CN1694874B - Benzodiazepine derivatives and pharmaceutical compositions containing them - Google Patents
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- CN1694874B CN1694874B CN038251906A CN03825190A CN1694874B CN 1694874 B CN1694874 B CN 1694874B CN 038251906 A CN038251906 A CN 038251906A CN 03825190 A CN03825190 A CN 03825190A CN 1694874 B CN1694874 B CN 1694874B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
Benzodiazepine derivative of formula (I), and pharmaceutically acceptable salts thereof, are found to be active against RSV. Formula (I) Wherein: - R<1> represents C1-6 alkyl, aryl or heteroaryl; - R<2> represents hydrogen or C1-6 alkyl; - each R<3> is the same or different and represents halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio C1-6 haloalkyl, C1-6 haloalkoxy, amino, mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino, nitro, cyano, -CO2R , -CONR R<II>, -NH-CO-R , -S(O)R , -S(O)2R , -NH-S(O)2R , -S(O)NR R<II> or -S(O)2NR<I>R<II> wherein each R and R<II> is the same or different and represents hydrogen or C1-6 alkyl; - n is from 0 to 3; R<4> represents hydrogen or C1-6 alkyl; - R<6> represents C1-6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C1-6 alkyl)-, heteroaryl-(C1-6 alkyl)-, carbocyclyl-(C1-6 alkyl)-, heterocyclyl-(C1-6 alkyl)-, aryl-C(O)-C(O)-, heteroaryl-C(O)-C(O)-, carbocyclyl-C(O)-C(O)-, heterocyclyl-C(O)-C(O)- or, -XR<6>; - X represents -CO-, -S(O)- or-S(0)2-; and - R<6> represents C1-6 alkyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C1-6 alkyl)-, heteroaryl-(C1-6 alkyl)-, carbocyclyl-(C1-6 alkyl)-, heterocyclyl-(C1-6 alkyl)-, aryl-(C 1-6hydroxyalkyl)-, heteroaryl-(C1-6 hydroxyalkyl)-, carbocyclyl-(C1-6 hydroxyalkyl)-, heterocyclyl-(C 1-6 hydroxyalkyl)-, aryl-(C 1-6alkyl)-O-, heteroaryl-(C 1-6alkyl)-O-, carbocyclyl-(C1-6 alkyl)-O-, heterocyclyl-(C1-6 alkyl)-O- or -NR R<II> wherein each R and R<II> is the same or different and represents hydrogen, C1-6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl- (C1-6 alkyl)-, heteroaryl-(C1-6 alkyl)-, carbocyclyl-(C1-6 alkyl)- or heterocyclyl-(C1-6 alkyl)-.
Description
The present invention relates to a series of benzodiazepines of effective anti respiratory syncytial virus (RSV)
Derivative.
RSV is the major cause of all age bracket patient breathing system diseases.Concerning the adult, RSV often causes slight cold symptoms.Concerning the school-ager, it can cause flu and segmental bronchus cough.Concerning the infant, it can cause bronchiolitis (lung's tracheole inflammation) or pneumonia.Find that also it is the common cause of preschool children's middle ear infection (otitis media).The rsv infection of infantile period takes place relevant with childhood asthma.
At present, anti-RSV treatment comprises RSV use monoclonal antibody (being called palivizumab).Palivizumab act as prophylactic treatment RSV rather than therapeutic treatment RSV.Yet although this antibody is usually effective, it costs an arm and a leg.In fact, its high expense can not obtain common use concerning the people of the anti-RSV treatment of many needs.Therefore press for the method that effectively substitutes existing anti-RSV treatment.
Find general formula (I) benzodiazepine of following uniqueness surprisingly
The effective anti-RSV of derivative.
Therefore, primary embodiment of the present invention provides structural formula (I) benzodiazepine
Acceptable salt is used for the treatment of or prevents purposes on the rsv infection medicine in preparation on derivative or its pharmacology,
Wherein:
-R
1Represent C
1-6Alkyl, aryl or heteroaryl;
-R
2Represent hydrogen or C
1-6Alkyl;
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R
/,-CONR
/R
//,-NH-CO-R
/,-S (O) R
/,-S (O)
2R
/,-NH-S (O)
2R
/,-S (O) NR
/R
//Or-S (O)
2NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl;
-n is 0-3;
-R
4Represent hydrogen or C
1-6Alkyl;
-R
5Represent C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-XR
6
-X representative-CO-,-S (O)-or-S (O)
2-; And
-R
6Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-.Usually, R
/And R
//Not all be hydrogen.
In the preferred structure formula (I),
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R
/,-CONR
/R
//,-NH-CO-R
/,-S (O) R
/,-S (O)
2R
/,-NH-S (O)
2R
/Or-S (O) NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl;
-R
5Represent C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-XR
6
-X representative-CO-,-S (O)-or-S (O)
2-; And
-R
6Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-.Usually, R
/And R
//Not all be hydrogen.
C used herein
1-6Alkyl or part are for comprising the straight or branched alkyl or the part of 1-6 carbon atom, for example C
1-4Alkyl or part.C
1-4The example of alkyl and part comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.For fear of ambiguity, when two alkyl occurring in the group, moieties can be identical or different.
Hydroxyalkyl used herein typically refers to the described alkyl that is replaced by one or more hydroxyls.It is replaced by 1-3 hydroxyl usually.Preferred its replaced by a hydroxyl.Preferred hydroxyalkyl is (monohydroxy) ethyl.
Acyl group used herein is C
2-7Acyl group, for example-CO-R, wherein R is described C
1-6Alkyl.
Aryl used herein is generally C
6-10Aryl, for example phenyl or naphthyl.Be preferably phenyl.Aryl can not be substituted or is substituted in any position.Aryl comprises 0-3 substituting group usually.
Suitable substituent on the aryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-S (O)
2NR
/R
//-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl.The example of the suitable substituent on the aryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl.
Preferred substituents on the aryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R
/,-S (O) R
/,-S (O)
2R
/With-S (O)
2NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-4Alkyl.The example of the preferred substituents on the aryl comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halo oxyalkyl, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.
Especially preferred substituting group comprises fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R
/,-S (O)
2R
/With-S (O)
2NH
2, R wherein
/Represent C
1-2Alkyl.Especially preferred substituent example comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
Aryl used herein comprises and condenses ring system, and wherein aryl and monocycle carbocylic radical, heterocyclic radical or heteroaryl-condensed are perhaps with monocycle carbocylic radical, the heterocyclic radical or heteroaryl-condensed of fused benzene rings.Usually, described aryl and monocycle carbocylic radical in the ring system, the heterocyclic radical or heteroaryl-condensed of condensing.Preferred such ring system: wherein the monocyclic heterocycles base of aryl and fused benzene rings or heteroaryl-condensed ring system or with the ring system of the monocycle carbocylic radical of fused benzene rings, especially wherein aryl and heterocyclic radical or heteroaryl-condensed ring system.This example that condenses ring system condenses the group of formation benzothienyl or dihydro benzo furyl for phenyl ring wherein and thienyl or with tetrahydrofuran base.The further example of this fused rings is wherein phenyl ring and dioxane base, pyrryl or 2, and 3-dihydro 1-Indanone base condenses the group that forms benzo dioxine base, indyl or 9H-fluorenes-9-ketone group.
Carbocylic radical used herein is generally the saturated or unsaturated monocyclic hydrocarbon ring of the non-aromatics with 3-6 carbon atom.Be preferably stable hydrocarbon ring (being cycloalkyl) with 3-6 carbon atom.Example comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Preferred cyclopentyl or cyclohexyl.Cycloalkyl can not be substituted or is substituted in any position.It comprises 0-3 substituting group usually.
Suitable substituent on the carbocylic radical comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, oxo ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-S (O)
2NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl.The example of the suitable substituent on the carbocylic radical comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl.
Preferred substituents on the carbocylic radical comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group and oxo.The example of the preferred substituents on the carbocylic radical comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.Especially preferred substituting group comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl, nitro and oxo.Especially preferred substituent example comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1- 4Alkoxyl group, C
1-4Haloalkyl and nitro.Especially preferred substituent further example comprises fluorine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
Heterocyclic radical used herein is generally the saturated or unsaturated carbocyclic of non-aromatics with 5-10 carbon atom, and wherein one or more (for example 1-3) carbon atoms are selected from the heteroatoms displacement of N, O and S.Preferred saturated heterocyclyl.Example comprises tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, imidazolidyl, pyrazolidyl, dioxolanyl, thiazolidyl, THP trtrahydropyranyl, piperidyl, dioxane base, piperazinyl, morpholinyl, thio-morpholinyl He thioxane base.Further example comprises dithiolane Ji, oxazolidinyl, tetrahydro thiapyran base and dithiane base.Preferred piperazinyl, piperidyl and morpholinyl.
Heterocyclic radical used herein comprises that heterocyclic radical and phenyl condensed condense ring system.Preferred such fused rings is that wherein 5-to 6-unit's heterocyclic radical and phenyl condensed condense ring system.The example that condenses ring system like this is for wherein 1H-tetrahydroglyoxaline-2 (3H)-ketone group or imidazolidin-2-one base and phenyl ring condense the group that forms 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group.Yet most preferably heterocyclic radical is the monocyclic heterocycles base.
Heterocyclic radical can not be substituted or is substituted in any position.It has 0-2 substituting group usually.
Suitable substituent on the heterocyclic radical comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, oxo ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-S (O)
2NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl.The example of the suitable substituent on the heterocyclic radical comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl.
Preferred substituents on the heterocyclic radical comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group and oxo.The example of the preferred substituents on the heterocyclic radical comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.Especially preferred substituting group comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl, nitro and oxo.Especially preferred substituent example comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1- 4Alkoxyl group, C
1-4Haloalkyl and nitro.Especially preferred substituent further example comprises fluorine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.Most preferably heterocyclic radical is not substituted or by 1-2 C
1-2Alkyl replaces.
Halogen used herein is generally chlorine, fluorine, bromine or iodine.Preferred chlorine, fluorine or bromine.More preferably chlorine or fluorine.
Alkoxyl group used herein is generally the described alkyl that connects Sauerstoffatom.Alkylthio is generally the described alkyl that connects sulfenyl.Haloalkyl or halogenated alkoxy are generally described alkyl or the alkoxyl group that is replaced by one or more described halogen atoms.It is replaced by 1-3 described halogen atom usually.Preferred haloalkyl and halogenated alkoxy comprise whole haloalkyl and perhalogeno alkoxyl group, for example-and CX
3With-OCX
3, wherein X is described halogen atom, for example chlorine or fluorine.Especially preferred haloalkyl is-CF
3With-CCl
3Especially preferred halogenated alkoxy is-OCF
3With-OCCl
3
Heteroaryl used herein is generally 5-to 10-unit aromatic ring, and for example 5-or 6-unit encircles, and it comprises at least one heteroatoms that is selected from O, S and N (for example 1-3 heteroatoms).Example comprises pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, furyl, thienyl, pyrazolidyl, pyrryl, oxadiazole base, isoxazolyl, thiadiazolyl group, thiazolyl, imidazolyl and pyrazolyl.Further example Bao Kuo oxazolyl and isothiazolyl.Preferred heteroaryl is pyridyl, thienyl, oxazolyl, isoxazolyl, furyl and pyrazolyl.The example of preferred heteroaryl is pyridyl, thienyl, isoxazolyl and furyl.Heteroaryl used herein comprises that heteroaryl and phenyl condensed condense ring system.Preferred such fused rings is 5-to 6-unit's heteroaryl and phenyl condensed ring system.The example that condenses ring system like this is benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzoxazolyl, quinolyl, quinazolyl and isoquinolyl.Yet most preferably heterocyclic radical is the monocyclic heterocycles base.
Heteroaryl can not be substituted or is substituted in any position.It has a common 0-3 substituting group.
Suitable substituent on the heteroaryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-S (O)
2NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl.The example of the suitable substituent on the heteroaryl comprises halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl.
Preferred substituents on the heteroaryl comprises halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.Especially preferred substituting group comprises fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.Further preferred substituted comprises fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Haloalkyl and two (C
1-2Alkyl) amino.
Heteroaryl used herein comprises heteroaryl and monocyclic described aryl, carbocylic radical or heterocyclic radical condenses or with other heteroaryl-condensed ring system that condenses.Preferred such ring system is heteroaryl and aryl (for example phenyl) condensed ring system.This example that condenses ring system is that thienyl and phenyl ring condense the group that forms benzothienyl.This further example that condenses ring system is that furyl and phenyl ring condense the group that forms benzofuryl.
Work as R
1During for aryl or heteroaryl, R
1Usually be not substituted or be selected from following substituting group and replace: halogen, C by 1-3
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl or C
1-6Halogenated alkoxy.Preferred R
1Be not substituted or be selected from following substituting group and replace: fluorine, chlorine, bromine, C by 1-2
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl or C
1-4Halogenated alkoxy.More preferably R
1Be not substituted or by a fluorine, chlorine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl or C
1-2Halo-alkoxy substituent replaces.
R
1Be generally C
1-6Alkyl or aryl.Preferred R
1Be C
1-2Alkyl or aryl.More preferably R
1Be C
1-2Alkyl or phenyl.More preferably R
1Be phenyl.
R
2Be generally hydrogen or C
1-4Alkyl.Preferred R
2Be hydrogen.
R
3Be generally halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino or two (C
1-4Alkyl) amino.Preferred R
3Be fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl, C
1-2Halogenated alkoxy, amino, (a C
1-2Alkyl) amino or two (C
1-2Alkyl) amino.More preferably R
3Be methyl, trifluoromethyl, fluorine, chlorine or bromine.R most preferably
3Be methyl or chlorine.Most preferred example is R
3Be chlorine.
N is generally 0,1 or 2.Preferred n is 0 or 1.
R
4Be generally hydrogen or C
1-4Alkyl.Preferred R
4Be hydrogen or C
1-2Alkyl.More preferably R
4Be hydrogen or methyl.R most preferably
4Be hydrogen.
Work as R
5During for heterocyclic radical, it connects by carbon atom usually.R
5Be generally C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6Typical case R
5Example be: R
5Be C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-or-XR
6
Preferred R
5Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperidyl, morpholinyl and piperazinyl; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-, phenyl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6Preferred R
5Example be: R
5Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperidyl, morpholinyl and piperazinyl; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-or-XR
6
More preferably R
5Be C
1-4Alkyl, phenyl, thienyl, furyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, phenyl-CH
2-, furyl-CH
2-, phenyl-C (O)-C (O)-, thienyl-C (O)-C (O)-or-XR
6More preferably R
5Example be: R
5Be C
1-4Alkyl, phenyl, thienyl, furyl, isoxazolyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, phenyl-CH
2-, furyl-CH
2-or-XR
6
R most preferably
5Be phenyl-CH
2-, furyl-CH
2-,-C (O)-C (O)-thienyl or-XR
6R most preferably
5Example be: R
5Be phenyl-CH
2-, furyl-CH
2-or-XR
6
X is generally-CO-,-S (O)-or-S (O)
2-.Preferred X is-CO-or-S (O)
2-.
Work as R
6For-NR
/R
//And R
/Or R
//When comprising aryl, heteroaryl, carbocylic radical or heterocyclic radical, R
6Usually be not substituted or be selected from following substituting group and replace: halogen, C by 1-3
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro and cyano group.Preferred aryl groups, heteroaryl, carbocylic radical or heterocyclic radical are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy and nitro.Preferred aryl groups, heteroaryl, carbocylic radical or heterocyclic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.More preferably aryl, heteroaryl, carbocylic radical or heterocyclic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro.More preferably aryl, heteroaryl, carbocylic radical or heterocyclic radical part are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent.Work as R
/Or R
//During for heteroaryl or heterocyclic radical, it connects by carbon atom.
R
/And R
//Usually not all be hydrogen.Usually, each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, aryl, heteroaryl, carbocylic radical, aryl-(C
1-4Alkyl)-or heteroaryl-(C
1-4Alkyl)-.Typical case R
/And R
//Example be: each R
/And R
//Identical or different and represent hydrogen; C
1-4Alkyl; Phenyl; Heteroaryl, for example thienyl; Carbocylic radical, for example cyclohexyl or cyclopentyl; Or phenyl-(C
1-4Alkyl)-.Typical case R
/And R
//Further example be: each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-.Preferred each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, phenyl, phenyl-CH
2-, cyclohexyl or cyclopentyl.More preferably R
/And R
//One of represent hydrogen.R most preferably
/And R
//One of another is C for hydrogen
1-4Alkyl, phenyl, phenyl-CH
2-, cyclohexyl or cyclopentyl.In addition, preferred R
/And R
//One of another is C for hydrogen
1-4Alkyl, phenyl, thienyl or phenyl-CH
2-.
R
6Be generally C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-(C
1-4Hydroxyalkyl)-, heteroaryl-(C
1- 4Hydroxyalkyl)-, carbocylic radical-(C
1-4Hydroxyalkyl)-, heterocyclic radical-(C
1-4Hydroxyalkyl)-, aryl-(C
1-4Alkyl)-O-, heteroaryl-(C
1-4Alkyl)-O-, carbocylic radical-(C
1-4Alkyl)-O-, heterocyclic radical-(C
1-4Alkyl)-O-or-NR
/R
//, R wherein
/And R
//Definition the same.Typical case R
6Example be: R
6Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-or-NR
/R
//, R wherein
/And R
//Definition the same.
Preferred R
6Be C
1-6Alkyl; C
1-6Alkoxyl group; C
1-6Alkylthio; Aryl, for example phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group and indyl; Heteroaryl, for example thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl and benzofuryl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperazinyl, piperidyl, morpholinyl and 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group; Phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-, phenyl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Alkyl)-or-NR
/R
//, R wherein
/And R
//Definition the same.Preferred R
6Example be: R
6Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example N-heterocyclic radical; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-or-NR
/R
//, R wherein
/And R
//Definition the same.
More preferably R
6Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-, 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group or-NR
/R
//, R wherein
/And R
//Definition the same.R most preferably
6Example be: R
6Be C
1-4Alkyl; Phenyl; Thienyl; Furyl; Pyridyl; Cyclopentyl; Cyclohexyl; Benzothienyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, N-piperazinyl for example, or-NR
/R
//, R wherein
/And R
//Definition the same.
