embodiment 23

(1S or 1R)-N-(4,4-difluoro butyl)-2-(diphenyl-methyl)-3-oxo isoindole quinoline-1-methane amide (isomer E1)

(1R or 1S)-N-(4,4-difluoro butyl)-2-(diphenyl-methyl)-3-oxo isoindole quinoline-1-methane amide (isomer E2)

(1.63mmol 0.71g) separates, and described HPLC system disposition has ReproSil, 10 μ, 250mm x 20mm post to N-(4,4-difluoro butyl)-2-(diphenyl-methyl)-3-oxo isoindole quinoline-1-methane amide (embodiment 22) by preparation HPLC system.Use heptane/IPA (30/70) as moving phase, obtain containing isomer E1 fraction 1, contain the fraction 2 of isomer E2.

Vacuum concentration fraction 1 obtains isomer E1 (0.316g, 44.5%), ee=100%;

Vacuum concentration fraction 2 obtains isomer E2 (0.308g, 43.4%), ee=99.6%.

Embodiment 24

N-benzyl-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide

(2.72g, 18.1mmol) (2.30ml 18.1mmol) joins in the flask, adds methyl alcohol (15ml) then, stirs the mixture under the room temperature 2 hours with the 1-phenylethylamine with the 2-carbamoyl benzoate.(2.12g 18.1mmol) joins in the mixture, spends the night at the stirring at room reactant will to be dissolved in (isocyano-methyl) benzene among the MeCN (25ml).Finish this reaction, evaporating solvent in the next morning.Be dissolved in crude product among the DCM (20ml) and water (10ml) extraction, collect organic phase, evaporate most of solvent, add EtOAc and evaporating solvent then.By purification by flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column uses heptane and EtOAc as eluent) and crude product, then carry out vacuum concentration, obtain title compound (4.16g, 62%).

¹³C-NMR (500MHz, CDCl ₃) δ 170.73,170.47,169.09,168.26,142.14,142.02,140.45,140.37,137.34,137.14,132.79,132.75,131.09,130.99,129.38,129.35,129.21,129.10,128.96,128.71,128.50,128.27,128.15,128.02,127.96,127.68,127.58,127.49,124.32,124.26,122.93,122.78,63.75,63.31,52.56,52.12,43.89,43.39,18.19,17.58; To (C ₂₄H ₂₂N ₂O ₂+ H) ⁺The HRMS calculated value: 371.1760; For the measured value of separately non-corresponding isomer (ES[M+H] ⁺): 371.1768 and 371.1771.

Embodiment 25

(1S or 1R)-N-benzyl-3-oxo-2-[(1R or 1S)-and the 1-phenylethyl] isoindoline-1-methane amide (E1);

(1S or 1R)-N-benzyl-3-oxo-2-[(1S or 1R)-and the 1-phenylethyl] isoindoline-1-methane amide (E2);

(1R or 1S)-N-benzyl-3-oxo-2-[(1R or 1S)-and the 1-phenylethyl] isoindoline-1-methane amide (E3);

(1R or 1S)-N-benzyl-3-oxo-2-[(1S or 1R)-and the 1-phenylethyl] isoindoline-1-methane amide (E4);

By preparation HPLC system four kinds of steric isomers of N-benzyl-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide (embodiment 24) are separated, described preparation HPLC system disposition has Chirapak AD-H 5 μ 250mm x 20mm posts, use heptane/EtOH (85/15) as moving phase, obtain containing isomer E1 fraction 1, contain the fraction 2 of isomer E2 and isomery E3 and contain the fraction 3 of isomer E4.Vacuum concentration fraction 1 gets isomer 1 (E1) (0.602g, 22.8%): [α] _D ²⁰=+121.9 (c 1.0, MeCN); To (C ₂₄H ₂₂N ₂O ₂+ H) ⁺The HRMS calculated value: 371.1759, measured value (ES[M+H] ⁺): 371.1760.

Vacuum concentration fraction 3 obtains isomer 4 (E4) (0.516g, 19.5%): [α] _D ²⁰=-121.3 (c 1.0, MeCN); To (C ₂₄H ₂₂N ₂O ₂+ H) ⁺The HRMS calculated value: 371.1759, measured value (ES[M+H] ⁺): 371.1779.

Concentrate fraction 2, by preparation HPLC system's separating isomerism body 2 and isomer 3, described HPLC system disposition has Chirapak IA, 5 μ, 250mm x 20mm post.Use heptane/EtOH (80/20) as moving phase, obtain containing isomer E2 fraction 1, obtain containing the fraction 2 of isomer E3.

Vacuum concentration fraction 1 obtains isomer 2 (E2) (0.571g, 21.6%): [α] _D ²⁰=+161.0 (c 1.0, MeCN); To (C ₂₄H ₂₂N ₂O ₂+ H) ⁺The HRMS calculated value: 371.1759, measured value (ES[M+H] ⁺): 371.1761.

Vacuum concentration fraction 2 obtains isomer 3 (E3) (0.718g, 27.1%): [α] _D ²⁰=-153.0 (c 1.0, MeCN) to (C ₂₄H ₂₂N ₂O ₂+ H) ⁺The HRMS calculated value: 371.1759, measured value (ES[M+H] ⁺): 371.1758.

Embodiment 26

N-(3-benzyl chloride base)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide

With 3-amino-2,2-dimethyl propylene-1-alcohol (0.276mmol) is dissolved among the MeCN (1ml), and joins in the 2-carbamoyl benzoate (0.276mmol) that is dissolved among the MeOH (1ml) stirring at room 30 minutes.1-chloro-3-(isocyano-methyl) benzene (0.248mmol) that will be dissolved among the MeCN (2ml) joins in the mixture, makes reactant in stirred overnight at room temperature.Finish reaction, evaporating solvent the next morning.Be dissolved in crude product among the DCM (4ml) and water (3ml) extraction, collect organic phase, evaporating solvent.Crude product is dissolved among the DMSO (1ml), filter, and by the preparation HPLC carry out purifying, described preparation HPLC uses and has the Water FractionLynxIII HPLC system that quality triggers the fraction collector, this system disposition has Xbridge Prep C18150x 19mm post, and adopting gradient is 100%A (5%MeCN+95%0.2%NH ₃) to 100%B (95%MeCN+5%0.2%NH ₃) MeCN/0.2%NH ₃Buffering system is as moving phase.Then carry out vacuum concentration, obtain title compound (0.025g, 23%).

¹H-NMR* (600MHz, DMSO-d ₆, DMSO*) δ 9.29-9.17 (m, 1H), 7.77-7.46 (m, 4H), 7.4-7.15 (m, 4H), 5.48-5.4 (s, 1H), 4.74-4.63 (m, 1H), 4.4-4.26 (m, 2H), 3.79-3.71 (d, 1H), 3.19-3.05 (m), 2.76-2.64 (d), 0.88-0.75 (s, 6H); To (C ₂₁H ₂₃ClN ₂O ₃+ H) ⁺The HRMS calculated value: 387.1475, measured value (ES [M+H] ⁺): 387.1475.

Embodiment 27

2-[2-(4-chloro-phenyl-) propyl group]-N-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide

With the 2-carbamoyl benzoate (0.060g, 0.44mmol), 2-(4-chloro-phenyl-) third-1-amine hydrochlorate (0.068g, 0.40mmol) and TEA (0.062ml 0.44mmol) joins in the flask, and is dissolved in the methyl alcohol (2ml) stirring at room 2 hours.To be dissolved in 4-(isocyano-the methyl)-5-methyl-2-phenyl-1 among the MeCN (2ml), and the 3-oxazole (0.079g 0.40mmol) joins in the mixture, stirring at room reactant 2 days, and evaporating solvent.Crude product is dissolved in DCM (4ml) and water (3ml) extraction, collects organic phase, evaporating solvent.By purification by flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column uses heptane and EtOAc as eluent) and crude product, then carry out vacuum concentration, obtain title compound (0.017g, 8.5%). ¹H-NMR(500MHz，CDCl ₃)δ8.22-7.34(m，9H)，7.21-7.01(m，4H)，6.56-6.34(m，1H)，4.64-3.98(m，3H)，3.42-3.12(m，2H)，2.53-2.16(m，3H)，1.4-1.08(m，3H)。

Embodiment 28

N-(tertiary butyl)-2-[(1-methyl-5-phenyl-1H-pyrazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide

Be dissolved in 1-(1-methyl-5-phenyl-1H-pyrazole-3-yl) methylamine (0.400mmol) among the MeCN (1ml) and join in the 2-carbamoyl benzoate (0.400mmol) that is dissolved among the MeOH (1ml) stirring at room 1 hour.Isocyano-uncle butane (0.400mmol) is joined in the mixture, make reactant in stirring at room 2 days.Evaporating solvent is dissolved in crude product among the DCM (4ml) and water (3ml) extraction, collects organic phase, evaporating solvent.By purification by flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column uses heptane and EtOAc as eluent) and crude product, then carry out vacuum concentration, obtain title compound (0.078g, 48.4%). ¹H-NMR (500MHz, CDCl ₃) δ 7.94-7.36 (m, 9H), 6.39-6.28 (m, 1H), 5.28-5.07 (m, 2H), 4.39-4.23 (d, 1H), 3.92-3.79 (s, 3H), 1.44-1.2 (s, 9H); To (C ₂₄H ₂₆N ₄O ₂+ H) ⁺The HRMS calculated value: 403.2134, measured value (ES[M+H] ⁺): 403.2156.

Embodiment 29

2-(biphenyl-2-ylmethyl)-6-bromo-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide

With 1-biphenyl-2-base methylamine (0.225g, 1.23mmol) and 5-bromo-3-hydroxyl-2-cumarone-1 (3H)-ketone (preparation W) (0.283g 1.24mmol) adds in the flask, adds methyl alcohol (1ml), makes mixture in stirring at room 3 hours.(0.139ml 1.23mmol) adds mixture with isocyano-uncle butane then.Make reactant in stirred overnight at room temperature.Evaporating solvent is dissolved in crude product among the DCM (4ml) and water (3ml) extraction, collects organic phase, evaporating solvent.By purification by flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column uses heptane and EtOAc as eluent) and crude product, then carry out vacuum concentration, obtain title compound (0.191g, 32.4%). ¹³C-NMR (500MHz, CDCl ₃) δ 168.58,166.16,143.65,142.49,140.52,133.37,132.34,130.62,130.46,129.15,128.62,128.35,128.15,127.99,127.87,127.28,126.31,125.21,124.92,62.87,51.61,42.93,31.88,28.99,27.52,27.24,22.58,13.28; To (C26H25BrN2O2+H) ⁺The HRMS calculated value: 477.1178, measured value (ES[M+H] ⁺): 477.1173.

Embodiment 30

2-(biphenyl-2-ylmethyl)-5-bromo-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide

With 1-biphenyl-2-base methylamine (0.106g, 0.578mmol) and 5-bromo-2-carbamoyl benzoate (commercially available) (0.132g 0.578mmol) adds in the flask, adds methyl alcohol (1ml), makes mixture in stirring at room 30 minutes.(0.065ml 0.578mmol) adds in the mixture with isocyano-uncle butane then.With reactant in stirring at room 16 hours.Evaporating solvent is dissolved in crude product among the DCM (4ml) and water (3ml) extraction, collects organic phase, evaporating solvent.By purification by flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column uses heptane and EtOAc as eluent) and crude product, then carry out vacuum concentration, obtain title compound (0.143g, 51.8%). ¹H-NMR (500MHz, CDCl ₃) δ 7.89-7.82 (m, 1H), 7.78-7.71 (m, 1H), 7.56-7.24 (m, 10H), 5.47-5.33 (d, 1H), 4.72-4.63 (s, 1H), 4.23-4.07 (d, 1H), 1.39-1.13 (s, 9H); To (C26H25Br N2O2+H) ⁺The HRMS calculated value: 477.1178, measured value (ES [M+H] ⁺): 477.1184.

Embodiment 31

2-(biphenyl-2-ylmethyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide

1-biphenyl-2-base methylamine (0.400mmol) is dissolved among the MeCN (1ml), and join the 2-carbamoyl benzoate (0.400mmol) that is dissolved among the MeOH (1ml), stirred 30 minutes under the room temperature, to be dissolved in 1 among the MeCN (2ml), 1-two fluoro-4-butyl isocyanides (preparation P) (0.400mmol) join in the mixture, the reactant room temperature is stirred spend the night.Finish reaction in the next morning, and evaporating solvent.Crude product is dissolved in DCM (4ml) and water (3ml) extraction, collects organic phase, evaporating solvent.Crude product is dissolved among the DMSO (1ml), filter, and by the preparation HPLC carry out purifying, described preparation HPL uses and has the Waters FractionLynx I HPLC system that quality triggers the fraction collector, this system disposition has Xbridge Prep C18150x 19mm post, and adopting gradient is from 100%A (5%MeCN+95%0.2%NH ₃) to 100%B (95%MeCN+5%0.2%NH ₃) MeCN/0.2%NH ₃Buffering system is as moving phase.Then carry out vacuum concentration, obtain title compound (0.057g, 33%). ¹H-NMR* (600MHz, DMSO-d ₆, DMSO*) δ 8.526-8.3 (m, 1H), 7.75-7.03 (m, 13H), 6.2-5.85 (m, 1H), 5.27-5.07 (d, 1H), 4.83-4.66 (s, 1H), 4.13-3.85 (d, 1H), 3.1-2.83 (m), 1.81-1.55 (m, 2H), 1.5-1.27 (m, 2H); To (C26H24 F N2 O2+H) ⁺The HRMS calculated value: 435.1884, measured value (ES[M+H] ⁺): 435.1865.

Embodiment 32

2-(biphenyl-2-ylmethyl)-N-[(2,2-two fluoro-1,3-benzo dioxole-5 base)-6-fluoro-3-oxo isoindole quinoline-1-methane amide

1-biphenyl-2-base methylamine (0.370mmol) is dissolved among the MeCN (1ml), and join 5-fluoro-3-hydroxyl-2-cumarone-1 (3H)-ketone of being dissolved among the MeOH (1ml) (preparation X) (0.370mmol) in, stirred 30 minutes under the room temperature, to be dissolved in the isocyano-(2 among the MeCN (2ml), 2-two fluoro-1,3-benzo dioxole-5 base) methane (preparation R) (0.370mmol) joins in the mixture, with reactant in stirring at room 3 days.Evaporating solvent is dissolved in crude product among the DCM (4ml) and water (3ml) extraction, collects organic phase, evaporating solvent.Crude product is dissolved among the DMSO (1ml), filter, and by the preparation HPLC carry out purifying, described preparation HPL uses and has the WatersFractionLynx I HPLC system that quality triggers the fraction collector, this system disposition has Xbridge Prep C18 150x 19mm post, and adopting gradient is from 100%A (5%MeCN+95%0.2%NH ₃) to 100%B (95%MeCN+5%0.2%NH ₃) MeCN/0.2%NH ₃Buffering system is as moving phase.Then carry out vacuum concentration, obtain title compound (0.053g, 26%). ¹H-NMR* (600MHz, DMSO-d, DMSO*) δ 8.95-8.83 (m, 1H), 7.76-7.64 (m, 1H), 7.48-6.87 (m, 14H), 5.18-5.08 (d, 1H), 4.84-4.78 (s, 1H), 4.2-3.95 (m); To (C30 H21 F3 N2O4+H) ⁺The HRMS calculated value: 531.1532, measured value (ES[M+H] ⁺): 531.1537.

Embodiment 33

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide

With the 2-carbamoyl benzoate in the methyl alcohol (55ml) (2.50g, 16.7mmol) and 1-biphenyl-(3.05g, mixture 16.7mmol) was in stirring at room 1 hour for 2-base methylamine.Add then isocyano-uncle butane (1.38g, 16.7mmol).Stir the gained mixture overnight under the room temperature, and carry out concentrating under reduced pressure.Obtain crystallization by in resistates, adding ethanol.Filter out crystal (2.06g) and vacuum-drying.By flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column, the ethyl acetate (gradient from 6% to 50%) in the use heptane is as eluent) purifying filtrate, remove solvent, obtain the 2.05g white solid.Merging is from crystallization and stratographic product, and with the methyl alcohol development, obtains the 2.88g white solid.Surplus materials carries out the after-crop product (corp) that purifying obtains 0.70g by preparation HPLC. ¹H NMR (500MHz, CD ₃OD) δ 7.71 (dm, 1H), 7.56 (m, 1H), 7.50 (m, 1H), 7.42 (dm, 1H), 7.38-7.24 (m, 9H), 5.37 (d, 1H), 4.71 (s, 1H), 4.15 (d, 1H), 1.22 (s, 9H); To (C ₂₆H ₂₆N ₂OrI-H) ⁺The HRMS calculated value: 399.2066; Measured value (ES[M+H] ⁺): 399.2073.

Embodiment 34

(R or S) 2-(biphenyl-2-the ylmethyl)-N-tertiary butyl-3-oxo isoindole quinoline-1-methane amide (isomer 1)

(S or R) 2-(biphenyl-2-the ylmethyl)-N-tertiary butyl-3-oxo isoindole quinoline-1-methane amide (isomer 2)

The n-heptane solution of use 25%2-propyl alcohol is gathered in the crops product (2.88g) with the first time of embodiment 33 and is separated into its enantiomer on Chiralpak IA.Concentrating under reduced pressure obtains 1.39g isomer 1 and 1.25g isomer 2.

Embodiment 35

N-benzyl-6-cyano group-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide

(i) N-benzyl-6-bromo-3-oxo-2-[(1R)-1-phenylethyl] isoindoline-1-methane amide

(0.12g 1.0mmol) joins in the 5-bromo-3-hydroxyl-slurries of 2-cumarone-1 (3H)-ketone in methyl alcohol (5ml) with (R)-(+)-1-phenyl-ethyl amine.Stirred this solution 30 minutes under the room temperature.(0.12g 1.0mmol), stirs the gained mixture overnight, and evaporates under the room temperature to add isocyano-benzyl alkane (benzyl isocyanide).By flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column, the ethyl acetate (gradient from 6% to 50%) in the use heptane is as eluent) carry out purifying, then vacuum concentration obtains title compound (0.33g, 72%), is white powder. ¹H NMR (500MHz, CD ₃OD) δ 7.68 (m, 2H), 7.52 (m, 1H), 7.44 (m, 1H), 7.36-7.20 (m, 8H), 7.68 (m, 1H), 5.61 and 5.32 (q, 1H, rotational isomer), 5.22 and 4.79 (s, 1H, rotational isomers), 4.37 (br s, 1H), 3.97 (m, 1H), 1.74 and 1.61 (d, 3H, rotational isomers); MS (ESI) m/z 449.0 ([M+H] ⁺).

(ii) N-benzyl-6-cyano group-3-oxo-2-[(1R)-1-phenylethyl] isoindoline-1-methane amide

By the argon gas bubbling with the N-benzyl among the DMF (3ml)-6-bromo-3-oxo-2-[(1R)-1-phenylethyl] isoindoline-1-methane amide (and 0.10g, 0.22mmol), zinc cyanide (0.040g, 0.34mmol) and Pd (PPh ₃) ₄(0.026g, mixture degassing 0.022mmol) 15 minutes.Then with this mixture in microwave reactor in 200 ℃ of heating 30 minutes, and vacuum concentration.By flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column, the ethyl acetate (gradient from 9% to 76%) in the use heptane is as eluent) carrying out purifying, vacuum concentration obtains title compound (0.064g, 72%) then, is white solid. ¹H NMR (500MHz, (CD ₃) ₂CO) δ 8.24 (br s, 1H), 7.94-7.81 (m, 3H), 7.52 (m, 1H), 7.36-7.19 (m, 8H), 7.13 (m, 1H), 5.63 and 5.21 (q, 1H), 5.41 and 5.04 (s, 1H), 4.43 (m, 1H), 4.15 (m, 1H), 1.84 and 1.67 (d, 3H, rotational isomers).MS (ESI) m/z 396.0 ([M+H]+); To (C ₂₆H ₂₁N ₃O ₂+ H) ⁺The HRMS calculated value: 396.1712; Measured value (ESI[M+H] ⁺): 396.1739.

Embodiment 36

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-cyano group-3-oxo isoindole quinoline-1-methane amide

Synthesize according to the step of describing among the above embodiment 35, and use 1-biphenyl-2-base methylamine to replace (R)-(+)-1-phenyl-ethyl amine, replace isocyano-benzyl alkane with isocyano-uncle butane.To (C ₂₇H ₂₅N ₃O ₂+ H) ⁺The HRMS calculated value: 424.2025; Measured value (ESI[M+H] ⁺): 424.2010.

Embodiment 37

2-(2-the bromobenzyl)-N-tertiary butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide

(i) N-(2-bromobenzyl)-N-[2-(tertiary butyl amino)-1-(2-furyl)-2-oxoethyl] fourth-2-alkynyl amide

With the fourth among the MeOH (20ml)-2-acetylenic acid (0.42g, 5.0mmol), 1-(2-bromophenyl) methylamine (0.93g, 5.0mmol) and the 2-furfural (0.48g, mixture 5.0mmol) was in stirring at room 1 hour, add then isocyano-uncle butane (0.42g, 5.0mmol).With the gained mixture in stirred overnight at room temperature and concentrating under reduced pressure.Crude product is purified and be used for next step.

