CN101321534A

CN101321534A - Benzodiazepines as HCV inhibitors

Info

Publication number: CN101321534A
Application number: CNA2006800412397A
Authority: CN
Inventors: J·-F·邦方蒂; F·M·M·杜布莱特; O·纽安吉尔; P·J·-M·B·拉博伊森; A·-S·H·M·雷布斯托克; C·W·M·博顿
Original assignee: Tibotec BVBA
Current assignee: Janssen Infectious Diseases Diagnostics BVBA; Janssen R&D Ireland ULC
Priority date: 2005-09-02
Filing date: 2006-09-01
Publication date: 2008-12-10

Abstract

The present invention relates to the use of benzodiazepines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates Io benzodiazepine compounds per se and their use as medicines. The present invention also concerns processes for the preparation of such compounds, pharmaceutical compositions comprising them, and combinations of said compounds with other anti-HCV agents.

Description

Benzodiazepine as the HCV inhibitor

The present invention relates to benzodiazepine

As the purposes of HCV replication inhibitors and at treatment or resist purposes in the pharmaceutical composition that HCV infects.In addition, the present invention relates to relate to chemical compound itself.The invention still further relates to method, the pharmaceutical composition that comprises described chemical compound and described chemical compound and other anti-HCV combination of agents of the such chemical compound of preparation.

Since found in 1989 its be most of viral non--pathogen (people such as Choo of first, non--hepatitis B, Science 244,359-362,1989) afterwards, hepatitis C virus (HCV) has become focus (Lauer, the G.M and the Walker of a large amount of medical researches, B.D., New Eng.J Med.345,41-52,2001).HCV is a member that hepatitis virus belongs to flaviviridae (Flaviviridae) in (hepacivirus), (flavivirus) is in close relations with Flavivirus, Flavivirus comprises the multiple virus relevant with human diseases, for example dengue virus and yellow fever virus, itself and animal pestivirus (pestivirus) family are also in close relations, and pestivirus comprises bovine viral diarrhea virus (BVDV).HCV is the single strand RNA virus of justice, the genome with about 9,600 bases.This genome comprises 5 ' and 3 ' end untranslated region, and it adopts RNA secondary structure and central open reading-frame, described central open reading-frame coding is one have about 3,010-3,030 amino acid whose polyprotein.Ten gene outcomes of polyprotein coding, described gene outcome are to be produced from the precursor polyprotein by the endoproteolysis cutting after the common translation of coordinated series and the translation, and described cutting is mediated by host and virus protease.Virus structural protein comprises core nucleocapsid protein and two envelope glycoprotein E1 and E2.Some basic viral enzyme functions (unwindase, polymerase, protease) of non--structure (NS) encoding histone, and protein with unknown function.Virus genomic duplicating by being mediated by the RNA polymerase that depends on RNA of non-structural protein 5b (NS5B) coding.Except polymerase, viral unwindase function of in difunctional NS3 albumen, encoding and protease function the two also to demonstrate for duplicating of HCV RNA in the infection model chimpanzee be necessary (Kolykhalov, A.A., Mihalik, K., Feinstone, S.M., and Rice, C.M.JVirol.74,2046-2051,2000).Except the NS3 serine protease, HCV is also at NS2 regional code metalloproteases.

HCV preferentially duplicates in hepatocyte, but is not directly cytopathogenic, thereby causes the infection of persistence.Especially, lack strong T-lymphocyte reaction and virus, as if promoted chronically infected height ratio for the high tendentiousness of sudden change.There are 6 main HCV genotype and the hypotype more than 50, their distribution differences geographically.1 type HCV is the main genotype of US and European.For example, 1 type HCV accounts for the 70-75% that the total HCV of the U.S. infects.The genetic heterogeneity widely of HCV has important diagnostic and clinical implication, has perhaps explained at vaccine development and lacks difficulty aspect treatment replied.Estimate that the whole world has 100,017,000 people to infect hepatitis C virus (HCV).After having experienced initial actute infection, most of infected individual develops into chronic hepatitis, it can make progress and is hepatic fibrosis, thereby cause hepatitis interstitialis chronica, latter stage hepatopathy and HCC (hepatocarcinoma) (National Institutes of Health ConsensusDevelopment Conference Statement:Management of Hepatitis C.Hepatology, 36,5 Suppl.S3-S20,2002).Only just cause about 10,000 people's death are arranged every year owing to HCV infects the hepatitis interstitialis chronica cause, and it is the main reason of liver transplantation in the U.S..HCV can propagate by contacting contaminated blood or blood product, for example behind blood transfusion or intravenous use medicine.The trend of HCV sickness rate after the blood transfusion that the introducing of the diagnostic test that uses in screening of blood has caused reducing.Yet, known latter stage hepatopathy slow progress, it is serious medical science and financial burden (Kim, W.R.Hepatology, 36,5 Suppl.S30-S34,2002) that existing infection will continue in the many decades in future.