Preferred The compounds of this invention is these compounds, wherein:
-R
1Be C
1-6Alkyl or aryl;
-R
2Be hydrogen or C
1-4Alkyl;
-R
3Be halogen, hydroxyl, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino or two (C
1-4Alkyl) amino, perhaps preferred R
3Be fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl, C
1-2Halogenated alkoxy, amino, (a C
1-2Alkyl) amino or two (C
1-2Alkyl) amino;
-n is 0,1 or 2;
-R
4Be hydrogen or C
1-4Alkyl;
R
5Be C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6
-X is-CO-,-S (O)-or-S (O)
2-; And
-R
6Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1- 4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-, aryl-(C
1-4Hydroxyalkyl)-, heteroaryl-(C
1-4Hydroxyalkyl)-, carbocylic radical-(C
1-4Hydroxyalkyl)-, heterocyclic radical-(C
1-4Hydroxyalkyl)-, aryl-(C
1-4Alkyl)-O-, heteroaryl-(C
1-4Alkyl)-O-, carbocylic radical-(C
1-4Alkyl)-O-, heterocyclic radical-(C
1-4Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, aryl, heteroaryl, carbocylic radical, aryl-(C
1-4Alkyl)-or heteroaryl-(C
1-4Alkyl)-,
R
1Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl or C
1-6Halogenated alkoxy;
R
5And R
6Aryl in the group and heteroaryl moieties are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-S (O)
2NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl;
R
5And R
6Carbocylic radical in the group and heterocyclic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, oxo ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) N-R
/R
//,-S (O)
2NR
/R
//,-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl; And
R
6Aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-moieties is not substituted or is replaced by 1-2 hydroxyl substituent.
In these preferred compounds of the present invention, preferred R
/And R
//Aryl in the group, heteroaryl and carbocylic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro and cyano group.
The example of preferred compound of the present invention is these compounds: R wherein
1, R
2, R
3, R
4It is identical with the definition of n with the definition of preferred compound of the present invention,
-R
5Be C
1-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1-4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-or-XR
6
-X is-CO-,-S (O)-or-S (O)
2-; And
-R
6Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, carbocylic radical-(C
1- 4Alkyl)-, heterocyclic radical-(C
1-4Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, aryl, heteroaryl, carbocylic radical, aryl-(C
1-4Alkyl)-or heteroaryl-(C
1-4Alkyl)-,
R
5And R
6Aryl in the group, heteroaryl, carbocylic radical and heterocyclic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.
Further preferred The compounds of this invention is these compounds, wherein:
-R
1Be C
1-2Alkyl or phenyl;
-R
2Be hydrogen or C
1-4Alkyl;
-R
3Be methyl, trifluoromethyl, fluorine, chlorine or bromine;
-n is 0 or 1;
-R
4Be hydrogen or C
1-2Alkyl;
-R
5Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperidyl, morpholinyl and piperazinyl; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-, phenyl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-or-XR
6, precondition is to work as R
5During for heterocyclic radical, it connects by carbon atom;
-X is-CO-,-S (O)-or-S (O)
2-; And
-R
6Be C
1-6Alkyl; C
1-6Alkoxyl group; C
1-6Alkylthio; Aryl, for example phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group and indyl; Heteroaryl, for example thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl and benzofuryl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperazinyl, piperidyl, morpholinyl and 1H-benzo [d] tetrahydroglyoxaline-2-(3H)-ketone group; Phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-, phenyl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Hydroxyalkyl)-, heteroaryl-(C
1-2Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen; C
1-4Alkyl; Phenyl; Heteroaryl, for example thienyl; Carbocylic radical, for example cyclohexyl or cyclopentyl; Or phenyl-(C
1-4Alkyl)-,
R
1Phenyl moiety in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl or C1-4 halogenated alkoxy;
R
5And R
6Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R
/,-S (O) R
/,-S (O)
2R
/With-S (O)
2NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-4Alkyl;
R
5And R
6Heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group; And
R
5And R
6Carbocylic radical in the group and heterocyclic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group and oxo; And
R
6Phenyl-(C
1-2Alkyl)-and heteroaryl-(C
1-2Alkyl)-moieties is not substituted or is replaced by a hydroxyl substituent.
In these further preferred The compounds of this invention, preferred R
/And R
//Phenyl in the group, heteroaryl and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy and nitro.
Further the example of preferred The compounds of this invention is these compounds: R wherein
1, R
2, R
3, R
4It is identical with the definition of n with the definition of further preferred The compounds of this invention,
-R
5Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example piperidyl, morpholinyl and piperazinyl; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-or-XR
6, precondition is to work as R
5During for heterocyclic radical, it connects by carbon atom;
-X is-CO-,-S (O)-or-S (O)
2-; And
-R
6Be C
1-4Alkyl; Aryl, for example phenyl and dihydro benzo furyl; Heteroaryl, for example thienyl, furyl, isoxazolyl, pyridyl and benzothienyl; Carbocylic radical, for example cyclopentyl and cyclohexyl; Heterocyclic radical, for example N-heterocyclic radical; Phenyl-(C
1-2Alkyl)-, benzyl for example; Heteroaryl-(C
1-2Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-,
R
5And R
6Aryl in the group, heteroaryl, carbocylic radical and heterocyclic radical part are not substituted or are selected from following substituting group by 1-2 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group.
In these further preferred The compounds of this invention, further preferred R
/And R
//Cyclohexyl in the group, cyclopentyl and phenyl moiety are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
Especially preferred The compounds of this invention is an acceptable salt on structural formula (Ia) compound and its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be methyl or chlorine;
-n is 0 or 1;
-R
4Be hydrogen or methyl;
-R
5Be phenyl-CH
2-, furyl-CH
2-, thienyl-C (O)-C (O)-or-XR
6
-X is-CO-or-S (O)
2-; And
-R
6Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-, 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-,
R
1Phenyl moiety in the group is not substituted or by a fluorine, chlorine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl or C
1-2Halo-alkoxy substituent replaces;
R
5And R
6Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R
/,-S (O)
2R
/With-S (O)
2NH
2, R wherein
/Represent C
1-2Alkyl;
R
5And R
6Heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Haloalkyl and two (C
1-2Alkyl) amino; And
R
6Heterocyclic radical in the group and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
Especially preferred structural formula (Ia) examples for compounds is an acceptable salt on structural formula (Ia ') compound and its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be chlorine;
-n is 0 or 1;
-R
5Be phenyl-CH
2-, furyl-CH
2-or-XR
6
-X is-CO-or-S (O)
2-; And
-R
6Be C
1-4Alkyl; Phenyl; Thienyl; Furyl; Pyridyl; Cyclopentyl; Cyclohexyl; Benzothienyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, N-piperazinyl for example, or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-,
R
5And R
6Phenyl in the group, thienyl, furyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, isoxazolyl, piperidyl, morpholinyl and piperazinyl part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro.
In these especially preferred The compounds of this invention, preferred R
/And R
//Cyclohexyl in the group, cyclopentyl and phenyl moiety are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent.
Comprise structural formula (I) compound of one or more chiral centres can enantiomer or the diastereisomericallypure pure form use, perhaps use with the mixture of isomers form.For fear of ambiguity, all steric isomers of compound shown in chemical structure described herein comprises comprise racemize and non-racemic mixture and pure enantiomer and/or pure diastereomer.
Preferred The compounds of this invention is an optically active isomer.Therefore, for example, comprise the preferred compound of the structural formula of a chiral centre (I) only and comprise the R enantiomer of pure form substantially, the S enantiomer of pure form and the enantiomeric mixture that comprises excessive R enantiomer or excessive S enantiomer substantially.For fear of ambiguity, if desired, structural formula (I) compound can solvate forms use.
On the pharmacology used herein acceptable salt be with pharmacology on the salt that forms of acceptable acid or alkali.Acceptable acid comprises mineral acid for example hydrochloric acid, sulfuric acid, phosphoric acid, tetra-sodium, Hydrogen bromide or nitric acid on the pharmacology, and organic acid for example citric acid, fumaric acid, toxilic acid, oxysuccinic acid, xitix, succsinic acid, tartrate, phenylformic acid, acetate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid or tosic acid.Acceptable alkali comprises basic metal (for example sodium or potassium) and alkaline-earth metal (for example calcium or magnesium) oxyhydroxide and organic bases for example alkylamine, aralkylamine or heterocyclic amine on the pharmacology.
Especially preferred The compounds of this invention comprises:
1) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
2) 1,1-diethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
3) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide;
4) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-butyramide;
5) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyramide;
6) 2,2-dimethyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide;
7) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclopentane formamide;
8) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclohexane carboxamide;
9) 3-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-benzamide;
10) 4-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-benzamide;
11) 2-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-benzamide;
12) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-trifluoromethyl-benzamide;
13) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
14) thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine-3-yl)-3-acid amides;
15) furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
16) piperidines-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
17) morpholine-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
18) 4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
19) 3-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
20) 4-methyl-piperazine-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
21) 3,4-two chloro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-benzamide;
22) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-trifluoromethyl-benzamide;
23) 4-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
24) 2-methyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
25) 2-chloro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
26) 2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
27) 2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
28) (S)-2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
29) benzo [b] thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
30) 2,3-dihydro-cumarone-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
31) isoxazole-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-methane amide;
32) benzo [b] thiophene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
33) thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
34) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Isonicotinamide;
35) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-niacinamide;
36) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Toluidrin;
37) propane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-sulphonamide;
38) butane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-sulphonamide;
39) 2-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzsulfamide;
40) 3-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzsulfamide;
41) 4-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzsulfamide;
42) 2-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzsulfamide;
43) 3-(2-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone;
44) 3-(3-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone;
45) 3-(4-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone;
46) 3-(2-methoxyl group-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
2-ketone;
47) 3-(3-methoxyl group-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
2-ketone;
48) 5-phenyl-3-(2-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone;
49) 5-phenyl-3-(3-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone;
50) 5-phenyl-3-(4-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone;
51) 3-[(furans-2-ylmethyl)-amino]-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone;
52) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
53) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyramide;
54) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Toluidrin;
55) furans-2-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
56) thiophene-2-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
57) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclohexane carboxamide;
58) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-methoxyl group-benzamide;
59) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-4-methoxyl group-benzamide;
60) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-nitro-benzamide;
61) 2-(2-methoxyl group-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
62) 2-(3-methoxyl group-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
63) 2-(4-methoxyl group-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
64) 2-(4-nitro-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
65) 2-(3-nitro-phenyl) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
66) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-(2-trifluoromethyl-phenyl)-ethanamide;
67) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-(3-trifluoromethyl-phenyl)-ethanamide;
68) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-(4-trifluoromethyl-phenyl)-ethanamide;
69) 1-(2-methoxyl group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
70) 1-(2-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
71) 1-(2-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
72) 1-(4-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
73) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-and 3-is right-tolyl-urea;
74) 1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
75) 1-(4-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
76) (S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
77) 4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
78) (S)-4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
79) 5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
80) (S)-5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
81) 6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
82) (S)-6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
83) (S)-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-4-trifluoromethyl-benzamide;
84) 2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
85) (S)-2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
86) 2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
87) (S)-2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
88) 1H-indoles-7-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
89) (S)-1H-indoles-7-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
90) 3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
91) (S)-3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
92) N-[7-chloro-5-(2-fluoro-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-4-methoxyl group-benzamide;
93) 1-(2-fluoro-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
94) 1-(4-methoxyl group-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
95) 1-(3-methyl-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
96) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-(4-trifluoromethyl-phenyl)-urea;
97) 4-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
98) 4-methoxyl group-3-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) benzamide;
99) 3-methoxyl group-2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
100) 5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) benzamide;
101) 5-fluoro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
102) 2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
103) 5-methoxyl group-2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
104) 3-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
105) 3-(2-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) propionic acid amide;
106) 3-(3-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide;
107) 3-(4-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide;
108) N-[5-(3-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3 bases]-2-methoxyl group-benzamide;
109) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-4-methoxyl group-benzamide;
110) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-2-nitro-benzamide;
111) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-4-nitro-benzamide;
112) 4-methoxyl group-N-[2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide;
113) 2-methoxyl group-N-[2-oxo-5-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide;
114) 4-methoxyl group-N-[2-oxo-5-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide;
115) 2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-benzamide;
116) 2,4-dimethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
117) 2-bromo-5-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
118) 2-methoxyl group-N-[5-(3-methoxyl group-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide
119) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-4-nitro-benzamide;
120) 2-methoxyl group-N-(8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
121) 2-chloro-4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
122) 2-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
123) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzyl carbamate;
124) 1-(3,5-dimethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
125) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-(4-trifluoromethoxy-phenyl)-urea;
126) 1-(4-bromo-2-trifluoromethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
127) 1-(4-bromo-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
128) 1-(2,3-two chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
129) 1-(2,6-dimethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
130) 1-(2-chloro-6-methyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
131) 1-(4-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
132) 1-(2-methylthio group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
133) 1-(2,6-two chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
134) the 5-tertiary butyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
135) 2,5-dimethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
136) 1-(2,6-two fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
137) 1-(3-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
138) 1-(3-methoxyl group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
139) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-(3-trifluoromethyl-phenyl)-urea;
140) 1-(3-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
141) 2-methoxyl group-4-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
142) 4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
143) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-to benzoyl amino acid methyl esters;
144) 2-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
145) 2,6-two fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-benzamide;
146) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-propoxy--benzamide;
147) 2-iodo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
148) 3-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-to benzoyl amino acid methyl esters;
149) 4-amino-5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide;
150) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-between-tolyl-urea;
151) 2-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-benzamide;
152) 2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-5-sulfamyl-benzamide;
153) 2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-phenyl-propionic acid amide;
154) 3-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-phenyl-propionic acid amide;
155) 3-(2-fluoro-phenyl)-1-methyl isophthalic acid-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
156) 2-methoxyl group-N-methyl-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide;
157) the 1-tertiary butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-urea;
158) 1-cyclohexyl (Cycloheyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
159) 1-ethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
160) 1-butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea;
161) 4,5-dimethyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
162) piperidines-1-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
163) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl] ethanamide;
164) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-isobutyramide;
165) furans-2-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide;
166) thiophene-2-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide;
167) N-[5-(3 chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-cyclohexane carboxamide;
168) piperidines-1-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide;
169) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl] Isonicotinamide;
170) 5-methyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
171) pyrazine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
172) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-isobutyramide;
173) thiophene-2-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide;
174) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-cyclohexane carboxamide;
175) piperidines-1-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide;
176) piperidines-4-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide;
177) N-(8-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclohexane carboxamide;
178) thiophene-2-N-(8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
179) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-thiophene-2-base-urea;
180) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-thiene-3-yl--urea;
181) pyridine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
182) 1H-pyrazoles-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
183) 6-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-niacinamide;
184) 2-oxyethyl group-naphthalene-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
185) 9-oxo-9H-fluorenes-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
186) 2-oxo-2,3-dihydro-benzoglyoxaline-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
187) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) t-butyl carbamate;
188) (S)-4,5-two bromo-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
189) (S)-cumarone-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide;
190) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Urethylane;
191) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urethanum;
192) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyl carbamate; With
193) 2-oxo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-thiophene-2-base-ethanamide.
And acceptable salt on their pharmacology.
Structural formula (I) compound can be prepared as follows: pass through oxoethanoic acid (HCO-CO under the Dean-Stark condition
2H), benzotriazole and suitable benzyl carbamate in back flow reaction, obtain following important shielded structural formula (II) amino acid in toluene,
Then can be with structural formula (II) amino acid of therefore acquisition and suitable chlorizating agent (for example oxalyl chloride) reaction, the 2-aminobenzophenone with following structural formula (III) reacts again,
What obtain is following intermediate structure formula (IV) acid amides,
It need not to characterize.
Structural formula (IV) compound is separated through ammonia then, then encircles closure in containing the acetate of ammonium acetate, obtains the benzodiazepine of following structure formula V protection
The available then acetate that contains hydrogen bromide of structure formula V compound goes protection, and what obtain following structural formula (VI) removes to protect amine.
Structural formula (I) compound (R wherein
5Be XR
6And X is-CO-) can be by structural formula defined above (VI) compound and acid anhydrides prepared in reaction in appropriate solvent, this reacts preferred pyridine and carries out in ambient temperature; Perhaps have the alkali preparation with chloride of acid in appropriate solvent, this reaction preferably exists triethylamine to carry out in ambient temperature in THF.Perhaps, this compound can exist alkali and coupling agent prepared in reaction by structural formula (VI) compound and acid in appropriate solvent, this reaction preferably in THF, in ambient temperature, have triethylamine and O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HBTU) carries out.
If the chloride of acid that uses is the amino-carbon acyl chlorides, then structural formula (I) compound is uncle's urea.Work as R
6Be NH-R
/The time, such compound can pass through structural formula (VI) compound and isocyanate reaction preparation.Reaction is preferably carried out in ambient temperature in THF.In addition, isocyanic ester can be reflected at alkali (being generally triethylamine) existence and carry out in THF down with corresponding amine and carbonyl chloride in-situ preparing.
Structural formula (I) compound (R wherein
5For-XR
6And X is-S (O)
2-) can pass through structural formula (V1) compound and suitable SULPHURYL CHLORIDE prepared in reaction.Similarly, structural formula (I) compound (R wherein
5Be XR
6And X is-S (O)-) can pass through structural formula (VI) compound and suitable sulphinyl chlorine prepared in reaction.
Structural formula (I) compound (R wherein
5Be not XR
6) can prepare by currently known methods.For example, structural formula (VI) compound can with formula R
5-L compound (wherein L is a leavings group, for example chlorine atom, methylsulfonic acid ester group or trifluoromethanesulfonic acid ester group) reaction.Work as R
5During for aryl or heteroaryl, L can be-B (OH)
2And this reaction can be carried out in the presence of neutralized verdigris.Those skilled in the art are familiar with this class boric acid coupled reaction certainly.R wherein
5For the compound of aryl or heteroaryl also can pass through the Buchwald prepared in reaction, perhaps by structural formula (VI) compound and suitable fluoro aryl or fluorine heteroaryl compound prepared in reaction.R wherein
5For the compound of heteroaryl also can pass through structural formula (VI) compound and suitable chlorine heteroaryl or bromine heteroaryl compound prepared in reaction.R wherein
5For the compound of carbocylic radical also can prepare by currently known methods, R wherein for example
5For the compound of cyclohexyl can pass through structural formula (VI) compound and pimelinketone prepared in reaction, there is reductive agent in reaction.
Structural formula (I) compound (R wherein
5Be aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-) also can pass through the preparation of structural formula (VI) compound and aldehyde reaction, there is reductive agent in reaction.Preferred being reflected between structural formula (VI) compound and the aldehyde of this class carried out, and is reflected in the mixture of methylene dichloride and acetate to exist (triacetyl oxygen base) sodium borohydride to carry out under ambient temperature.
At the preparation benzodiazepine
In the skeleton, can use under the situation about needing and be purchased structural formula (III) compound aminobenzophenone.The structural formula that can not be purchased (III) compound can prepare by currently known methods, for example Weinreb type acid amides and the R by following structural formula (VII)
1-Li gene or Grignard reagent (R for example
1-MgBr) prepared in reaction.