(ii) 2-(2-bromobenzyl)-N-tertiary butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide

Will be from N-(2-bromobenzyl)-N-[2-(tertiary butyl amino)-1-(2-furyl)-2-oxoethyl of above-mentioned steps (i)] fourth-2-alkynyl amide (2.10g, 0.487mmol) and the mixture of Ytterbiumtriflate (III) (0.302g, 0.487mmol) in dimethylbenzene (100ml) reflux and heat 1.5h down.Filter out white precipitate, obtain the 0.87g pure products.Concentrated filtrate is by flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column, the ethyl acetate (gradient from 30% to 70%) in the use heptane is as eluent) carry out purifying, obtain 0.32g after-crop product, making ultimate production is 1.19g (57%). ¹H NMR(500MHz，(CD ₃OD)δ7.60(m，1H)，7.36-7.27(m，2H)，7.21(m，1H)，7.08(m，1H)，6.95(m，1H)5.23(d，1H)，4.66(s，1H)，4.37(d，1H)，2.55(s，3H)，1.30(s，9H)。

Embodiment 38

2-(biphenyl-2-the ylmethyl)-N-tertiary butyl-4-methyl-5-[(methyl sulphonyl) amino]-3-oxo isoindole quinoline-1-methane amide

(i) N-(biphenyl-2-ylmethyl)-N-{2-(tertiary butyl amino)-1-[1-(methyl sulphonyl)-1H-pyrroles-2-yl]-the 2-oxoethyl } fourth-2-alkynyl amide

With the fourth in the methyl alcohol (6ml)-2-acetylenic acid (0.050g; 0.60mmol), 1-biphenyl-2-base methylamine (0.11g, 0.60mmol) and 1-(methyl sulphonyl)-1H-pyrrole-2-aldehyde (J.Am.Chem.Soc., 1998; 1741) (0.10g, 0.60mmol) mixture was stirring at room 1 hour.Add then isocyano-uncle butane (0.050g, 0.60mmol).With gained mixture stirring at room 3 days, white precipitate.Leach precipitation and vacuum-drying, obtain the white powder of 0.23g (76%), it is used for next step without being further purified.MS(ESI)m/z 506.2([M+H] ⁺)。

(ii) 2-(biphenyl-2-the ylmethyl)-N-tertiary butyl-4-methyl-5-[(methyl sulphonyl) amino]-3-oxo isoindole quinoline-1-methane amide

Will be from N-(biphenyl-2-ylmethyl)-N-{2-(tertiary butyl amino)-1-[1-(methyl sulphonyl)-1H-pyrroles-2-yl of step (i)]-the 2-oxoethyl } (0.050g is 0.099mol) at diox (4ml) and 1-butyl-3-methyl isophthalic acid H-imidazoles-3-phosphofluoric acid ester (BMIMPF for fourth-2-alkynyl amide ₆, 0.2ml) solution in heated 30 minutes in 200 ℃ in microwave reactor.The concentrating under reduced pressure mixture, resistates distributes between ethyl acetate and water.Separate each layer, with two batches of ethyl acetate extraction waters.The organic layer that merges is with two parts of water washings, through MgSO ₄Drying, concentrating under reduced pressure.By flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column, the ethyl acetate (gradient from 12% to 100%) in the use heptane is as eluent) carrying out purifying, vacuum concentration obtains title compound (0.055g, 56%) then, is white solid. ¹H NMR(500MHz，(CD ₃) ₂CO)δ8.00(br s，1H)，7.53(d，1H)，7.37-7.20(m，10H)，5.32(d，1H)，4.62(s，1H)，4.10(d，1H)，2.97(s，3H)，2.67(s，3H)，1.21(s，9H)；MS(ESI)m/z 506.2([M+H] ⁺)。

Embodiment 39

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-[(methyl sulphonyl) amino]-3-oxo isoindole quinoline-1-methane amide

Synthesize according to the method for describing in the foregoing description 38, use propynoic acid to replace fourth-2-acetylenic acid.MS(ESI)m/z 492.1([M+H]+)。

Embodiment 40

N-(tertiary butyl)-2-(4-benzyl chloride base)-5-hydroxyl-oxo isoindole quinoline-1-methane amide

(i) N-[2-(tertiary butyl amino)-1-(2-furyl)-2-oxoethyl]-N-(4-benzyl chloride base)-3-(trimethyl silyl) third-2-alkynyl amide

With 3-(trimethyl silyl) third-2-acetylenic acid (0.071g, 0.50mmol), 1-(4-chloro-phenyl-) methylamine (0.071g, 0.50mmol) and 2-furfural (0.048g, 0.50mmol) mixture in MeOH (2ml) is in stirring at room 1 hour, add then isocyano-uncle butane (0.042g, 0.50mmol).With the gained mixture at stirred overnight at room temperature and concentrating under reduced pressure.Crude product is used for next step without being further purified.MS(ESI)m/z 444.9([M+H] ⁺)。

(ii) N-(tertiary butyl)-2-(4-benzyl chloride base)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide

Will be from N-[2-(tertiary butyl amino)-1-(2-furyl)-2-oxoethyl of above-mentioned steps (i)]-N-(4-benzyl chloride base)-3-(trimethyl silyl) third-2-alkynyl amide (0.223g, 0.5mmol), Ytterbiumtriflate (III) (0.124g, 0.40mmol) and 1-butyl-3-methyl isophthalic acid H-imidazoles-3-phosphofluoric acid ester (BMIMPF ₆, 0.3ml) the mixture in the Zai diox (15ml) heated concentrating under reduced pressure 30 minutes at 200 ℃ in microwave reactor.By flash chromatography (SP1 ^TMRapid system is from Biotage ^TM, silica column, the ethyl acetate (gradient from 30% to 70%) in the use heptane is as eluent) carrying out purifying, vacuum concentration obtains 0.032g (17%) title compound then. ¹H NMR (500MHz, (CD ₃) ₂SO) δ 9.87 (s, 1H), 8.13 (s, 1H), 7.41 (dm, 2H), 7.26 (dm, 1H), 7.22 (dm, 2H), 7.03 (m, 1H), 6.98 (m, 1H), 5.07 (d, 1H), 4.78 (s, 1H), 3.97 (d, 1H), 1.24 (s, 9H); MS (ESI) m/z 373.0 ([M+H] ⁺); To (C ₂₀H ₂₁ClN ₂O ₃+ H) ⁺The HRMS calculated value: 373.1319; Measured value (ESI[M+H] ⁺): 373.1338.

Embodiment 41

N-(tertiary butyl)-2-(4-benzyl chloride base)-7-hydroxyl-3-oxo isoindole quinoline-1-methane amide

Title compound is separated as the by product in synthetic N-(tertiary butyl)-2-(4-benzyl chloride base)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide.To (C ₂₀H ₂₁ClN ₂O ₃+ H) ⁺The HRMS calculated value: 373.1319; Measured value (ESI[M+H] ⁺): 373.1324.

Embodiment 42

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-7-hydroxyl-3-oxo isoindole quinoline-1-methane amide

Title compound is separated as the by product in Synthetic 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide.To (C ₂₆H ₂₆N ₂O ₃+ H) ⁺The HRMS calculated value: 415.2022; Measured value (ESI[M+H] ⁺): 415.2005.

Embodiment 43

2-(biphenyl-4-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide

With the fourth among the MeOH (2ml)-2-acetylenic acid (0.025g, 0.30mmol), 1-biphenyl-4-base methylamine (0.055g, 0.30mmol) and the 2-furfural (0.29g, mixture 0.30mmol) was in stirring at room 30 minutes, add then isocyano-uncle butane (0.025g, 0.30mmol).The gained mixture was stirring at room 3 days, and concentrating under reduced pressure.Obtain 0.125g (97%) title compound.This crude product is purified and be used for next step; MS (ESI) m/z 429.0 ([M+H] ⁺).

(ii) 2-(biphenyl-4-the ylmethyl)-N-tertiary butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide

Will be from N-(biphenyl-2-ylmethyl)-N-[2-(tertiary butyl amino)-1-(2-furyl)-2-oxoethyl of above-mentioned steps (i)] fourth-2-alkynyl amide (0.125g, 0.29mmol) and Ytterbiumtriflate (III) (mixture in 0.037g, the 0.06mmol) Zai diox (20ml) in microwave reactor at 200 ℃ of heating 30 minutes, and concentrating under reduced pressure.Resistates in phase separator at DCM and saturated NaHCO ₃Distribute between the aqueous solution.Water is with the DCM extraction that surpasses two batches, with the organic layer vacuum concentration that merges.Carry out purifying by the preparation HPLC that uses FractionLynx I HPLC system, described HPLC system disposition has Gemini 5u C18 110A 21.2x 100mm post, adopts 0.2%NH ₃Middle gradient is the CH of 5-95% ₃CN is as moving phase.Vacuum concentration obtains title compound (0.073g, 57%) then. ¹H NMR (500MHz, (CD ₃) ₂SO) δ 9.61 (s, 1H), 8.10 (s, 1H), 7.61 (m, 4H), 7.59 (m, 2H), 7.32 (m, 1H), 7.26 (dm, 2H), 7.06 (dm, 1H), 6.95 (dm, 1H), 5.12 (d, 1H), 4.73 (s, 1H), 3.91 (d, 1H), 1.23 (s, 9H); MS (ESI) m/z 429.2 ([M+H] ⁺); To (C ₂₇H ₂₈N ₂O ₃+ H) ⁺The HRMS calculated value: 429.2178; Measured value (ESI[M+H] ⁺): 429.2144.

Embodiment 44

N-(tertiary butyl)-2-[(4 '-fluorine biphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide

By the argon gas bubbling with 2-(2-bromobenzyl)-N-tertiary butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (the foregoing description 37) (0.078g, 0.18mmol), (4-fluorophenyl) boric acid (0.030g, 0.22mmol), Pd (PPh ₃) ₄(0.010g, 0.009mmol) and CsCO ₃The aqueous solution (0.117g is dissolved in the 0.2ml water) is 1, and the mixture in the 2-glycol dimethyl ether (1.0ml) outgased 5 minutes in the microwave reactor bottle of 2ml.Then described mixture was heated 15 minutes at 130 ℃ in microwave reactor, and vacuum concentration.In resistates, add hydrochloric acid (the 2M solution of 2ml), and in phase separator with 3 batches of DCM aqueous phase extracted.The organic layer that concentrating under reduced pressure merges.Carry out purifying by the preparation HPLC that uses FractionLynx II HPLC system, described HPLC system disposition Sunfire 5 μ m C18 OBD19x 150mm posts adopt 0.1M HCO ₂Gradient is the CH of 5-95% among the H ₃CN is as moving phase.Vacuum concentration obtains title compound (0.078g, 97%) then. ¹H NMR (500MHz, (CD ₃) ₂SO) δ 9.61 (s, 1H), 7.90 (s, 1H), 7.32 (m, 4H), 7.20 (m, 4H), 7.00 (dm, 1H), 6.91 (dm, 1H), 5.07 (d, 1H), 4.54 (s, 1H), 3.84 (d, 1H), 2.41 (s, 3H), 1.08 (s, 9H); MS (ESI) m/z 447.4 ([M+H] ⁺); To (C ₂₇H ₂₇FN ₂O ₃+ H) ⁺The HRMS calculated value: 447.2084; Measured value (ESI[M+H] ⁺): 447.2092.

Embodiment 45

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-1-hydroxyl-3-oxo isoindole quinoline-1-methane amide

(i) 2-[2-(4-chloro-phenyl-) ethyl] and isoquinoline 99.9-1,3 (2H, 4H)-diketone

Under nitrogen atmosphere in toluene (5ml) with 1H-different chromene-1,3 (4H)-diketone (1.50g, 6.94mmol) and 2-(4-chloro-phenyl-) ethamine (1.08g 6.94mmol) mixes, and the gained mixture was refluxed 20 hours.By make the mixture cooling with the 20ml dilution with toluene, form white solid, obtain title compound (1.40g, 67%) by filtering to collect. ¹H-NMR(500MHz，CDCl ₃)δ8.23(d，1H)，7.61(t，1H)，7.48(t，1H)，7.31-7.23(m，5H)，4.23-4.18(m，2H)，4.04(s，2H)，2.94-2.89(m，2H)。

(ii) 2-[2-(4-chloro-phenyl-) ethyl] isoquinoline 99.9-1,3,4 (2H)-triketones

With 2-[2-(4-chloro-phenyl-) ethyl] and isoquinoline 99.9-1,3 (2H, 4H)-diketone (0.50g, 1.67mmol) and SeO ₂(0.19g 16.7mmol) mixes in toluene (10ml), and reflux 16 hours.The solids removed by filtration material, concentrating under reduced pressure filtrate.Resistates filters by silica gel plug, uses the DCM wash-out.Removal of solvent under reduced pressure obtains title compound (0.52g, 99%).[M+H](ES)314.0。

(iii) N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-1-hydroxyl-3-oxo isoindole quinoline-1-methane amide

With 2-[2-(4-chloro-phenyl-) ethyl] isoquinoline 99.9-1,3, (0.15g, 0.47mmol) (0.076g 0.71mmol) mixes in toluene (2ml) 4 (2H)-triketones, and 60 ℃ were heated the gained mixture 16 hours with benzylamine.Decompression removes down and desolvates.By using the purification by flash chromatography resistates of BiotageSP1 (being moving phase with ethyl acetate/heptane), and further using and be equipped with Kromasil C8 post, is that the reversed-phase HPLC of moving phase carries out purifying with MeCN/ water (0.1M ammonium acetate).With the lyophilize of product fraction, obtain title compound (0.023g, 12%).HRMS: to (C ₂₄H ₂₁ClN ₂O ₃+ H) ⁺Calculated value: 421.1319; Measured value (ES[M+H] ⁺) 421.1336. ¹H-NMR(500MHz，DMSO-d ₆)δ7.69-7.61(m，3H)，7.58-7.51(m，2H)，7.36-7.16(m，9H)，4.40-4.28(m，2H)，3.64-3.56(m，1H)，3.28-3.20(m，1H)，2.93-2.75(m，2H)。

Embodiment 46

N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide

(9.12mmol, 2.00g) (preparation AI) stirred 20 minutes with 2-carbamoyl benzoate (9.12mmol 1.37g) is dissolved in the methyl alcohol in (10ml), and adds 1-[(3 ', 4 '-DfBP-2-yl) methylamine.(9.12mmol 0.76g) adds in the mixture with 2-isocyano--2-methylpropane then.The stirring at room reactant spends the night.Evaporation removes and desolvates.Crude product is by purification by flash chromatography (heptane/EtOAc 90/10 beginning with the degree such as grade is elevated to 50% with EtOAc concentration, (silica gel 600.004-0.063mm) then).Merge the fraction that contains product, evaporation removes and desolvates.The gained material does not have enough purity, and therefore by preparing HPLC to its purifying, described preparation HPLC brings up to 95% with acetonitrile concentration then with acetonitrile/buffer reagent 20/80 beginning of degree such as grade, and buffer reagent is H ₂The mixture of O/ACN/FA (94.8/5/0.2) (0.1M, post KR-100-7-C8,50mm x 250mm, flow velocity: 40ml/min), merge the fraction that contains product, the evaporative removal acetonitrile obtains title compound (2.10g, 53.1%).1H-NMR(500MHz，CDCl ₃)：δ7.60-7.54(m，2H)；7.54-7.48(m，1H)；7.42-7.37(m，1H)；7.33-7.27(m，3H)；7.22-7.13(m，2H)；7.12-7.06(m，1H)；7.02-6.96(m，1H)；6.08(s，1H)；5.18(d，1H)；4.56(s，1H)；4.37-4.30(d，1H)，1.15(s，9H)。

Embodiment 47

(1R or 1S)-N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide

(1S or 1R)-N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide

By preparing the HPLC system with N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-(4.83mmol 2.10g) separates 3-oxo isoindole quinoline-1-methane amide (implementing 46), and described preparation HPLC system disposition has Chirapak AD, 5 μ, 250mm x 20mm post.Use heptane/EtOH (75/25) as moving phase, obtain containing isomer E1 fraction 1, obtain containing the fraction 2 of isomer E2.

Vacuum concentration fraction 1 obtains isomer E1 (0.903g, 43.0%), ee=99.9%; To (C ₂₆H ₂₄F ₂N ₂O ₂+ H) ⁺The HRMS calculated value: 435.1884; Measured value (ES[M+H] ⁺) 435.1881.Vacuum concentration fraction 2 obtains isomer E2 (0.908g, 43.2%), ee=99.9%; To (C ₂₆H ₂₄F ₂N ₂O ₂+ H) ⁺The HRMS calculated value: 435.1884; Measured value (ES[M+H] ⁺) 435.1894.

Embodiment 48

N-(tertiary butyl)-2-[(4 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide

(0.5mmol 110mg), stirred 20 minutes methylamine with 2-carbamoyl benzoate (0.5mmol 75mg) is dissolved in the methyl alcohol (10ml), adds 1-[(4 ', 4 '-DfBP-2-yl).(0.50mmol 42mg) adds in the mixture with 2-isocyano--2 methylpropane then.The stirring of reactant room temperature is spent the night.Evaporation removes and desolvates.(begin the acetonitrile/buffer reagent 20/80 with the degree such as grade, then acetonitrile concentration is elevated to 95%, buffer reagent is H to crude product by preparation HPLC ₂The mixture of O/ACN/FA (94.8/5/0.2) (0.1M, post KR-100-7-C8,50mm x 250mm, flow velocity 40ml/min).Merge the fraction that contains product, acetonitrile is removed in evaporation, obtains title compound (138mg, 63.5%).1H-NMR(500MHz，CDCl ₃)：δ7.76-7.72(m，1H)；7.60-7.52(m，2H)；7.49-7.44(m，1H)，7.29-7.18(m，3H)；7.14-7.08(m，2H)；7.06-6.98(m，2H)；5.62(s，1H)；5.11(d，1H)；4,59(s，1H)；4,35(d，1H)；1.10(s，9H)。To (C ₂₆H ₂₄F ₂N ₂O ₂+ H)+the HRMS calculated value: 435.1884; Measured value (ES[M+H]+): 435.1904.

Embodiment 49

N-butyl-2-[2-(4-chloro-phenyl-)-2-methyl-propyl group]-3-oxo-1H-isoindole-1-methane amide

With the 2-carbamoyl benzoate (0.060g, 0.40mmol), 2-(4-chloro-phenyl-)-2-methyl-third-1-amine hydrochlorate (0.088g, 0.40mmol) and NEt ₃(55 μ L 0.40mmol) mixed in MeOH (2ml), with gained mixture stirring at room 20 minutes.(42 μ L, 0.40mmol), the gained mixture was stirring at room 18 hours to add the 1-butyl isocyanide.Mixture distributes between methylene dichloride (7ml) and water (1ml).In separator, separating each layer, concentrating under reduced pressure organic layer.Resistates is with using Sunfire prep C18 post, with 0.1MHCO ₂The MeCN of 5-95% in the H solution is that the reversed-phase HPLC of moving phase carries out purifying, obtains title compound (0.087g, 54%).HRMS: to (C ₂₃H ₂₇ClN ₂O ₂+ H) ⁺Calculated value: 399.1839; Measured value (ES[M+H] ⁺) 399.1839. ¹H-NMR＊(500MHz，DMSO-d ₆，DMSO＊)δ8.23-8.19(m，1H)，7.65-7.62(m，1H)，7.55-7.51(m，1H)，7.47-7.42(m，2H)，7.37-7.30(m，4H)，4.51(s，1H)，4.09(d，1H)，3.13(d，1H)，3.03-2.93(m，2H)，1.37-1.31(m，2H)，1.28-1.20(m，8H)，0.84(t，3H)。

Embodiment 50

According to or by similar approach described herein, be prepared following compound from suitable intermediate (as described previously those), and (be specially HRMS calculated value (M+H) and HRMS measured value (M+H) with accurate mass (HRMS) spectroscopic data.Detect the ammonium adducts in some instances, be shown as (M+NH4) like this).

N-benzyl-2-(1-methyl isophthalic acid-phenylethyl)-3-oxo isoindole quinoline-1-methane amide (385.1916; 385.1902);

N-benzyl-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide (385.1916; 385.1899);

N-[3-(difluoro-methoxy) benzyl]-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide (437.1676; 437.1670);

N, 2-dibenzyl-6-bromo-3-oxo isoindole quinoline-1-methane amide (435.0708; 435.0693)

6-bromo-2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide (505.1302; 505.1307);

2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-6-fluoro-3-oxo isoindole quinoline-1-methane amide (445.2103; 445.2104);

6-bromo-2-(2-cyclopentyl benzyl)-N-methyl-3-oxo isoindole quinoline-1-methane amide (427.1021; 427.1015);

2-(2-cyclopentyl benzyl)-6-fluoro-N-methyl-3-oxo isoindole quinoline-1-methane amide (367.1821; 367.1822);

6-chloro-2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide (461.1807; 461.1797);

6-chloro-2-(2-cyclopentyl benzyl)-N-methyl-3-oxo isoindole quinoline-1-methane amide (383.1526; 383.1523);

2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide (427.2197; 427.2200);

2-(2-cyclopentyl benzyl)-N-methyl-3-oxo isoindole quinoline-1-methane amide (349.1916; 349.1913);

N-benzyl-6-chloro-3-oxo-2-[(1S)-the 1-phenylethyl] isoindoline-1-methane amide (405.1369; 405.1365);

6-chloro-N-(2-methoxy ethyl)-3-oxo-2-[2,2,2-three fluoro-1-(3-fluorophenyl) ethyl] isoindoline-1-methane amide (445.0942; 445.0936);

N-benzyl-6-chloro-2-(two pyridin-3-yl methyl)-3-oxo isoindole quinoline-1-methane amide (469.1431; 469.1407);

6-chloro-N-methyl-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (383.0774; 383.0798)

2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-N-methyl-3-oxo isoindole quinoline-1-methane amide (361.1119; 361.1130);

6-fluoro-N-methyl-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (313.1352; 313.1359);

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-N-methyl-3-oxo isoindole quinoline-1-methane amide (377.0823; 377.0821);

6-chloro-N-methyl-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (329.1056; 329.1062);

2-[2-(4-chloro-phenyl-) propyl group]-N-methyl-3-oxo isoindole quinoline-1-methane amide (343.1213; 343.1231);

6-chloro-N-ethyl-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (343.1213; 343.1238);

N-benzyl-5-[(methyl sulphonyl) amino]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (464.1644; 464.1651);

N-benzyl-4-methyl-5-[(methyl sulphonyl) amino]-3-oxo-2-] (1R)-the 1-phenylethyl] isoindoline-1-methane amide (478.1800; 478.1820);

N-benzyl-5-cyano group-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (396.1712; 396.1734);

N-benzyl-5-bromo-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (449.0864; 449.0868);

N-benzyl-6-bromo-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (449.0864; 449.0872);

N-[3-(difluoro-methoxy) benzyl]-6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (437.1688; 437.1702);

N-(3, the 4-dichloro benzyl)-6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (439.0991; 439.1017);

N-(3-benzyl chloride base)-6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (4055.1381; 405.1379);

6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide (439.1644; 439.1643);

6-chloro-N-[3-(difluoro-methoxy) benzyl]-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (453.1392; 453.1390);

6-chloro-N-(3, the 4-dichloro benzyl)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (455.0696; 455.0714);

6-chloro-N-(3-benzyl chloride base)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (421.1085; 421.1044);

6-chloro-2-(3-hydroxyl-2,2-methyl-propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide (455.1349; 455.1355);

N-(3, the 4-dichloro benzyl)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (421.1085; 421.1091);

N-[3-(difluoro-methoxy) benzyl]-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (419.1782; 419.1767);

2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide (421.1739; 421.1747);

N-(4,4-difluoro butyl)-6-fluoro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (445.1350; 445.1346);

6-chloro-N-(4,4-difluoro butyl)-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (461.1055; 461.1014);

6-chloro-N-(4,4-difluoro butyl)-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (407.1338; 407.1321);

N-(4,4-difluoro butyl)-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (373.1727; 373.1748);