Because existing treatment only is partly effective and is subject to the side effect of not expecting, so the treatment of this chronic disease does not meet clinical needs yet.The treatment of HCV is based on the combination of ((pegylated) of Pegylation) interferon-alpha (IFN-α) and ribavirin at present.This combination treatment has produced in the patient who has infected genotype 1 virus and to have surpassed 40% lasting virusology and reply, and has produced about 80% virusology and reply in the patient who has infected genotype 2 and 3 viruses.Except the limited effect for 1 type HCV, combination treatment also has pronounced side effects, and tolerate for a lot of patients poor.For example, in the record experiment of the interferon of Pegylation and ribavirin, pronounced side effects causes the patient of about 10-14% to end treatment.The major side effects of combination treatment comprises influenza-like symptom, the hematology is unusual and neural mental symptom.Develop a kind of more effective, more convenient and to tolerate better therapy be main public health target.

A field of special concern is to seek the inhibitor that NS5b above-mentioned depends on the RNA polymerase of RNA, because the structure congener in close relations of this polymerase does not exist in the host cell that does not infect, and such inhibitor will provide higher specific binding mode.Inhibitor in studying at present can be categorized as nucleosidic inhibitors (NIs) or non-nucleosidic inhibitors (NNIs).NIs combines the avtive spot of high conservative with nucleoside substrate direct competitive.Can reach higher specificity by NNIs, described NNIs can only be that the common unique allosteric site of structurally associated polymerase interacts outside the avtive spot of high conservative.Preliminary clinical trial has caused high failure rate, and the needs of therefore seeking new NS5b inhibitor just seem extremely important.

Therefore, for causing suppressing the low molecular weight compound that HCV duplicates very high medical need is arranged.

Be surprised to find some benzodiazepine

Derivant demonstrates antiviral activity in the mammal that has infected HCV.Therefore these chemical compounds can be used for treatment or resist HCV and infect.

WO00/66106 discloses 1, the 4-benzodiazepine

-2-ketone and 1, the 4-benzodiazepine -2,5-dione compounds, benzodiazepine

The enantiomer of chemical compound, officinal salt, prodrug or derivant.These benzodiazepines

Chemical compound can be used for the treatment of the multiple dysregulation disease relevant with cell death (dysregulatory disorders), for example autoimmune disease, inflammatory situation, hyperplasia situation, viral infection and atherosclerosis.

WO99/58117 relates to the purposes that reduces apoptotic chemical compound.Described chemical compound is a benzodiazepine

The part of peripheral acceptor.

WO00/12547 relates to by 1 of derived chemotactic peptide, the 4-benzodiazepine

Or 1, the 4-benzothiazepine

It can suppress the interaction between conjugated protein of annexin and annexin, especially annexin and binding film join the interaction between the proteic virus protein, and described virus protein is the Glycoprotein B of HBsAg, the cytomegalovirus of HBV or conjugated protein from any annexin of influenza virus for example.These 1, the 4-benzodiazepine

Or 1, the 4-benzothiazepine

Derivant can be used to prevent or treat wherein relate to annexin family member and the annexin interactional disease between conjugated protein, for example HBV and/or HDV infection, cytomegalovirus infection or influenza infection.

EP0574781 discloses-1 of 2-amino-5-heterocycle-replacement, 4-benzodiazepine

And the purposes in the treatment AIDS disease relevant with AIDS.