Preferred this is reflected among the THF and carries out in-100 ℃.
Structural formula (VII) compound is known compound or can prepares by similar currently known methods.For example, the isatoic anhydride and the N of their available following structural formulas (VIII), the O-dimethyl hydroxylamine is prepared in reaction under the standard reaction condition.
Structural formula (II), (III), (VII) and starting raw material (VIII) are known compound, perhaps can be according to similar currently known methods preparation.
Can be by further synthetic structural formula (I) compound that so obtains of handling of ordinary method, so that obtain other structural formula (I) compound.The benzodiazepine of structural formula (I)
Available suitable acid or alkaline purification salify.
Although the approach to claimed compound introduction provides suitable synthetic method for bench scale preparation, also to determine to have the alternative route of production approach potentiality.Two kinds of methods are all used identical starting raw material (2-amino-benzophenone) (1), yet in alternative route, by bromoacetyl bromide (or equal reagent) starting reaction, encircle the closed benzodiazepine that forms with ammoniacal liquor then
Ring system.These are reflected at, and (for example methylene dichloride) carries out in suitable temperature (scope can be-20 ℃ to 150 ℃) in the appropriate solvent.In order to protect the NH functional group, in this stage, with unsubstituting phenenyl and diaza
With alkali and alkylating agent reaction.For example sodium hydride is dissolved in DMF, adds 4-methoxyl group-benzyl chloride then, obtain the intermediate (2) that shows down.This material and alkali (for example potassium tert.-butoxide) is (for example THF or DMF) further reaction in appropriate solvent, use Isopentyl nitrite (or alternate similar reagents) cancellation then, obtain oxime intermediate (3), can be converted into the racemize primary amine with methods such as hydrogen and suitable catalyzer.Then with this amine process Dynamic Kinetic Resolution (Dynamic Kinetic Resolution (DKR)) step, the reaction of racemic amines exists suitable opticity acid and suitable aldehyde, with high yield and unusual high required (S)-amine salt (4) precipitation of the excessive acquisition of enantiomerism.The suitable acid that is used for this conversion can be for example camphorsulfonic acid, Boc-phenylalanine etc., and suitable aldehyde can be phenyl aldehyde (for example 3,5-dichloro-salicylaldehyde).
Then, the optical amine that so forms is converted to required derivative (for example acid amides or urea).Acid amides forms and can use suitable carboxylic acid and coupling agent, perhaps carbonyl chloride or other suitable reagent, and the preparation urea is with suitable isocyanic ester, or selection and carbonyl chloride react then and suitable amine prepared in reaction.
Then, these derivatives that so form are removed protecting group.Reaction can exist under the Lewis acid (for example aluminum chloride, boron trifluoride, titanium tetrachloride etc.) to be finished.These are reflected in the suitable inert solvent (for example methylene dichloride) and carry out.Temperature of reaction can be-20 ℃ to 150 ℃, but carries out in room temperature or when being lower than room temperature usually.
As mentioned above, The compounds of this invention is effective anti-RSV compound.Therefore the present invention provides a kind of methods of treatment to the patient who suffers from or easily suffer from rsv infection, and this method comprises and gives acceptable salt on structural formula (I) compound of significant quantity or its pharmacology to described patient.
RSV is popular in below two years old among the infant.Especially the infant below two years old who suffers from chronic lung disease in serious threat.Therefore, described medicine is generally used for treating the ill children below two years old.Described children suffer from chronic lung disease usually.
In addition 32 weeks of gestation or the recommended for infants that are less than 32 week births are carried out anti-RSV prevention, till they have half years old.Therefore, described medicine is generally used for preventing 32 weeks of gestation or is less than the children's below 6 years old of 32 weeks birth rsv infection.
Have been found that rsv infection with inflammatory reaction (Noah et al, ClinicalImmunology 2000, Vol 97,43-49).The invention still further relates to the combination medicine of acceptable salt and anti-inflammatory compound on structural formula (I) compound or its pharmacology, and use this combination medicine treatment RSV.Described anti-inflammatory compound is generally steroide, for example budesonide or fluticasone; Non-steroids, for example leukotriene antagonist, phosphodiesterase 4 inhibitors or TNF alpha inhibitor or interleukin 8 or interleukin 9 inhibitor.
Therefore, in one embodiment, acceptable salt associating steroid anti-inflammatory compound, for example budesonide or fluticasone on structural formula (I) compound or its pharmacology.In a preferred embodiment, steroide is given with low dosage and is minimized immunosuppressive action.In a further embodiment, acceptable salt associating non-steroidal anti-inflammatory compounds on structural formula (I) compound or its pharmacology, for example Singulair (Merck) or Accolate (Astra Zeneca) of leukotriene antagonist for example, phosphodiesterase 4 inhibitors is roflumilast (Altana) for example, the TNF alpha inhibitor is Enbrel (Amgen), Remicade (Centocor), Humira (Abbott) or CDP870 (Celltech) for example, or NSAIDS.In further embodiment, structural formula (I) compound associating interleukin 8 or interleukin 9 inhibitor.Therefore the present invention also relates to the product that comprises acceptable salt and anti-inflammatory compound on structural formula (I) compound or its pharmacology, its simultaneously, the independent or sequential RSV that is used for the treatment of.
The invention still further relates to the combination medicine of acceptable salt and anti influenza compound on structural formula (I) compound or its pharmacology, use RSV and influenza infection that this combination medicine treatment occurs together.Therefore the present invention also relates to the product that comprises acceptable salt and anti influenza compound on structural formula (I) compound or its pharmacology, its simultaneously, independent or sequential RSV and the influenza infection that occurs together that be used for the treatment of.
Further wonderful discovery is, The compounds of this invention can effectively anti-human metapneumovirus (human metapneumovirus), measles, parainfluenza virus and parotitis.Therefore the present invention provides acceptable salt on structural formula (I) compound or its pharmacology to be used for the treatment of purposes on human metapneumovirus, measles, parainfluenza virus and the parotitis medicine in preparation.Wonderful in addition discovery is, The compounds of this invention can effectively anti-yellow fever virus (B5 virus strain), singapore hemorrhagic fever 2 C-type virus Cs and west Nile virus.Therefore the present invention provides acceptable salt on structural formula (I) compound or its pharmacology to be used for the treatment of purposes on yellow fever virus (B5 virus strain), singapore hemorrhagic fever 2 C-type virus Cs and the west Nile virus medicine in preparation.
The compounds of this invention can give by different dosage form.Therefore, their Orally-administrables, but for example tablet, dragee, lozenge, water suspension or oil suspension dispersion powder or granule.But The compounds of this invention is administered parenterally also, no matter be in subcutaneous, intravenously, intramuscular, the breastbone, transdermal or infusion administration.Described compound also can the suppository administration.
In a preferred embodiment, The compounds of this invention interior or interior administration of segmental bronchus by nose.The present invention also provides sucker or the atomizer that comprises following composition medicine: (a) benzodiazepine of structural formula defined above (I)
Acceptable salt and (b) acceptable carrier or thinner on the pharmacology on derivative or its pharmacology.
The present invention also provides a kind of medicinal compositions, and it comprises described benzodiazepine
Acceptable carrier or thinner on acceptable salt and the pharmacology on derivative or its pharmacology.
Described medicinal compositions preferably comprises the The compounds of this invention of 85wt% at the most.More preferably comprise the The compounds of this invention of 50wt% at the most.Preferred medicinal compositions is aseptic and does not contain pyrogeneous substance.In addition, medicinal compositions provided by the invention comprises the The compounds of this invention that is substantially pure optical isomer usually.
The compounds of this invention usually with pharmacology on acceptable carrier or thinner prepare and give.For example, the Peroral solid dosage form type can comprise the thinner with active compound, for example lactose, glucose, sucrose, Mierocrystalline cellulose, W-Gum or yam starch; Lubricant, for example silicon-dioxide, talcum powder, stearic acid, Magnesium Stearate or calcium and/or polyoxyethylene glycol; Tackiness agent, for example starch, Sudan Gum-arabic, gelatin, methylcellulose gum, carboxymethyl cellulose or polyvinylpyrrolidone; Disintegrating agent, for example starch, Lalgine, alginate or sodium starch glycolate; Foaming mixtures; Dyestuff; Sweeting agent; Wetting agent, for example Yelkin TTS, polysorbate, lauryl sulfate; And normally used nontoxic and pharmacology inactive substance in the medicine preparation.Such pharmaceutical preparation can be used currently known methods production, for example, and by mixing, granulation, compressing tablet, sweet tablet or coating method preparation.
Oral liquid dispersant can be syrup, emulsion and suspensoid.Syrup can comprise carrier, for example, and sucrose or sucrose and glycerol and/or mannitol and/or sorbyl alcohol.
Suspensoid and emulsion can comprise carrier, for example natural gum, agar, sodiun alginate, pectin, methylcellulose gum, carboxymethyl cellulose or polyvinyl alcohol.The suspensoid of intramuscularly or solution can comprise acceptable carrier on the pharmacology of active compound, for example the Xylotox (if necessary) of sterilized water, sweet oil, ethyl oleate, di-alcohols (as propylene glycol) and appropriate amount.
The solution of injection or infusion can comprise carrier, and for example, sterilized water perhaps is preferably the sterile isotonic salt brine solution.
The patient is treated the The compounds of this invention of significant quantity.According to the frequency and the approach of the activity of specific compound, the type that will treat patient's age, body weight and individual state, disease and severity and administration, typical doses is about 0.001-50mg/kg (body weight).Preferably every day, dosage level was 5mg-2g.
The benzodiazepine of some structural formula (I)
Derivative is essentially novel cpd.The present invention includes acceptable salt on these novel cpds and its pharmacology.Therefore the present invention also provides acceptable salt on following structural formula (Ib) compound and its pharmacology,
Wherein:
-R
1Represent C
1-6Alkyl, aryl or heteroaryl;
-R
2Represent hydrogen, C
1-6Alkyl;
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R
/,-CONR
/R
//,-NH-CO-R
/,-S (O) R
/,-S (O)
2R
/,-NH-S (O)
2R
/,-S (O) NR/R
//Or-S (O)
2NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl;
-n is 0-3;
-R
4Represent hydrogen or C
1-6Alkyl;
-R
5/Represent C
3-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-X
/, precondition is to work as R
5/During for heteroaryl, it is not the quinaldine based or 6-chloro-pyrazinyl of 2-, works as R
5/Be heteroaryl-(C
1-6Alkyl)-time, it is not 2-indyl methyl, 2-(3-indyl) ethyl or 2-furyl methyl, works as R
5/During for aryl, it is not unsubstituted phenyl, and works as R
5/Be aryl-(C
1-6Alkyl)-time, it is not unsubstituted phenyl-(C
1-2Alkyl)-or 4-chloro-phenyl--(C
2-3Alkyl)-;
-X
/Representative-CO-R
6/,-S (O)-R
6//Or-S (O)
2-R
6/ //
-R
6Represent C
1Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1- 6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is (a) to work as R
6/During for aryl, it is not unsubstituted naphthyl, unsubstituted phenyl, phenyl-monohalide base, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-hydroxy phenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-cyano-phenyl, 4-n-propyl phenyl, 4-tert-butyl-phenyl, 4-n-pentyl phenyl, 4-dimethylaminophenyl, 4-methylthio group phenyl, 3-trifluoromethylthio phenyl, 3,4-Dimethoxyphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4,5,6-pentafluorophenyl group, 4-chloro-2-aminophenyl or 4-1,1-dimethyl ethyl phenyl (b) is worked as R
6/During for heteroaryl, it is not that 2-pyrryl, 2-pyrazinyl, 2-are quinaldine based, 2-quinoxalinyl, 1-methyl indone base (1-methylindonly), 2-methyl-indyl, 2-benzofuryl, 2-benzothienyl, 3-thienyl, 3-indyl, unsubstituted 2-indyl, 5-fluoro indole-2-base, 5-chloro-indole-2-base, 5-bromo indole-2-base, 5-oxyindole-2-base or 5-methoxyl group indoles-2-base, (c) works as R
6/Be aryl-(C
1-6Alkyl)-time, it is not 4-benzo-thiophene-(CH
2)-, unsubstituted phenyl-(CH
2)-, 4-trifluoromethyl-(CH
2)-, unsubstituted phenyl-(CH
2)
3-, single trifluoromethyl-(CH
2)
2-, 3-p-methoxy-phenyl-(CH
2)
2-, 4-chloro-2-aminophenyl-(CH
2)
2-, 2,4 dichloro benzene base-(CH
2)
2-, mono chloro benzene base-(CH
2)
2-, 2,4-trifluoromethyl-(CH
2)
2-, 4-cyano-phenyl-(CH
2)
2-or 3-cyano-phenyl-(CH
2)
2-, (d) work as R
6/Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH of 1-3 for x
2)
x-, unsubstituted furyl-(CH
2)
2-, unsubstituted thienyl-(CH
2)
3-, (e) work as R
6/During for carbocylic radical, it is not a cyclohexyl, (f) works as R
6/Be carbocylic radical-(C
1-6Alkyl)-time, it is not unsubstituted cyclohexyl-(CH
2)
1-3-, (g) work as R
6/During for heterocyclic radical, it is not N-pyrrolidyl or 2-dihydro benzo furyl, (h) works as R
6/Be aryl-(C
1-6Alkyl)-during O-, it is not unsubstituted phenyl-(CH
2)-O-, and (i) work as R
/During for hydrogen, R
//Be not unsubstituted phenyl, 4-halogenophenyl, 3-halogenophenyl, p-methoxy-phenyl, nitrophenyl, 2-chloro-phenyl-, 4-aminomethyl phenyl, dichlorophenyl, 3,5-3,5-dimethylphenyl, 3-aminomethyl phenyl, 3-cyano-phenyl, 3-aminophenyl, 3-aminocarbonyl-phenyl, 3-phenylformic acid, 3-ethyl benzoate, 6-amino-3-pyridyl, 5-(2-chlorine) pyridyl, 5-(2-methoxyl group) pyridyl, 5-indanyl, unsubstituted cyclohexyl, 1,1-dimethyl ethyl, unsubstituted phenyl-CH
2-, unsubstituted naphthyl or benzotriazole-3-base, work as R
/During for methyl, R
//It is not cyclopropyl-phenyl;
-R
6//Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-; And
-R
6/ //Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is to work as R
6/ //During for aryl, it is not the 4-aminomethyl phenyl, and precondition is that structural formula (Ib) compound is not N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide.
In structural formula (Ib), preferred
-each R
3Identical or different and represent halogen, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R
/,-CONR
/R
//,-NH-CO-R
/,-S (O) R
/,-S (O)
2R
/,-NH-S (O)
2R
/Or-S (O) NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl;
-R
5/Represent C
2-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-X
/, precondition is to work as R
5/During for heteroaryl, it is not the quinaldine based or 6-chloro-pyrazinyl of 2-, and works as R
5/Be heteroaryl-(C
1-6Alkyl)-time, it is not 2-indyl methyl or 2-(3-indyl) ethyl;
-X
/Representative-CO-R
6/,-S (O)-R
6//Or-S (O)
2-R
6/ //
-R
6/Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-, precondition is that (a) works as R
6/During for aryl, it is not unsubstituted naphthyl, unsubstituted phenyl, phenyl-monohalide base, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-hydroxy phenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-cyano-phenyl, 4-n-propyl phenyl, 4-tert-butyl-phenyl, 4-n-pentyl phenyl, 4-dimethylaminophenyl, 4-methylthio group phenyl, 3-trifluoromethylthio phenyl, 3,4-Dimethoxyphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl or 2,3,4,5, the 6-pentafluorophenyl group (b) is worked as R
6/During for heteroaryl, it is not that 2-pyrryl, 2-pyrazinyl, 2-are quinaldine based, 2-methyl-indyl, 2-benzofuryl, 2-benzothienyl, 3-thienyl, 3-indyl, unsubstituted 2-indyl, 5-fluoro indole-2-base, 5-chloro-indole-2-base, 5-bromo indole-2-base, 5-oxyindole-2-base or 5-methoxyl group indoles-2-base, (c) works as R
6/Be aryl-(C
1-6Alkyl)-time, it is not 4-benzo-thiophene-(CH
2)-, (d) works as R
6/Be heteroaryl-(C
1-6Alkyl)-time, it is not-indyl-(CH
2)
x-, wherein x is 1-3 and (e) works as R
/During for hydrogen, R
//Be not 4-halogenophenyl, 3-aminomethyl phenyl, 3-cyano-phenyl, 3-aminophenyl, 3-aminocarbonyl-phenyl, 3-phenylformic acid, 3-ethyl benzoate, 6-amino-3-pyridyl, 5-(2-chlorine) pyridyl, 5-(2-methoxyl group) pyridyl, 5-indanyl or benzotriazole-3-base;
-R
6//Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-; And
-R
6/ //Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-, precondition is to work as R
6/ //During for aryl, it is not the 4-aminomethyl phenyl.
R in the preferred structure formula (Ib)
1, R
2, R
3And R
4Group comprises R in the said structure formula (I)
1, R
2, R
3And R
4Preferred group.Preferred structure formula (Ib) compound comprises especially preferred structural formula listed above (I) compound.
In structural formula (Ib), R
2Be generally hydrogen.
Preferred structure formula (Ib) compound is these compounds, wherein:
-R
5/Represent C
3-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl) ,-aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-X
/, precondition is to work as R
5/During for heteroaryl, it is not quinaldine based or pyrazinyl, works as R
5/Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH
2)
x-, wherein x is 1 or 2, perhaps furyl methyl is worked as R
5/During for aryl, it is not a phenyl, and works as R
5/Be aryl-(C
1-6Alkyl)-time, it is not phenyl-(C
1-3Alkyl)-;
-X
/Representative-CO-R
6/,-S (O)-R
6//Or-S (O)
2-R
6/ //
-R
6/Represent C
1Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1- 6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
///, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is that (a) works as R
6/During for aryl, it is not a phenyl or naphthyl, (b) works as R
6/During for heteroaryl, it is not thienyl, pyrryl, pyrazinyl, quinaldine based, quinoline oxazolidinyl, indyl, benzofuryl or benzothienyl, (c) works as R
6/Be aryl-(C
1-6Alkyl)-time, it is not benzo-thiophene-(CH
2)-or phenyl-(CH
2)
1-3-, (d) work as R
6/Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH
2)
x-(wherein x is 1-3), thienyl-(CH
2)
3-or furyl-(CH
2)
2-, (e) work as R
6/During for carbocylic radical, it is not a cyclohexyl ,-, (f) work as R
6/During for heterocyclic radical, it is not pyrrolidyl or dihydro benzo furyl, (g) works as R
6/Be carbocylic radical-(C
1-6Alkyl)-time, it is not cyclohexyl-(C
1-3Alkyl)-, (h) work as R
6/Be aryl-(C
1-6Alkyl)-during O-, it is not phenyl-(CH
2)-O-and (i) work as R
/During for hydrogen, R
//Be not phenyl, pyridyl, indanyl, C
4Alkyl, cyclohexyl (cyclohenyl), naphthyl, phenyl-CH
2-, the benzotriazole base, and work as R
/During for methyl, R
//It is not cyclopropyl-phenyl;
-R
6//Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-; And
-R
6/ //Represent C
1-18Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-, precondition is to work as R
6/ //During for aryl, it is not an aminomethyl phenyl.