N-(tertiary butyl)-6-fluoro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (409.1539; 409.1524);

N-(tertiary butyl)-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (391.1633; 391.1629);

N-(tertiary butyl)-6-chloro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (425.1243; 425.1239);

6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl)-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (463.1256; 463.1240);

3-oxo-N-(4,4,4-trifluoro butyl)-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (445.1350; 445.1341);

6-chloro-3-oxo-N-(4,4,4-trifluoro butyl)-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (479.0961; 479.0967);

N-(tertiary butyl)-6-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (355.1821; 355.1814);

6-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl]-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (409.1539; 409.1566);

N-(tertiary butyl)-6-chloro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (371.1526; 371.1530);

6-chloro-3-oxo-2-[(1R)-the 1-phenylethyl]-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (425.1243; 425.1255);

The 3-oxo-2-[(1R)-the 1-phenylethyl]-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (391.1633; 391.1649);

6-chloro-N-[4-(methyl acyl sulfo group) benzyl]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (483.1145; 483.1145);

N-benzyl-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (425.1477; 425.1455);

N-[(4-amino-2-methyl pyrimidine-5-yl) methyl]-6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (484.1307; 4844.1289);

2-(biphenyl-2-ylmethyl)-N-[(5-methylpyrazine-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (449.1977; 449.1978);

2-(biphenyl-2-ylmethyl)-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide (434.1868; 434.1839);

N-[(4-amino-2-methyl pyrimidine-5-yl) methyl]-2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo isoindole quinoline-1-methane amide (498.1696; 498.1682);

N-[(4-amino-2-methyl pyrimidine-5-yl) methyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide (464.2086; 464.2096);

N-butyl-2-[(4-fluorophenyl) (pyridin-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (418.1930; 418.1921);

N-butyl-3-oxo-2-[phenyl (pyridine-2-yl) methyl] isoindoline-1-methane amide (400.2025; 400.2018);

N-butyl-2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (434.1635; 434.1618);

The 2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (486.1384; 486.1342);

6-chloro-2-(diphenyl methyl)-N-ethyl-3-oxo isoindole quinoline-1-methane amide (405.1369; 405.1332);

2-(biphenyl-2-ylmethyl)-6-chloro-N-ethyl-3-oxo isoindole quinoline-1-methane amide (405.1369; 405.1336);

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-propyl group isoindoline-1-methane amide (419.1526; 419.1521);

2-(diphenyl methyl)-N-ethyl-3-oxo isoindole quinoline-1-methane amide (371.1759; 371.1759);

2-(biphenyl-2-ylmethyl)-N-ethyl-3-oxo isoindole quinoline-1-methane amide (371.1759; 371.1758);

2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide (403.1821; 403.1805);

N-(4-luorobenzyl)-2-[(4-fluorophenyl) (pyridin-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (470.1680; 470.1664);

N-benzyl-2-[(4-fluorophenyl) (pyridin-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (452.1774; 452.1761);

2-[2-(4-chloro-phenyl-) propyl group]-N-[(5-methylpyrazine-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (435.1587; 435.1592);

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-N-[(5-methylpyrazine-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (469.1198; 469.1177);

2-(biphenyl-2-ylmethyl)-6-chloro-N-[(5-methylpyrazine-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (483.1587; 483.1582);

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide (454.1089; 454.1069);

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide (522.0963; 522.0932);

N-[(4-amino-2-methyl pyrimidine-5-yl) methyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (450.1696; 450.1699);

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide (536.1352; 536.1326);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide (488.1352; 488.1335);

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide (468.1478; 468.1448);

2-(biphenyl-2-ylmethyl)-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide (502.1742; 502.1722);

N-benzyl-6-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (389.1665; 389.1656);

N-[4-(methylsulfonyl) benzyl]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (449.1535; 449.1510);

6-fluoro-N-[4-(methylsulfonyl) benzyl]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide (467.1440; 467.1443);

N-benzyl-6-chloro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (459.1087; 459.1079);

N-benzyl-6-fluoro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (443.1382; 443.1373);

6-chloro-N-[4-(methylsulfonyl) benzyl]-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (537.0862; 537.0843);

6-chloro-N-[2-chloro-4-(methylsulfonyl) benzyl]-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (579.0912; 579.0919);

N-[2-chloro-4-(methylsulfonyl) benzyl]-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (545.1301; 545.1290);

6-chloro-2-(diphenyl methyl)-N-[2-fluoro-4-(methylsulfonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (563.1207; 563.1201);

2-(diphenyl methyl)-N-[2-fluoro-4-(methylsulfonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (529.1597; 529.1584);

6-chloro-2-(diphenyl methyl)-N-[4-(methylsulfonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (545.1301; 545.1316);

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide (468.1478; 468.1479);

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide (454.1089; 454.1075);

2-(biphenyl-2-ylmethyl)-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide (434.1868; 434.1853);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-cyano group-3-oxo isoindole quinoline-1-methane amide (424.2025; 424.2027);

6-chloro-2-(diphenyl methyl)-3-oxo-N-propyl group isoindoline-1-methane amide (419.1526; 419.1544);

2-[2-(4-chloro-phenyl-) propyl group]-N-ethyl-6-fluoro-3-oxo isoindole quinoline-1-methane amide (375.1275; 375.1263);

2-(diphenyl methyl)-N-ethyl-6-fluoro-3-oxo isoindole quinoline-1-methane amide (389.1665; 389.1671);

2-[2-(4-chloro-phenyl-) propyl group]-N-ethyl-3-oxo isoindole quinoline-1-methane amide (357.1369; 357.1374);

2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide (389.1432; 389.1431);

2-(diphenyl methyl)-6-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide (403.1821; 403.1837);

2-(biphenyl-2-ylmethyl)-3-oxo-N-propyl group isoindoline-1-methane amide (385.1916; 385.1903);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-propyl group isoindoline-1-methane amide (371.1526; 371.1546);

2-(diphenyl methyl)-3-oxo-N-propyl group isoindoline-1-methane amide (385.1916; 385.1930);

2-(diphenyl methyl)-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (471.1695; 471.1715);

2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (457.1306; 457.1325);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (439.1400; 439.1401);

2-(biphenyl-2-ylmethyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (453.1790; 453.1784);

2-(diphenyl methyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (453.1790; 453.1807);

N-(tertiary butyl)-2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (434.1635; 434.1620);

N-(4-luorobenzyl)-3-oxo-2-[phenyl (pyridine-2-yl) methyl] isoindoline-1-methane amide (452.1774; 452.1789);

N-benzyl-2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (468.1478; 468.1465);

N-benzyl-3-oxo-2-[phenyl (pyridine-2-yl) methyl] isoindoline-1-methane amide (434.1868; 434.1871);

2-(2, the 2-dimethyl propyl)-N-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (418.2130; 418.2128);

2-(2, the 2-dimethyl propyl)-N-[(1-methyl-5-phenyl-1H-pyrazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (417.2290; 417.2298);

N-benzyl-2-[(1-methyl-5-phenyl-1H-pyrazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (437.1977; 437.1993);

N-benzyl-2-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (438.1817; 438.1825);

N-benzyl-2-(biphenyl-2-ylmethyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (463.2021; 463.2019);

2-(biphenyl-2-ylmethyl)-5-hydroxy-4-methyl-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (483.1895; 483.1881);

2-(biphenyl-2-ylmethyl)-5-hydroxy-4-methyl-3-oxo-N-propyl group isoindoline-1-methane amide (415.2021; 415.2033);

2-(biphenyl-2-ylmethyl)-N-butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (429.2178; 429.2196);

2-(biphenyl-2-ylmethyl)-N-ethyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (401.1865; 401.1870);

N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (465.1989; 465.2002);

N-(tertiary butyl)-2-[(2 ', 4 '-DCBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (497.1398; 497.1393);

N-(tertiary butyl)-2-[(3 ', 4 '-DCBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (497.1398; 497.1392);

N-(tertiary butyl)-2-[(2 '-chlordiphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (463.1788; 463.1804);

N-(tertiary butyl)-2-[(3 '-chloro-4 '-fluorine biphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (481.1694; 481.1681);

N-(tertiary butyl)-2-[(4 '-chlordiphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (463.1788; 463.1764);

N-(tertiary butyl)-2-[(4 '-fluoro-2 '-methyl diphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (461.2240; 461.2221);

N-(tertiary butyl)-2-[(2 ', 4 '-DfBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (465.1989; 465.1987);

N-(tertiary butyl)-2-[(2 ', 5 '-DfBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (465.1989; 465.1998);

N-(tertiary butyl)-2-[(3 '-fluorine biphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (447.2084; 447.2097);

N-butyl-3-oxo-2-(2-phenoxy benzyl) isoindoline-1-methane amide (415.2021; 415.2060);

N-] 3-(difluoro-methoxy) benzyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (417.1989; 417.2034);

2-(3, the 3-dimethylbutyl)-3-oxo-N-[3-(trifluoromethoxy) benzyl] isoindoline-1-methane amide (435.1895; 435.1855);

2-(2, the 2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethoxy) benzyl] isoindoline-1-methane amide (421.1739; 421.1717);

N-[3-(difluoro-methoxy) benzyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (403.1833; 403.1873);

6-chloro-2-(diphenyl methyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (487.1400; 487.1445);

6-chloro-2-(diphenyl methyl)-N-(2-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide (483.1475; 483.1472);

N-benzyl-6-chloro-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (467.1526; 467.1544);

N-(tertiary butyl)-6-chloro-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (433.1682; 433.1709);

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (487.1400; 487.1390);

2-(biphenyl-2-ylmethyl)-6-chloro-N-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (492.1478; 492.1513);

N-benzyl-2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo isoindole quinoline-1-methane amide (467.1526; 467.1513);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-chloro-3-oxo isoindole quinoline-1-methane amide (433.1682; 433.1723);

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (473.1010; 473.1010);

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(methylsulfonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (531.0912; 531.0937);

N-(tertiary butyl)-6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (419.1293; 419.1326);

N-benzyl-6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (453.1136; 453.1156);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-4,5-dimethoxy-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (488.1934; 488.1938);

2-[1-(1,5-dimethyl-1H-pyrazoles-4-yl) ethyl]-5,7-dimethoxy-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (517.2062; 517.2051);

5,7-dimethoxy-2-(2-methoxy-benzyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (515.1793; 515.1784);

2-(2-luorobenzyl)-5,7-dimethoxy-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (503.1594; 503.1598);

N-(tertiary butyl)-5,7-dimethoxy-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (413.2076; 413.2094);

3-oxo-2-(2-phenoxy benzyl)-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (469.1739; 469.1732);

2-[2-(4-chloro-phenyl-) propyl group]-N-[(2,2-two fluoro-1,3-benzo dioxole-5-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (499.1236; 499.1221);

N-(3, the 4-dichloro benzyl)-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (405.1136; 405.1137);

2-(2, the 2-dimethyl propyl)-N-(1H-indol-3-yl methyl)-3-oxo isoindole quinoline-1-methane amide (376.2025; 376.2009);

2-(2, the 2-dimethyl propyl)-3-oxo-N-{2-[3-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide (419.1946; 419.1918);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-fluoro-3-oxo isoindole quinoline-1-methane amide (417.1978; 417.1967);

N-benzyl-2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo isoindole quinoline-1-methane amide (451.1821; 451.1820);

2-[2-(4-chloro-phenyl-) ethyl]-N-[(2,2-two fluoro-1,3-benzo dioxole-5-yl) methyl]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (503.0985; 503.0987);

2-[2-(4-chloro-phenyl-) ethyl]-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (443.1149; 443.1151);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) ethyl]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (389.1432; 389.1446);

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (423.1275; 423.1266);

6-fluoro-2-[2-(4-fluorophenyl) ethyl]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (427.1445; 427.1434);

N-benzyl-6-fluoro-2-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (407.1571; 407.1566);

6-fluoro-2-[2-(4-fluorophenyl) propyl group]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide (441.1601; 441.1592);

N-benzyl-6-fluoro-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (421.1727; 421.1709);

N-(tertiary butyl)-6-fluoro-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (387.1884; 387.1868);

2-(biphenyl-2-ylmethyl)-1-methyl-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (525.1848; 525.1854);

2-[2-(4-chloro-phenyl-) propyl group]-4,7-two fluoro-1-methyl-N-[4-(methyl sulphonyl) benzyls]-3-oxo isoindole quinoline-1-methane amide

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-1-methyl-3-oxo isoindole quinoline-1-methane amide (399.1839; 399.1825);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (459.2283; 459.2263);

N-benzyl-2-(diphenyl methyl)-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (463.2021; 463.1992);

2-(diphenyl methyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (501.1790; 501.1780);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-1-methyl-3-oxo isoindole quinoline-1-methane amide (399.1839; 399.1826);

N-butyl-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (399.2072; 399.2089);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-methoxyl group-4-methyl-3-oxo isoindole quinoline-1-methane amide (443.2334; 443.2317);

2-(biphenyl-2-ylmethyl)-1-[(tertiary butyl amino) carbonyl]-4-methyl-3-oxo-2,3-dihydro-1H-isoindole-5-base dimethylcarbamate (500.2549; 500.2561);

2-(biphenyl-2-ylmethyl)-5-hydroxyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (463.2021; 463.1998);

5-hydroxyl-2-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (431.1970; 431.1963);

2-(4-benzyl chloride base)-5-hydroxyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (421.1319; 421.1311);

N-(4-luorobenzyl)-5-hydroxyl-2-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (435.1720; 435.1714);

2-[2-(3, the 4-dichlorophenyl) ethyl]-N-(4-luorobenzyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide (473.0835; 473.0795);

2-(4-benzyl chloride base)-N-(4-luorobenzyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide (425.1068; 425.1054);

2-(biphenyl-2-ylmethyl)-N-(4-luorobenzyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide (467.1771; 467.1772);

N-(tertiary butyl)-2-[2-(3, the 4-dichlorophenyl) ethyl]-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide (421.1085; 421.1022);

N-(3, the 4-dichloro benzyl)-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (391.0980; 391.0989);

N-[2-(1H-indol-3-yl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (376.2025; 376.2027)

N-(3-benzyl chloride base)-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (357.1369; 357.1352);

N-[4-(difluoro-methoxy) benzyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (389.1676; 389.1673);

2-isobutyl--3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide (391.1633; 391.1613);

N-(1H-indol-3-yl methyl)-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (362.1868; 362.1859);

N-[2-(1,3-benzo dioxole-5-yl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (381.1814; 381.1801);

N-[2-(3-fluorophenyl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (355.1821; 355.1813);

2-isobutyl--3-oxo-N-{2-[3-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide (405.1790; 405.1775);

N-[2-(3, the 4-dichlorophenyl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (405.1136; 405.1135);

N-[2-(4-chloro-phenyl-) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1523);

N-[2-(3-chloro-phenyl-) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1520);

N-[2-(2-chloro-phenyl-) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1513);

N-[2-(2,4 dichloro benzene base) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (405.1136; 405.1129);

N-[2-(2, the 6-dichlorophenyl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide (405.1136; 405.1125);

2-(3, the 3-dimethylbutyl)-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (404.2338; 404.2336);

N-(3-benzyl chloride base)-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (385.1682; 385.1676);

N-(3, the 4-dichloro benzyl)-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (419.1293; 419.1273);

2-(3, the 3-dimethylbutyl)-N-(1H-indol-3-yl methyl)-3-oxo isoindole quinoline-1-methane amide (390.2181; 390.2174);

N-[4-(difluoro-methoxy) benzyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (417.1989; 417.1975)

2-(3, the 3-dimethylbutyl)-N-[2-(3-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (383.2134; 383.2103);

N-[2-(1,3-benzo dioxole-5-yl) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (409.2127; 409.2125);

N-[2-(3-cyano-phenyl) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (390.2181; 390.2171);

2-(3, the 3-dimethylbutyl)-3-oxo-N-{2-[3-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide (433.2103; 433.2092);

N-[2-(3-chloro-phenyl-) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (399.1839; 399.1830);

N-[2-(3, the 4-dichlorophenyl) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (433.1449; 433.1431);

N-[2-(4-chloro-phenyl-) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (399.1839; 399.1831);

N-[2-(2-chloro-phenyl-) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (399.1839; 399.1841);

N-[2-(2,4 dichloro benzene base) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (433.1449; 433.1428);

2-(2, the 2-dimethyl propyl)-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (390.2181; 390.2172);

N-(3-benzyl chloride base)-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1515);

N-[4-(difluoro-methoxy) benzyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (403.1833; 403.1833);

2-(2, the 2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide (405.1790; 405.1787);

N-[2-(1,3-benzo dioxole-5-yl) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (395.1970; 395.1967);

2-(2, the 2-dimethyl propyl)-N-[2-(3-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (369.1978; 369.1977);

N-[2-(3-cyano-phenyl) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (376.2025; 376.2029);

N-[2-(2-chloro-phenyl-) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (385.1682; 385.1675);

N-[2-(3-chloro-phenyl-) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (385.1682; 385.1671);

N-[2-(2,4 dichloro benzene base) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (419.1293; 419.1290);

2-[2-(4-chloro-phenyl-) ethyl]-N-ethyl-3-oxo-N-(2-pyridine-2-base ethyl) isoindoline-1-methane amide (448.1791; 448.1776);

2-[2-(4-chloro-phenyl-) ethyl]-3-(1,3-dihydro-2H-isoindole-2-base carbonyl) 1-isoindolinone (417.1369; 417.1382);

2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (487.1400; 487.1352);

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-N-ethyl-3-oxo isoindole quinoline-1-methane amide (433.1682; 433.1662);

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo isoindole quinoline-1-methane amide (419.1526; 419.1516);

N-(tertiary butyl)-3-oxo-2-{2-[4-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide (405.1790; 405.1766);

N-butyl-3-oxo-2-{2-[4-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide (405.1790; 405.1771);

N-benzyl-3-oxo-2-{2-[4-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide (439.1633; 439.1621);

N-(tertiary butyl)-5-hydroxyl-2-[2-(1H-indol-3-yl) ethyl]-4-methyl-3-oxo isoindole quinoline-1-methane amide (406.2130; 406.2102);

N-(tertiary butyl)-2-[2-(4-fluorophenyl) propyl group]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (399.2084; 399.2061);

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (489.1613; 489.1611);

N-(tertiary butyl)-2-(2, the 2-diphenyl-ethyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (443.2334; 443.2317);

N-(tertiary butyl)-2-(diphenyl methyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (429.2178; 429.2160);

N-(tertiary butyl)-2-(9H-fluorenes-9-yl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (427.2021; 427.2007);

N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo-2-{2-[4-(trifluoromethyl) phenoxy group] benzyl } isoindoline-1-methane amide (513.2001; 513.1967);

2-(biphenyl-3-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (429.2178; 429.2139);

N-butyl-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (369.1978; 369.1956);

N-butyl-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1507);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1534);

N-(tertiary butyl)-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (369.1978; 369.1954);

N-benzyl-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (403.1821; 403.1789);

N-benzyl-2-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (389.1665; 389.1668);

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide (405.1369; 405.1367);

N-[2-(1H-indol-3-yl) ethyl]-3-oxo-2-[4-(piperidines-1-base carbonyl) benzyl] isoindoline-1-methane amide (521.2552; 521.2518);

2-(biphenyl-2-ylmethyl)-N-(2, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide (469.1727; 469.1689);

2-(biphenyl-2-ylmethyl)-N-(4-cyano group-2,6-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide (494.1680; 494.1667);

N-(2, the 4-difluorobenzyl)-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (469.1727; 469.1695);

N-(2-benzyl chloride base)-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (467.1526; 467.1486);

2-(diphenyl methyl)-N-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (465.1978; 465.1948);

2-(biphenyl-2-ylmethyl)-N-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (465.1978; 465.1957);

2-(diphenyl methyl)-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (451.1821; 451.1785);

N-(2, the 4-difluorobenzyl)-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide (470.1680; 470.1645);

N-(2-benzyl chloride base)-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide (468.1478; 468.1437);

N-[2-(4-fluorophenyl) ethyl)-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide (466.1930; 466.1917);

N-benzyl-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide (434.1868; 434.1839);

N-(4-luorobenzyl)-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide (452.1774; 452.1760);

N-butyl-5-methoxyl group-2-(2-methyl-2-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide (395.2334; 395.2298);

2-(biphenyl-2-ylmethyl)-N-butyl-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (429.2178; 429.2147);

N-butyl-2-[2-(4-fluorophenyl) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (399.2084; 399.2057);

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (415.1788; 415.1772);

N-(tertiary butyl)-5-methoxyl group-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (431.2334; 431.2338);

N-(tertiary butyl)-2-[2-(4-fluorophenyl) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (399.2084; 399.2060);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (415.1788; 415.1774);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (429.2178; 429.2162);

N-benzyl-5-methoxyl group-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (465.2178; 465.2154);

N-benzyl-5-methoxyl group-2-(2-methyl-2-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide (429.2178; 429.2183);

N-benzyl-2-(biphenyl-2-ylmethyl)-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (463.2021; 463.1988);

N-butyl-5,6-dimethoxy-2-(2-methyl-2-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide (425.2440; 425.2408);

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (449.1632; 449.1597);

N-butyl-5,6-dimethoxy-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (461.2440; 461.2424);

N-butyl-2-[2-(4-fluorophenyl) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (429.2189; 429.2148);

2-(biphenyl-2-ylmethyl)-N-butyl-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (459.2283; 459.2237);

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (445.1894; 445.1857);

N-(tertiary butyl)-5,6-dimethoxy-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (461.2440; 461.2417);

N-benzyl-5,6-dimethoxy-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (495.2283; 495.2259);

N-benzyl-5,6-dimethoxy-2-(2-methyl-2-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide (459.2283; 459.2267);

N-benzyl-2-[2-(4-fluorophenyl) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (463.2033; 463.2008);

N-benzyl-2-(biphenyl-2-ylmethyl)-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (493.2127; 493.2099);

N-benzyl-2-(diphenyl methyl)-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (493.2127; 493.2092);

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (479.1737; 479.1711);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-1-methyl-3-oxo isoindole quinoline-1-methane amide (413.2229; 413.2210);

2-(biphenyl-2-ylmethyl)-N-butyl-1-methyl-3-oxo isoindole quinoline-1-methane amide (413.2229; 413.2204);

N-benzyl-N-(2-[2-(4-chloro-phenyl-) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine ethyl ester (491.1737; 491.1708);

2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (433.1682; 433.1641);

2-[2-(4-chloro-phenyl-) ethyl]-N, N-diethyl-3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1500);

N-benzyl-N-butyl-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide (461.1995; 461.1977);

N-[2-(2, the 6-dichlorophenyl) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide (433.1449; 433.1440);