People such as Cort é s E C: " 11-[(neighbour-,-and right-replace)-phenyl]-8-chloro-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

The effectively synthetic and spectroscopic assay of-1-ketone " .Journal of Heterocyclic Chemistry 2004,41 (2), 277-280.This publication discloses the 11-aryl-8-chloro-3 of the pharmacological activity that has possibility in the central nervous system, 3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

Synthesizing of-1-ketone.

People such as Cort é s Cort é s E: " 11-[(is adjacent and right-replace)-phenyl]-8-[(neighbour,, right-methoxyl group) phenyl sulfur]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

Synthetic and the spectral characteristic of-1-ketone " .Journal of Heterocyclic Chemistry 2002,39 (1), 55-59.This publication discloses 12 kind 2,3,4,5,10 of pharmacological characteristics with potentially useful, 11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

The preparation of-1-ketone; It is by 3-{[4-(adjacent,, right-methoxyl group) phenyl sulfur]-1, the 2-phenylenediamine }-5, the condensation and the cyclisation of 5-dimethyl-2-cyclonene and (adjacent and right-replace) benzaldehyde.

People such as Matsuo K: " 3 of 11-replacement, 3-dimethyl-2,3,4,5-tetrahydrochysene-1H-dibenzo [b, e] [1,4] diaza

Synthetic and the reaction of-1-ketone " .Chemical ﹠amp; PharmaceuticalBulletin 1985,33 (9), 4057-62.This publication discloses by 3-(2-acyl amino anilino-)-5,3 of the 11-replacement of the cyclodehydration of 5-dimethyl-2-cyclohexene-1-ketone and polyphosphoric acid preparation, 3-dimethyl-2,3,4,5-tetrahydrochysene-1H-dibenzo [b, e] [1,4] diaza -1-ketone, it has shown in mice analgesic activity medium when 50mg/kg.

WO 04/001058 described as the transcriptional regulatory agent as infection reagent some 2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

-1-ketone derivatives.

US 2005/123906 described as protein modulators some 2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4]-diaza

-1-ketone derivatives.

WO 05/007141 described as RING domain ubiquitin ligase inhibitor some 2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

-1-ketone derivatives.

US 2003/229065 described as the transcriptional regulatory agent as infection reagent some 2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza -1-ketone derivatives.

Described in the following list of references other 2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

-1-ketone derivatives, it is not mentioned any clear and definite medicinal effectiveness usually:

Chemistry of Heterocyclic Compounds(New York，NY，United States)(Translation ofKhimiya Geterotsiklichcskikh Socdincnii)(2004)，40(7)，949-955；

Journal of Heterocyclic Chemistry(2004)，41(2)，277-280；Rigas TehniskasUniversitates Zinatniskie Raksti，Serija 1：

Materialzinatne un Lietiska Kimija(2002)，4，84-88：Rigas Tehniskas UniversitatesZinatniskie Raksti，Serija 1：

Materialzinatne un Lietiska Kimija(2001)，(3)，24-27；

Journal of Heterocyclic Chemistry(2002)，39(1)，55-59；

THEOCHEM(1999)，489(1)，7-17；

Heterocyclic Communications(1996)，2(1)，47-50；

Alexandria Journal of Pharmaceutical Sciences(1993)，7(2)，137-9；

Journal of the Chinese Chemical Society(Taipei，Taiwan)(1993)，40(2)，189-94；

Journal of the Indian Chemical Society(1992)，69(9)，596-8；

Bulletin des Societes Chimiques Belges(1992)，101(9)，801-6；

Chemistry Express(1992)，7(2)，133-6；

Journal of the Indian Chemical Society(1990)，67(7)，609-10；

Acta Crystallographica，Section C：Crystal Structure Communications(1987)，C43(6)，1161-3；

Chemical & Pharmaceutical Bulletin(1985)，33(9)，4057-62；

Journal of Heterocyclic Chemistry(1982)，19(2)，321-6；

JP 47029385; With

Chemical & Pharmaceutical Bulletin(1972)，20(7)，1588-9。

Therefore the present invention relates to the purposes of formula (I) chemical compound in the active medicine of mammal inhibition HCV that preparation is used for being infected by HCV, and described chemical compound is the benzodiazepine of formula (I)

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen independently; C _3-7Cycloalkyl; Aryl; Het; Perhaps C _1-6Alkyl should

C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen,

C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

R ²Be hydrogen;