Preferred structure formula (Ib) examples for compounds is and above-mentioned preferred structure formula (Ib) compound defines identical compound, wherein:
-R
5/Represent C
2-6Alkyl, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-X
/, precondition is to work as R
5/During for heteroaryl, it is not quinaldine based or pyrazinyl, and works as R
5/Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH
2)
x-, wherein x is 1 or 2;
-R
6/Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-, precondition is that (a) works as R
6/During for aryl, it is not a phenyl or naphthyl, (b) works as R
6/During for heteroaryl, it is not thienyl, pyrryl, pyrazinyl, quinaldine based, indyl, benzofuryl or benzothienyl, (c) works as R
6/Be aryl-(C
1-6Alkyl)-time, it is not benzo-thiophene-(CH
2)-, (d) works as R
6/Be heteroaryl-(C
1-6Alkyl)-time, it is not indyl-(CH
2)
x-, wherein x is 1-3, (e) works as R
/During for hydrogen, R
//Be not phenyl, pyridyl, indanyl or benzotriazole base;
-R
6//Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-; And
-R
6/ //Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-, precondition is to work as R
6/ //During for aryl, it is not an aminomethyl phenyl.
Further the compound of preferred structure formula (Ib) is these compounds, wherein:
-R
5/Be C
3-6Alkyl, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl), aryl-C (O)-C (O)-, heteroaryl-C (O)-C (O)-, carbocylic radical-C (O)-C (O)-, heterocyclic radical-C (O)-C (O)-or-X
/
-X
/For-CO-R
6/,-S (O)-R
6//Or-S (O)
2-R
6/ //
-R
6/Be C
1Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl, heterocyclic radical, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-;
-R
6//Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-3Alkyl, heterocyclic radical, heteroaryl, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-; And
-R
6/ //Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-, aryl-(C
1-6Hydroxyalkyl)-, heteroaryl-(C
1-6Hydroxyalkyl)-, carbocylic radical-(C
1-6Hydroxyalkyl)-, heterocyclic radical-(C
1-6Hydroxyalkyl)-, aryl-(C
1-6Alkyl)-O-, heteroaryl-(C
1-6Alkyl)-O-, carbocylic radical-(C
1-6Alkyl)-O-, heterocyclic radical-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl), carbocylic radical-(C
1-6Alkyl)-or heterocyclic radical-(C
1-6Alkyl)-.
Further preferred structure formula (Ib) examples for compounds is and the identical compound of further preferred structure formula (Ib) compound definition, wherein:
-R
5/Be C
2-6Alkyl, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl), heterocyclic radical-(C
1-6Alkyl) or-X
/
-X
/For-CO-R
6/,-S (O)-R
6//Or-S (O)
2-R
6/ //
-R
6/Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl or heterocyclic radical;
-R
6//Represent C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, carbocylic radical-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-; And
-R
6/ //Be C
1-6Alkyl, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
3-6Cycloalkyl, heterocyclic radical, C
3-6Cycloalkyl-(C
1-6Alkyl)-, heterocyclic radical-(C
1-6Alkyl)-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, heterocyclic radical, aryl, heteroaryl, aryl-(C
1-6Alkyl)-or heteroaryl-(C
1-6Alkyl)-.
In described further preferred construction formula (Ib) compound, preferred R
5/, R
6/, R
6//And R
6/ //Cycloalkyl in the group, heterocyclic radical and carbocylic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group,
In described further preferred construction formula (Ib) compound, more preferably R
/And R
//Cycloalkyl in the group, heterocyclic radical, carbocylic radical, aryl and heteroaryl moieties are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro and cyano group.
In described further preferred construction formula (Ib) compound, preferred R
5/, R
6/, R
6//And R
6/ //Cycloalkyl in the group, heterocyclic radical and carbocylic radical part are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro and cyano group,
In described further preferred construction formula (Ib) compound, more preferably R
/And R
//Cycloalkyl in the group, heterocyclic radical, carbocylic radical, aryl and heteroaryl moieties are not substituted or are selected from following substituting group by 1-3 and replace: halogen, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro and cyano group.
Especially preferred novel cpd of the present invention is an acceptable salt on following structural formula (Ic) compound and its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be methyl or chlorine;
-n is 0 or 1;
-R
4Be hydrogen or methyl;
-R
5' be phenyl-CH
2-thienyl-C (O)-C (O)-or-X ';
-X ' is-CO-R
6' ,-CONR ' R " ,-S (O)
2R
6' " or-S (O)
2-NR
/R
//And-R
6' be C
1Alkyl, C
1-4Alkoxyl group, benzo dioxine base, 9H-fluorenes-9-ketone group, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, cyclopentyl, piperazinyl, piperidyl, morpholinyl, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
2Alkyl)-O-or 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group;
-R
6' " be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, 9H-fluorenes-9-ketone group, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-CH
2-CH (OH)-, phenyl-CH (OH)-CH
2-, phenyl-(C
1-2Alkyl)-O-or 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group;
-each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-; And
-each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH
2)-, be wherein:
R
1Be not substituted in the phenyl moiety in the group or replaced: fluorine, chlorine, C by a following substituting group
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl or C
1-2Halogenated alkoxy;
R
5', R
6' and R
6' " aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-6Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R
/,-S (O)
2R
/With-S (O)
2NH
2, R wherein
/Represent C
1-2Alkyl;
R
5', R
6' and R
6' " heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Haloalkyl and two (C
1-2Alkyl) amino;
R
6' " heterocyclic radical in the group and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro;
R
/And R
//In aryl, heteroaryl and the carbocylic radical part is not substituted or be selected from following substituting group by 1-2 replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro; And
R
/And R
//In aryl, heteroaryl and the carbocylic radical part is not substituted or be selected from following substituting group by 1-2 replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro, precondition are that structural formula (Ic) compound is not N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide.
The example of especially preferred novel cpd of the present invention is an acceptable salt on following structural formula (Ic ') compound and its pharmacology,
Wherein:
-R
1Be phenyl or methyl;
-R
3Be chlorine;
-n is 0 or 1;
-R
5/Be phenyl-CH
2-, furyl-CH
2-or-X
/
-X
/For-CO-R
6/,-CO-NR
/R
//,-S (O)
2-R
6/ //Or-S (O)
2-NR
/R
//
-R
6/Be C
1-4Alkyl; The 2-thienyl; Furyl; Pyridyl; Cyclopentyl; Cyclohexyl; The 3-benzothienyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, for example N-piperazinyl;
-R
6/ //Be C
1-4Alkyl; Phenyl; Thienyl; Furyl; Pyridyl; Cyclopentyl; Cyclohexyl; Benzothienyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Or piperazinyl, for example N-piperazinyl;
-each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-, and
-each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-,
R
5And R
6/Phenyl in the group, thienyl, furyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, isoxazolyl, piperidyl, morpholinyl and piperazinyl part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro,
R
6/ //Thienyl in the group, furyl, pyridyl, cyclopentyl, cyclohexyl, benzothienyl, dihydro benzo furyl, isoxazolyl, piperidyl, morpholinyl and piperazinyl part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro,
R
6/ //Phenyl moiety in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
2-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro,
R
/And R
//Cyclohexyl in the group and cyclopentyl part are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent,
R
/And R
//Phenyl moiety in the group is not substituted or is replaced by a methoxyl group or nitro substituent, and
R
/And R
//Phenyl in the group, cyclohexyl and cyclopentyl part are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent.
Further preferred novel cpd of the present invention is an acceptable salt on structural formula (Ic) compound and its pharmacology, wherein:
-R
5/For-X
/
-X
/For-CO-R
6/,-CO-NR
/R
//,-S (O)
2-R
6/ //Or-S (O)
2-NR
/R
//
-R
6/Be C
1-4Alkyl; Pyridyl; Cyclopentyl; Cyclohexyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, for example N-piperazinyl;
-R
6/ //Be C
1-4Alkyl; Pyridyl; Cyclopentyl; Cyclohexyl; Dihydro benzo furyl; Isoxazolyl; Piperidyl, for example N-piperidyl; Morpholinyl, for example N-morpholinyl; Piperazinyl, for example N-piperazinyl;
-each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl or cyclopentyl; And
-each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, cyclohexyl, cyclopentyl, phenyl or phenyl-CH
2-,
R
6/And R
6/ //Pyridyl in the group, cyclopentyl, cyclohexyl, dihydro benzo furyl, isoxazolyl, piperidyl, morpholinyl, piperazinyl part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Haloalkyl and nitro, and
R
/, R
//, R
/And R
//Phenyl in the group, cyclohexyl and cyclopentyl part are not substituted or are replaced by a fluorine, chlorine, methyl, methoxyl group or nitro substituent.
Further preferred novel cpd of the present invention is an acceptable salt on following structural formula (Id) compound and its pharmacology,
R wherein
6* be aryl, it is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, nitro, cyano group, formamyl, (a C
1-6Alkyl) formamyl, two (C
1-6Alkyl) formamyl, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/,-CONR
/R
//,-S (O) R
/,-S (O)
2R
/,-S (O) NR
/R
//,-S (O)
2NR
/R
//-NH-S (O)
2R
/Or-NH-CO-R
/, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-6Alkyl, precondition are R
6* be not the 4-chloro-phenyl-.
In structural formula (Id) compound, R
6* be generally phenyl, it is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, C
1-6Halogenated alkoxy, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino, nitro, cyano group ,-CO
2R
/,-S (O) R
/,-S (O)
2R
/With-S (O)
2NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen or C
1-4Alkyl, precondition are R
6* be not the 4-halogenophenyl.
In structural formula (Id) compound, preferred R
6* be phenyl, it is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1-4Halogenated alkoxy, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro ,-CO
2R
/,-S (O)
2R
/With-S (O)
2NH
2, R wherein
/Represent C
1-2Alkyl, precondition are R
6* be not the phenyl-monohalide base.
In structural formula (Id) compound, more preferably R
6* be phenyl, it is not substituted or is selected from following substituting group by 1-2 and replaces: C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl, C
1-2Halogenated alkoxy and nitro.
Acceptable salt on compound that further preferred novel cpd of the present invention is a following structural formula (Ie) and the pharmacology thereof,
Wherein R ' * is an aryl, and it is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, C
1- 4Halogenated alkoxy and nitro.
In structural formula (Ie) compound, preferred R ' * is a phenyl, and it is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio, C
1-2Haloalkyl and nitro.
In structural formula (Ie) compound, more preferably unsubstituted phenyl of R ' * or the phenyl that replaced by a fluorine, chlorine or bromine substituting group.
The invention still further relates to that acceptable salt is used for the treatment of in the method for human or animal body on novel cpd defined above or its pharmacology.The invention still further relates to the medicinal compositions that comprises acceptable diluent on novel cpd defined above and the pharmacology or carrier.Preferred medicinal compositions comprises acceptable salt on the pharmacology of novel cpd defined above.The definition of acceptable salt is the same on the pharmacology.Novel cpd of the present invention gives in mode defined above usually, and described compound is prepared at administering mode defined above usually.
Preferred medicinal compositions comprises the optically active isomer of novel cpd of the present invention.Therefore, for example, the novel cpd of the present invention that preferably only contains a chiral centre comprises the R enantiomer of pure form substantially, the S enantiomer of pure form and the enantiomeric mixture that comprises excessive R enantiomer or excessive S enantiomer substantially.Especially preferably the medicinal compositions that comprises the The compounds of this invention that is substantially pure optically active isomer.For fear of ambiguity, if desired, novel cpd of the present invention can solvate forms use.
The following example illustrates the present invention.Yet they do not limit the present invention in any way.In this, importantly understand the fc-specific test FC that embodiment partly uses and only be used to show anti-RSV activity, many tests can be used to measure the anti-RSV activity of given compound, thereby the negative findings in any one concrete mensuration is not conclusive.
Embodiment
In this section, all temperature are with a ℃ expression.Flash column chromatography carries out with Merck 9385 silicon-dioxide.Solid-Phase Extraction (SPE) chromatography is carried out with gradient elution progressively under the 15mmHg vacuum with Jones chromatography (Si) post.Tlc (TLC) is carried out on plastic plate.
The LC-MS condition
Sample moves on MicroMass ZMD with detecting sun-anionic electron spray(ES) simultaneously.
Post: YMC-PACK FL-ODS AQ, 50 * 4.6mm I.D S-5 μ m.
Gradient: 95: 5-5: 95 v/v H
2O/CH
3CN+0.05% formic acid (4.0 minutes) continues 3 minutes, gets back to 95: 5 v/v H
2O/CH
3CN+0.05% formic acid (0.2 minute) keeps 95: 5 v/vH
2O/CH
3CN+0.05% formic acid (3 minutes).
Detect and survey: PDA 250-340nm.
Flow velocity: 1.5ml/ minute
Preparation intermediate 1
Benzotriazole-1-base-benzyloxycarbonyl amino-acetate
The mixture of oxoethanoic acid monohydrate (4.60g), benzotriazole (5.95g) and benzyl carbamate (7.55g) was refluxed 18 hours in being heated in toluene (100ml) under the Dean-Stark condition.Then mixture is cooled to room temperature, filters and collect the gained throw out.Use diethyl ether recrystallization gained throw out then, obtain Off-white solid (11.66g)
1H NMR(d6 DMSO，δ)5.07(q+s，3H)7.25(d，1H)7.3-7.63(m，6H)7.92-8.10(m，2H)9.32(d，1H)
LC/MS measured value ES-=325RT=4.68 minute
Preparation intermediate 2
(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzyl carbamate
Cooling (0 ℃) solution that intermediate 1 (11.6g) is dissolved in dry THF (100ml) stirs under nitrogen atmosphere, splashes into the solution-treated that oxalyl chloride (4.4g) is dissolved in dry methylene chloride (50ml) then, then handles with dry dimethyl formamide (2ml).Stir the gained mixture 2 hours, and used 2-(amino-phenyl)-phenyl-ketone (6.1g) and N-methylmorpholine (7.07g) to be dissolved in the solution-treated 30 minutes of dry THF (50ml) then.Reaction mixture is warming up to room temperature, removes by filter inorganic salt.Mother liquor is handled and lasting the stirring 18 hours with the methanol solution (100ml) of 7M ammonia.Evaporating solvent, resistates distributes between ethyl acetate and 1M sodium hydroxide.The extract of evaporation drying is dissolved in raw oil the acetate (200ml) that comprises ammonium acetate (13.4g).Mixture was in stirring at room 18 hours.Evaporating solvent is suspended in ethyl acetate with resistates: diethyl ether (1: 3) (200ml) in.Add 1M sodium hydroxide until pH=8, mixture is cooled to 0-5 ℃ then, filter and collect the solid (6.94g) that produces.
1H NMR(d6 DMSO，δ)5.05(s，1H)5.09(m，2H)7.25-7.69(m，14H)8.38(d，1H)10.85(s，1H)
LC/MS measured value ES+=386 RT=5.46 minute
Preparation intermediate 3
3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
Intermediate 2 (1.07g) is dissolved in 48% hydrobromic acetate (30ml) post-heating to 70 ℃ 30 minutes.Cooling mixture is with diethyl ether (30ml) dilution.Filter and collect the yellow solid that forms.Then this material is distributed between ethyl acetate and 1M solution of potassium carbonate.Evaporate behind the dry extract, the oil that obtains is ground with diethyl ether, obtain Off-white solid (0.35g).
1H NMR(d6 DMSO，δ)4.25(s，1H)7.17-7.66(m，9H)10.65(brs，1H)
LC/MS RT=3.23 minute, but do not have associating molion.
Preparation intermediate 4
[benzotriazole-1-base (2-benzoyl-4-chloro-phenyl amino formyl radical)-methyl]-benzyl carbamate
By the chloride of acid of the method for introducing previously with 5g intermediate 1 preparation intermediate 1.The chloride of acid that makes is dissolved in the stirred solution of THF (40ml) in 0 ℃ of adding (2-amino-5-chloro-phenyl)-phenyl-ketone (3.48g) and N-methylmorpholine (3.1g).Then mixture is warming up to room temperature, stirred 1 hour.Remove by filter throw out, obtain the gumminess solid behind the evaporating solvent, directly use to need not to purify or characterize.
Preparation intermediate 5
(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzyl carbamate
The methanol solution (100ml) that intermediate 4 is dissolved in 7M ammonia was in stirring at room 5 hours.Evaporating solvent, resistates distributes between ethyl acetate and 1M sodium hydroxide.The organic layer of evaporation drying is dissolved in resistates the acetate (200ml) that comprises ammonium acetate (5.8g).The gained mixture is in stirring at room 18 hours, evaporating solvent then.Water-soluble and the ethyl acetate with resistates, with sodium hydroxide with pH regulator to about 8.The organic extract of evaporation drying is used the diethyl ether grinding residues, obtains beige solid (3.27g).
LC/MS measured value ES+=420,422 (C
23H
13ClN
3O
3=419.5)
Preparation intermediate 6
3-amino-7-chloro-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
The solution that intermediate 5 (3.25g) is dissolved in the acetate (85ml) of 45% hydrogen bromide be heated to 70 ℃ 2 hours.Cooling mixture dilutes with diethyl ether then.Filter the hydrobromide salt that obtains title compound, dry back obtains bright yellow solid (2.7g)
NMR(δ，d6 DMSO)5.18(d，1H)7.32(d，1H)7.40(d，1H)7.47-7.53(m，5H)7.77(dd，1H)9.07(brs，2H)11.41(s，1H)
Preparation intermediate 7
[(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-base formamyl)-phenyl-methyl]-t-butyl carbamate.
With intermediate 3 (34.9g), (S)-2-t-butoxycarbonyl amino-3-phenyl-propionic acid (55.3g), triethylamine (100ml) and O-benzotriazole-1-base-N, N, N ', the solution that N '-tetramethyl-urea hexafluorophosphate (116g) is dissolved in methylene dichloride (1000ml) stirred 18 hours under room temperature and nitrogen atmosphere.Evaporating solvent then, resistates distributes between 10% citric acid solution and ethyl acetate.Organic phase is further washed after drying (MgSO with 2M sodium hydroxide, water and salt solution
4).The evaporation organic phase obtains oily matter, need not to purify to be used for following step.