N-[2-(4-chloro-phenyl-) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (385.1682; 385.1677);

N-[2-(2, the 6-dichlorophenyl) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (419.1293; 419.1270);

N-butyl-5-methoxyl group-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide (431.2334; 431.2332);

N-benzyl-2-[2-(4-fluorophenyl) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide (433.1927; 433.1907);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide (445.1894; 445.1870);

N-(tertiary butyl)-2-[(4 '-fluoro-2 '-methyl diphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide; (431.2134; 431.2122);

N-(tertiary butyl)-2-[(4 '-methyl diphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (431.2229; 413.2214);

N-(tertiary butyl)-2-[(4 '-methoxyl biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (429.2178; 429.2179);

N-(tertiary butyl)-2-[(4 '-fluorine biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (417.1978; 417.1974);

N-(2-[(3 ', and 4 '-DfBP-2-yl) methyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester (451.1469; 451.1465);

N-(2-[(4 '-fluoro-2 '-methyl diphenyl-2-yl) methyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester (447.1720; 447.1724);

N-(2-[(4 '-fluorine biphenyl-2-yl) methyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester (433.1563; 433.1558);

N-(2-[(4 '-methyl diphenyl-2-yl) methyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester (429.1814; 429.1809);

2-[(3 ', 4 '-DfBP-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (547.1503; 547.1497);

2-[(4 '-fluoro-2 '-methyl diphenyl-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (543.1753; 543.1778);

2-[(4 '-methoxyl biphenyl-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (541.1797; 541.1797);

2-[(4 '-fluorine biphenyl-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (529.1597; 529.1594);

2-[(4 '-methyl diphenyl-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (525.1848; 525.1854);

N-(tertiary butyl)-2-(4-benzyl chloride base)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (387.1475; 387.1486);

N-(tertiary butyl)-5-hydroxyl-2-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (383.1970; 383.2007);

2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (472.1791; 472.1816);

N-(tertiary butyl)-7-hydroxyl-2-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (383.1970; 383.1978);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide (415.2021; 415.2018);

2-[2-(3, the 4-dichlorophenyl) ethyl]-5-hydroxyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (469.1085; 469.1005);

N-(3, the 4-difluorobenzyl)-2-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide (409.1363; 409.1375);

N-(3-benzyl chloride base)-2-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide (407.1162; 407.1162);

2-(4-hydroxybenzyl)-3-oxo-N-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide (441.1426; 441.1477);

N-[3, two (trifluoromethyl) benzyls of 5-]-2-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide (509.1300; 509.1384);

N-(3-benzyl chloride base)-2-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (416.1165; 416.1188);

N-[3, two (trifluoromethyl) benzyls of 5-]-2-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (518.1303; 518.1320);

2-(3-cyano group benzyl)-N-(3, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide (418.1367; 418.1381);

2-(3-cyano group benzyl)-3-oxo-N-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide (450.1429; 450.1442);

N-[4-(aminocarboxyl) benzyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (462.1584; 462.1599);

N-[4-(aminocarboxyl) benzyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide (476.1974; 476.1927);

2-(3, the 4-difluorobenzyl)-N-{4-[(dimethylamino) methyl] benzyl }-3-oxo isoindole quinoline-1-methane amide

2-(3-benzyl chloride base)-N-{4-[(dimethylamino) methyl] benzyl }-3-oxo isoindole quinoline-1-methane amide

2-[3, two (trifluoromethyl) benzyls of 5-]-the N-{4-[(dimethylamino) methyl] benzyl }-3-oxo isoindole quinoline-1-methane amide

2-(3, the 4-difluorobenzyl)-N-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide (409.1363; 409.1383);

2-(3-benzyl chloride base)-N-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide (407.1162; 407; 1158);

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide (509.1300; 509.1281);

2-(3-benzyl chloride base)-N-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (416.1165; 416.1172);

N-(3-cyano group benzyl)-2-(3, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide (418.1367; 418.1353);

2-[2-(4-chloro-phenyl-) propyl group]-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (444.1478; 444.1504);

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (518.1303; 518.1278);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide (401.1632; 401.1666);

The N-{4-[(dimethylamino) methyl] benzyl }-3-oxo-2-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide (482.2055; 482.2060);

N-(4-hydroxybenzyl)-3-oxo-2-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide (441.1426; 441.1414);

N-(3-cyano group benzyl)-3-oxo-2-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide (450.1429; 450.1461);

2-(biphenyl-3-ylmethyl)-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (458.1868; 458.1872);

2-(biphenyl-4-ylmethyl)-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (458.1868; 458.1894);

N-butyl-3-oxo-2-[2-(2-Phenoxyphenyl) ethyl] isoindoline-1-methane amide (429.2178; 429.2170);

N-butyl-2-(2-{4-[(diethylamino) carbonyl] phenyl } ethyl)-3-oxo isoindole quinoline-1-methane amide (436.2600; 436.2588);

N-butyl-2-[2-(3-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (355.1821; 355.1839);

N-butyl-3-oxo-2-{2-[2-(trifluoromethoxy) phenyl] ethyl } isoindoline-1-methane amide (421.1739; 421.1722);

2-(2-biphenyl-4-base ethyl)-N-butyl-3-oxo isoindole quinoline-1-methane amide (413.2229; 413.2253);

N-butyl-2-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (355.1821; 355.1834);

N-butyl-2-[2-(3, the 5-Dimethoxyphenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (397.2127; 397.2129);

N-butyl-3-oxo-2-[2-(4-Phenoxyphenyl) ethyl] isoindoline-1-methane amide (429.2178; 429.2179);

N-butyl-2-[2-(2-ethoxyl phenenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (381.2178; 381.2173);

2-[2-(1,3-benzo dioxole-5-yl) ethyl]-N-butyl-3-oxo isoindole quinoline-1-methane amide (381.1814; 381.1814);

N-(tertiary butyl)-3-oxo-2-[2-(2-Phenoxyphenyl) ethyl] isoindoline-1-methane amide (429.2178; 429.2170);

N-(tertiary butyl)-3-oxo-2-{2-[2-(trifluoromethoxy) phenyl] ethyl } isoindoline-1-methane amide; (421.1739; 421.1741);

2-(2-biphenyl-4-base ethyl)-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide (413.2229; 413.2261);

N-(tertiary butyl)-2-[2-(3, the 5-Dimethoxyphenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (397.2127; 397.2129);

N-(tertiary butyl)-3-oxo-2-[2-(4-Phenoxyphenyl) ethyl] isoindoline-1-methane amide; (429.2178; 429.2147);

N-(tertiary butyl)-2-[2-(2-ethoxyl phenenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (381.2178; 381.2169);

2-[2-(1,3-benzo dioxole-5-yl) ethyl]-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide (381.1814; 381.1810);

N-[2-(1H-indol-3-yl) ethyl]-3-oxo-2-[2-(2-Phenoxyphenyl) ethyl] isoindoline-1-methane amide (516.2287; 516.2333);

2-(2-{4-[(diethylamino) carbonyl] phenyl } ethyl)-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (523.2709; 523.2714);

2-[2-(3-fluorophenyl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (442.1930; 442.1936);

N-[2-(1H-indol-3-yl) ethyl]-3-oxo-2-{2-[2-(trifluoromethoxy) phenyl] ethyl } isoindoline-1-methane amide (508.1848; 508.1853);

2-[2-(4-fluorophenyl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (442.1930; 442.1929);

2-[2-(3, the 5-Dimethoxyphenyl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (484.2236,484.2237);

2-(2-biphenyl-4-base ethyl)-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (500.2338; 500.2371);

N-[2-(1H-indol-3-yl) ethyl]-3-oxo-2-[2-(4-Phenoxyphenyl) ethyl] isoindoline-1-methane amide (516.2287; 516.2280);

2-[2-(2-ethoxyl phenenyl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (468.2287; 468.2276);

2-[2-(1,3-benzo dioxole-5-yl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (468.1923; 468.1889);

(1R)-2-[(1S)-1-(4-fluorophenyl) ethyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-2-[2-(dimethylamino)-2-phenylethyl]-3-oxo isoindole quinoline-1-methane amide (457.2603; 457.2610);

N-[4-(dimethylamino) benzyl]-2-(2, the 2-diphenyl-ethyl)-3-oxo isoindole quinoline-1-methane amide (490.2494; 490.2497);

2-(1-benzyl-2-fluoro ethyl)-N-[(5-methyl-isoxazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (408.1723; 408.1700);

N-(tertiary butyl)-2-(2-chloro-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (375.1275; 375.1276);

2-(3, the 4-difluorobenzyl)-N-(4-luorobenzyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (441.1426; 441.1414);

2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide (424.1472; 424.1458);

2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (437.1676; 437.1667);

2-(3, the 4-difluorobenzyl)-5-hydroxyl-3-oxo-4-phenyl-N-(2-phenylethyl) isoindoline-1-methane amide (499.1833; 499.1788);

N-(2-benzyl chloride base)-2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (457.1130; 457.1088);

2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (491.1394; 491.1378);

N-(tertiary butyl)-2-(2-benzyl chloride base)-5-hydroxyl-3-oxo-4-(trimethyl silyl) isoindoline-1-methane amide;

N-(tertiary butyl)-2-(2-benzyl chloride base)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (387.1475; 387.1461);

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide (491.2334; 491.2325);

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(tertiary butyl)-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide (551.1769; 551.1776);

2-[2-(4-chloro-phenyl-) propyl group]-the N-{3-[(dimethylamino) carbonyl]-the 4-luorobenzyl }-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(4-cyano-phenyl)-3-oxo isoindole quinoline-1-methane amide;

2-(1-benzyl-2-fluoro ethyl)-N-butyl-3-oxo isoindole quinoline-1-methane amide (369.1978; 369.1972);

2-(1-benzyl-2-fluoro ethyl)-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (421.1727; 421.1689);

2-(1-benzyl-2-fluoro ethyl)-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide (446.2243; 446.2229);

N-[4-(amino methyl) phenyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (434.1635; 434.1641);

2-[2-(4-chloro-phenyl-) propyl group]-N-(4-{[(difluoro ethanoyl) amino] methyl } phenyl)-3-oxo isoindole quinoline-1-methane amide (512.1522; 512.1567);

N-[4-(aminocarboxyl) phenyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (448.1428; 448.1418);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-(fluorine methoxyl group)-4-methyl-3-oxo isoindole quinoline-1-methane amide (447.1850; 447.1835);

N-[4-(dimethylamino) benzyl]-3-oxo-2-(4-phenyl butyl) isoindoline-1-methane amide (442.2494; 442.2494);

N-[4-(dimethylamino) benzyl]-2-(2-hydroxy-4-phenyl ethyl)-3-oxo isoindole quinoline-1-methane amide; (430.2130; 430.2120);

N-[4-(dimethylamino) benzyl]-3-oxo-2-[2-(1H-pyrazol-1-yl) benzyl] isoindoline-1-methane amide; (466.2243; 466.2235);

N-[4-(dimethylamino) benzyl]-3-oxo-2-(4-phenoxy benzyl) isoindoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-3-oxo-2-[(1-phenyl-1H-pyrazoles-4-yl) methyl] isoindoline-1-methane amide (466.2243; 466.2254);

N-[4-(dimethylamino) benzyl]-2-[1-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (476.2338; 476.2325);

2-(2-chloro-4-luorobenzyl)-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (487.0894; 487.0908);

N-[4-(dimethylamino) benzyl]-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide (428.2338; 428.2318);

N-[4-(methyl sulphonyl) benzyl]-3-oxo-2-[(1H-pyrazol-1-yl) benzyl] isoindoline-1-methane amide (501.1596; 501.1581);

2-(2-hydroxyl-2-phenylethyl)-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (465.1484; 465.1487);

2-(2, the 2-diphenyl-ethyl)-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (525.1848; 525.1848);

2-(diphenyl methyl)-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (511.1691; 511.1691);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide (420.1478; 420.1482);

N-[4-(methyl sulphonyl) benzyl]-3-oxo-2-(1,2,3,4-naphthane-1-yl) isoindoline-1-methane amide (475.1691; 475.1682);

2-(2-chloro-4-luorobenzyl)-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide (410.1071; 410.1057);

2-[1-(4-fluorophenyl) ethyl]-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide (390.1617; 390.1623);

(1S)-2-[(2R)-2-(4-chloro-phenyl-) propyl group]-N-(3-methoxy-propyl)-1-methyl-3-oxo isoindole quinoline-1-methane amide (415.1788; 415.1790);

(1R)-2-[(2R)-2-(4-chloro-phenyl-) propyl group]-N-(3-methoxy-propyl)-1-methyl-3-oxo isoindole quinoline-1-methane amide (415.1788; 415.1797);

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-methoxy-propyl)-1-methyl-3-oxo isoindole quinoline-1-methane amide (415.1788; 415.1776);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-hydroxyl-3-oxo-4-(trimethyl silyl) isoindoline-1-methane amide (473.2027; 473.2016);

N-(tertiary butyl)-2-(3, the 4-difluorobenzyl)-5-hydroxyl-3-oxo-4-(trimethyl silyl)-isoindoline-1-methane amide (447.1915; 447.1912);

N-(tertiary butyl)-2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (389.1676; 389.1661);

N-(tertiary butyl)-2-(3, the 4-difluorobenzyl)-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide (451.1883; 451.1846);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (415.1788; 415.1793);

2-(2-chloro-4-luorobenzyl)-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (452.0977; 452.0974);

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N, two (3-cyano group-4-the luorobenzyl)-3-oxo isoindole quinoline-1-methane amides (443.1319 of 2-; 443.1297);

N-(3-cyano group-4-luorobenzyl)-3-oxo-2-(2-phenylethyl) isoindoline-1-methane amide (414.1617; 414,1617);

N-(3-cyano group-4-luorobenzyl)-2-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (418.1367; 418.1362);

2-benzyl-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (400.1461; 400.1465);

N-(3-cyano group-4-luorobenzyl)-2-(3, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide (436.1273; 436.1272);

2-(biphenyl-2-ylmethyl)-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (476.1774; 476.1775);

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (462.1384; 462.1371);

2-(2-chloro-4-luorobenzyl)-N-(3-{[(difluoro ethanoyl) amino] methyl }-the 4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (534.1207; 534.1210);

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-{[(difluoro ethanoyl) amino] methyl }-the 4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-[3-(amino methyl)-4-luorobenzyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (466.1697; 466.1700);

N-[3-(aminocarboxyl)-4-luorobenzyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (480.1490; 480.1479);

N-[3-(aminocarboxyl)-4-luorobenzyl]-2-(2-chloro-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (470.1083; 470.1077);

N-(tertiary butyl)-3-oxo-2-(4-phenyl butyl) isoindoline-1-methane amide (365.2229; 365.2231);

N-(tertiary butyl)-3-oxo-2-(1,2,3,4-naphthane-1-yl) isoindoline-1-methane amide (363.2072; 363.2064);

N-(tertiary butyl)-3-oxo-2-(4-phenoxy benzyl) isoindoline-1-methane amide (415.2021; 415.2055);

N-(tertiary butyl)-3-oxo-2-[2-(1H-pyrazol-1-yl) benzyl] isoindoline-1-methane amide (389.1977; 389.1992);

N-(tertiary butyl)-2-(2, the 2-diphenyl-ethyl)-3-oxo isoindole quinoline-1-methane amide (413.2229; 413.2237);

N-(tertiary butyl)-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide (399.2072; 399.2099);

N-(1,3-benzo dioxole-5-ylmethyl)-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (381.1814; 381.1772);

2-(2-chloro-4-luorobenzyl)-N-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (412.1228; 412.1213);

N-(1,3-benzo dioxole-5-ylmethyl)-(2-chloro-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (453.1017; 453.0986);

2-(2-chloro-4-luorobenzyl)-N-[4-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide (475.1036; 475.1006);

2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo-N-(2-pyridin-4-yl ethyl) isoindoline-1-methane amide (508.1459; 508.1463);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(2-pyridin-4-yl ethyl) isoindoline-1-methane amide (434.1635; 434.1630);

2-[3, two (trifluoromethyl) benzyls of 5-]-N-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (496.1459; 496.1419);

2-[2-(4-chloro-phenyl-) propyl group]-N-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (422.1635; 422.1634);

2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide (485.1443; 485.1420);

2-[3, two (trifluoromethyl) benzyls of 5-]-N-[4-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-(1,3-benzo dioxole-5-ylmethyl)-2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-(1-benzyl-pyrrole alkane-3-yl)-2-(2-chloro-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (478.1697; 478.1697);

N-(1-benzyl-pyrrole alkane-3-yl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (488.2104; 488.2104);

2-(2-chloro-4-luorobenzyl)-N-{[5-(2-furyl) isoxazole-3-base] methyl }-3-oxo isoindole quinoline-1-methane amide (466.0970; 466.0988);

2-(2, the 2-dimethyl propyl)-N-{[5-(2-furyl) isoxazole-3-base] methyl }-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-{[5-(2-furyl) isoxazole-3-base] methyl }-3-oxo isoindole quinoline-1-methane amide (550.1201; 550.1180);

2-[2-(4-chloro-phenyl-) propyl group]-N-[3-(1H-imidazoles-1-yl) propyl group]-3-oxo isoindole quinoline-1-methane amide (437.1744; 437.1733);

2-[3, two (trifluoromethyl) benzyls of 5-]-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide (536.1772; 536.1783);

2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide (462.1948; 462.1909);

N-(1-benzyl-pyrrole alkane-3-yl)-2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo isoindole quinoline-1-methane amide (562.1929; 562.1935);

2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide (497.1301; 497.1281);

N-(tertiary butyl)-3-oxo-2-[(1-phenyl-1H-tetrazolium-5-yl) methyl] isoindoline-1-methane amide (391.1882; 391.1883);

2-[2-(4-chloro-phenyl-) propyl group]-N-[3-(dimethylamino) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(dimethylamino) ethyl]-3-oxo isoindole quinoline-1-methane amide (400.1791; 400.1766);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide (420.1478; 420.1465);

N-[2-(4-benzoyl piperazine-1-yl) ethyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(1-pyridin-3-yl ethyl) isoindoline-1-methane amide (434.1635; 434.1627);

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-p-methoxy-phenyl)-3-oxo isoindole quinoline-1-methane amide (435.1475; 435.1462);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(1-pyridin-4-yl ethyl) isoindoline-1-methane amide (434.1635; 434.1620);

2-[2-(4-chloro-phenyl-) propyl group]-N-(4-cyano-phenyl)-3-oxo isoindole quinoline-1-methane amide (430.1322; 430.1315);

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-methoxy-propyl)-3-oxo isoindole quinoline-1-methane amide (401.1632; 401.1633);

N-(1,3-benzo dioxole-5-ylmethyl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (463.1424; 463.1411);

2-[2-(4-chloro-phenyl-) propyl group]-N-(3, the 4-dimethoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (479.1737; 479.1748);

2-[2-(4-chloro-phenyl-) propyl group]-N-[(3-methyl-5-phenyl-isoxazole azoles-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (500.1741; 500.1745);

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-7-fluoro-3-oxo isoindole quinoline-1-methane amide (403.1588; 403.1577);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-7-fluoro-3-oxo isoindole quinoline-1-methane amide (403.1588; 403.1569);

N-(tertiary butyl)-3-oxo-2-[2-(phenyl sulfonyl) ethyl] isoindoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-fluorophenoxy) propyl group]-3-oxo isoindole quinoline-1-methane amide (385.1927; 385.1899);

N-(tertiary butyl)-3-oxo-2-(2-phenoxy propyl) isoindoline-1-methane amide (367.2021; 367.2033);

N-benzyl-2-[(5-methyl-isoxazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-[2-(phenyl sulfonyl) ethyl] isoindoline-1-methane amide (435.1378; 435.1366);

N-benzyl-3-oxo-2-(2-phenoxy group ethyl) isoindoline-1-methane amide (387.1708; 387.1705);

N-benzyl-3-oxo-2-(2-phenoxy propyl) isoindoline-1-methane amide (401.1865; 401.1888);

N-benzyl-2-[2-(4-fluorophenoxy) propyl group]-3-oxo isoindole quinoline-1-methane amide (419.1771; 419.1798);

N-benzyl-2-[(1-benzyl-1H-pyrazoles-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (437.1977; 437.1988);

N-benzyl-2-[(5-methyl-3-phenyl-isoxazole azoles-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (438.1817; 438.1818);

N-benzyl-3-oxo-2-[(3-phenyl-isoxazole azoles-5-yl) methyl] isoindoline-1-methane amide (424.1661; 424.1669);

N-(tertiary butyl)-5,6-two chloro-2-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5,6-two chloro-2-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (409.0886; 409.0912);

N-(tertiary butyl)-5,6-two chloro-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (421.1085; 421.1078);

N-(tertiary butyl)-5,6-two chloro-2-[4-(difluoro-methoxy) benzyls]-3-oxo isoindole quinoline-1-methane amide (457.0897; 457.0864);

N-(tertiary butyl)-5-fluoro-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (371.1771; 371.1768);

N-(4-luorobenzyl)-3-oxo-2-(2-pyridin-4-yl ethyl) isoindoline-1-methane amide (390.1617; 390.1628);

2-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide (428.1586; 428.1586);

N-(2-furyl methyl)-3-oxo-2-(2-phenyl propyl) isoindoline-1-methane amide (375.1708; 375.1698);

2-[2-(4-chloro-phenyl-) ethyl]-N-[(5-methyl-2-furyl) methyl]-3-oxo isoindole quinoline-1-methane amide (409.1319; 409.1317);

N-(4-luorobenzyl)-2-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (378.1617; 378.1609);

N-(2-benzyl chloride base)-2-[2-(1H-indol-3-yl)-1-methylethyl]-3-oxo isoindole quinoline-1-methane amide (458.1635; 458.1631);

N-(tertiary butyl)-5,6-two chloro-2-[2-(4-chloro-2-aminomethyl phenyl)-2,2-two fluoro ethyls]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5,6-two chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (453.0903; 453.0917);

N-(tertiary butyl)-2-[2-(4-chloro-2-aminomethyl phenyl)-2,2-two fluoro ethyls]-3-oxo isoindole quinoline-1-methane amide (421.1494; 421.1518);

N-benzyl-2-[2-(4-chloro-2-aminomethyl phenyl)-2,2-two fluoro ethyls]-3-oxo isoindole quinoline-1-methane amide (455.1338; 455.1351);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (487.1400; 487.1414);

2-[3-(difluoro-methoxy) benzyl]-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (419.1602; 419.1599);

N-(2-benzyl chloride base)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (453.1136; 453.1123);