C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

C _3-7Cycloalkyl, this C _3-7Cycloalkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted,

C _3-7Cycloalkyl C _1-6Alkyl, this C _3-7Cycloalkyl C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

C _2-6Alkenyl, this C _2-6Alkenyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

C _4-7Cycloalkenyl group, this C _4-7Cycloalkenyl group is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

C _4-8Cycloalkenyl group C _1-6Alkyl, this C _4-8Cycloalkenyl group C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

Aryl ²Perhaps

Het ²；

R ⁶Be hydrogen;

Optional by carboxyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, Het-C _1-6The C that alkyl amino-carbonyl replaces _1-6Alkyl;

-C (=O)-C _1-7Alkyl, this C _1-7Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl, C _3-7Cycloalkyl and carboxyl;

-C (=O)-C _2-6Alkenyl;

-C (=O)-C _3-7Cycloalkyl, this C _3-7Cycloalkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

-C (=O)-aryl;

-C(＝O)-Het；

-C(＝O)-NR ^12aR ^12b，

R wherein ^12aAnd R ^12bBe hydrogen, C independently of one another _3-7Cycloalkyl, aryl, Het or C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

-C(＝O)-OR ^13a，

R wherein ¹³Be hydrogen, C _2-6Alkenyl, C _3-7Cycloalkyl, Het or optional by C _3-7The C that cycloalkyl or Het replace _1-6Alkyl;

-C (=O)-C _1-6Alkyl oxy carbonyl C _1-6Alkyl;

-C (=O)-Het-sulfur C _1-6Alkyl; Or

-C (=O)-Het-oxygen C _1-6Alkyl; Or

R ²And R ⁶Insertion group in the formula (I) of following inferior formula

Form the ring of following formula:

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; Optional by halogen, hydroxyl, Het ,-OR ^14aOr-NR ^14aR ^14bThe C that replaces _1-6Alkyl; Optional by amino, hydroxyl, C _1-6The C that alkoxyl, hydroxycarbonyl group, aryl or Het replace _1-6Alkoxyl; Aryloxy group; Het-oxygen; Carboxyl; C _1-6Alkyl-carbonyl oxygen; C _1-6Alkoxy carbonyl; Aryl carbonyl;-NR ^14aR ^14bOr-C (=O)-NR ^14aR ^14b

R wherein ^14aAnd R ^14bBe hydrogen independently of one another; C _3-7Cycloalkyl; Aryl; Het; Or C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, list-or two C _1-6Alkyl amino, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

R ⁵Be hydrogen; C _3-7Cycloalkyl; The perhaps optional C that is replaced by following groups _1-6Alkyl: C _3-7Cycloalkyl, aryl, Het ,-C (=O) NR ^15aR ^15b,-NR ^15aR ^15b,-C (=O) R ¹⁷,-NR ^15aC (=O) R ¹⁷,-NR ^15aSO _pR ¹⁸,-SO _pR ¹⁸,-SO _pNR ^15aR ^15b,-C (=O) OR ¹⁶Or-NR ^15aC (=O) OR ^16a

Wherein

P is 0,1 or 2;

R ^15aAnd R ^15bBe hydrogen independently; C _3-7Cycloalkyl; Aryl; Het; Perhaps C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

R ¹⁶Be hydrogen; C _2-6Alkenyl; C _3-7Cycloalkyl; Het; Perhaps optional by C _3-7The C that cycloalkyl or Het replace _1-6Alkyl;

R ^16aBe C _2-6Alkenyl; C _3-7Cycloalkyl; Het; Perhaps optional by C _3-7The C that cycloalkyl or Het replace _1-6Alkyl;

R ¹⁷Be hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl or aryl;

R ¹⁸Be hydrogen; Many halogen C _1-6Alkyl; C _3-7Cycloalkyl; Aryl; Het; Perhaps optional by C _3-7The C that cycloalkyl, aryl or Het replace _1-6Alkyl;

Aryl as the part of group or group is phenyl, naphthyl, indanyl or 1,2,3, and 4-tetrahydrochysene-naphthyl, each group can be chosen wantonly independently and be replaced by following group:

(a) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group (alkylenedioxy), C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen-C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, cyano group C _1-6Alkyl, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl; Perhaps