LC/MS RT=5.98 minute, measured value ES
+=498
1H NMR(DMSO，δ)1.29(s，9H)2.72-2.84(m，1H)，3.05-3.18(m，1H)，4.32-4.44(m，1H)，5.20-5.25(m，1H)，6.97-7.05(m，1H)，7.16-7.68(m，14H)，9.17-9.21(d，1H)，10.90(s，1H)。
Preparation intermediate 8
2-amino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-phenyl-ethanamide.
Ethyl acetate (1L) cooling (10 ℃) solution with the disposable adding HCl of intermediate 7 (81.94g) (34g).Reactant stirred 1 hour in this temperature, be warming up to 20 ℃ after restir 2 hours.Cool off reactant to 0 ℃ then, add entry (300mL) with the speed that keeps temperature to be lower than 10 ℃.(2 * 150mL) washing water layers return water layer to reaction flask to use ethyl acetate then.Reactant is cooled to 0 ℃ once more, adds strong aqua until pH=9.0 with the speed that keeps temperature to be lower than 5 ℃.(5 * 150mL) washing reaction things, the organic extract with salt solution (100mL) washing merges with evaporating solvent after the dried over mgso, produces yellow oil with ethyl acetate.The ethyl acetate solution of yellow oil and 5% methyl alcohol is stirred fast up to forming the heavy-gravity white depositions.Filtering precipitate, the revaporization mother liquor.The natural gum of remnants and the ethyl acetate of 5% methyl alcohol are stirred once more up to forming the thickness throw out.This program is repeated several times.By TLC (SiO
2, DCM: EtOH: NH
3, 200: 8: 1) and excessive to throw out analysis each time with the evaluation diastereomer.Every kind of diastereomer that each batch is pure or pure is substantially placed on one side, mixture at first is dissolved in the dichloromethane mixture of 5% methyl alcohol, returns the settling step of evaporation stage then.Each batch comprised pure or pure substantially required diastereomer (R
f=0.25, higher spot) merges and in the ethyl acetate of 5% methyl alcohol, stir and made slurries in 10 minutes, filter then, produce required diastereomer (＞99%d.e.) white powder pure sample product (26.1g).
LC/MS RT=3.83 minute measured value ES
+=399
1H NMR(CDCl
3，δ)1.36(bs，2H)，2.72(dd，1H，)，3.24(dd，1H，)，3.63(dd，1H，)，5.46(d，1H，)，7.44-7.03(m，14H)，8.43(s，1H)，8.79(d，1H，)。
Preparation intermediate 9
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-phenyl-2-(3-phenyl-thioureido)-ethanamide
The solution that intermediate 8 (26.1g) is dissolved in methylene dichloride (500ml) is handled with isocyanide sulfenyl-benzene (14.7g), and mixture was in stirring at room 18 hours.Evaporation removes and desolvates and excess reagent, and resistates is dissolved in methylene dichloride, collects with gasoline dilution after-filtration, obtains colorless solid (36.1g)
LC/MS measured value ES
-=532RT=5.47 minute
1H NMR(CDCl
3，δ)3.83-5.0(m，2H)，5.58-6.87(m，2H)，6.68(d，1H)，6.89-7.40(m，19H)，7.56(d，1H)，8.20(bs，1H)，9.52(bs，1H)。
Preparation intermediate 10
(S)-and 3-amino-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
(24g) is heated to 50C with intermediate 9, uses trifluoroacetic acid (64ml) to handle then.Stirred the mixture fast 40 minutes, and be evaporated to driedly then, obtain yellow oil.This material is purified through silica gel chromatography.Use methylene dichloride: methyl alcohol: acetate: water; 90: 10: 1: 1 wash-out obtained the acetate (13.1g) of the described amine of light yellow spumescence.
LC/MS RT=3.64 minute measured value ES
+=252
1H NMR(CDCl
3，δ)2.17(s，3H)4.68(brs，1H)6.98-7.47(m，9H)9.56(brs，1H)10.68(brs，1H)
The free alkali of this material can followingly be emanated.This material of 0.5g is dissolved in methylene dichloride (1ml) back adding 0.880 ammoniacal liquor (1ml) makes its alkalization, filter and collect after drying, obtain colourless throw out (380mg)
Embodiment 1
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide
The solution that intermediate 3 (300mg) is dissolved in pyridine (5ml) is handled with diacetyl oxide (183mg).Mixture evaporates after 1.5 hours in stirring at room.Resistates distributes between water and methylene dichloride.Use the sherwood oil grinding residues behind the extract of evaporation drying, obtain colorless solid title compound (231mg)
LC/MS RT=3.82 minute measured value ES-=292
NMR(δ，d6 DMSO)1.99(s，3H)5.25(d，1H)7.21-7.66(m，9H)9.06(s，1H)10.81(s，1H)
Embodiment 2
1,1-diethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
(100mg) is dissolved in the methylene dichloride that comprises diisopropylethylamine (62mg) with intermediate 3: dimethyl formamide (9: 1; Solution 2ml) is handled with diethylamino formyl chloride (0.05ml).The gained mixture was stirred 18 hours under room temperature and nitrogen atmosphere, between water and methylene dichloride, distribute then.The evaporation organic extract, resistates is purified through silica gel SPE post.With the eluent ethyl acetate that contains 10% methyl alcohol, obtain colorless solid title compound (34mg).
LC/MS RT=4.37 minute measured value ES+=351
1H NMR(d6DMSO，δ)1.11(t，6H)2.50(br，4H)5.20(d，1H)6.83(d，1H)7.20-7.66(m，9H)10.78(brs，1H)
Embodiment 3
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide
This material only is to use propionyl chloride (0.035ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (11mg)
LC/MS RT=4.03 minute measured value ES+=308
1H NMR(d6 DMSO，δ)1.03(t，3H)2.31(q，2H)5.26(d，1H)7.20-7.67(m，9H)8.94(d，1H)10.80(s，1H)
Embodiment 4
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-butyramide
This material only is to use butyryl chloride (0.041ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (31mg)
LC/MS RT=4.31 minute measured value ES+=320
1H NMR(d6 DMSO，δ)0.90(brt，3H)1.55(br，2H)2.27(brq，2H)5.26(brd，1H)7.20-7.70(m，9H)8.95(brd，1H)10.80(s，1H)
Embodiment 5
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyramide
This material only is to use isobutyryl chloride (41ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (35mg)
LC/MS RT=4.30 minute measured value ES+=322
1H NMR (d6 DMSO, δ) 1.03 (d, 6H) 2.72 (septet, 1H) 5.23 (d, 1H) 7.20-7.68 (m, 9H) 8.90 (d, 1H) 10.77 (brs, 1H)
Embodiment 6
2,2-dimethyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide
This material only is to use 2,2-dimethyl propylene acyl chlorides (0.049ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (22mg)
LC/MS RT=4.74 minute measured value ES+=336
1H NMR(d6 DMSO，δ)1.20(s，9H)5.23(d，1H)7.20-7.68(m，9H)8.22(d，1H)10.80(br，1H)
Embodiment 7
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclopentane formamide
This material only is to use pentamethylene carbonyl chloride (0.048ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (40mg).
LC/MS RT=4.81 minute measured value ES+=348
1H NMR(d6 DMSO，δ)1.48-1.90(m，8H)2.89(m，1H)5.24(d，1H)7.20-7.68(m，9H)8.90(d，1H)10.77(brs，1H)
Embodiment 8
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclohexane carboxamide
This material only is to use hexanaphthene carbonyl chloride (0.053ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (57mg).
LC/MS RT=5.54 minute measured value ES+=362
1H NMR(d6 DMSO，δ)1.10-1.43(5H)1.60-1.82(m，5H)2.44(m，1H)5.22(d，1H)7.20-7.67(m，9H)8.81(d，1H)10.75(s，1H)
Embodiment 9
3-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 3-methoxyl group-Benzoyl chloride (0.056ml) with the method preparation that embodiment 1 introduces.Obtain colorless solid title compound (23mg).
LC/MS RT=5.10 minute measured value ES+=386
1H NMR(d6 DMSO，δ)3.84(s，3H)5.51(d，1H)7.11-7.71(m，13H)9.51(d，1H)10.87(s，1H)
Embodiment 10
4-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 4-methoxyl group-Benzoyl chloride (68mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (60mg).
LC/MS RT=5.00 minute measured value ES+=386
1H NMR(d6 DMSO，δ)3.83(s，3H)5.50(d，1H)7.02(d，2H)7.21-7.79(m，9H)8.02(d，2H)9.28(d，1H)10.85(s，1H)
Embodiment 11
2-methoxyl group N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 2-methoxyl group-Benzoyl chloride (0.059ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (69mg).
LC/MS RT=5.12 minute measured value ES+=386
1H NMR(d6 DMSO，δ)4.05(s，3H)5.44(d，1H)7.11(t，1H)7.24-7.70(m，11H)7.97(dd，1H)9.50(d，1H)10.97(s，1H)
Embodiment 12
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-trifluoromethyl-benzamide
This material only is to use 3-trifluoromethyl-Benzoyl chloride (0.06ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (88mg).
LC/MS RT=5.27 minute measured value ES+=424
1H NMR(d6 DMSO，δ)5.41(d，1H)7.22-7.82(m，13H)9.71(d，1H)10.86(brs，1H)
Embodiment 13
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use Benzoyl chloride (0.046ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (41mg).
LC/MS RT=4.96 minute measured value ES+=356
1H NMR(d6 DMSO，δ)5.51(d，1H)7.22-7.70(m，12H)8.03(m，2H)9.44(d，1H)10.87(s，1H)
Embodiment 14
Thiophene-2-carboxylic acid (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diazepine-3-yl)-3-acid amides
This material only is to use thiophene-2-carbonyl chloride (0.043ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (81mg).
LC/MS RT=4.87 minute measured value ES+=362
1H NMR(d6 DMSO，δ)5.46(d，1H)7.19-7.82(m，11H)8.20(m，1H)9.57(d，1H)10.88(s，1H)
Embodiment 15
Furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use furans-2-carbonyl chloride (0.039ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (17mg).
LC/MS RT=4.53 minute measured value ES+=346
1H NMR(d6 DMSO，δ)5.42(d，1H)6.68(m，1H)7.24-7.70(m，10H)7.90(m，1H)9.02(d，1H)10.95(s，1H)
Embodiment 16
Piperidines-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use piperidines-1-carbonyl chloride (0.049ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (34mg).
LC/MS RT=4.47 minute measured value ES+=363
1H NMR(d6 DMSO，δ)1.40-1.62(m，6H)3.36-3.42(m，4H)5.21(d，1H)7.20-7.67(m，10H)10.76(s，1H)
Embodiment 17
Morpholine-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use morpholine-4-carbonyl chloride (0.046ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (22mg).
LC/MS RT=3.88 minute measured value ES+=365
1H NMR(d6 DMSO，δ)3.36-3.42(m，4H)3.55-3.62(m，4H)5.21(d，1H)7.22-7.67(m，10H)10.80(s，1H)
Embodiment 18
4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 4-nitro-Benzoyl chloride (74mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (90mg).
LC/MS RT=5.25 minute measured value ES+=401
1H NMR(d6 DMSO，δ)5.50(d，1H)7.23-7.70(m，9H)8.25(d，2H)8.33(d，2H)9.94(d，1H)10.92(s，1H)
Embodiment 19
3-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 3-nitro-Benzoyl chloride (74mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (94g).
LC/MS RT=5.25 minute measured value ES+=401
1H NMR(d6 DMSO，δ)5.51(d，1H)7.22-7.85(m，10H)8.40-8.48(m，2H)8.86m，1H)10.06(d，1H)10.91(s，1H)
Embodiment 20
4-methyl-piperazine-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use 4-methyl isophthalic acid-piperazine carbonyl chloride (79mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (35mg).
LC/MS RT=3.29 minute measured value ES-=376
1H NMR(d6 DMSO，δ)2.19(s，3H)2.28(m，4H)3.40(m，4H)5.19(d，1H)7.19-7.65(m，10H)10.75(s，1H)
Embodiment 21
3,4-two chloro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 3,4-two chloro-Benzoyl chlorides (83mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (42mg).
LC/MS RT=3.29 minute measured value ES+=424,426
1H NMR(d6 DMSO，δ)5.48(d，1H)7.22-7.70(m，9H)7.78(d，1H)7.98(dd，1H)8.31(d，1H)9.82(d，1H)10.91(s，1H)
Embodiment 22
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-trifluoromethyl-benzamide
This material only is to use 2-trifluoromethyl-Benzoyl chloride (83mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (90mg).
LC/MS RT=5.47 minute measured value ES+=424
1H NMR(d6DMSO，δ)5.41(d，1H)7.25-7.83(m，13H)9.81(d，1H)10.93(s，1H)
Embodiment 23
4-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 4-bromo-Benzoyl chloride (87mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (159mg).
LC/MS RT=5.76 minute measured value ES+=434,436
1H NMR(d6 DMSO，δ)5.5(d，1H)7.23-7.68(m，9H)7.72(d，2H)7.98(d，2H)9.7(d，1H)10.94(s，1H)
Embodiment 24
2-methyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 2-methyl-Benzoyl chloride (62mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (113mg).
LC/MS RT=5.29 minute measured value ES+=370
1H NMR(d6 DMSO，δ)2.42(s，3H)5.45(d，1H)7.23-7.55(m，12H)7.65(dt，1H)9.39(d，1H)10.90(s，1H)
Embodiment 25
2-chloro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 2-chloro-Benzoyl chloride (70mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (108mg).
LC/MS RT=5.28 minute measured value ES+=390,392
1H NMR(d6DMSO，δ)5.43(d，1H)7.26-7.7(m，13H)9.71(d，1H)10.94(s，1H)
Embodiment 26
2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 2-nitro-Benzoyl chloride (74mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (50mg).
LC/MS RT=4.94 minute measured value ES+=401
1H NMR(d6DMSO，δ)5.42(d，1H)7.25-7.89(m，12H)8.07(d，1H)10.05(d，1H)10.96(s，1H)
Embodiment 27a
2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-benzamide
With intermediate 3 (40mg), 2-methoxyl group-4-nitro-phenylformic acid (47mg), triethylamine (0.07ml) and O-benzotriazole-1-base-N, N, N ', the N '-mixture of tetramethyl-urea hexafluorophosphate (121mg) in dry tetrahydrofuran (3ml) stirred 18 hours under 20 ℃ and nitrogen atmosphere.Then mixture is distributed between solution of potassium carbonate and methylene dichloride.Organic phase is evaporated after by the Hydrophobic glass strainer.Resistates is purified through silica gel SPE post.Earlier use the methylene dichloride wash-out, use methylene dichloride then: ethanol: 0.880 ammoniacal liquor; Earlier with 400 then with 200: 8: 1 wash-outs, the oil of acquisition grinds with diethyl ether, obtains colorless solid title compound (51mg).
LC/MS RT=5.28 minute measured value ES+=431
1H NMR(CDCl
3，δ)4.09(s，3H)5.69(d，1H)7.08-7.49(m，9H)7.80-7.86(m，2H)8.27(s，1H)8.31(s，1H)9.52(d，1H)
Embodiment 27b
(S)-2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material just replaces intermediate 3 with intermediate 10 with the method preparation that embodiment 27 introduces, and obtains colorless solid title compound (37mg)
1H NMR(DMSO，δ)4.13(s，3H)5.44(d，1H)7.29-7.70(m，9H)7.97-8.10.(m，3H)9.63(d，1H)11.05(s，1H)
Embodiment 28
Benzo [b] thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use benzo [b] thiophene-3-carbonyl chloride (39mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (60mg).
LC/MS RT=5.85 minute measured value ES+=412
1H NMR(d6 DMSO，δ)5.57(d，1H)7.27-7.71(m，11H)8.06(m，1H)8.47(m，1H)8.83(s，1H)9.57(d，1H)10.95(s，1H)
Embodiment 29
2,3-dihydro-cumarone-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use 2,3-dihydro-cumarone-5-carbonyl chloride (36mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (75mg).
LC/MS RT=5.16 minute measured value ES+=398
1H NMR(d6 DMSO，δ)3.24(t，2H)4.61(t，2H)5.48(d，1H)6.84(d，1H)7.22-7.95(m，11H)9.25(d，1H)10.89(s，1H)
Embodiment 30
Isoxazole-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use isoxazole-5-carbonyl chloride (26mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (22mg).
LC/MS RT=4.58 minute measured value ES+=347
1H NMR(d6 DMSO，δ)5.44(d，1H)7.23-7.72(m，10H)8.80(d，1H)9.98(d，1H)11.03(s，1H)
Embodiment 31
Benzo [b] thiophene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use benzo [b] thiophene-2-carbonyl chloride (39mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (33mg).
LC/MS RT=5.90 minute measured value ES+=412
1H NMR(d6 DMSO，δ)5.49(d，1H)7.25-7.72(m，11H)7.95-8.07(m，2H)8.56(s，1H)9.92(d，1H)10.96(s，1H)
Embodiment 32
Thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use thiophene-3-carbonyl chloride (29mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (30mg).
LC/MS RT=4.96 minute measured value ES+=362
1H NMR(d6 DMSO，δ)5.47(d，1H)7.23-7.70(m，11H)8.48(m，1H)9.40(d，1H)10.91(s，1H)
Embodiment 33
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Isonicotinamide
This material only is to use different nicotinoyl chlorine hydrochloride (71mg) and super normal triethylamine with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (22mg).
LC/MS RT=3.98 minute measured value ES+=357
1H NMR(d6 DMSO，δ)5.50(d，1H)7.24-7.70(m，9H)7.93(d，2H)8.76(d，2H)9.89(d，1H)10.91(s，1H)
Embodiment 34
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-niacinamide
This material only is to use nicotinoyl chlorine hydrochloride and super normal triethylamine with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (16mg).
LC/MS RT=3.90 minute measured value ES+=357
1H NMR(d6 DMSO，δ)5.51(d，1H)7.23-7.70(m，10H)8.37(ddd，1H)8.75(dd，1H)9.15(d，1H)9.90(d，1H)10.93(s，1H)
Embodiment 35
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Toluidrin
This material only is to use methylsulfonyl chloride (0.031ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (40mg).
LC/MS RT=4.20 minute measured value ES+=330
1H NMR(d6 DMSO，δ)3.13(s，3H)4.81(brd，1H)7.22-7.70(m，9H)8.43(brd，1H)10.95(brs，1H)
Embodiment 36
Propane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-sulphonamide
This material only is to use propane-1-SULPHURYL CHLORIDE (0.054ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (56mg).