2-[4-(difluoro-methoxy) benzyl]-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (419.1602; 419.1601);

N-(2-benzyl chloride base)-2-(2, the 5-dimethyl benzyl)-3-oxo isoindole quinoline-1-methane amide (419.1526; 419.1513);

2-(biphenyl-2-ylmethyl)-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (451.1821; 451.1804);

N-(2-benzyl chloride base)-2-[(1R)-1-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (435.1475; 435.1466);

N-(2-benzyl chloride base)-2-[(1R)-1-(3-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (435.1475; 435.1469);

N-(2-benzyl chloride base)-2-[(1S)-1-(1-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (455.1526; 455.1518);

N-benzyl-3-oxo-2-(4-phenoxy benzyl) isoindoline-1-methane amide (449.1865; 449.1849);

N-(2-benzyl chloride base)-3-oxo-2-(3-phenyl propyl) isoindoline-1-methane amide (419.1526; 419.1524);

N-(2-benzyl chloride base)-3-oxo-2-(2-phenylethyl) isoindoline-1-methane amide (405.1369; 405.1336);

N-(2-benzyl chloride base)-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide (419.1526; 419.1520);

N-(2-benzyl chloride base)-2-(1-methyl-3-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide (433.1682; 433.1693);

N-(2-benzyl chloride base)-3-oxo-2-(2-phenyl propyl) isoindoline-1-methane amide (419.1526; 419.1516);

2-(biphenyl-2-ylmethyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (501.1790; 501.1790);

2-(biphenyl-2-ylmethyl)-N-(2-benzyl chloride base)-3-oxo isoindole quinoline-1-methane amide (467.1526; 467.1514);

3-oxo-2-(1-phenyl propyl)-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (453.1790; 453.1809);

3-oxo-2-(2-phenyl propyl)-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (453.1790; 453.1777);

2-(1-methyl-3-phenyl propyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (467.1946; 467.1926);

3-oxo-2-(2-phenylethyl)-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (439.1633; 439.1626);

N-benzyl-2-[2-(5-bromo-2-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (479.0970; 479.0968);

3-oxo-2-(3-phenyl propyl)-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (453.1790; 453.1769);

N-benzyl-2-[2-(3-bromo-4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (479.0970; 479.0972);

2-(2-methyl butyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (405.1790; 405.1786);

N-benzyl-2-(2, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide (393.1414; 393.1432);

2-(cyclohexyl methyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (431.1946; 431.1945);

2-(3-luorobenzyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (443.1382; 443.1384);

2-(2-ethoxy benzyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide (469.1739; 469.1753);

3-oxo-2-[4-(trifluoromethoxy) benzyl]-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(3, the 4-Dimethoxyphenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (493.1894; 493.1895);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-[2-(2-thienyl) ethyl] isoindoline-1-methane amide (439.1247; 439.1242);

2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (463.1788; 463.1794);

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (433.1682; 433.1679);

2-[2-(4-chloro-phenyl-) propyl group]-N-(2-methoxy ethyl)-3-oxo isoindole quinoline-1-methane amide (387.1475; 387.1483);

2-[2-(4-chloro-phenyl-) propyl group]-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (437.1432; 437.1448);

N-benzyl-2-[4-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide (423.1520; 423.1511);

N-benzyl-2-[3-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide (423.1520; 423.1518);

N-butyl-2-(1-naphthyl methyl)-3-oxo isoindole quinoline-1-methane amide (373.1916; 373.1883);

N-benzyl-2-suberyl-3-oxo isoindole quinoline-1-methane amide (363.2072; 363.2062);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-[2-(4-bromophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-(1-ethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-[3-(1H-pyrroles-1-yl) benzyl] isoindoline-1-methane amide (422.1868; 422.1874);

N-benzyl-2-(3-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide (375.1508; 375.1501);

N-benzyl-2-[2-(2-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (401.1865; 401.1854;

N-benzyl-2-(2-ethoxy benzyl)-3-oxo isoindole quinoline-1-methane amide (401.1865; 401.1869);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-3-oxo-2-(2-phenyl propyl) isoindoline-1-methane amide;

N-benzyl-2-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide (382.1555; 382.1558);

N-benzyl-2-(3, the 5-dimethoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (417.181; 417.1806);

N-benzyl-2-[1-(1-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (421.1916; 421.1899);

N-benzyl-3-oxo-2-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide (425.1477; 425.1482);

N-(2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl)-Beta-alanine ethyl ester (503.1405; 503.1403);

2-(1-naphthyl methyl)-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (403.1841; 403.1844);

N-(2-[2-(3, the 4-dichlorophenyl) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl)-Beta-alanine ethyl ester (449.1035; 449.1038);

4-(the 1-[(benzylamino) carbonyl]-3-oxo-1,3-dihydro-2H-isoindole-2-yl } methyl) methyl benzoate (415.1657; 415.1665);

3-oxo-2-[3-(trifluoromethyl) benzyl]-the N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (421.1559; 421.1552);

2-[1-(1-naphthyl) ethyl]-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (417.1998; 417.1983);

3-oxo-2-[4-(trifluoromethyl) benzyl]-the N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (421.1559; 421.1546);

2-[2-(4-bromophenyl) ethyl]-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (445.0947; 445.0931);

2-(2-chloro-6-phenoxy benzyl)-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (479.1557; 479.1568);

2-(3, the 4-dichloro benzyl)-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide (421.0906; 421.0896);

N-benzyl-2-(1-benzyl-pyrrole alkane-3-yl)-3-oxo isoindole quinoline-1-methane amide (426.2181; 426.2169);

N-benzyl-2-(1-benzyl-pyrrole alkane-3-yl)-4,5-dimethoxy-3-oxo isoindole quinoline-1-methane amide (486.2392; 486.2405);

N-benzyl-2-(3, the 4-difluorobenzyl)-4,5-dimethoxy-3-oxo isoindole quinoline-1-methane amide (453.1626; 453.1620);

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-4,5-dimethoxy-3-oxo isoindole quinoline-1-methane amide (479.1737; 479.1729);

N-benzyl-4,5-dimethoxy-2-(1-methyl-3-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (360.1712; 360.1697);

N-benzyl-3-oxo-2-(1-phenyl-2-tetramethyleneimine-1-base ethyl) isoindoline-1-methane amide (440.2338; 440.2336);

N-benzyl-2-[2-(4-p-methoxy-phenyl)-2-oxoethyl]-3-oxo isoindole quinoline-1-methane amide (415.1657; 415.1674);

The N-benzyl-2-[(1R)-1-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (401.1865; 401.1883);

N-benzyl-2-(3, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide (393.1414; 393.1403);

The N-benzyl-2-[(1R)-1-(3-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (401.1865; 401.1859);

N-benzyl-2-(2, the 5-dimethyl benzyl)-3-oxo isoindole quinoline-1-methane amide (385.1916; 385.1924);

N-benzyl-2-(1-methyl-3-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide (399.2072; 399.2062);

N-benzyl-3-oxo-2-{2-[3-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide (439.1633; 439.1634);

N-benzyl-2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo isoindole quinoline-1-methane amide (493.1350; 493.1341);

N-benzyl-2-[2-(6-chloro-1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide (444.1478; 444.1484);

N, 2-dibenzyl-3-oxo isoindole quinoline-1-methane amide (357.1603; 357.1613);

N-benzyl-2-(cyclohexyl methyl)-3-oxo isoindole quinoline-1-methane amide (363.2072; 363.2079);

N-benzyl-3-oxo-2-(2-thienyl methyl) isoindoline-1-methane amide (363.1167; 363.1162);

2-(1,3-benzo dioxole-5-ylmethyl)-N-cyclohexyl-3-oxo isoindole quinoline-1-methane amide (393.1814; 393.1807);

2-(2-methoxy-benzyl)-N-(4-methylcyclohexyl)-3-oxo isoindole quinoline-1-methane amide (393.2178; 393.2169);

N-{[3-oxo-2-(3-tetramethyleneimine-1-base propyl group)-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate (402.2392; 402.2388);

N-(tertiary butyl)-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (353.1865; 353.1861);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-(2-bromobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-N-cyclohexyl-3-oxo isoindole quinoline-1-methane amide (397.1682; 397.1648);

N-(2, the 3-Dimethylcyclohexyl)-3-oxo-2-(2-thienyl methyl) isoindoline-1-methane amide (383.1793; 383.1778);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide (474.1930; 474.1937);

2-(2-benzyl chloride base)-N-(4-methylcyclohexyl)-3-oxo isoindole quinoline-1-methane amide (397.1682; 397.1671);

N-butyl-2-(2-hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide (341.2229; 341.2213);

The N-benzyl-2-[(2R)-2-hydroxyl-1, the 2-diphenyl-ethyl]-3-oxo isoindole quinoline-1-methane amide (463.2021; 463.2000);

2-(biphenyl-2-ylmethyl)-N-butyl-3-oxo isoindole quinoline-1-methane amide (399.2072; 399.2090);

2-(biphenyl-2-ylmethyl)-N-sec.-propyl-3-oxo isoindole quinoline-1-methane amide (385.1916; 385.1915);

N-{[2-(2-bromobenzyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate (459.0919; 459.0904);

2-[2-(4-chloro-phenyl-) propyl group]-N-sec.-propyl-3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1545);

N-{[3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoindole-1-yl] carbonyl } glycine methyl ester (353.1501; 353.1496);

N-(tertiary butyl)-2-[1-(2-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (387.2072; 387.2083);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-[1-(2-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (462.1930; 462.1919);

2-[2-(3,4-diethoxy phenyl) ethyl]-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (473.2440; 473.2461);

2-benzyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (371.1759; 371.1755);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide (441.2039; 441.2030);

N-benzyl-2-(3-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (387.1708; 387.1705);

2-(2-chloro-4-luorobenzyl)-N-cyclopentyl-3-oxo isoindole quinoline-1-methane amide (387.1275; 387.1291);

2-(2-chloro-4-luorobenzyl)-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide (410.1071; 410.1057);

2-(2, the 5-dimethoxy-benzyl)-3-oxo-N-(diphenyl-ethyl) isoindoline-1-methane amide (431.1970; 431.1964);

N-(sec-butyl)-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide (371.1526; 371.1496);

N-benzyl-2-(2, the 3-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide (393.1414; 393.1390);

2-(2-chloro-4-luorobenzyl)-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (423.1275; 423.1260;

2-[2-(4-chloro-phenyl-) ethyl]-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (419.1526; 419.1539);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-(2-methyl-benzyl)-3-oxo isoindole quinoline-1-methane amide (412.1773; 412.1747);

N-(tertiary butyl)-2-(cyclohexyl methyl)-3-oxo isoindole quinoline-1-methane amide (329.2229; 329.2238);

2-(1-methyl-3-phenyl propyl)-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide (413.2229; 413.2227);

N-benzyl-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide (349.1916; 349.1906);

N-(tertiary butyl)-2-(hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide (341.2229; 341.2216);

N-(tertiary butyl)-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

N-{[2-(cyclohexyl methyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate (387.2283; 387.2270);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-(2-hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide (416.2086; 416.2081);

N-{[2-(biphenyl-2-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate (457.2127; 457.2120);

N-benzyl-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide (337.1916; 337.1917);

N-benzyl-2-(3-methyl butyl)-3-oxo isoindole quinoline-1-methane amide (337.1916; 337.1907);

N-benzyl-3-oxo-2-[2-(2-thienyl) ethyl] isoindoline-1-methane amide (377.1323; 377.1326);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-3-oxo-2-(2-phenylethyl) isoindoline-1-methane amide (412.1773; 412.1770);

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (419.1526; 419.1497);

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (385.1682; 385.1663);

N-benzyl-2-(2-methyl-benzyl)-3-oxo isoindole quinoline-1-methane amide (371.1759; 371.1779);

N-benzyl-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide (387.1708; 387.1711);

N-benzyl-3-oxo-2-(2-phenylethyl) isoindoline-1-methane amide (371.1759; 371.1746);

N-benzyl-2-[1-(2-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (421.1916; 421.1919);

N-(2[2-(4-chloro-phenyl-) propyl group]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester (401.1268; 401.1258);

N-(2[1-(2-naphthyl) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) tert-butyl glycinate (445.2127; 445.2119);

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (460.1540; 460.1520);

N-butyl-2-[1-(2-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide (387.2072; 387.2103);

N-benzyl-2-(2-bromobenzyl)-3-oxo isoindole quinoline-1-methane amide (435.0708; 435.0700);

N-benzyl-2-(2-hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide (375.2072; 375.2065);

N-benzyl-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide (433.1916; 433.1916);

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide (385.1682; 385.1676);

2-[2-(4-chloro-phenyl-)-2-methyl-propyl]-the N-[(1-sec.-propyl)-5-oxo-pyrrolidine-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (482.221; 482.218);

2-[2-(4-chloro-phenyl-) propyl group]-the N-[(1-sec.-propyl)-5-oxo-pyrrolidine-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

1H-isoindole-1-methane amide, 2-[2-(4-chloro-phenyl-) propyl group]-2,3-dihydro-N-[2-[(1-methylethyl) amino]-the 2-oxoethyl]-the 3-oxo-, (428.1741; 428.174);

N-(tertiary butyl)-2-[(4 ', 5-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (435.1884; 435.1892);

N-(tertiary butyl)-2-[(5-fluorine biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (417.1978; 417.1976);

N-(tertiary butyl)-2-[(4-fluorine biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide (417.1978; 417.1978);

2-[2-(4-chloro-phenyl-)-2-methyl-propyl]-the N-[(1-sec.-propyl)-5-oxo-pyrrolidine-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

1H-isoindole-1-methane amide, 2-[2-(4-chloro-phenyl-) propyl group]-2,3-dihydro-N-[2-[(1-methylethyl) amino]-2 oxoethyls]-the 3-oxo-;

2-(2, the 2-dimethyl propyl)-6-fluoro-3-oxo-N-(1-phenylethyl) isoindoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-6-fluoro-N-(3-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-6-fluoro-N-(2-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-N-(3-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-N-(2-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(1-methyl isophthalic acid-phenylethyl)-3-oxo-N-(1-phenylethyl) isoindoline-1-methane amide;

6-fluoro-3-oxo-N, two (1-phenylethyl) isoindolines of 2--1-methane amide;

N-(1-methyl isophthalic acid-phenylethyl)-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

3-oxo-N, two (1-phenylethyl) isoindolines of 2--1-methane amide;

N-(3-luorobenzyl)-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

N-(2-luorobenzyl)-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

(1R or 1S)-2-[(2S or 2R)-2-(4-chloro-phenyl-) propyl group]-3-oxo-N-propyl group isoindoline-1-methane amide;

(1S or 1R)-2-[(2R or 2S)-2-(4-chloro-phenyl-) propyl group]-3-oxo-N-propyl group isoindoline-1-methane amide;

(1R or 1S)-2-[(2R or 2S)-2-(4-chloro-phenyl-) propyl group]-3-oxo-N-propyl group isoindoline-1-methane amide;

(R or S) 2-(biphenyl-2-ylmethyl)-6-chloro-N-ethyl-3-oxo isoindole quinoline-1-methane amide;

(S or R) 2-(biphenyl-2-ylmethyl)-6-chloro-N-ethyl-3-oxo isoindole quinoline-1-methane amide;

N-(4-luorobenzyl)-2-[1-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[1-(4-chloro-phenyl-) ethyl]-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[1-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[1-(4-chloro-phenyl-)-1-methylethyl]-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-6-fluoro-2-[1-(4-fluorophenyl)-1-methylethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[1-(4-chloro-phenyl-)-1-methylethyl]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

N-(4-luorobenzyl)-2-[1-(4-fluorophenyl)-1-methylethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-6-fluoro-2-(1-methyl isophthalic acid-phenylethyl)-3-oxo isoindole quinoline-1-methane amide;

2-[1-(4-fluorophenyl)-1-methylethyl]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

N-(4-luorobenzyl)-2-(1-methyl isophthalic acid-phenylethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(1-methyl isophthalic acid-phenylethyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(5-cyano group amyl group)-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-6-bromo-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-4-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(4,4-difluoro butyl)-4-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-4-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-ethyl-4-fluoro-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(biphenyl-2 ylmethyl)-4-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2 ylmethyl)-N-(4,4-difluoro butyl)-4-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2 ylmethyl)-4-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide;

2-(biphenyl-2 ylmethyl)-N-ethyl-4-fluoro-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-4-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide.

Claims

1, the compound of formula I or its pharmacy acceptable salt:

Wherein

R ³Expression hydrogen, C ₁-C ₁₂Alkyl (described alkyl group randomly is selected from following group and replaces by one or more: halogen ,-OR ²⁵,-COR ²⁶, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, trialkylsilkl ,-COXR ²⁷, aryl or Het ⁵);

R ^29a, R ^29bAnd R ^29cWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ²⁹(C wherein ₁-C ₆Alkyl, aryl and Het ²⁹Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ³⁰); R ^29bAnd R ^29cCan represent C together ₃-C alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

Aryl is optional independently when occurring each time to be replaced by following group :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, C ₃-C ₈Cycloalkyl, C ₂-C ₆Thiazolinyl, phenyl, Het ⁸,-OR ⁵⁰,-(CH ₂) _mR ⁵¹,-SR ⁵²,-C (O) R ⁵³,-COXR ⁵⁴,-N (R ^55a) (R ^55b) ,-SO ₂R ⁵⁶,-OS (O) ₂R ⁵⁷,-(CH ₂) _mN (R ^58a) (R ^58b) ,-(CH ₂) _mNR ^59aC (O) N (R ^59b) (R ^59c) ,-C (O) OR ⁶⁰,-C (O) N (R ^61a) (R ^61b) ,-N (R ^62aC (O) R ^62b,-N (R ^63a) C (O) OR ^63b,-OC (O) N (R ^64a) (R ^64b) ,-N (R ^65a) S (O) ₂R ^65bAnd OC (O) R ⁶⁶

R ^71aAnd R ^71bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ⁶⁵(C wherein ₁-C ₆Alkyl, aryl and Het ₆₅Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl and Het ₆₆), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

X represents nitrogen-atoms or Sauerstoffatom;

M is 0～10 integer;

N is 0～4 integer;

K is 1～5 integer;

Condition is:

A) R ²Or R ³The fragment of not representing following formula:

Wherein,

Het ⁷⁵～Het ⁷⁶Represent to contain one or more heteroatomic 5-12 unit heterocyclic groups that are selected from oxygen, nitrogen and/or sulphur when occurring each time independently, described group randomly is selected from following substituting group and replaces by one or more :-OH, oxo, halogen, cyano group, nitro, C _1-6Alkyl, C _1-6Alkoxyl group, aryl, aryloxy ,-N (R ^93a) R ^93b,-C (O) R ^93c,-C (O) OR ^93d,-C (O) N (R ^93e) R ^93f,-N (R ^93g) C (O) R ^93hWith-N (R ⁹³ⁱ) S (O) ₂R ^93j, OC (O) R ^93kWith other Het;

R ⁸⁶～R ⁹³When occurring each time, represent hydrogen or C independently _1-6Alkyl;

2-(4-nitrophenyl)-3-(tetramethyleneimine-1-carbonyl) 1-isoindolinone;

N, 2-dibenzyl-3-oxo isoindole quinoline-1-methane amide;

N, 2-diethyl-3-oxo isoindole quinoline-1-methane amide;

N, 2-dibutyl-3-oxo isoindole quinoline-1-methane amide;

N, the two dodecyls of 2--3-oxo isoindole quinoline-1-methane amide;

N, two (4-the methoxy-benzyl)-3-oxo isoindole quinolines of 2--1-methane amide;

3-oxo-N, 2-dipropyl isoindoline-1-methane amide;

N, 2-diheptyl-3-oxo isoindole quinoline-1-methane amide;

3-oxo-N, 2-phenylbenzene isoindoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-propyl group isoindoline-1-methane amide;

N-(tertiary butyl)-1-methyl-3-oxo-2-propyl group-isoindoline-1-methane amide;

N, 1-dimethyl-3-oxo-2 propyl group isoindoline-1-methane amide;

N-cyclohexyl-3-oxo-2-propyl group isoindoline-1-methane amide;

N-(phenyl)-3-oxo-2-propyl group isoindoline-1-methane amide;

2-benzyl-N-the tertiary butyl-3-oxo isoindole quinoline-1-methane amide;

2-benzyl-N, 1-dimethyl-3-oxo isoindole quinoline-1-methane amide;

2-benzyl-3-oxo-N-(2-styroyl) isoindoline-1-methane amide;

2-benzyl-N-butyl-3-oxo isoindole quinoline-1-methane amide;

2-benzyl-N-(2-methoxy ethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-hydroxyethyl) 3-oxo-N-(2-styroyl) isoindoline-1-methane amide;

N-butyl-2-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(cyclohexyl)-3-oxo-N-(2-styroyl)-isoindoline-1-methane amide;

N-butyl-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

2-cyclohexyl-N-(2-methoxy ethyl)-3-oxo isoindole quinoline-1-methane amide;

N, 2-dibenzyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N, 2-dibenzyl-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide;

2-cyclohexyl-N-hexyl-3-oxo isoindole quinoline-1-methane amide;

N, 2-dihexyl-3-oxo isoindole quinoline-1-methane amide;

N-hexyl-(2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide;

N-hexyl-2 (4-hydroxyl butyl)-3-oxo isoindole quinoline-1-methane amide;

N, 2-dicyclohexyl-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-2-hexyl-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-2 (2-hydroxyethyl)-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-2 (4-hydroxyl butyl)-3-oxo isoindole quinoline-1-methane amide;

N-diamantane-1-base-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

N-diamantane-1-base-2-hexyl-3-oxo isoindole quinoline-1-methane amide;

N-cyclopentyl-2-(3-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-3-oxo-2-(2-thienyl methyl) isoindoline-1-methane amide;

2-benzyl-N-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

N-cyclohexyl-2-(2-furyl methyl)-3-oxo isoindole quinoline-1-methane amide;

1-hydroxy-2-methyl-3-oxo-N-(pyridine-2-ylmethyl) isoindoline-1-methane amide;

2-benzoyl-1-hydroxyl-3-oxo-N-phenyl isoindoline-1-methane amide;

3-oxo-N, 2-phenylbenzene isoindoline-1-methane amide;

N-(methyl)-2-benzoyl-1-hydroxyl-3-oxindole quinoline-1-methane amide;

N-(phenyl)-2-benzoyl-1-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

1-hydroxy-2-methyl-3-oxo isoindole quinoline-1-carbohydrazide;

1-hydroxyl-3-oxo-phenyl isoindoline-1-carbohydrazide;

C) described compound is not:

N-sec.-propyl-2-(3-methyl butyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

2, compound according to claim 1, wherein R ¹Expression C ₁-C ₇(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COXR ¹⁰, aryl or Het ¹); R in addition ¹Expression Het ²

3, compound according to claim 1, wherein R ¹Expression C ₁-C ₇(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COXR ¹⁰, phenyl, naphthyl or Het ¹).