LC/MS RT=4.79 minute measured value ES+=358
1H NMR(d6 DMSO，δ)1.03(t，3H)1.84(m，2H)3.14(t，2H)4.79(d，1H)7.23-7.69(m，9H)8.49(d，1H)10.94(s，1H)
Embodiment 37
Butane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-sulphonamide
This material only is to use butane-1-SULPHURYL CHLORIDE (0.062ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (30mg).
LC/MS RT=5.18 minute measured value ES+=372
1H NMR(d6 DMSO，δ)0.93(t，3H)1.44(m，2H)1.80(m，2H)3.14(t，2H)4.78(brd，1H)7.21-7.68(m，9H)8.47(brd，1H)10.94(brs，1H)
Embodiment 38
2-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzsulfamide
This material only is to use 2-bromo-benzene sulfonyl chloride (122mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (137mg).
LC/MS RT=5.53 minute measured value ES+=470,472
1H MR(d6 DMSO，δ)4.95(s，1H)7.03-7.71(m，12H)7.88(m，1H)8.22(m，1H)8.70(br，1H)11.04(s，1H)
Embodiment 39
3-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzsulfamide
This material only is to use 3-bromo-benzene sulfonyl chloride (122mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (90mg).
LC/MS RT=5.63 minute measured value ES+=470,472
1H NMR(d6 DMSO，δ)4.81(s，1H)6.89(m，2H)7.20-7.70(m，9H)7.82(m，1H)7.94(m，1H)9.3(br，1H)10.97(s，1H)
Embodiment 40
4-bromo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzsulfamide
This material only is to use 4-bromo-benzene sulfonyl chloride (122mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (130mg).
LC/MS RT=5.66 minute measured value ES+=470,472
1H NMR(d6 DMSO，δ)4.80(brd，1H)6.75(m，2H)7.20-7.70(m，7H)7.78-7.91(m，4H)9.40(brd，1H)10.95s，1H)
Embodiment 41
2-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzsulfamide
This material only is to use 2-fluoro-benzene sulfonyl chloride (93mg) with the method preparation that embodiment 1 introduces.Obtain colorless solid title compound (140mg).
LC/MS RT=5.26 minute measured value ES+=410
1H NMR(d6 DMSO，δ)4.94(d，1H)7.07(m，2H)7.23-7.97(m，11H)9.36(d，1H)10.97(s，1H)
Embodiment 42
3-(2-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
The solution that intermediate 3 (50mg) and (triacetyl oxygen base) sodium borohydride (106mg) is dissolved in methylene dichloride (6ml) and acetate (1ml) is handled with 2-nitro-phenyl aldehyde (45mg).The gained mixture stirred under nitrogen atmosphere 18 hours.The careful saturated sodium bicarbonate solution that adds is used the dichloromethane extraction mixture.Organic layer evaporates then by the Hydrophobic glass strainer.Resistates is purified through silica gel SPE post.With the gasoline gradient elution of 10-18% ethyl acetate, obtain colorless solid title compound (33mg)
LC/MS RT=4.83 minute measured value ES+=387
1H NMR(d6 DMSO，δ)3.4(br，1H)4.17(brs，1H)4.31(q，2H)7.15-7.95(m，13H)10.74(s，1H)
Embodiment 43
3-(3-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
This material only is to use 3-nitro-phenyl aldehyde (45mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (32mg).
LC/MS RT=4.95 minute measured value ES+=387
1H NMR(d6 DMSO，δ)3.45(br，1H)4.16(brs，1H)4.23(brm，2H)7.15-7.63(m，10H)7.85(d，1H)8.08(dd，1H)8.30(s，1H)10.76(s，1H)
Embodiment 44
3-(4-nitro-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
This material only is to use 4-nitro-phenyl aldehyde (45mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (33mg).
LC/MS RT=4.88 minute measured value ES+=387
1H NMR(d6 DMSO，δ)3.42(br，1H)4.11-4.30(brm，3H)7.16-7.63(m，9H)7.70(d，2H)8.20(d，2H)10.77(s，1H)
Embodiment 45
3-(2-methoxyl group-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
This material only is to use 2-methoxyl group-phenyl aldehyde (41mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (48mg).
LC/MS RT=4.95 minute measured value ES+=372
1H NMR(d6 DMSO，δ)3.73(s，3H)3.97(q，2H)4.17(s，1H)6.85-6.96(m，2H)7.15-7.63(m，11H)10.72(s，1H)
Embodiment 46
3-(3-methoxyl group-benzylamino)-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
This material only is to use 3-methoxyl group-phenyl aldehyde (41mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (43g).
LC/MS RT=5.03 minute measured value ES+=372
1H NMR(d6 DMSO，δ)3.71(s，3H)3.81-4.18(m，3H)6.74(m，1H)6.80-6.86(m，2H)7.15-7.64(m，10H)10.74(s，1H)
Embodiment 47
5-phenyl-3-(2-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
This material only is to use 2-trifluoromethyl-phenyl aldehyde (52mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (29mg).
LC/MS RT=5.02 minute measured value ES+=410
1H NMR(d6 DMSO，δ)4.18(s，1H)4.23(brs，2H)7.15-7.70(m，12H)7.91(d，1H)10.76(s，1H)
Embodiment 48
5-phenyl-3-(3-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diamino is assorted
-2-ketone
This material only is to use 3-trifluoromethyl-phenyl aldehyde (52mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (34mg).
LC/MS RT=5.28 minute measured value ES-=408
1H NMR(d6 DMSO，δ)4.12(q，2H)4.18(s，1H)7.15-7.78(m，13H)10.74(s，1H)
Embodiment 49
5-phenyl-3-(4-trifluoromethyl-benzylamino)-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
This material only is to use 4-trifluoromethyl-phenyl aldehyde (52mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (25mg).
LC/MS RT=5.27 minute measured value ES-=408
1H NMR(d6 DMSO，δ)4.13(q，2H)4.20(s，1H)7.15-7.70(m，13H)10.76(s，1H)
Embodiment 50
3-[(furans-2-ylmethyl)-amino]-5-phenyl-1,3-dihydro-benzo [e] [1,4] diaza
-2-ketone
This material only is to use 2-furfural (29mg) with the method preparation that embodiment 42 introduces.Obtain colorless solid title compound (56mg).
LC/MS RT=4.07 minute measured value ES+=332
1H NMR(d6 DMSO，δ)3.05(m，1H)3.80-4.13(m，2H)4.18(d，1H)6.19(brs，1H)6.32(brs，1H)7.15-7.65(m，10H)
Embodiment 51
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide
This material only is to use intermediate 6 (57mg) with the method preparation that embodiment 1 introduces.Obtain colorless solid title compound (17mg).
LC/MS RT=4.21 minute measured value ES+=328,330
1H NMR(d6 DMSO，δ)3.34(s，3H)5.26(d，1H)7.28-7.31(m，2H)7.31-7.58(m，5H)7.71(dd，1H)9.14(d，1H)10.96(s，1H)
Embodiment 52
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyramide
This material only is to use intermediate 6 and isobutyl chloride (0.021ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (49mg).
LC/MS RT=4.78 minute measured value ES+=356,358
1H NMR (d6 DMSO, δ) 1.04 (d, 6H) 2.72 (septet, 1H) 5.27 (d, 1H) 7.29-7.55 (m, 7H) 7.71 (dd, 1H) 9.00 (d, 1H) 10.92 (s, 1H)
Embodiment 53
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Toluidrin
This material only is to use intermediate 6 and methylsulfonyl chloride (0.015ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (18mg).
LC/MS RT=4.61 minute measured value ES+=364,366
1H NMR(d6 DMSO，δ)3.13(s，3H)4.85(brd，1H)7.29-7.58(m，7H)7.71(dd，1H)8.46(brd，1H)11.04(brs，1H)
Embodiment 54
Furans-2-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use intermediate 6 and 2-furans carbonyl chloride (0.020ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (50mg).
LC/MS RT=5.07 minute measured value ES+=380,382
1H NMR(d6 DMSO，δ)5.45(d，1H)6.68(m，1H)7.28-7.70(m，7H)7.73(dd，1H)7.91(m，1H)9.15(d，1H)11.07(s，1H)
Embodiment 55
Thiophene-2-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use intermediate 6 and 2 thiophen carbonyl chloride (0.021ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (49mg).
LC/MS RT=5.40 minute measured value ES+=396,398
1H NMR(d6 DMSO，δ)5.49(d，1H)7.22-7.83(m，10H)8.21(dd，1H)9.67(d，1H)11.04(s，1H)
Embodiment 56
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclohexane carboxamide
This material only is to use intermediate 6 and hexanaphthene carbonyl chloride (0.027) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (52mg).
LC/MS RT=5.61 minute measured value ES+=396,398
1H NMR(d6 DMSO，δ)1.2-1.33(m，5H)1.60-1.83(m，5H)2.45(m，1H)5.25(d，1H)7.27-7.73(m，8H)8.93(d，1H)10.92(s，1H)
Embodiment 57
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-methoxyl group-benzamide
This material only is to use intermediate 6 and 2-methoxyl group-Benzoyl chloride (0.030ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (55mg).
LC/MS RT=5.58 minute measured value ES+=420,422
1H NMR(d6 DMSO，δ)4.05(s，3H)5.47(d，1H)7.12(t，1H)7.25-7.61(m，9H)7.72(dd，1H)7.98(dd，1H)9.54(d，1H)11.14(s，1H)
Embodiment 58
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-4-methoxyl group-benzamide
This material only is to use intermediate 6 and 4-methoxyl group-Benzoyl chloride (0.027ml) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (61mg).
LC/MS RT=5.48 minute measured value ES+=420,422
1H NMR(d6 DMSO，δ)3.84(s，3H)5.53(d，1H)7.03(d，2H)7.31-7.59(m，8H)8.04(d，2H)9.39(d，1H)11.01(s，1H)
Embodiment 59
N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-nitro-benzamide
This material only is to use intermediate 6 and 2-nitro-Benzoyl chloride (0.027) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (61mg).
LC/MS RT=5.25 minute measured value ES+=435,437
1H NMR(d6 DMSO，δ)5.45(d，1H)7.36-7.88(m，11H)8.07*d，1H)10.03(d，1H)11.03(s，1H)
Embodiment 60
2-(2-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide
This material only is to use (2-methoxyl group-phenyl)-Acetyl Chloride 98Min. (33mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (13mg).
LC/MS RT=4.98 minute measured value ES+=400
1H NMR(d6 DMSO，δ)3.63(s，2H)3.79(s，3H)5.25(d，1H)6.89-6.99(m，2H)7.20-7.33(m，5H)7.45-7.68(m，6H)9.01(d，1H)10.87(s，1H)
Embodiment 61
2-(3-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide
This material only is to use (3-methoxyl group-phenyl)-Acetyl Chloride 98Min. (33mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (12mg).
LC/MS RT=4.95 minute measured value ES+=400
1H NMR(d6 DMSO，δ)3.62(m，2H)3.75(s，3H)5.23(d，1H)6.78-6.96(m，3H)7.19-7.70(m，10H)9.33(d，1H)10.86(s，1H)
Embodiment 62
2-(4-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide
This material only is to use (4-methoxyl group-phenyl)-Acetyl Chloride 98Min. (33mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (20mg).
LC/MS RT=4.86 minute measured value ES+=400
1H NMR(d6 DMSO，δ)3.58(s，2H)3.73(s，3H)5.22(d，1H)6.87(d，2H)7.23-7.71(m，11H)9.25(d，1H)10.85(s，1H)
Embodiment 63
2-(4-nitro-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-ethanamide
This material only is to use (4-nitro-phenyl)-Acetyl Chloride 98Min. (36mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (18mg).
LC/MS RT=5.03 minute measured value ES+=415
1H NMR(d6 DMSO，δ)3.86(s，2H)5.24(d，1H)7.24-7.70(m，11H)8.19(d，2H)9.53(d，1H)10.88(s，1H)
Embodiment 64
2-(3-nitro-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-ethanamide
This material only is to use (3-nitro-phenyl)-Acetyl Chloride 98Min. (36mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (25mg).
LC/MS RT=5.02 minute measured value ES+=415
1H NMR(d6 DMSO，δ)3.86(s，2H)5.24(d，1H)7.24-7.67(m，10H)7.89(d，1H)8.12(dd，1H)8.26(s，1H)9.53(d，1H)10.89(s，1H)
Embodiment 65
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-(2-trifluoromethyl-phenyl)-ethanamide
This material only is to use (2-trifluoromethyl-phenyl)-Acetyl Chloride 98Min. (41mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (9mg).
LC/MS RT=5.43 minute measured value ES+=438
1H NMR(d6 DMSO，δ)3.92(s，2H)5.26(d，1H)7.24-7.70(m，13H)9.41(d，1H)10.87(s，1H)
Embodiment 66
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-(3-trifluoromethyl-phenyl)-ethanamide
This material only is to use 3-trifluoromethyl-phenyl with the method preparation that embodiment 2 introduces)-Acetyl Chloride 98Min. (41mg).Obtain colorless solid title compound (20mg).
LC/MS RT=5.56 minute measured value ES+=438
1H NMR(d6 DMSO，δ)3.80(s，2H)5.24(d，1H)7.24-7.75(m，13H)9.49(d，1H)10.89(s，1H)
Embodiment 67
N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-(4-trifluoromethyl-phenyl)-ethanamide
This material only is to use (4-trifluoromethyl-phenyl)-Acetyl Chloride 98Min. (41mg) with the method preparation that embodiment 2 introduces.Obtain colorless solid title compound (13mg).
LC/MS RT=5.57 minute measured value ES+=438
1H NMR(d6 DMSO，δ)3.79(s，2H)5.23(d，1H)7.24-7.70(m，13H)9.48(d，1H)10.87(s，1H)
Embodiment 68
1-(2-methoxyl group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
The solution that 2-methoxyl group-aniline (37mg) is dissolved in dry methylene chloride (3ml) is handled with triethylamine (0.04ml) earlier, uses the toluene (0.08ml) of 20% carbonyl chloride to handle then.Mixture adds intermediate 3 (37mg) then in stirring at room 1 hour, continues to stir 18 hours.Mixture distributes between water and ethyl acetate.Organic layer evaporates after by the Hydrophobic glass strainer, and resistates is purified through silica gel SPE post.With the dichloromethane gradient wash-out of 0-5% methyl alcohol, obtain colorless solid title compound (24mg).
LC/MS RT=5.05 minute measured value ES+=401
1H NMR(d6 DMSO，δ)3.86(s，3H)5.21(d，1H)6.78-7.02(m，3H)7.23-7.70(m，9H)7.98(m 1H)8.26(d，1H)8.60(s，1H)10.89(s，1H)
Embodiment 69
1-(2-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-urea
This material only is to use 2-nitro-aniline (21mg) with the method preparation that embodiment 68 introduces.Obtain yellow solid title compound (23mg).
LC/MS RT=5.30 minute measured value ES+=416
1H NMR(d6 DMSO，δ)5.19(d，1H)7.15-7.70(m，11H)8.05(dd，1H)8.17(d，1H)8.82(d，1H)9.68(s，1H)10.95(s，1H)
Embodiment 70
1-(2-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
This material only is to use 2-chloro-aniline (0.017ml) with the method preparation that embodiment 68 introduces.Obtain colorless solid title compound (21mg).
LC/MS RT=5.34 minute measured value ES+=405
1H NMR(d6 DMSO，δ)5.21(d，1H)6.94-7.70(m，12H)8.08(m，1H)8.47(d，1H)8.57(s，1H)10.93(s，1H)
Embodiment 71
1-(4-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Mixture in dry THF (4ml) is handled with triethylamine (0.05ml) with intermediate 3 (30mg) and 4-chloro-1-isocyanato-benzene (0.011ml).Mixture distributes between water and methylene dichloride then in stirring at room 18 hours.Organic layer evaporates after by the Hydrophobic glass strainer.Resistates grinds with sherwood oil, obtains beige solid title compound (34mg).
LC/MS RT=5.45 minute measured value ES+=405
1H NMR(d6 DMSO，δ)5.17(d，1H)7.25-7.70(m，14H)9.18(s，1H)10.95(s，1H)
Embodiment 72
1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-and 3-is right-tolyl-urea
This material only is to use 1-isocyanato-4-methyl-benzene (0.011ml) with the method preparation that embodiment 71 introduces.Obtain Off-white solid title compound (32mg).
LC/MS RT=5.18 minute measured value ES+=385
1H NMR(d6 DMSO，δ)2.22(s，3H)5.19(d，1H)7.05(d，2H)7.23-7.70(m，12H)8.92(s，1H)10.92(s，1H)
Embodiment 73a
1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
This material only is to use 2-fluoro-1-isocyanato-benzene (0.010ml) with the method preparation that embodiment 71 introduces.Obtain beige solid title compound (29mg).
LC/MS RT=5.09 minute measured value ES+=389
1H NMR(d6 DMSO，δ)5.21(d，1H)6.90-7.70(m，12H)8.07(m，2H)8.93(s，1H)10.94(s，1H)
Embodiment 73b
(S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-urea
This material only is to use intermediate 10 with the method preparation that embodiment 73 introduces.Obtain colorless solid title compound (33mg).
1H NMR(DMSO，δ)5.24(d，1H)6.90-7.75(m，12H)8.11-8.17(m，2H)8.95(d，1H)10.95(s，1H)
Embodiment 74
1-(4-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
This material only is to use 4-fluoro-1-isocyanato-benzene (0.010ml) with the method preparation that embodiment 71 introduces.Obtain Off-white solid title compound (26mg).
LC/MS RT=5.02 minute measured value ES+=389
1H NMR(d6 DMSO，δ)5.18(d，1H)7.08(t，2H)7.25-7.70(m，12H)9.07(s，1H)10.94(s，1H)
Embodiment 75a
4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide.
This material only is to use 4-methylsulfonyl-2-methoxyl group-phenylformic acid (69mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (54mg).
1H NMR(DMSO，δ)3.33(s，3H)4.13(s，3H)5.44(d，1H)7.33-7.71(m，11H)8.10(d，1H)9.61(d，1H)11.06(s，1H)
Embodiment 75b
(S)-4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 4-methylsulfonyl-2-methoxyl group-phenylformic acid (46mg) with the method preparation that embodiment 76b introduces.Obtain colorless solid title compound (55mg)
1H NMR(DMSO，δ)3.33(s，3H)4.13(s，3H)5.44(d，1H)7.33-7.71(m，11H)8.10(d，1H)9.61(d，1H)11.06(s，1H)
Embodiment 76a
5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 5-ethanoyl-2-oxyethyl group-phenylformic acid (41mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (45mg)
1H NMR(DMSO，δ)1.59(t，3H)2.59(s，3H)4.42(q，2H)5.44(d，1H)7.30-7.54(m，10H)8.17(ddd，1H)8.58(d，1H)9.71(d，1H)11.07(s，1H)
Embodiment 76b
(S)-5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 5-ethanoyl-2-oxyethyl group-phenylformic acid (83mg) with the method preparation that embodiment 76b introduces.Obtain colorless solid title compound (108mg)
1H NMR(DMSO，δ)1.59(t，3H)2.59(s，3H)4.42(q，2H)5.44(d，1H)7.30-7.54(m，10H)8.17(ddd，1H)8.58(d，1H)9.71(d，1H)11.07(s，1H)
Embodiment 77a
6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 6-fluoro-4H-benzo [1,3] dioxine-8-carboxylic acid (36.2mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (40mg)
1H NMR(DMSO，δ)5.02(s，2H)5.42(d，1H)5.54(s，2H)7.26-7.70(m，12H)9.37(d，1H)11.06(s，1H)
Embodiment 77b
(S)-6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use 6-fluoro-4H-benzo [1,3] dioxine-8-N-(86mg) with the method preparation that embodiment 76b introduces.Obtain colorless solid title compound (65mg)
1H NMR(DMSO，δ)5.02(s，2H)5.42(d，1H)5.54(s，2H)7.26-7.70(m，12H)9.37(d，1H)11.06(s，1H)
Embodiment 78
(S)-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-4-trifluoromethyl-benzamide
This material only is to use 2-methoxyl group-4-trifluoromethyl-phenylformic acid (26mg) with the method preparation that embodiment 76b introduces.Obtain colorless solid title compound (32mg).
1H NMR(DMSO，δ)4.12(s，3H)5.44(d，1H)7.30-7.68(m，11H)8.09(d，1H)9.59(d，1H)11.06(s，1H)
Embodiment 79a
2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 2,4,5-three fluoro-phenylformic acid (39mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (56mg).
1H NMR(DMSO，δ)5.42(d，1H)7.29-7.85(m，11H)9.43-9.47(m，1H)11.02(s，1H)
Embodiment 79b
(S)-2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 2,4,5-three fluoro-phenylformic acid (70mg) with the method preparation that embodiment 75b introduces.Obtain colorless solid title compound (74mg).
1H NMR(DMSO，δ)5.42(d，1H)7.29-7.85(m，11H)9.43-9.47(m，1H)11.02(s，1H)
Embodiment 80a
2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 2-hydroxy-benzoic acid (30mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (40mg).
1H NMR(DMSO，δ)5.47(d，1H)6.92(t，1H)7.00(d，1H)7.34-7.66(m，10H)8.01(dd，1H)10.07(brs，1H)11.01(s，1H)
Embodiment 80b
(S)-2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
This material only is to use 2-hydroxy-benzoic acid (55mg) with the method preparation that embodiment 75b introduces.Obtain colorless solid title compound (63mg).
1H NMR(DMSO，δ)5.48(d，1H)6.95(t，1H)7.04(d，1H)7.28-7.70(m，10H)8.06(dd，1H)9.94(d，1H)11.02(s，1H)11.74(brs，1H)
Embodiment 81a
1H-indoles-7-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use 1H-indole-7-carboxylic acid (35mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (49mg).
1H NMR(DMSO，δ)5.65(d，1H)6.54(m，1H)7.17-8.10(m，13H)9.56(d，1H)
Embodiment 81b
(S)-1H-indoles-7-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use 1H-indole-7-carboxylic acid (64mg) with the method preparation that embodiment 75b introduces.Obtain colorless solid title compound (69mg).
1H NMR(DMSO，δ)5.65(d，1H)6.54(m，1H)7.17-8.10(m，13H)9.56(d，1H)
Embodiment 82a
3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use 3-methoxyl group-naphthalene-2-carboxylic acid (40mg) with the method preparation that embodiment 27 introduces.Obtain colorless solid title compound (73mg).
1H NMR(DMSO，δ)4.15(s，3H)5.51(d，1H)7.37-7.63(m，12H)7.95(d，1H)8.03(d，1H)8.58(s，1H)9.69(d，1H)11.05(s，1H)
Embodiment 82b
(S)-3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
This material only is to use 3-methoxyl group-naphthalene-2-carboxylic acid (80mg) with the method preparation that embodiment 75b introduces.Obtain colorless solid title compound (113mg).
1H NMR(DMSO，δ)4.15(s，3H)5.51(d，1H)7.31-7.68(m，12H)7.95(d，1H)8.03(d，1H)8.58(s，1H)9.71(d，1H)11.08(s，1H)
Following compounds is also with similar above-mentioned method preparation:
Embodiment 83) N-[7-chloro-5-(2-fluoro-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-4-methoxyl group-benzamide
Embodiment 84) 1-(2-fluoro-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 85) 1-(4-methoxyl group-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 86) 1-(3-methyl-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 87) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-(4-trifluoromethyl-phenyl)-urea
Embodiment 88) 4-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 89) 4-methoxyl group-3-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) benzamide
Embodiment 90) 3-methoxyl group-2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 91) 5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) benzamide
Embodiment 92) 5-fluoro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 93) 2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 94) 5-methoxyl group-2-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 95) 3-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 96) 3-(2-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) propionic acid amide
Embodiment 97) 3-(3-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide
Embodiment 98) 3-(4-methoxyl group-phenyl)-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide
Embodiment 99) N-[5-(3-chloro-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-2-methoxyl group-benzamide
Embodiment 100) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-4-methoxyl group-benzamide
Embodiment 101) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-2-nitro-benzamide
Embodiment 102) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-4-nitro-benzamide
Embodiment 103) 4-methoxyl group-N-[2-oxo-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide
Embodiment 104) 2-methoxyl group-N-[2-oxo-5-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide
Embodiment 105) 4-methoxyl group-N-[2-oxo-5-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide
Embodiment 106) 2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 107) 2,4-dimethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 108) 2-bromo-5-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 109) 2-methoxyl group-N-[5-(3-methoxyl group-phenyl)-2-oxo-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-benzamide
Embodiment 110) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-4-nitro-benzamide
Embodiment 111) 2-methoxyl group-N-(8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 112) 2-chloro-4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 113) 2-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 114) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzyl carbamate
Embodiment 115) 1-(3,5-dimethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 116) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-(4-trifluoromethoxy-phenyl)-urea
Embodiment 117) 1-(4-bromo-2-trifluoromethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 118) 1-(4-bromo-benzyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 119) 1-(2,3-two chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 120) 1-(2,6-dimethyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 121) 1-(2-chloro-6-methyl-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 122) 1-(4-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 123) 1-(2-methylthio group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 124) 1-(2,6-two chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 125) the 5-tertiary butyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 126) 2,5-dimethoxy-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 127) 1-(2,6-two fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 128) 1-(3-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 129) 1-(3-methoxyl group-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 130) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-(3-trifluoromethyl-phenyl)-urea
Embodiment 131) 1-(3-chloro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 132) 2-methoxyl group-4-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 133) 4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 134) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-to benzoyl amino acid methyl esters
Embodiment 135) 2-fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 136) 2,6-two fluoro-N (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 137) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The 3-yl)-2-propoxy--benzamide
Embodiment 138) 2-iodo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 139) 3-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-to benzoyl amino acid methyl esters
Embodiment 140) 4-amino-5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 141) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
The base)-3-between-tolyl-urea
Embodiment 142) 2-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 143) 2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-5-sulfamyl (sylfamoyl)-benzamide
Embodiment 144) 2-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-phenyl-propionic acid amide
Embodiment 145) 3-hydroxy-n-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-phenyl-propionic acid amide
Embodiment 146) 3-(2-fluoro-phenyl)-1-methyl isophthalic acid-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 147) 2-methoxyl group-N-methyl-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
Embodiment 148) the 1-tertiary butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 149) 1-cyclohexyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 150) 1-ethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 151) 1-butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
Embodiment 152) 4,5-dimethyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 153) piperidines-1-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 154) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl] ethanamide
Embodiment 155) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-isobutyramide
Embodiment 156) furans-2-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
Embodiment 157) thiophene-2-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
Embodiment 158) N-[5-(3 chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-cyclohexane carboxamide
Embodiment 159) piperidines-1-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
Embodiment 160) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl] Isonicotinamide
Embodiment 161) 5-methyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 162) pyrazine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 163) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-isobutyramide
Embodiment 164) thiophene-2-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
Embodiment 165) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-cyclohexane carboxamide
Embodiment 166) piperidines-1-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
Embodiment 167) piperidines-4-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
Embodiment 168) N-(8-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclohexane carboxamide
Embodiment 169) thiophene-2-N-(8-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 170) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-thiophene-2-base-urea
Embodiment 171) 1-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-3-thiene-3-yl--urea
Embodiment 172) pyridine-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 173) 1H-pyrazoles-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 174) 6-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-niacinamide
Embodiment 175) 2-oxyethyl group-naphthalene-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 176) 9-oxo-9H-fluorenes-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 177) 2-oxo-2,3-dihydro-benzoglyoxaline-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 178) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) t-butyl carbamate
Embodiment 179) (S)-4,5-two bromo-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 180) (S)-cumarone-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
Embodiment 181) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Urethylane
Embodiment 182) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urethanum
Embodiment 183) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyl carbamate
Embodiment 184) 2-oxo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-thiophene-2-base-ethanamide
Active embodiment 1
With following proposal test implementation example 1-74 and 83-124.
The XTT analytical plan
60 holes, inside of 96 hole tissue culturing plates with 100 μ l or 150 μ l substratum with the Vero cell with 3 * 10
4Cells/well (toxicity research be 1 * 10
4Cells/well) add, in 37 ℃ be incubated overnight or up to cell near merging.For preliminary screening, 25 μ l compounds directly are added to every hole 100 μ l substratum, culture plate is duplicate.Prepare the 3rd orifice plate to study toxicity simultaneously.
Be follow-up study, the 70 μ l compounds in duplicate hole directly added substratum with the 3.2x ultimate density, along the formation hole with its 1/2 serial dilution.Preparation double plate is convenient to study simultaneously toxicity.
Obtain m.o.i. ≈ 0.2 with 25 μ l rsv infection cells.100 μ l sterile distilled waters are joined the external holes of plate, then in 33 ℃ of incubations 6 days.0.25 μ l/ml PMS is joined the XTT stock solution, ultimate density 25 μ M PMS.XTT/PMS solution with 25 μ l tepors adds every hole then, then in 37 ℃ of incubations 5 hours.With plate thermal agitation (DynaTechVari-Shaker) 10 minutes, cool off 15 minutes rear encloseds.Measure absorbancy in 450nM, with Microsoft Excel software analysis data.
The maximum value OD of record
450nm(infection, untreated control cells) is equivalent to 100% and suppresses.The minimum value OD of record
450nm(control cells of infection) is equivalent to 0% and suppresses.At OD
450nmDraw logarithm 10 concentration curves, calculate IC from 50% value of graphic representation record or with regression analysis
50Value (table 1).
According to following scheme test implementation example 75-82 and 125-184.
The XTT analytical plan
In order to study compound activity and toxicity, with 100 μ l substratum with the Hep-2 cell with 4 * 10
4Cells/well is inoculated into 60 holes, inside of 96 hole tissue culturing plates, is incubated overnight or up near cytogamy in 37 ℃.
Cell is obtained 80% cell killing with the 25 μ l rsv infections of measuring titre.Add 25 μ M test-compounds to every hole.Final DMSO concentration is 0.5%.200 μ l sterile distilled waters are joined the external holes of plate, in 37 ℃ of incubations 6 days.0.25 μ l/ml PMS is joined the XTT stock solution, ultimate density 25uM PMS.XTT/PMS solution with 25 μ l tepors joined every hole then, in 37 ℃ of incubations 1 hour.
The maximum value OD of record
450nm(infection, untreated control cells) is equivalent to 100% and suppresses.The minimum value OD of record
450nm(control cells of infection) is equivalent to 0% and suppresses.At OD
450nmDraw logarithm 10 concentration curves, calculate IC from 50% value of graphic representation record or with regression analysis
50Value.
The LC-MS data of embodiment 75a-184 also see Table 2.
Table 1
| Embodiment | XTT IC50(uM) | TD50(2d) | TD50(6d) |
| 1 | |||
| 2 | 4 | ||
| 3 | 2.5 | ||
| 4 | 5 | ||
| 5 | 2.5 | ||
| 6 | 6 | ||
| 7 | 2 | ||
| 8 | 2 | ||
| 9 | 2 | 70 | 100 |
| 10 | 1.5 | ||
| 11 | 0.5 | 100 | |
| 12 | 2.5 | ||
| 13 | 1.5 | 100 | |
| 14 | 1.5 | 100 | |
| 15 | 1 | ||
| 16 | 2 | ||
| 17 | 5 | ||
| 18 | 2 | ||
| 19 | 2 | 100 | 100 |
| Embodiment | XTT IC50(uM) | TD50(2d) | TD50(6d) |
| 20 | 25 | ||
| 21 | 6 | 100 | 100 |
| 22 | 4 | ||
| 23 | 5 | ||
| 24 | 3 | ||
| 25 | 2 | ||
| 26 | 2 | ||
| 27a | 0.3 | 100 | |
| 27b | ＜0.3 | ＞100 | |
| 28 | 5 | ||
| 29 | 2 | ||
| 30 | 3 | ||
| 31 | 5 | ||
| 32 | 2 | ||
| 33 | 2.5 | ||
| 34 | 3 | ||
| 35 | 6 | ||
| 36 | 15 | ||
| 37 | 15 | ||
| 38 | 6 | 50 | 40 |
| 39 | 10 | 60 | 50 |
| 40 | 10 | 50 | 15 |
| Embodiment | XTT IC50(uM) | TD50(2d) | TD50(6d) |
| 41 | 10 | 100 | 100 |
| 42 | 20 | ||
| 43 | 30 | ||
| 44 | 10 | ||
| 45 | 20 | ||
| 46 | 30 | ||
| 47 | 30 | 100 | 50 |
| 48 | 100 | 50 | |
| 49 | 50 | 100 | 100 |
| 50 | 50 | ||
| 51 | 5 | ||
| 52 | 3 | ||
| 53 | 5 | ||
| 54 | 1.5 | 30 | |
| 55 | 3 | 30 | |
| 56 | 5 | ||
| 57 | 0.7 | ||
| 58 | 1.2 | 30 | |
| 59 | 5 | ||
| 60 | 5 | ||
| 61 | 3 | ||
| 62 | 1.5 |
| Embodiment | XTT IC50(uM) | TD50(2d) | TD50(6d) |
| 63 | 1.7 | ||
| 64 | 1 | ||
| 65 | 2 | 100 | |
| 66 | 1.5 | 30 | |
| 67 | 1.5 | 100 | |
| 68 | 1 | ||
| 69 | 1.5 | ||
| 70 | 1.5 | 100 | |
| 71 | 3 | 50 | |
| 72 | 1.5 | 100 | |
| 73a | 1 | 100 | |
| 73b | 0.7 | ＞50 | |
| 74 | 1.5 | 100 |
Table 2
Claims (39)
1. the benzodiazepine of following structural formula (I)
Acceptable salt is used for the treatment of or prevents purposes on the medicine of rsv infection in preparation on derivative or its pharmacology,
Wherein:
-R
1Represent aryl;
-R
2Represent hydrogen;
-each R
3Represent halogen;
-n is 0-3;
-R
4Represent hydrogen;
-R
5Represent aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-or-XR
6
-X representative-CO-or-S (O)
2-; And
-R
6Represent C
1-6Alkyl, C
1-6Alkoxyl group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, aryl;
Wherein
Aryl is C
6-10Aryl, heteroaryl are to contain 1,2 or 3 first heteroaryl of heteroatomic 5-10 that is selected from O, S and N, and carbocylic radical is C
3-6Carbocylic radical, heterocyclic radical are to contain 1,2 or 3 heteroatomic C that is selected from O, S and N
5-10Heterocyclic radical.
2. the purposes of claim 1, wherein R
3Be fluorine, chlorine or bromine.
3. claim 1 or 2 purposes, wherein R
5Be aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-or-XR
6
4. the purposes of claim 3, wherein R
5Be phenyl-(C
1-2Alkyl)-, heteroaryl-(C
1-2Alkyl)-or-XR
6
5. the purposes of claim 4, wherein R
5Be phenyl-CH
2-, furyl-CH
2-or-XR
6
6. claim 1 or 2 purposes are wherein worked as R
6For-NR
/R
//During group, each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, aryl, carbocylic radical.
7. the purposes of claim 6 is wherein worked as R
6For-NR
/R
//During group, each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, phenyl, cyclohexyl or cyclopentyl.
8. the purposes of claim 7 is wherein worked as R
6For-NR
/R
//During group, R
/And R
//One of be hydrogen.
9. claim 1 or 2 purposes, wherein R
6Be C
1-6Alkyl, C
1-6Alkoxyl group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-4Alkyl)-, heteroaryl-(C
1-4Alkyl)-, aryl-(C
1-4Alkyl)-O-or-NR
/R
//
10. the purposes of claim 9, wherein R
6Be C
1-6Alkyl, C
1-6Alkoxyl group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-, heteroaryl-(C
1-2Alkyl)-or-NR
/R
//
11. the purposes of claim 10, wherein R
6Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-, 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group or-NR
/R
//
12. the purposes of claim 1 or 2, the wherein benzodiazepine of structural formula (I)
Derivative is the benzodiazepine of following structural formula (Ia)
Derivative:
Wherein:
-R
1Be phenyl;
-R
3Be chlorine;
-n is 0 or 1;
-R
4Be hydrogen;
-R
5Be phenyl-CH
2-, furyl-CH
2-,-XR
6
-X is-CO-or-S (O)
2-; And
-R
6Be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-, 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, phenyl, cyclohexyl or cyclopentyl,
R
1Phenyl moiety in the group is not substituted or by a fluorine, chlorine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio or C
1-2The haloalkyl substituting group replaces;
R
5And R
6Aryl moiety in the group is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro and-CO
2R
/, R wherein
/Represent C
1-2Alkyl;
R
5And R
6Heteroaryl moieties in the group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine and C
1-2Alkyl; And
R
6Heterocyclic radical in the group and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine and C
1-4Alkyl.
13. (S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea or (S)-4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide or their pharmacology on acceptable salt be used for the treatment of or prevent purposes on the medicine of rsv infection in preparation.
14. the purposes of claim 1 or 2, wherein said medicine is used for the treatment of the child patient below two years old.
15. the purposes of claim 14, wherein said children suffer from chronic lung disease.
16. six years old following childhood infection RSV that the purposes of claim 14, wherein said medicine are used to prevent 32 weeks of gestation or are less than the birth of 32 weeks.
17. the purposes of claim 1 or 2, wherein said medicine are suitable in the nose or administration in the segmental bronchus.
18. the purposes of claim 1 or 2, wherein said medicine further comprise the anti-inflammatory compound or the anti influenza compound of while, independence or sequential use.