4, compound according to claim 1, wherein R ¹Expression (1-benzyl-pyrrole alkane-3 base), (1-fluoro-3-phenyl-propane-2-yl), (1-methyl-5-phenyl-pyrazole-3-yl) methyl, (1-methylpyrrole-2 base) methyl, (2, the 3-difluorophenyl) methyl, (2, the 4-difluorophenyl) methyl, (2, the 5-Dimethoxyphenyl) methyl, (2, the 5-3,5-dimethylphenyl) methyl, (2-bromophenyl) methyl, (2-chloro-4-fluoro-phenyl) methyl, (2-chloro-6-phenoxy group-phenyl) methyl, (2-chloro-phenyl-) methyl, (2-dimethylamino-2-phenyl-ethyl), (2-ethoxyl phenenyl) methyl, (2-fluorophenyl) methyl, (2-p-methoxy-phenyl) methyl, (2-methyl-2-phenyl-propyl group), (2-aminomethyl phenyl) methyl, (2-Phenoxyphenyl) methyl, (2-phenyl) methyl, (2-pyridin-3-yl phenyl) methyl, (3, the 4-dichlorophenyl) methyl, (3, the 4-difluorophenyl) methyl, (3, the 5-Dimethoxyphenyl) methyl, (3-chloro-phenyl-) methyl, (3-cyano group-4-fluoro-phenyl) methyl, (3-cyano-phenyl) methyl, (3-fluorophenyl) methyl, (3-hydroxyl-2,2-dimethyl-propyl group), (3-p-methoxy-phenyl) methyl, (3-phenyl 1,2-oxazole-5-yl) methyl, (3-phenyl) methyl, (3-pyrroles-1-base phenyl) methyl, (4-chloro-phenyl-) methyl, (4-dimethylaminophenyl) methyl, (4-fluorophenyl) methyl, (4-hydroxy phenyl) methyl, (4-methoxycarbonyl phenyl) methyl, (4-Phenoxyphenyl) methyl, (4-phenyl) methyl, (5-methyl-2-phenyl-1,3-oxazole-4 base) methyl, (5-methyl-3-phenyl-1,2-oxazole-4 base) methyl, (phenyl-pyridine-2-base-methyl); [(1R)-1-(4-p-methoxy-phenyl) ethyl], [(1S)-the 1-phenylethyl], [(1R)-the 1-phenylethyl], [(1R)-2-(4-chloro-phenyl-)-1-(4,4,4-trifluoro butyl formamyl) ethyl], [(1R)-2-(4-chloro-phenyl-)-1-methoxycarbonyl-ethyl], [(1S)-1-naphthalene-1-base ethyl], [(2R)-2-(4-chloro-phenyl-) propyl group], [(2S)-2-(4-chloro-phenyl-) propyl group], [(4-chloro-phenyl-)-pyridin-4-yl-methyl], [(4-fluorophenyl)-pyridin-3-yl-methyl], [(4-fluorophenyl)-pyridin-3-yl-methyl], [(4-fluorophenyl)-pyridin-3-yl-methyl], [2-(2, the 4-dichlorophenyl) phenyl] methyl, [2-(2, the 4-difluorophenyl) phenyl] methyl, [2-(2, the 5-difluorophenyl) phenyl] methyl, [2-(2-chloro-phenyl-) phenyl] methyl, [2-(3, the 4-dichlorophenyl) phenyl] methyl, [2-(3, the 4-difluorophenyl) phenyl] methyl, [2-(3-chloro-4-fluoro-phenyl) phenyl] methyl, [2-(3-fluorophenyl) phenyl] methyl, [2-(4-chloro-2-methyl-phenyl)-2,2-two fluoro-ethyls], [2-(4-chloro-2-aminomethyl phenyl)-2,2-two fluoro-ethyls], [2-(4-chloro-phenyl-) phenyl] methyl, [2-(4-fluoro-2-methyl-phenyl) phenyl] methyl, [2-(4-fluorophenoxy) phenyl] methyl, [2-(4-fluorophenyl) phenyl] methyl, [2-(4-p-methoxy-phenyl)-2-oxo-ethyl], [2-(4-p-methoxy-phenyl) phenyl] methyl, [2-(4-aminomethyl phenyl) phenyl] methyl, [2-(trifluoromethyl) phenyl] methyl, [2-[4-(trifluoromethyl) phenoxy group] phenyl] methyl, [3-(difluoro-methoxy) phenyl] methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl, [4-(difluoro-methoxy) phenyl] methyl, [4-(trifluoromethyl) phenyl] methyl, 1-(1H-indol-3-yl) propane-2-base, 1-(4-fluorophenyl) ethyl, 1-naphthalene-1-base ethyl, 1-naphthalene-2-base ethyl, the 1-phenylethyl, the 1-phenyl propyl, 2-(1-cyclohexenyl) ethyl, 2-(2-ethoxyl phenenyl) ethyl, 2-(2-p-methoxy-phenyl) ethyl, 2-(2-Phenoxyphenyl) ethyl, 2-(3, the 4-dichlorophenyl) ethyl, 2-(3, the 5-Dimethoxyphenyl) ethyl, 2-(3-bromo-4-p-methoxy-phenyl) ethyl, 2-(3-fluorophenyl) ethyl, 2-(4-bromophenyl) ethyl, 2-(4-chloro-phenyl-) ethyl, 2-(4-chloro-phenyl-) propyl group, 2-(4-fluorophenoxy) propyl group, 2-(4-fluorophenyl) ethyl, 2-(4-fluorophenyl) propyl group, 2-(4-Phenoxyphenyl) ethyl, 2-(4-p-methoxy-phenyl) ethyl, 2-(4-p-methoxy-phenyl) ethyl, 2-(4-phenyl) ethyl, 2-(5-bromo-2-methoxyl group-phenyl) ethyl, 2-(6-chloro-1H-indol-3-yl) ethyl, 2, the 2-dimethyl propyl, 2, the 2-diphenyl-ethyl, 2-[2-(trifluoromethoxy) phenyl] ethyl, 2-[3-(trifluoromethyl) phenyl] ethyl, 2-[4-(diethylamino formyl radical) phenyl] ethyl, 2-[4-(trifluoromethyl) phenyl] ethyl, 2-benzo [1,3] dioxole-5-base ethyl, the 2-methyl butyl, the 2-methyl-propyl, 2-naphthalene-1-base propyl group, the 2-phenoxy propyl, the 2-phenyl propyl, 2-thiophene-2-base ethyl, 3, the 3-dimethylbutyl, the 3-phenyl propyl, 3-tetramethyleneimine-1-base propyl group, 4-phenyl butane-2-base; The 4-phenyl butyl; 9H-fluorenes-9-base, diphenyl-methyl, benzyl, suberyl, cyclohexyl, cyclohexyl methyl, naphthalene-1-ylmethyl, pentane-3-base, styroyl, thiophene-2-ylmethyl, 2-phenyl-propane-2-base, the 1-phenyl propyl, [2-(4-chloro-phenyl-)-2-methyl-propyl group], [4-fluoro-2-(4-fluorophenyl) phenyl] methyl, (4-fluoro-2-phenyl-phenyl) methyl, [5-fluoro-2-(4-fluorophenyl) phenyl] methyl, (5-fluoro-2-phenyl-phenyl) methyl, 1-(4-fluorophenyl) ethyl, 2-(4-chloro-phenyl-) propane-2-base, 2-(4-fluorophenyl) propane-2-base or 1-(4-chloro-phenyl-) ethyl.

5, according to each described compound, wherein R among the claim 1-4 ²Expression C ₁-C ₆(described alkyl group randomly is selected from following group and replaces by one or more alkyl: fluorine, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl ,-COR ¹⁷, trimethyl silyl ,-COXR ¹⁸, aryl or Het ³); R in addition ²Expression aryl or Het ⁴

6, according to each described compound, wherein R among the claim 1-5 ²Expression (1-benzyl-pyrrole alkane-3-yl); (1-methylpyrrole-2-yl) methyl; (2; 2-difluoro benzo [1; 3] methyl dioxole-5-yl); (2; the 3-Dimethylcyclohexyl); (2; the 4-difluorophenyl) methyl; (2-chloro-4-methyl sulphonyl-phenyl) methyl; (2-chloro-phenyl-) methyl; (2-fluoro-4-methyl sulphonyl-phenyl) methyl; (2-hydroxy phenyl) methyl; (2-methylpropane-2-yl) oxygen base carbonyl methyl; (3; the 4-dichlorophenyl) methyl; (3; the 4-difluorophenyl) methyl; (3; the 4-Dimethoxyphenyl) methyl; (3-formamyl-4-fluoro-phenyl) methyl; (3-chloro-phenyl-) methyl; (3-cyano group-4-fluoro-phenyl) methyl; (3-cyano-phenyl) methyl; (3-p-methoxy-phenyl); (3-methyl-5-phenyl-1; 2-oxazole-4-yl) methyl; (4-amino-2-methyl-pyrimidine-5-yl) methyl; (4-formamyl phenyl); (4-formamyl phenyl) methyl; (4-cyano group-2; 6-two fluoro-phenyl) methyl; (4-cyano-phenyl); (4-cyano-phenyl) methyl; (4-dimethylamino phenyl) methyl; (4-fluorophenyl) methyl; (4-hydroxy phenyl) methyl; (4-methylcyclohexyl); (4-methyl sulphonyl phenyl) methyl; (5-methyl isophthalic acid; 2-oxazole-3-yl) methyl; (5-methyl-2-furyl) methyl; (5-methyl-2-phenyl-1; 3-oxazole-4-yl) methyl; (5-methylpyrazine-2-yl) methyl; [2-(trifluoromethyl) phenyl] methyl; [3-(amino methyl) 4-fluoro-phenyl] methyl; [3-(difluoro-methoxy) phenyl] methyl; [3-(formyl-dimethylamino) 4-fluoro-phenyl] methyl; [3-(trifluoromethyl) phenyl] methyl; [3; two (trifluoromethyl) phenyl of 5-] methyl; [3-[[(2; 2-difluoro ethanoyl) amino] methyl] 4-fluoro-phenyl] methyl; [4-(acetylamino methyl) phenyl] methyl; [4-(amino methyl) phenyl]; [4-(difluoro-methoxy) phenyl] methyl; [4-(trifluoromethyl) phenyl] methyl; [4-[[(2; 2-difluoro ethanoyl) amino] methyl] phenyl]; [4-[[(2-acetyl fluoride base) amino] methyl] phenyl] methyl; [5-(2-furyl)-1; 2-oxazole-3-yl) methyl; [6-(trifluoromethyl) pyridin-3-yl) methyl; 1H-indol-3-yl methyl; 1-pyridin-4-yl ethyl; 2-(1H-indol-3-yl) ethyl; 2-(2; the 4-dichlorophenyl) ethyl; 2-(2; the 6-dichlorophenyl) ethyl; 2-(2-chloro-phenyl-) ethyl; 2-(3; the 4-dichlorophenyl) ethyl; 2-(3; the 4-Dimethoxyphenyl) ethyl; 2-(3-chloro-phenyl-) ethyl; 2-(3-fluorophenyl) ethyl; 2-(4-benzoyl-piperazine-1-yl) ethyl; 2-(4-chloro-phenyl-) ethyl; 2-(4-fluorophenyl) ethyl; 2-(4-p-methoxy-phenyl) ethyl; 2-[3-(trifluoromethyl) phenyl] ethyl; 2-benzo [1; 3] dioxole-5-base ethyl; 2-ethoxy carbonyl ethyl; the 2-furyl methyl; the 2-methoxy ethyl; 2-pyridine-2-base ethyl; 2-pyridin-4-yl ethyl; 2-thiophene-2-base ethyl; 3-imidazoles-1-base propyl group; the 3-methoxycarbonyl propyl; 4; 4; 4-trifluoro butyl; 4; 4-difluoro butyl; benzo [1,3] dioxole-5-ylmethyl; benzotriazole-1-ylmethyl; benzyl; butyl; cyclohexyl; ethyl; the methoxycarbonyl methyl; styroyl; propane-2-base; propyl group; the pyridin-3-yl methyl; the pyridin-4-yl methyl; the tertiary butyl; the trimethyl silyl methyl; (5-oxo-1-propane-2-base-tetramethyleneimine-3-yl) methyl; propane-2-base carbamyl ylmethyl; (2-fluorophenyl) methyl; (3-fluorophenyl) methyl; the 1-phenylethyl; 2-phenyl-propane-2-base or 5-cyano group amyl group.

7, compound according to claim 1, wherein R ¹Expression C ₁-C ₇(described alkyl group randomly is selected from following group and replaces by one or more alkyl: fluorine, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COXR ¹¹, aryl or Het ¹); R in addition ¹Expression Het ²And R ²Expression C ₁-C ₆(described alkyl group randomly is selected from following group and replaces by one or more alkyl: fluorine, C ₂-C ₆Thiazolinyl, C ₃-C ₇Cycloalkyl ,-COR ¹⁷, trimethyl silyl ,-COXR ¹⁸, aryl or Het ³); R in addition ²Expression aryl or Het ⁴

8, according to each described compound, wherein R among the claim 1-7 ³Expression hydrogen, C ₁-C ₄(described alkyl group randomly is selected from following group and replaces by one or more alkyl: fluorine, C ₂-C ₆Thiazolinyl, trialkylsilkl ,-COXR ²⁷, aryl or Het ⁵).

9, according to each described compound, wherein R among the claim 1-8 ³Expression hydrogen.

10, according to each described compound, wherein R among the claim 1-9 ⁴Expression hydrogen.

11, according to each described compound, wherein R among the claim 1-10 ⁵～R ⁷When occurring each time, represent independently hydrogen ,-OH, halogen, cyano group, C _1-6Alkyl ,-OR ³⁶,-C (O) N (R ^40a) (R ^40b) ,-N (R ^44a) S (O) ₂R ^44b

12, according to each described compound among the claim 1-11, wherein aryl when occurring each time independently randomly by-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl ,-OR ⁵⁰, C ₂-C ₆Thiazolinyl, aryl, Het ⁸Replace; R wherein ⁵⁰Expression C ₁-C ₆Alkyl or phenyl.

13, according to each described compound among the claim 1-12, wherein aryl is phenyl independently when occurring each time.

14, according to each described compound among the claim 1-13, the compound of its Chinese style I is:

Wherein, R ^aBe hydrogen or fluorine;

R ^bBe hydrogen or fluorine;

R ^cBe hydrogen or fluorine;

R ³Be the C that is randomly replaced by 1,2 or 3 fluorine end _1-4Alkyl;

R ⁵Be hydrogen or C _1-4Alkyl;

R ⁶Be hydrogen, OH, halogen or C _1-4Alkoxyl group;

R ⁷Be hydrogen or halogen.

15, according to each described compound among the claim 1-13, the compound of its Chinese style I is:

Wherein, R ^dBe hydrogen or C _1-4Alkyl;

R ^eBe hydrogen or C _1-4Alkyl;

R ^fBe hydrogen or C _1-4Alkyl;

R ^gBe hydrogen or halogen;

R ^hBe hydrogen or halogen;

R ^jBe hydrogen or halogen;

R ⁵Be hydrogen or halogen.

16, according to each described compound among the claim 1-13, its Chinese style I compound is:

Wherein, R ^kBe hydrogen or C _1-4Alkyl;

R ¹Be hydrogen or C _1-4Alkyl;

R ^mBe hydrogen or halogen;

R ²Be C _3-6Alkyl;

R ⁵Be hydrogen or halogen;

R ⁶Be hydrogen or halogen.

17, according to each described compound among the claim 1-13, its Chinese style I compound is:

Wherein, R ⁿBe hydrogen or halogen;

R ^pBe hydrogen or halogen;

R ⁵Be hydrogen or halogen.

18, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹For (2-phenyl) methyl, randomly replaced by 1-3 fluorine;

R ⁵～R ⁷Be independently selected from-OH, methyl, methoxyl group, chlorine, fluorine, cyano group, sulfonyloxy methyl amino, fluoro methoxyl group, difluoro-methoxy, trifluoromethanesulfonic acid base.

19, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be diphenyl-methyl, randomly replaced by one or more substituting groups that are selected from fluorine or chlorine;

R ²Be selected from ethyl, propyl group, butyl, the tertiary butyl, 4,4-difluoro butyl, 4,4,4-trifluoro butyl, benzyl, (2-chloro-4-methyl sulphonyl-phenyl) methyl, (4-methyl sulphonyl-phenyl) methyl, (2-fluoro-4-methyl sulphonyl-phenyl) methyl, (4-methyl sulphonyl-phenyl) methyl, (2-hydroxy phenyl) methyl, [2-(trifluoromethyl) phenyl] methyl, (2,4 difluorobenzene base) methyl, (2-chloro-phenyl-) methyl or 2-(4-fluorophenyl) ethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, methyl, methoxyl group, fluorine or chlorine.

20, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be 4-phenyl butane-2-base, randomly replaced by one or more substituting groups that are selected from fluorine or chlorine;

R ³Be hydrogen;

R ⁴Be hydrogen;

21, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be 3, the 3-dimethylbutyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

22, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be benzyl, randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, methyl, methoxyl group, bromine, chlorine, fluorine, trimethyl silyl.

23, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be (2-cyclopentyl phenyl) methyl;

R ²Be selected from 4,4-difluoro butyl, methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from bromine, fluorine, chlorine or cyano group.

24, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be the 1-phenylethyl, randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group, methoxyl group;

R ³Be hydrogen;

R ⁴Be hydrogen;

25, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be 3-hydroxyl-2, the 2-dimethyl propyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, fluorine, chlorine.

26, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be 2-(4-chloro-phenyl-) propyl group;

R ²Be selected from methyl, ethyl, n-propyl, propane-2-base, butyl, (4-amino-2-methyl-pyrimidine-5-yl) methyl, (5-methylpyrazine-2-yl) methyl, the pyridin-3-yl methyl, [6-(trifluoromethyl) pyridin-3-yl] methyl, (4-amino-2-methyl-pyrimidine-5-yl) methyl, [6-(trifluoromethyl) pyridin-3-yl] methyl, (5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl, 4,4,4-trifluoro butyl, (4-methyl sulphonyl phenyl) methyl, benzyl, (2,2-difluoro benzo [1,3] methyl dioxole-5-yl), (4-methyl sulphonyl phenyl) methyl, butyl, 2-(1H-indol-3-yl) ethyl, (4-formamyl phenyl) methyl, (4-cyano-phenyl) methyl, [3-(formyl-dimethylamino)-4-fluoro-phenyl] methyl, [3-(formyl-dimethylamino)-4-fluoro-phenyl] methyl, [4-(amino methyl) phenyl], [4-[[(2,2-difluoro ethanoyl) amino] methyl] phenyl], (4-formamyl phenyl), the pyridin-4-yl methyl, the 3-methoxy-propyl, (3-cyano group-4-fluoro-phenyl) methyl, [3-[[(2,2-difluoro ethanoyl) amino] methyl]-4-fluoro-phenyl] methyl, [3-(amino methyl)-4-fluoro-phenyl] methyl, [3-formamyl-4-fluoro-phenyl] methyl, 2-pyridin-4-yl ethyl, (1-methylpyrrole-2-yl) methyl, [4-(difluoro-methoxy) phenyl] methyl, (1-benzyl-pyrrole alkane-3-yl), 3-imidazoles-1-base propyl group, (4-dimethylaminophenyl) methyl, (4-methyl sulphonyl phenyl) methyl, the 3-dimethylaminopropyl, 1-pyridin-3-yl ethyl, (3-p-methoxy-phenyl), 1-pyridin-4-yl ethyl, (4-cyano-phenyl), the 3-methoxy-propyl, benzo [1,3] dioxole-5-ylmethyl, (3, the 4-dimethoxy phenyl) methyl, (3-methyl-5-phenyl-1,2-oxazole-4-yl) methyl, (5-methyl isophthalic acid, 2-oxazole-3-yl) methyl, [2-(trifluoromethyl) phenyl] methyl, (2-chloro-phenyl-) methyl, 2-(3, the 4-Dimethoxyphenyl) ethyl, 2-thiophene-2-base ethyl, 2-(4-methoxyphenyl) ethyl, styroyl, the 2-methoxy ethyl, (4-fluorophenyl) methyl, the methoxycarbonyl methyl, benzotriazole-1-ylmethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine, chlorine.

27, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be 2-(4-chloro-phenyl-) propyl group;

R ²Be the tertiary butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, bromine, fluorine, chlorine, methyl ,-OCH ₃,-OCH ₂F, trimethyl silyl.

28, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be 2-(4-fluorophenyl) propyl group;

R ²Be 4,4,4-trifluoro butyl, benzyl, the tertiary butyl, butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, bromine, fluorine, chlorine, methoxyl group.

29, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be 2, the 2-dimethyl propyl;

R ²Be [3-(trifluoromethoxy) phenyl] methyl, [3-(difluoro-methoxy) phenyl] methyl, (3, the 4-dichlorophenyl) methyl, 2-[3-(trifluoromethyl) phenyl] ethyl, 2-(1H-indol-3-yl) ethyl, (3-chloro-phenyl-) methyl, [4-(difluoro-methoxy) phenyl] methyl, [3-(trifluoromethyl) phenyl] methyl, 2-(3-fluorophenyl) ethyl, 2-(2-chloro-phenyl-) ethyl, 2-(3-chloro-phenyl-) ethyl, 2-(2, the 4-dichlorophenyl) ethyl, 2-(4-chloro-phenyl-) ethyl, 2-(2, the 6-dichlorophenyl) ethyl, benzo [1,3] dioxole-5-ylmethyl or phenmethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

30, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be 2-phenyl-propane-2-base;

R ²Be benzyl, 1-phenylethyl, (4-fluorophenyl) methyl, 4,4,4-trifluoro butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

31, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be the 1-phenyl propyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

32, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ¹Be [2-(4-chloro-phenyl-)-2-methyl-propyl group];

R ²Be normal-butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine or chlorine.

33, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be (2-chloro-phenyl-) methyl;

R ¹Be diphenyl-methyl, (2-pyridin-3-yl phenyl) methyl, (3, the 4-difluorophenyl) methyl, 1-(1H-indol-3-yl) propane-2-base, 2-(4-chloro-phenyl-) propyl group, (2, the 5-3,5-dimethylphenyl) methyl, [(1R)-1-(4-p-methoxy-phenyl) ethyl], 2-(1H-indol-3-yl) propyl group, [(1R)-1-(3-p-methoxy-phenyl) ethyl], [(1S)-1-naphthalene-1-base ethyl], 1-phenyl propyl, 2-phenyl propyl, 3-phenyl propyl, 2-styroyl, 4-phenyl butane-2-base, (2-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine and chlorine.

34, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be (3, the 4-dichlorophenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

35, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be (3-chloro-phenyl-) methyl;

R ¹Be (3-hydroxyl-2,2-dimethyl-propyl group), 2-methyl-propyl, 2,2-dimethyl propyl, 3,3-dimethylbutyl, (4-hydroxy phenyl) methyl or (3-cyano-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

36, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be (3-cyano group-4-fluoro-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

37, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be (3-cyano-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

38, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be (4-fluorophenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

39, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be (4-hydroxy phenyl) methyl;

R ¹Expression (3, the 4-difluorophenyl) methyl, (3-chloro-phenyl-) methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl or [4-(trifluoromethyl) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

40, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be [2-(trifluoromethyl) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine, chlorine, methoxyl group or methyl.

41, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be [3-(difluoro-methoxy) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

42, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be [3-(trifluoromethoxy) phenyl] methyl;

R ¹Expression 3,3-dimethylbutyl or 2,2 dimethyl propyls;

R ³Be hydrogen;

R ⁴Be hydrogen;

43, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be [3-(trifluoromethyl) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

44, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be [4-(difluoro-methoxy) phenyl] methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

45, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be [6-(trifluoromethyl) pyridin-3-yl] methyl;

R ¹Be 2-(4-chloro-phenyl-) propyl group or (2-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

46, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be 2-(1H-indol-3-yl) ethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

47, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be 2-(2,4 dichloro benzene base) ethyl;

R ¹Be 2-methyl-propyl, 3,3-dimethylbutyl or 2,2 dimethyl propyls;

R ³Be hydrogen;

R ⁴Be hydrogen;

48, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be 2-(2, the 6-dichlorophenyl) ethyl;

R ¹Be 2-methyl-propyl, 3,3-dimethylbutyl or 2,2 dimethyl propyls;

R ³Be hydrogen;

R ⁴Be hydrogen;

49, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be 4,4,4-trifluoro butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen ,-OH, methyl, bromine, fluorine and chlorine.

50, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be 4,4-difluoro butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

51, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be benzyl;

R ¹Be benzyl, diphenyl-methyl, [2-(trifluoromethyl) phenyl] methyl, (2-pyridin-3-yl phenyl) methyl, (4-Phenoxyphenyl) methyl, (2, the 4-difluorophenyl) methyl, [4-(difluoro-methoxy) phenyl] methyl, [3-(difluoro-methoxy) phenyl] methyl, (3-pyrroles-1-base phenyl) methyl, (3-fluorophenyl) methyl, (4-cyano-phenyl) methyl, (3, the 5-Dimethoxyphenyl) methyl, (2-p-methoxy-phenyl) methyl, (2-ethoxyl phenenyl) methyl, [4-(trifluoromethyl) phenyl] methyl, (3, the 4-difluorophenyl) methyl, (2, the 5-3,5-dimethylphenyl) methyl, [3, two (trifluoromethyl) phenyl of 5-] methyl, (2-aminomethyl phenyl) methyl, (2, the 3-difluorophenyl) methyl, (2-bromophenyl) methyl, [(4-fluorophenyl)-pyridin-3-yl-methyl], [(4-chloro-phenyl-)-pyridin-4-yl-methyl], (phenyl-pyridine-2-base-methyl), (1-methyl-5-phenyl-pyrazole-3-yl) methyl, (5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl, (5-methyl-3-phenyl-1,2-oxazole-4-yl) methyl, (3-phenyl 1,2-oxazole-5-yl) methyl, 2-(4-chloro-phenyl-) ethyl, 2-(4-fluorophenyl) ethyl, 2-[4-(trifluoromethyl) phenyl] ethyl, 2-(5-bromo-2-methoxyl group-phenyl) ethyl, 2-(3-bromo-4-methoxyl group-phenyl) ethyl, 2-(4-fluorophenyl) propyl group, 2-(4-chloro-phenyl-) propyl group, 4-phenyl butane-2-base, [2-(4-chloro-2-methyl-phenyl)-2,2-two fluoro ethyls], 2-naphthalene-1-base propyl group, (2-methyl-2-phenyl-propyl group), the 2-phenoxy propyl, 2-(4-fluorophenoxy) propyl group, 2-phenyl-propane-2-base, suberyl, 2-(2-p-methoxy-phenyl) ethyl, 1-naphthalene-1-base ethyl, 2-[3-(trifluoromethyl) phenyl] ethyl, 2-(6-chloro-1H-indol-3-yl) ethyl, 2-(4-chloro-phenyl-) propyl group, [(1R)-1-(4-p-methoxy-phenyl) ethyl], [(1R)-1-(3-p-methoxy-phenyl) ethyl], 4-phenyl butane-2-base, the 1-phenylethyl, the 2-phenylethyl, 1-naphthalene-2-base ethyl, 2-(1-cyclohexenyl) ethyl, 1-(4-fluorophenyl) ethyl, 2-(4-fluorophenyl) propane-2-base, 2-phenyl-propane-2-base, 1-phenyl propyl or (2-phenyl) methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine and chlorine ,-OH, methyl or methoxy.

52, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be normal-butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine, chlorine ,-OH, methyl, methoxyl group.

53, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be ethyl;

R ¹Be diphenyl-methyl, (2-phenyl) methyl or 2-(4-chloro-phenyl-) propyl group;

R ³Be hydrogen;

R ⁴Be hydrogen;

54, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be the 2-phenylethyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

55, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be propyl group;

R ¹Be (2-phenyl) methyl, diphenyl-methyl or 2-(4-chloro-phenyl-) propyl group;

R ³Be hydrogen;

R ⁴Be hydrogen;

56, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be pyridin-3-yl methyl or pyridin-4-yl methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

R ⁵～R ⁷Be independently selected from hydrogen, bromine, fluorine, chlorine ,-OH.

57, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be the tertiary butyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

58, according to each described compound or its enantiomer among the claim 1-13, wherein:

R ²Be the trimethyl silyl methyl;

R ³Be hydrogen;

R ⁴Be hydrogen;

59, compound or its pharmacy acceptable salt or its enantiomer, described compound is selected from one or more in the following compound:

(1R or 1S)-N-(4,4-difluoro butyl)-2-(diphenyl-methyl)-3-oxo isoindole quinoline-1-methane amide (E2);

(1S or 1R)-N-(4,4-difluoro butyl)-2-(diphenyl-methyl)-3-oxo isoindole quinoline-1-methane amide (E1);

(1S or 1R)-N-benzyl-3-oxo-2-[(1S or 1R)-and the 1-phenylethyl] isoindoline-1-methane amide (E3);

(1R or 1S)-N-benzyl-3-oxo-2-[(1R or 1S)-and the 1-phenylethyl] isoindoline-1-methane amide (E2);

N-benzyl-6-cyano group-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-[(methyl sulphonyl) amino]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-4-methyl-5-[(methyl sulphonyl) amino]-3-oxo isoindole quinoline-1-methane amide;

N-(3-benzyl chloride base)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-cyano group-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-6-chloro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-1-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(1-methyl-5-phenyl-1H-pyrazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-bromo-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(4 '-fluorine biphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-5-bromo-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-fluorophenoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-(4,4-difluoro butyl)-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide;

(R or S) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (E1);

(S or R) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide (E2);

2-(biphenyl-2-ylmethyl)-N-[(2,2-two fluoro-1,3-benzo dioxole-5-yl) methyl]-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-1-[(tertiary butyl amino) carbonyl]-4-methyl-3-oxo-2,3-dihydro-1H-isoindole-5-base methanesulfonates;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-(difluoro-methoxy)-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-(fluorine methoxyl group)-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-1-[(tertiary butyl amino) carbonyl]-4-methyl-3-oxo-2,3-dihydro-1H-isoindole-5-base triflate;

N-(tertiary butyl)-2-{ (1R)-1-(4-benzyl chloride base)-2-oxo-2-[(4,4,4-trifluoro butyl) amino] ethyl }-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-4,7-two fluoro-1-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-4-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-7-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(4-benzyl chloride base)-7-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(4-benzyl chloride base)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(4-{[(difluoro ethanoyl) amino] methyl } benzyl)-3-oxo isoindole quinoline-1-methane amide;

The N-{4-[(kharophen) methyl] benzyl }-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(4-{[(acetyl fluoride base) amino] methyl } benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-[4-(amino methyl) benzyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide;

(2R)-and 2-{1-[(tertiary butyl amino) carbonyl]-3-oxo-1,3-dihydro-2H-isoindole-2-yl }-3-(4-chloro-phenyl-) methyl propionate;

2-(biphenyl-2-ylmethyl)-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[(5-methyl-isoxazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

(1S or 1R)-N-butyl-2-[(2R or 2S)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E2);

(1R or 1S)-N-butyl-2-[(2R or 2S)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E3);

(1S or 1R)-N-butyl-2-[(2S or 2R)-2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide (E1);

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

(S or R) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide;

(R or S) 2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-the bromobenzyl)-N-tertiary butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(1-methyl isophthalic acid-phenylethyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide;

N-[3-(difluoro-methoxy) benzyl]-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

N, 2-dibenzyl-6-bromo-3-oxo isoindole quinoline-1-methane amide;

6-bromo-2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

6-bromo-2-(2-cyclopentyl benzyl)-N-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(2-cyclopentyl benzyl)-6-fluoro-N-methyl-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-(2-cyclopentyl benzyl)-N-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(2-cyclopentyl benzyl)-N-(4,4-difluoro butyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-cyclopentyl benzyl)-N-methyl-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-6-chloro-3-oxo-2-[(1S)-the 1-phenylethyl] isoindoline-1-methane amide;

6-chloro-N-(2-methoxy ethyl)-3-oxo-2-[2,2,2-three fluoro-1-(3-fluorophenyl) ethyl] isoindoline-1-methane amide;

N-benzyl-6-chloro-2-(two pyridin-3-yl methyl)-3-oxo isoindole quinoline-1-methane amide;

6-chloro-N-methyl-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-N-methyl-3-oxo isoindole quinoline-1-methane amide;

6-fluoro-N-methyl-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-N-methyl-3-oxo isoindole quinoline-1-methane amide;

6-chloro-N-methyl-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-methyl-3-oxo isoindole quinoline-1-methane amide;

6-chloro-N-ethyl-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-benzyl-5-[(methyl sulphonyl) amino]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-benzyl-4-methyl-5-[(methyl sulphonyl) amino]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-benzyl-5-cyano group-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-benzyl-5-bromo-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-benzyl-6-bromo-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-[3-(difluoro-methoxy) benzyl]-6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-(3, the 4-dichloro benzyl)-6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-(3-benzyl chloride base)-6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

6-fluoro-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

6-chloro-N-[3-(difluoro-methoxy) benzyl]-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

6-chloro-N-(3, the 4-dichloro benzyl)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

6-chloro-N-(3-benzyl chloride base)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-(3-hydroxyl-2,2-methyl-propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(3, the 4-dichloro benzyl)-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-[3-(difluoro-methoxy) benzyl]-2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3-hydroxyl-2,2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(4,4-difluoro butyl)-6-fluoro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

6-chloro-N-(4,4-difluoro butyl)-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

6-chloro-N-(4,4-difluoro butyl)-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-(4,4-difluoro butyl)-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-(tertiary butyl)-6-fluoro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(tertiary butyl)-6-chloro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl)-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

3-oxo-N-(4,4,4-trifluoro butyl)-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

6-chloro-3-oxo-N-(4,4,4-trifluoro butyl)-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(tertiary butyl)-6-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

6-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl]-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

N-(tertiary butyl)-6-chloro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

6-chloro-3-oxo-2-[(1R)-the 1-phenylethyl]-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

The 3-oxo-2-[(1R)-the 1-phenylethyl]-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

6-chloro-N-[4-(methyl acyl sulfo group) benzyl]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-benzyl-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-[(4-amino-2-methyl pyrimidine-5-yl) methyl]-6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-[(5-methylpyrazine-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide;

N-[(4-amino-2-methyl pyrimidine-5-yl) methyl]-2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo isoindole quinoline-1-methane amide;

N-[(4-amino-2-methyl pyrimidine-5-yl) methyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[(4-fluorophenyl) (pyridin-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-3-oxo-2-[phenyl (pyridine-2-yl) methyl] isoindoline-1-methane amide;

N-butyl-2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

The 2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-(diphenyl methyl)-N-ethyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-chloro-N-ethyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-propyl group isoindoline-1-methane amide;

2-(diphenyl methyl)-N-ethyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-ethyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide;

N-(4-luorobenzyl)-2-[(4-fluorophenyl) (pyridin-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[(4-fluorophenyl) (pyridin-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[(5-methylpyrazine-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-N-[(5-methylpyrazine-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-chloro-N-[(5-methylpyrazine-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide;

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide;

N-[(4-amino-2-methyl pyrimidine-5-yl) methyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-3-oxo-N-{[6-(trifluoromethyl) pyridin-3-yl] methyl } isoindoline-1-methane amide;

N-benzyl-6-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-[4-(methylsulfonyl) benzyl]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

6-fluoro-N-[4-(methylsulfonyl) benzyl]-the 3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide;

N-benzyl-6-chloro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-benzyl-6-fluoro-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

6-chloro-N-[4-(methylsulfonyl) benzyl]-3-oxo-2-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

6-chloro-N-[2-chloro-4-(methylsulfonyl) benzyl]-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-chloro-4-(methylsulfonyl) benzyl]-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-(diphenyl methyl)-N-[2-fluoro-4-(methylsulfonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-(diphenyl methyl)-N-[2-fluoro-4-(methylsulfonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-(diphenyl methyl)-N-[4-(methylsulfonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide;

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-cyano group-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-(diphenyl methyl)-3-oxo-N-propyl group isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-ethyl-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-(diphenyl methyl)-N-ethyl-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-ethyl-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide;

2-(diphenyl methyl)-6-fluoro-3-oxo-N-propyl group isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-3-oxo-N-propyl group isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-propyl group isoindoline-1-methane amide;

2-(diphenyl methyl)-3-oxo-N-propyl group isoindoline-1-methane amide;

2-(diphenyl methyl)-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-(diphenyl methyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

N-(tertiary butyl)-2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(4-luorobenzyl)-3-oxo-2-[phenyl (pyridine-2-yl) methyl] isoindoline-1-methane amide;

N-benzyl-2-[(4-chloro-phenyl-) (pyridin-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-[phenyl (pyridine-2-yl) methyl] isoindoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-N-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-N-[(1-methyl-5-phenyl-1H-pyrazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[(1-methyl-5-phenyl-1H-pyrazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[(5-methyl-2-phenyl-1,3-oxazole-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(biphenyl-2-ylmethyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-5-hydroxy-4-methyl-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-5-hydroxy-4-methyl-3-oxo-N-propyl group isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-butyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-ethyl-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(2 ', 4 '-DCBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(3 ', 4 '-DCBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(2 '-chlordiphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(3 '-chloro-4 '-fluorine biphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(4 '-chlordiphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(4 '-fluoro-2 '-methyl diphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(2 ', 4 '-DfBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(2 ', 5 '-DfBP-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(3 '-fluorine biphenyl-2-yl) methyl]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-butyl-3-oxo-2-(2-phenoxy benzyl) isoindoline-1-methane amide;

N-[3-(difluoro-methoxy) benzyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 3-dimethylbutyl)-3-oxo-N-[3-(trifluoromethoxy) benzyl] isoindoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethoxy) benzyl] isoindoline-1-methane amide;

N-[3-(difluoro-methoxy) benzyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-(diphenyl methyl)-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

6-chloro-2-(diphenyl methyl)-N-(2-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-6-chloro-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-6-chloro-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-6-chloro-N-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(biphenyl-2-ylmethyl)-6-chloro-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-chloro-3-oxo isoindole quinoline-1-methane amide;

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-6-chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-4,5-dimethoxy-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-[1-(1,5-dimethyl-1H-pyrazoles-4-yl) ethyl]-5,7-dimethoxy-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

5,7-dimethoxy-2-(2-methoxy-benzyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-(2-luorobenzyl)-5,7-dimethoxy-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(tertiary butyl)-5,7-dimethoxy-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

3-oxo-2-(2-phenoxy benzyl)-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[(2,2-two fluoro-1,3-benzo dioxole-5-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(3, the 4-dichloro benzyl)-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-N-(1H-indol-3-yl methyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-3-oxo-N-{2-[3-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(biphenyl-2-ylmethyl)-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-N-[(2,2-two fluoro-1,3-benzo dioxole-5-yl) methyl]-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-6-fluoro-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) ethyl]-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-6-fluoro-3-oxo isoindole quinoline-1-methane amide;

6-fluoro-2-[2-(4-fluorophenyl) ethyl]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

N-benzyl-6-fluoro-2-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-6-fluoro-2-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

6-fluoro-2-[2-(4-fluorophenyl) propyl group]-3-oxo-N-(4,4,4-trifluoro butyl) isoindoline-1-methane amide;

N-benzyl-6-fluoro-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-6-fluoro-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-1-methyl-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-4,7-two fluoro-1-methyl-N-[4-(methyl sulphonyl) benzyls]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-1-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(diphenyl methyl)-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

2-(diphenyl methyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-1-methyl-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-methoxyl group-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-1-[(tertiary butyl amino) carbonyl]-4-methyl-3-oxo-2,3-dihydro-1H-isoindole-5-base dimethylcarbamate;

2-(biphenyl-2-ylmethyl)-5-hydroxyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

5-hydroxyl-2-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

2-(4-benzyl chloride base)-5-hydroxyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

N-(4-luorobenzyl)-5-hydroxyl-2-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(3, the 4-dichlorophenyl) ethyl]-N-(4-luorobenzyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

2-(4-benzyl chloride base)-N-(4-luorobenzyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(4-luorobenzyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(3, the 4-dichlorophenyl) ethyl]-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

N-(3, the 4-dichloro benzyl)-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[2-(1H-indol-3-yl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-(3-benzyl chloride base)-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[4-(difluoro-methoxy) benzyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

2-isobutyl--3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(1H-indol-3-yl methyl)-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[2-(1,3-benzo dioxole-5-yl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[2-(3-fluorophenyl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

2-isobutyl--3-oxo-N-{2-[3-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide;

N-[2-(3, the 4-dichlorophenyl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[2-(4-chloro-phenyl-) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[2-(3-chloro-phenyl-) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[2-(2-chloro-phenyl-) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[2-(2,4 dichloro benzene base) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

N-[2-(2, the 6-dichlorophenyl) ethyl]-2-isobutyl--3-oxo isoindole quinoline-1-methane amide;

2-(3, the 3-dimethylbutyl)-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(3-benzyl chloride base)-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

N-(3, the 4-dichloro benzyl)-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 3-dimethylbutyl)-N-(1H-indol-3-yl methyl)-3-oxo isoindole quinoline-1-methane amide;

N-[4-(difluoro-methoxy) benzyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 3-dimethylbutyl)-N-[2-(3-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[2-(1,3-benzo dioxole-5-yl) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(3-cyano-phenyl) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 3-dimethylbutyl)-3-oxo-N-{2-[3-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide;

N-[2-(3-chloro-phenyl-) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(3, the 4-dichlorophenyl) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(4-chloro-phenyl-) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(2-chloro-phenyl-) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(2,4 dichloro benzene base) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(3-benzyl chloride base)-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-[4-(difluoro-methoxy) benzyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-[2-(1,3-benzo dioxole-5-yl) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-dimethyl propyl)-N-[2-(3-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[2-(3-cyano-phenyl) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(2-chloro-phenyl-) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(3-chloro-phenyl-) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(2,4 dichloro benzene base) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-N-ethyl-3-oxo-N-(2-pyridine-2-base ethyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-3-(1,3-dihydro-2H-isoindole-2-base carbonyl) 1-isoindolinone;

2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-N-ethyl-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-{2-[4-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide;

N-butyl-3-oxo-2-{2-[4-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide;

N-benzyl-3-oxo-2-{2-[4-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide;

N-(tertiary butyl)-5-hydroxyl-2-[2-(1H-indol-3-yl) ethyl]-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-fluorophenyl) propyl group]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(2, the 2-diphenyl-ethyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(diphenyl methyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(9H-fluorenes-9-yl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo-2-{2-[4-(trifluoromethyl) phenoxy group] benzyl } isoindoline-1-methane amide;

2-(biphenyl-3-ylmethyl)-N-(tertiary butyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-fluorophenyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[2-(1H-indol-3-yl) ethyl]-3-oxo-2-[4-(piperidines-1-base carbonyl) benzyl] isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(2, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(4-cyano group-2,6-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(2, the 4-difluorobenzyl)-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

N-(2-benzyl chloride base)-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

2-(diphenyl methyl)-N-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-(diphenyl methyl)-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(2, the 4-difluorobenzyl)-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide;

N-(2-benzyl chloride base)-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide;

N-[2-(4-fluorophenyl) ethyl)-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide;

N-benzyl-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide;

N-(4-luorobenzyl)-3-oxo-2-(2-pyridin-3-yl benzyl) isoindoline-1-methane amide;

N-butyl-5-methoxyl group-2-(2-methyl-2-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-butyl-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-fluorophenyl) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5-methoxyl group-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-fluorophenyl) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-5-methoxyl group-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-5-methoxyl group-2-(2-methyl-2-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(biphenyl-2-ylmethyl)-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

N-butyl-5,6-dimethoxy-2-(2-methyl-2-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

N-butyl-5,6-dimethoxy-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-fluorophenyl) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-butyl-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5,6-dimethoxy-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-5,6-dimethoxy-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-5,6-dimethoxy-2-(2-methyl-2-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-fluorophenyl) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(biphenyl-2-ylmethyl)-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(diphenyl methyl)-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-1-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-butyl-1-methyl-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-N-(2-[2-(4-chloro-phenyl-) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine ethyl ester;

2-[2-(4-chloro-phenyl-) ethyl]-N-methyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-N, N-diethyl-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-N-butyl-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[2-(2, the 6-dichlorophenyl) ethyl]-2-(3, the 3-dimethylbutyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(4-chloro-phenyl-) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(2, the 6-dichlorophenyl) ethyl]-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-butyl-5-methoxyl group-2-[2-(1-naphthyl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-fluorophenyl) propyl group]-5-methoxyl group-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5,6-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(4 '-fluoro-2 '-methyl diphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(4 '-methyl diphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(4 '-methoxyl biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(4 '-fluorine biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(2-[(3 ', and 4 '-DfBP-2-yl) methyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester;

N-(2-[(4 '-fluoro-2 '-methyl diphenyl-2-yl) methyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester;

N-(2-[(4 '-fluorine biphenyl-2-yl) methyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester;

N-(2-[(4 '-methyl diphenyl-2-yl) methyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester;

2-[(3 ', 4 '-DfBP-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-[(4 '-fluoro-2 '-methyl diphenyl-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-[(4 '-methoxyl biphenyl-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-[(4 '-fluorine biphenyl-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-[(4 '-methyl diphenyl-2-yl) methyl]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(4-benzyl chloride base)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5-hydroxyl-2-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-7-hydroxyl-2-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

2-[2-(3, the 4-dichlorophenyl) ethyl]-5-hydroxyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

N-(3, the 4-difluorobenzyl)-2-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(3-benzyl chloride base)-2-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(4-hydroxybenzyl)-3-oxo-N-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-[3, two (trifluoromethyl) benzyls of 5-]-2-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(3-benzyl chloride base)-2-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-[3, two (trifluoromethyl) benzyls of 5-]-2-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3-cyano group benzyl)-N-(3, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3-cyano group benzyl)-3-oxo-N-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-[4-(aminocarboxyl) benzyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-[4-(aminocarboxyl) benzyl]-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 4-difluorobenzyl)-N-{4-[(dimethylamino) methyl] benzyl }-3-oxo isoindole quinoline-1-methane amide;

2-(3-benzyl chloride base)-N-{4-[(dimethylamino) methyl] benzyl }-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-the N-{4-[(dimethylamino) methyl] benzyl }-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 4-difluorobenzyl)-N-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3-benzyl chloride base)-N-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(4-hydroxybenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3-benzyl chloride base)-N-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(3-cyano group benzyl)-2-(3, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(3-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-hydroxyl-3-oxo isoindole quinoline-1-methane amide;

The N-{4-[(dimethylamino) methyl] benzyl }-3-oxo-2-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(4-hydroxybenzyl)-3-oxo-2-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(3-cyano group benzyl)-3-oxo-2-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-(biphenyl-3-ylmethyl)-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-4-ylmethyl)-N-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-butyl-3-oxo-2-[2-(2-Phenoxyphenyl) ethyl] isoindoline-1-methane amide;

N-butyl-2-(2-{4-[(diethylamino) carbonyl] phenyl } ethyl)-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(3-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-3-oxo-2-{2-[2-(trifluoromethoxy) phenyl] ethyl } isoindoline-1-methane amide;

2-(2-biphenyl-4-base ethyl)-N-butyl-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-fluorophenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(3, the 5-Dimethoxyphenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-3-oxo-2-[2-(4-Phenoxyphenyl) ethyl] isoindoline-1-methane amide;

N-butyl-2-[2-(2-ethoxyl phenenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(1,3-benzo dioxole-5-yl) ethyl]-N-butyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-[2-(2-Phenoxyphenyl) ethyl] isoindoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-{2-[2-(trifluoromethoxy) phenyl] ethyl } isoindoline-1-methane amide;

2-(2-biphenyl-4-base ethyl)-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(3, the 5-Dimethoxyphenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-[2-(4-Phenoxyphenyl) ethyl] isoindoline-1-methane amide;

N-(tertiary butyl)-2-[2-(2-ethoxyl phenenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(1,3-benzo dioxole-5-yl) ethyl]-N-(tertiary butyl)-3-oxo isoindole quinoline-1-methane amide;

N-[2-(1H-indol-3-yl) ethyl]-3-oxo-2-[2-(2-Phenoxyphenyl) ethyl] isoindoline-1-methane amide;

2-(2-{4-[(diethylamino) carbonyl] phenyl } ethyl)-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(3-fluorophenyl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[2-(1H-indol-3-yl) ethyl]-3-oxo-2-{2-[2-(trifluoromethoxy) phenyl] ethyl } isoindoline-1-methane amide;

2-[2-(4-fluorophenyl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(3, the 5-Dimethoxyphenyl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-(2-biphenyl-4-base ethyl)-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[2-(1H-indol-3-yl) ethyl]-3-oxo-2-[2-(4-Phenoxyphenyl) ethyl] isoindoline-1-methane amide;

2-[2-(2-ethoxyl phenenyl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(1,3-benzo dioxole-5-yl) ethyl]-N-[2-(1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-2-[2-(dimethylamino)-2-phenylethyl]-3-oxo isoindole quinoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-2-(2, the 2-diphenyl-ethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(1-benzyl-2-fluoro ethyl)-N-[(5-methyl-isoxazole-3-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(2-chloro-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 4-difluorobenzyl)-N-(4-luorobenzyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide;

2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

2-(3, the 4-difluorobenzyl)-5-hydroxyl-3-oxo-4-phenyl-N-(2-phenylethyl) isoindoline-1-methane amide;

N-(2-benzyl chloride base)-2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(tertiary butyl)-2-(2-benzyl chloride base)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(tertiary butyl)-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-(tertiary butyl)-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide;

2-(1-benzyl-2-fluoro ethyl)-N-butyl-3-oxo isoindole quinoline-1-methane amide;

2-(1-benzyl-2-fluoro ethyl)-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(1-benzyl-2-fluoro ethyl)-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-[4-(amino methyl) phenyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(4-{[(difluoro ethanoyl) amino] methyl } phenyl)-3-oxo isoindole quinoline-1-methane amide;

N-[4-(aminocarboxyl) phenyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-(fluorine methoxyl group)-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-3-oxo-2-(4-phenyl butyl) isoindoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-2-(2-hydroxy-4-phenyl ethyl)-3-oxo isoindole quinoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-3-oxo-2-[2-(1H-pyrazol-1-yl) benzyl] isoindoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-3-oxo-2-[(1-phenyl-1H-pyrazoles-4-yl) methyl] isoindoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-[4-(dimethylamino) benzyl]-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide;

N-[4-(methyl sulphonyl) benzyl]-3-oxo-2-[(1H-pyrazol-1-yl) benzyl] isoindoline-1-methane amide;

2-(2-hydroxyl-2-phenylethyl)-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-(2, the 2-diphenyl-ethyl)-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-(diphenyl methyl)-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide;

N-[4-(methyl sulphonyl) benzyl]-3-oxo-2-(1,2,3,4-naphthane-1-yl) isoindoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide;

2-[1-(4-fluorophenyl) ethyl]-3-oxo-N-(pyridin-4-yl methyl) isoindoline-1-methane amide;

(1S)-2-[(2R)-2-(4-chloro-phenyl-) propyl group]-N-(3-methoxy-propyl)-1-methyl-3-oxo isoindole quinoline-1-methane amide;

(1R)-2-[(2R)-2-(4-chloro-phenyl-) propyl group]-N-(3-methoxy-propyl)-1-methyl-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-methoxy-propyl)-1-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-hydroxyl-3-oxo-4-(trimethyl silyl) isoindoline-1-methane amide;

N-(tertiary butyl)-2-(3, the 4-difluorobenzyl)-5-hydroxyl-3-oxo-4-(trimethyl silyl)-isoindoline-1-methane amide;

N-(tertiary butyl)-2-(3, the 4-difluorobenzyl)-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(3, the 4-difluorobenzyl)-5-hydroxyl-3-oxo-4-phenyl isoindoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-5-hydroxy-4-methyl-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N, two (3-cyano group-4-the luorobenzyl)-3-oxo isoindole quinoline-1-methane amides of 2-;

N-(3-cyano group-4-luorobenzyl)-3-oxo-2-(2-phenylethyl) isoindoline-1-methane amide;

N-(3-cyano group-4-luorobenzyl)-2-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-benzyl-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(3-cyano group-4-luorobenzyl)-2-(3, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-cyano group-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-N-(3-{[(difluoro ethanoyl) amino] methyl }-the 4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-[3-(amino methyl)-4-luorobenzyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-[3-(aminocarboxyl)-4-luorobenzyl]-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-[3-(aminocarboxyl)-4-luorobenzyl]-2-(2-chloro-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-(4-phenyl butyl) isoindoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-(1,2,3,4-naphthane-1-yl) isoindoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-(4-phenoxy benzyl) isoindoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-[2-(1H-pyrazol-1-yl) benzyl] isoindoline-1-methane amide;

N-(tertiary butyl)-2-(2, the 2-diphenyl-ethyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(diphenyl methyl)-3-oxo isoindole quinoline-1-methane amide;

N-(1,3-benzo dioxole-5-ylmethyl)-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-N-[(1-methyl isophthalic acid H-pyrrole quinoline-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(1,3-benzo dioxole-5-ylmethyl)-(2-chloro-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-N-[4-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo-N-(2-pyridin-4-yl ethyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(2-pyridin-4-yl ethyl) isoindoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-(1-benzyl-pyrrole alkane-3-yl)-2-(2-chloro-4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(1-benzyl-pyrrole alkane-3-yl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-N-{[5-(2-furyl) isoxazole-3-base] methyl }-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-{[5-(2-furyl) isoxazole-3-base] methyl }-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[3-(1H-imidazoles-1-yl) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-[3, two (trifluoromethyl) benzyls of 5-]-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-(1-benzyl-pyrrole alkane-3-yl)-2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[4-(methyl sulphonyl) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-[(1-phenyl-1H-tetrazolium-5-yl) methyl] isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(dimethylamino) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(1-pyridin-3-yl ethyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-p-methoxy-phenyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(1-pyridin-4-yl ethyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(4-cyano-phenyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(3-methoxy-propyl)-3-oxo isoindole quinoline-1-methane amide;

N-(1,3-benzo dioxole-5-ylmethyl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(3, the 4-dimethoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[(3-methyl-5-phenyl-isoxazole azoles-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-7-fluoro-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-7-fluoro-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-fluorophenoxy) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-(2-phenoxy propyl) isoindoline-1-methane amide;

N-benzyl-3-oxo-2-[2-(phenyl sulfonyl) ethyl] isoindoline-1-methane amide;

N-benzyl-3-oxo-2-(2-phenoxy group ethyl) isoindoline-1-methane amide;

N-benzyl-3-oxo-2-(2-phenoxy propyl) isoindoline-1-methane amide;

N-benzyl-2-[2-(4-fluorophenoxy) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[(1-benzyl-1H-pyrazoles-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[(5-methyl-3-phenyl-isoxazole azoles-4-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-[(3-phenyl-isoxazole azoles-5-yl) methyl] isoindoline-1-methane amide;

N-(tertiary butyl)-5,6-two chloro-2-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5,6-two chloro-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5,6-two chloro-2-[4-(difluoro-methoxy) benzyls]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5-fluoro-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(4-luorobenzyl)-3-oxo-2-(2-pyridin-4-yl ethyl) isoindoline-1-methane amide;

2-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo-N-[3-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(2-furyl methyl)-3-oxo-2-(2-phenyl propyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-N-[(5-methyl-2-furyl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(4-luorobenzyl)-2-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(2-benzyl chloride base)-2-[2-(1H-indol-3-yl)-1-methylethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-5,6-two chloro-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-2-aminomethyl phenyl)-2,2-two fluoro ethyls]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-2-aminomethyl phenyl)-2,2-two fluoro ethyls]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-[3-(difluoro-methoxy) benzyl]-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

N-(2-benzyl chloride base)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

2-[4-(difluoro-methoxy) benzyl]-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

N-(2-benzyl chloride base)-2-(2, the 5-dimethyl benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(2-benzyl chloride base)-2-[(1R)-1-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(2-benzyl chloride base)-2-[(1R)-1-(3-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(2-benzyl chloride base)-2-[(1S)-1-(1-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-(4-phenoxy benzyl) isoindoline-1-methane amide;

N-(2-benzyl chloride base)-3-oxo-2-(3-phenyl propyl) isoindoline-1-methane amide;

N-(2-benzyl chloride base)-3-oxo-2-(2-phenylethyl) isoindoline-1-methane amide;

N-(2-benzyl chloride base)-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide;

N-(2-benzyl chloride base)-2-(1-methyl-3-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-(2-benzyl chloride base)-3-oxo-2-(2-phenyl propyl) isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-(2-benzyl chloride base)-3-oxo isoindole quinoline-1-methane amide;

3-oxo-2-(1-phenyl propyl)-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

3-oxo-2-(2-phenyl propyl)-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-(1-methyl-3-phenyl propyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

3-oxo-2-(2-phenylethyl)-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-benzyl-2-[2-(5-bromo-2-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

3-oxo-2-(3-phenyl propyl)-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-benzyl-2-[2-(3-bromo-4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-(2-methyl butyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-benzyl-2-(2, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(cyclohexyl methyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-(3-luorobenzyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-(2-ethoxy benzyl)-3-oxo-N-[2-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(3, the 4-Dimethoxyphenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-[2-(2-thienyl) ethyl] isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-[2-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(2-methoxy ethyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-N-(4-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[4-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[3-(difluoro-methoxy) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-(1-naphthyl methyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-suberyl-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-[3-(1H-pyrroles-1-yl) benzyl] isoindoline-1-methane amide;

N-benzyl-2-(3-luorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(2-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(2-ethoxy benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(4-cyano group benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(3, the 5-dimethoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[1-(1-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-[4-(trifluoromethyl) benzyl] isoindoline-1-methane amide;

N-(2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl)-the Beta-alanine ethyl ester;

2-(1-naphthyl methyl)-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

N-(2-[2-(3, the 4-dichlorophenyl) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl)-the Beta-alanine ethyl ester;

4-(the 1-[(benzylamino) carbonyl]-3-oxo-1,3-dihydro-2H-isoindole-2-yl } methyl) methyl benzoate;

3-oxo-2-[3-(trifluoromethyl) benzyl]-the N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

2-[1-(1-naphthyl) ethyl]-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

3-oxo-2-[4-(trifluoromethyl)-benzyl]-the N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

2-[2-(4-bromophenyl) ethyl]-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

2-(2-chloro-6-phenoxy benzyl)-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

2-(3, the 4-dichloro benzyl)-3-oxo-N-[(trimethyl silyl) methyl] isoindoline-1-methane amide;

N-benzyl-2-(1-benzyl-pyrrole alkane-3-yl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(1-benzyl-pyrrole alkane-3-yl)-4,5-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(3, the 4-difluorobenzyl)-4,5-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-4,5-dimethoxy-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[(1-methyl isophthalic acid H-pyrroles-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-(1-phenyl-2-tetramethyleneimine-1-base ethyl) isoindoline-1-methane amide;

N-benzyl-2-[2-(4-p-methoxy-phenyl)-2-oxoethyl]-3-oxo isoindole quinoline-1-methane amide;

The N-benzyl-2-[(1R)-1-(4-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(3, the 4-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

The N-benzyl-2-[(1R)-1-(3-p-methoxy-phenyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(2, the 5-dimethyl benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(1-methyl-3-phenyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-{2-[3-(trifluoromethyl) phenyl] ethyl } isoindoline-1-methane amide;

N-benzyl-2-[3, two (trifluoromethyl) benzyls of 5-]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-[2-(6-chloro-1H-indol-3-yl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N, 2-dibenzyl-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(cyclohexyl methyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-(2-thienyl methyl) isoindoline-1-methane amide;

2-(1,3-benzo dioxole-5-ylmethyl)-N-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

2-(2-methoxy-benzyl)-N-(4-methylcyclohexyl)-3-oxo isoindole quinoline-1-methane amide;

N-{[3-oxo-2-(3-tetramethyleneimine-1-base propyl group)-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate;

N-(tertiary butyl)-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-N-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

N-(2, the 3-Dimethylcyclohexyl)-3-oxo-2-(2-thienyl methyl) isoindoline-1-methane amide;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-benzyl chloride base)-N-(4-methylcyclohexyl)-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-(2-hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide;

The N-benzyl-2-[(2R)-2-hydroxyl-1, the 2-diphenyl-ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-butyl-3-oxo isoindole quinoline-1-methane amide;

2-(biphenyl-2-ylmethyl)-N-sec.-propyl-3-oxo isoindole quinoline-1-methane amide;

N-{[2-(2-bromobenzyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate;

2-[2-(4-chloro-phenyl-) propyl group]-N-sec.-propyl-3-oxo isoindole quinoline-1-methane amide;

N-{[3-oxo-2-(2-phenylethyl)-2,3-dihydro-1H-isoindole-1-yl] carbonyl } glycine methyl ester;

N-(tertiary butyl)-2-[1-(2-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-[1-(2-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(3,4-diethoxy phenyl) ethyl]-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

2-benzyl-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-[4-(dimethylamino) benzyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(3-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-N-cyclopentyl-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-3-oxo-N-(pyridin-3-yl methyl) isoindoline-1-methane amide;

2-(2, the 5-dimethoxy-benzyl)-3-oxo-N-(diphenyl-ethyl) isoindoline-1-methane amide;

N-(sec-butyl)-2-[2-(4-chloro-phenyl-) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(2, the 3-difluorobenzyl)-3-oxo isoindole quinoline-1-methane amide;

2-(2-chloro-4-luorobenzyl)-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

2-[2-(4-chloro-phenyl-) ethyl]-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-(2-methyl-benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(cyclohexyl methyl)-3-oxo isoindole quinoline-1-methane amide;

2-(1-methyl-3-phenyl propyl)-3-oxo-N-(2-phenylethyl) isoindoline-1-methane amide;

N-benzyl-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-(hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

N-{[2-(cyclohexyl methyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-(2-hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide;

N-{[2-(biphenyl-2-ylmethyl)-3-oxo-2,3-dihydro-1H-isoindole-1-yl] carbonyl } tert-butyl glycinate;

N-benzyl-2-(2, the 2-dimethyl propyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(3-methyl butyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-[2-(2-thienyl) ethyl] isoindoline-1-methane amide;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-3-oxo-2-(2-phenylethyl) isoindoline-1-methane amide;

N-benzyl-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(2-methyl-benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(2-methoxy-benzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-3-oxo-2-(2-phenylethyl) isoindoline-1-methane amide;

N-benzyl-2-[1-(2-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-(2[2-(4-chloro-phenyl-) propyl group]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) glycine methyl ester;

N-(2[1-(2-naphthyl) ethyl]-3-oxo-2,3-dihydro-1H-isoindole-1-yl } carbonyl) tert-butyl glycinate;

N-(1H-1,2,3-benzotriazole-1-ylmethyl)-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[1-(2-naphthyl) ethyl]-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(2-bromobenzyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(2-hexamethylene-1-alkene-1-base ethyl)-3-oxo isoindole quinoline-1-methane amide;

N-benzyl-2-(biphenyl-2-ylmethyl)-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-chloro-phenyl-) propyl group]-3-oxo isoindole quinoline-1-methane amide;

N-butyl-2-[2-(4-chloro-phenyl-)-2-methyl-propyl group]-3-oxo-1H-isoindole-1-methane amide;

The N-tertiary butyl-2-[(4,4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

(1R or 1S)-N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

(1S or 1R)-N-(tertiary butyl)-2-[(3 ', 4 '-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

1H-isoindole-1-methane amide, 2-[2-(4-chloro-phenyl-) propyl group]-2,3-dihydro-N-[2-[(1-methylethyl) amino]-the 2-oxoethyl]-the 3-oxo-;

N-(tertiary butyl)-2-[(4 ', 5-DfBP-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(5-fluorine biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-[(4-fluorine biphenyl-2-yl) methyl]-3-oxo isoindole quinoline-1-methane amide;

2-[2-(4-chloro-phenyl-) propyl group]-2,3-dihydro-N-[2-[(1-methylethyl) amino]-2 oxoethyls]-3-oxo-1H-isoindole-1-methane amide;

6-fluoro-3-oxo-N, two (1-phenylethyl) isoindolines of 2--1-methane amide;

3-oxo-N, two (1-phenylethyl) isoindolines of 2--1-methane amide;

N-(3-luorobenzyl)-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

N-(2-luorobenzyl)-3-oxo-2-(1-phenylethyl) isoindoline-1-methane amide;

N-benzyl-6-bromo-3-oxo-2-(1-phenyl propyl) isoindoline-1-methane amide;

N-benzyl-4-fluoro-3-oxo-2-[(1R)-the 1-phenylethyl] isoindoline-1-methane amide.

60, the compound of the formula I that is used for the treatment of or its pharmacy acceptable salt, its:

R wherein ¹Expression C ₁-C ₁₂(described alkyl group randomly is selected from following group and replaces by one or more alkyl: halogen, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, cyano group, oxo ,-OR ⁸,-COR ⁹,-SR ¹⁰,-COXR ¹¹, N (R ^12a) (R ^12b) ,-N (R ^13a) C (O) OR ^13b,-OC (O) N (R ^14a) (R ^14b) ,-SO ₂R ¹⁵, aryl or Het ¹); R in addition ¹Expression aryl or Het ²

R ^14aAnd R ^14bWhen occurring each time, represent hydrogen, C independently ₁-C ₆Alkyl, aryl or Het ¹³(C wherein ₁-C ₆Alkyl, aryl and Het ¹³Group randomly is selected from following substituting group and replaces by one or more :-OH, halogen, cyano group, nitro, C ₁-C ₆Alkyl, aryl or Het ¹⁴), or represent C together ₃-C ₆Alkylidene group, it is chosen wantonly and is interrupted by Sauerstoffatom;

X represents nitrogen-atoms or Sauerstoffatom;

M is 0～10 integer;

N is 0～4 integer;

K is 1～5 integer;

Condition is:

A) R ²Or R ³Do not represent the following formula fragment:

Wherein,

R ⁸⁶～R ⁹³When occurring each time, represent hydrogen or C independently _1-6Alkyl; And

C) described compound is not:

N-sec.-propyl-2-(3-methyl butyl)-3-oxo isoindole quinoline-1-methane amide;

N-(tertiary butyl)-2-cyclohexyl-3-oxo isoindole quinoline-1-methane amide;

61, each described formula I compound is used for the treatment of purposes in the ARR medicine in preparation among the claim 1-60.

62, among the claim 1-60 each described formula I compound be used for the treatment of purposes in the medicine of atrial arrhythmia or ventricular arrhythmia in preparation.

63, pharmaceutical composition, it comprises as each described compound among the claim 1-60 of the treatment significant quantity of activeconstituents and one or more pharmaceutically acceptable thinners, vehicle and/or inert support.

64, according to the described pharmaceutical composition of claim 63, be used for the treatment of irregular pulse.

65, treat ARR method, the Mammals that it comprises to the treatment of this kind of needs comprises that the people treats each described formula I compound among the claim 1-60 of significant quantity.

66, be used for the treatment of ARR medicament, it comprises as each described formula I compound among the claim 1-60 of activeconstituents.

67, each described compound among the claim 1-60 is used for the treatment of irregular pulse.

68, the method for preparing formula I compound as described herein.