19. the purposes of claim 18, wherein said anti-inflammatory compound are budesonide or fluticasone.
20. the purposes of claim 18, wherein said anti-inflammatory compound are leukotriene antagonist, phosphodiesterase 4 inhibitors or TNF alpha inhibitor.
21. the purposes of claim 18, wherein said anti-inflammatory compound are interleukin 8 or interleukin 9 inhibitor.
22. the purposes of claim 1 or 2, the anti-inflammatory compound or the anti influenza compound of wherein said medicine and each definition of claim 19-21 give simultaneously.
23. a product, it comprises the anti-inflammatory compound or the anti influenza compound of acceptable salt and each definition of claim 19-21 on structural formula (I) compound of each definition of claim 1-12 or its pharmacology.
24. the product of claim 23 is used for the treatment of the purposes on the medicine of simultaneous RSV and influenza infection in preparation.
25. acceptable salt is used for the treatment of the purposes on the medicine of following disease on the structural formula of each definition of claim 1-12 (I) compound or its pharmacology in preparation: human metapneumovirus, measles, parainfluenza virus, parotitis, yellow fever virus B5 virus strain, singapore hemorrhagic fever 2 C-type virus Cs or west Nile virus.
26. the benzodiazepine of structural formula below a kind (Ib)
Acceptable salt on derivative or its pharmacology,
Wherein:
-R
1Represent aryl;
-R
2Represent hydrogen;
-each R
3Represent halogen;
-n is 0-3;
-R
4Represent hydrogen;
-R
5/Represent aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-or-X
/, precondition is to work as R
5/Be heteroaryl-(C
1-6Alkyl)-time, it is not 2-indyl methyl, 2-(3-indyl) ethyl or 2-furyl methyl, and works as R
5/Be aryl-(C
1-6Alkyl)-time, it is not unsubstituted phenyl-(C
1-2Alkyl)-or 4-chloro-phenyl--(C
2-3Alkyl)-;
-X
/Representative-CO-R
6/Or-S (O)
2-R
6/ //
-R
6/Represent C
1Alkyl, C
1-6Alkoxyl group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, aryl, precondition are that (a) works as R
6/During for aryl, it is not unsubstituted naphthyl, unsubstituted phenyl, phenyl-monohalide base, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 4-hydroxy phenyl, 4-trifluoromethyl, 4-nitrophenyl, 4-cyano-phenyl, 4-n-propyl phenyl, 4-tert-butyl-phenyl, 4-n-pentyl phenyl, 4-dimethylaminophenyl, 4-methylthio group phenyl, 3-trifluoromethylthio phenyl, 3,4-Dimethoxyphenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4,5,6-pentafluorophenyl group, 4-chloro-2-aminophenyl or 4-1,1-dimethyl ethyl phenyl (b) is worked as R
6/During for heteroaryl, it is quinaldine based for 2-pyrryl, 2-pyrazinyl, 2-, 2-quinoxalinyl, 1-methyl indone base, 2-methyl-indyl, 2-benzofuryl, 2-benzothienyl, 3-thienyl, 3-indyl, do not replace 2-indyl, 5-fluoro indole-2-base, 5-chloro-indole-2-base, 5-bromo indole-2-base, 5-oxyindole-2-base or 5-methoxyl group indoles-2-base, (c) works as R
6/Be aryl-(C
1-6Alkyl)-time, it is not 4-benzo-thiophene-(CH
2)-, unsubstituted phenyl-(CH
2)-, 4-trifluoromethyl-(CH
2)-, unsubstituted phenyl-(CH
2)
3-, single trifluoromethyl-(CH
2)
2-, 3-p-methoxy-phenyl-(CH
2)
2-, 4-chloro-2-aminophenyl-(CH
2)
2-, 2,4 dichloro benzene base-(CH
2)
2-, mono chloro benzene base-(CH
2)
2-, 2,4-trifluoromethyl-(CH
2)
2-, 4-cyano-phenyl-(CH
2)
2-or 3-cyano-phenyl-(CH
2)
2-, (d) work as R
6/Be heteroaryl-(C
1-6Alkyl)-time, it is not that wherein x is indyl-(CH of 1-3
2)
x-, unsubstitued furyl-(CH
2)
2-, substituted thiophene base-(CH not
2)
3-, (e) work as R
6/During for carbocylic radical, it is not a cyclohexyl, (f) works as R
6/During for heterocyclic radical, it is not N-pyrrolidyl or 2-dihydro benzo furyl, (g) works as R
6/Be aryl-(C
1-6Alkyl)-during O-, it is not unsubstituted phenyl-(CH
2)-O-and (h) work as R
/During for hydrogen, R
//Be not unsubstituted phenyl, 4-halogenophenyl, 3-halogenophenyl, p-methoxy-phenyl, nitrophenyl, 2-chloro-phenyl-, 4-aminomethyl phenyl, dichlorophenyl, 3,5-3,5-dimethylphenyl, 3-aminomethyl phenyl, 3-cyano-phenyl, 3-aminophenyl, 3-aminocarbonyl-phenyl, 3-phenylformic acid, 3-ethyl benzoate, 6-amino-3-pyridyl, 5-(2-chlorine) pyridyl, 5-(2-methoxyl group) pyridyl, 5-indanyl, unsubstituted ring hexyl, 1,1-dimethyl ethyl, unsubstituted phenyl-CH
2-, unsubstituting naphthyl or benzotriazole-3-base, and work as R
/During for methyl, R
//It is not cyclopropyl-phenyl;
And
-R
6/ //Represent C
1-6Alkyl, C
1-6Alkoxyl group, aryl, heteroaryl, carbocylic radical, heterocyclic radical, aryl-(C
1-6Alkyl)-, heteroaryl-(C
1-6Alkyl)-, aryl-(C
1-6Alkyl)-O-or-NR
/R
//, each R wherein
/And R
//Identical or different and represent hydrogen, C
1-6Alkyl, carbocylic radical, aryl, precondition are to work as R
6/ //During for aryl, it is not the 4-aminomethyl phenyl, and precondition is that structural formula (Ib) compound is not N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
Wherein
-aryl is C
6-10Aryl, heteroaryl are to contain 1,2 or 3 heteroatomic C that is selected from O, S and N
5-10Heteroaryl, carbocylic radical are C
3-6Carbocylic radical, heterocyclic radical are to contain 1,2 or 3 heteroatomic C that is selected from O, S and N
5-10Heterocyclic radical.
27. a sucker or an atomizer that comprises medicine, wherein said medicine comprises:
(a) structural formula (Ib) benzodiazepine of claim 26 definition
On derivative or its pharmacology acceptable salt and
(b) acceptable carrier or thinner on the pharmacology.
28. the benzodiazepine of structural formula below a kind (Ic)
Acceptable salt on derivative or its pharmacology,
Wherein:
-R
1Be phenyl;
-R
3Be chlorine;
-n is 0 or 1;
-R
4Be hydrogen;
-R
5' be phenyl-CH
2-or X ';
-X ' is-CO-R
6' ,-CONR ' R " ,-S (O)
2R
6" ' or-S (O)
2-NR
/R
//And
-R
6' be C
1Alkyl, C
1-4Alkoxyl group, benzo dioxine base, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, cyclopentyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
2Alkyl)-O-or 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group;
-R
6" ' be C
1-4Alkyl, C
1-4Alkoxyl group, phenyl, naphthyl, dihydro benzo furyl, benzo dioxine base, indyl, thienyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, benzothienyl, benzofuryl, cyclopentyl, cyclohexyl, piperazinyl, piperidyl, morpholinyl, phenyl-(C
1-2Alkyl)-, phenyl-(C
1-2Alkyl)-O-or 1H-benzo [d] tetrahydroglyoxaline-2 (3H)-ketone group;
-each R ' and R is " identical or different and represent hydrogen, C
1-4Alkyl, phenyl, cyclohexyl or cyclopentyl; And
-each R
/And R
//Identical or different and represent hydrogen, C
1-4Alkyl, phenyl, cyclohexyl or cyclopentyl, wherein:
R
1Phenyl moiety in the group is not substituted or by a fluorine, chlorine, C
1-2Alkyl, C
1-2Alkoxyl group, C
1-2Alkylthio or C
1-2The haloalkyl substituting group replaces;
R
5', R
6' and R
6" aryl moiety the in ' group is not substituted or is selected from following substituting group by 1-3 and replaces: fluorine, chlorine, bromine, iodine, C
1-4Alkyl, C
2-4Acyl group, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-6Haloalkyl, amino, (a C
1-4Alkyl) amino, two (C
1-4Alkyl) amino, nitro and-CO
2R
/, R wherein
/Represent C
1-2Alkyl;
R
5', R
6' and R
6" heteroaryl moieties the in ' group is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine and C
1-2Alkyl;
R
6" heterocyclic radical the in ' group and carbocylic radical part are not substituted or are selected from following substituting group by 1-2 and replace: fluorine, chlorine, bromine and C
1-4Alkyl;
R
/And R
//In aryl, heteroaryl and the carbocylic radical part is not substituted or be selected from following substituting group by 1-2 replaces: fluorine, chlorine, bromine and C
1-2Alkyl; And
R
/And R
//In aryl, heteroaryl and the carbocylic radical part is not substituted or be selected from following substituting group by 1-2 replaces: fluorine, chlorine, bromine and C
1-2Alkyl,
Precondition is that structural formula (Ic) compound is not N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide;
Wherein
Aryl is C
6-10Aryl, heteroaryl are to contain 1,2 or 3 first heteroaryl of heteroatomic 5-10 that is selected from O, S and N, and carbocylic radical is C
3-6Carbocylic radical, heterocyclic radical are to contain 1,2 or 3 heteroatomic C that is selected from O, S and N
5-10Heterocyclic radical.
29. the benzodiazepine of structural formula below a kind (Id)
Acceptable salt on derivative or its pharmacology,
R wherein
6*Be aryl, it is not substituted or is selected from following substituting group by 1-3 and replaces: halogen, C
1-6Alkyl, C
2-7Acyl group, hydroxyl, C
1-6Alkoxyl group, C
1-6Alkylthio, C
1-6Haloalkyl, nitro, amino, (a C
1-6Alkyl) amino, two (C
1-6Alkyl) amino ,-CO
2R
/, R wherein
/Represent hydrogen or C
1-6Alkyl, precondition are R
6*It is not the 4-chloro-phenyl-;
Wherein
Aryl is C
6-10Aryl.
30. the benzodiazepine of structural formula below a kind (Ie)
Acceptable salt on derivative or its pharmacology,
R ' wherein
*Be aryl, it is not substituted or is selected from following substituting group by 1-2 and replaces: fluorine, chlorine, bromine, C
1-4Alkyl, C
1-4Alkoxyl group, C
1-4Alkylthio, C
1-4Haloalkyl and nitro;
Wherein
Aryl is C
6-10Aryl.
31. benzodiazepine
Derivative is selected from following compound
1) 1,1-diethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
2) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide
3) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-butyramide
4) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyramide
5) 2,2-dimethyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-propionic acid amide
6) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclopentane formamide
7) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclohexane carboxamide
8) piperidines-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
9) morpholine-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
10) 4-methyl-piperazine-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
11) benzo [b] thiophene-3-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
12) isoxazole-5-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
13) benzo [b] thiophene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
14) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Toluidrin
15) propane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-sulphonamide
16) butane-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-sulphonamide
17) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyramide
18) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Isonicotinamide
19) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-niacinamide
20) N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-ethanamide
21) (S)-2-methoxyl group-4-nitro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
22) (S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
23) 2-chloro-4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
24) 1-(4-nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
25) 4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
26) 2-methoxyl group-4-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
27) 4-methylsulfonyl-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
28) N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-to benzoyl amino acid methyl esters
29) 5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
30) 3-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-to benzoyl amino acid methyl esters
31) 2-methylthio group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
32) 4-amino-5-chloro-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
33) 4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
34) (S)-2,4,5-three fluoro-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
35) (S)-5-ethanoyl-2-oxyethyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide
36) 2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-5-sulfamyl-benzamide
37) the 1-tertiary butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
38) 1-cyclohexyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
39) 1-ethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
40) 1-butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea
41) 4,5-dimethyl-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
42) piperidines-1-N-(7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
43) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) ethanamide
44) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-isobutyramide
45) N-[5-(3 chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-cyclohexane carboxamide
46) piperidines-1-N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
47) N-[5-(3-chloro-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl] Isonicotinamide
48) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-isobutyramide
49) N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-cyclohexane carboxamide
50) piperidines-1-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
51) piperidines-4-N-[5-(3-methoxyl group-phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl]-methane amide
52) N-(8-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-cyclohexane carboxamide
53) 6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
54) 1H-pyrazoles-4-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
55) 6-dimethylamino-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-niacinamide
56) 2-oxyethyl group-naphthalene-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
57) 9-oxo-9H-fluorenes-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
58) 2-oxo-2,3-dihydro-benzoglyoxaline-1-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
59) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl) t-butyl carbamate
60) (S)-6-fluoro-4H-benzo [1,3] dioxine-8-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
61) (S)-4,5-two bromo-furans-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
62) (S)-3-methoxyl group-naphthalene-2-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-methane amide
63) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-Urethylane
64) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urethanum
65) (2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-isobutyl carbamate
66) 2-oxo-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-2-thiophene-2-base-ethanamide,
Or acceptable salt on their pharmacology.
32. benzodiazepine
Derivative (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea.
33. a medicinal compositions, it comprises each benzodiazepine of claim 26-31
Acceptable diluent or carrier on acceptable salt and the pharmacology on derivative or its pharmacology.
34. the composition of claim 33, it comprises each benzodiazepine of claim 26-31
The optically active isomer of derivative.
35. the composition of claim 33 or 34, but it is tablet, dragee, lozenge, water suspension or oil suspension dispersion powder or granule form.
36. the benzodiazepine of preparation claim 1-12 defined formula (I) in each
The method of acceptable salt on derivative or its pharmacology, this method comprises:
(a) make the reaction of 2-amino-benzophenone and bromoacetyl bromide, encircle closure with ammonia then;
(b) by reacting the NH group of protecting on the gained compound with alkali and alkylating reagent;
(c) protected intermediates that will obtain thus and alkali react in suitable solvent, obtain the oxime intermediate thus;
The oxime intermediate that (d) will obtain thus changes into corresponding racemic primary amine;
(e) in the presence of the sour and suitable aldehyde of suitable opticity, this racemic amine is carried out Dynamic Kinetic Resolution, to be settled out the salt of (S)-amine.
37. the method for claim 36, it further comprises:
(f) optically active amines that obtains in the step (e) is changed into acid amides or urea.
38. the method for claim 36 or 37, wherein the protecting group of introducing in step (b) is the 4-methoxy-benzyl.
39. the method for claim 36 or 37, the benzodiazepine of its Chinese style (I)
Be (S)-1-(2-fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-urea, or (S)-4-methylsulfonyl-2-methoxyl group-N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo [e] [1,4] diaza
-3-yl)-benzamide.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0221923.6A GB0221923D0 (en) | 2002-09-20 | 2002-09-20 | Chemical compounds |
| GB0221923.6 | 2002-09-20 | ||
| GB0302078.1 | 2003-01-29 | ||
| GB0302078A GB0302078D0 (en) | 2003-01-29 | 2003-01-29 | Chemical compounds |
| PCT/GB2003/004050 WO2004026843A1 (en) | 2002-09-20 | 2003-09-22 | Benzodiazepine derivatives and pharmaceutical compositions containing them |
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| CN1694874B true CN1694874B (en) | 2010-06-09 |
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| GB201911944D0 (en) * | 2019-08-20 | 2019-10-02 | Reviral Ltd | Pharmaceutical compounds |
| GB202010408D0 (en) * | 2020-07-07 | 2020-08-19 | Reviral Ltd | Pharmaceutical compounds |
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| WO1993017011A1 (en) * | 1992-02-21 | 1993-09-02 | Merck Sharp & Dohme Limited | Benzodiazepine derivatives, as cck and gastrin antagonists |
| WO1995014471A1 (en) * | 1993-11-22 | 1995-06-01 | Merck & Co., Inc. | Antiarrhythmic benzodiazepines |
| CN1126207A (en) * | 1994-02-14 | 1996-07-10 | 萨诺费公司 | Polysubstituted 3-acylamino-5-phenyl-1,4-benzodiazepin-2-one derivatives, process for their preparation and the pharmaceutical compositions containing them |
| CN1129442A (en) * | 1993-08-25 | 1996-08-21 | 山之内制药株式会社 | Benzodiazepine * derivatives |
| CN1158568A (en) * | 1994-08-18 | 1997-09-03 | 麦克公司 | 2,3-dihydro-1-1(2,2,2-trifluoroethyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepines |
| WO2000066106A2 (en) * | 1999-04-30 | 2000-11-09 | The Regents Of The University Of Michigan | Use of benzodiazepines for treating autoimmune diseases induced by apoptosis |
| WO2001074783A1 (en) * | 2000-04-03 | 2001-10-11 | Dupont Pharmaceuticals Company | Cyclic lactams as inhibitors of a βετα protein production |
| WO2001090084A1 (en) * | 2000-05-24 | 2001-11-29 | Merck Sharp & Dohme Limited | Benzodiazepine derivatives as app modulators |
-
2002
- 2002-09-20 GB GBGB0221923.6A patent/GB0221923D0/en not_active Ceased
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2003
- 2003-09-22 CN CN038251906A patent/CN1694874B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1041941A (en) * | 1988-07-07 | 1990-05-09 | 藤沢药品工业株式会社 | The preparation method of benzodiazepine derivatives |
| CN1059141A (en) * | 1990-07-19 | 1992-03-04 | 藤泽药品工业株式会社 | Benzodiazepine derivatives |
| WO1993017011A1 (en) * | 1992-02-21 | 1993-09-02 | Merck Sharp & Dohme Limited | Benzodiazepine derivatives, as cck and gastrin antagonists |
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| CN1158568A (en) * | 1994-08-18 | 1997-09-03 | 麦克公司 | 2,3-dihydro-1-1(2,2,2-trifluoroethyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepines |
| WO2000066106A2 (en) * | 1999-04-30 | 2000-11-09 | The Regents Of The University Of Michigan | Use of benzodiazepines for treating autoimmune diseases induced by apoptosis |
| WO2001074783A1 (en) * | 2000-04-03 | 2001-10-11 | Dupont Pharmaceuticals Company | Cyclic lactams as inhibitors of a βετα protein production |
| WO2001090084A1 (en) * | 2000-05-24 | 2001-11-29 | Merck Sharp & Dohme Limited | Benzodiazepine derivatives as app modulators |
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| GB0221923D0 (en) | 2002-10-30 |
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