(b) the optional phenyl that is replaced by (a) above one, two or three defined substituent group-or naphthyl-alkoxyl; Perhaps

(c) the optional phenyl that is replaced by (a) above one, two or three defined substituent group-or naphthyl-ketonic oxygen; And

As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, amino carbonyl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl;

Aryl as the part of group or group ²Be phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydrochysene-naphthyl, described each group can be chosen wantonly independently and be selected from following group replacement by one, two or three:

(a) halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen-C _1-6Alkoxyl, C _1-6Alkyl-carbonyl oxygen, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholine; Optional phenyl-naphthyl-the alkoxyl that is replaced by halogen; The optional phenyl that is replaced by following groups-or naphthyl-ketonic oxygen: halogen, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Or

(b) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n is 0 or 1, and X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²⁰-,-NR ²⁰-C _1-6Alkane two bases-,-NR ²⁰-CO-C _1-6Alkane two bases-,-CO-NR ²⁰-C _1-6Alkane two bases-,-O-,-CO-NR ²⁰-,-NR ²⁰-CO-,-NR ²⁰-SO ₂-,-SO ₂-NR ²⁰-,-O-C _1-6Alkane two-,-O-CO-,-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6The R of alkane two bases-wherein ²⁰Be hydrogen, C _3-7Cycloalkyl, aryl, Het, C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

Het as the part of group or group ²Be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, oxo base, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Perhaps Het ²By formula-(X) _n-aryl or-(X) _nThe group of-Het replaces, and wherein n is 0 or 1, and X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²¹-,-NR ²¹-C _1-6Alkane two bases-,-NR ²¹-CO-C _1-6Alkane two bases-,-CO-NR ²¹-C _1-6Alkane two bases-,-O-,-O-C _1-6Alkane two bases-,-O-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6Alkane two bases-

R wherein ²¹Be hydrogen, C _3-7Cycloalkyl, aryl, Het, C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxy aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted.

In one embodiment, the present invention relates to the purposes of formula (I) chemical compound in the active medicine of mammal inhibition HCV that preparation is used for being infected by HCV, described chemical compound is the benzodiazepine of formula (I)

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen independently; C _3-7Cycloalkyl; Aryl; Het; Perhaps C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

R ²Be hydrogen;

C _2-6Alkenyl, it is chosen wantonly independently and is selected from following substituent group replacement by one, two or three: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

C _4-7Cycloalkenyl group, it is chosen wantonly independently and is selected from following substituent group replacement by one, two or three: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

Aryl ²Perhaps

Het ²；

R ⁶Be hydrogen;

C _1-6Alkyl;

-C (=O)-aryl;

-C(＝O)-Het；

-C(＝O)-NR ^12aR ^12b，

R wherein ^12aAnd R ^12bBe hydrogen, C independently of one another _3-7Cycloalkyl, aryl, Het or C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

-C(＝O)-OR ^13a，

-C (=O)-C _1-6Alkyl oxy carbonyl C _1-6Alkyl;

-C (=O)-Het-sulfur C _1-6Alkyl; Perhaps

-C (=O)-Het-oxygen C _1-6Alkyl; Perhaps

R ²And R ⁶Insertion group in the formula (I) of following inferior formula:

Form the ring of following formula:

R ^4aAnd R ^4bBe hydrogen, halogen, cyano group, C independently _1-6Alkyl, C _1-6Alkoxyl, aryl carbonyl or-NR ^14aR ^14b

R wherein ^14aAnd R ^14bBe hydrogen independently of one another; C _3-7Cycloalkyl; Aryl; Het; Or C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

R ⁵Be hydrogen; C _3-7Cycloalkyl; Or the optional C that is replaced by following groups _1-6Alkyl: C _3-7Cycloalkyl, aryl, Het ,-C (=O) NR ^15aR ^15b,-NR ^15aR ^15b,-C (=O) R ¹⁷,-NR ^15aC (=O) R ¹⁷,-NR ^15aSO _pR ¹⁸,-SO _pR ¹⁸,-SO _pNR ^15aR ^15b,-C (=O) OR ¹⁶Or-NR ^15aC (=O) OR ^16a

Wherein

P is 0,1 or 2;

R ^15aAnd R ^15bBe hydrogen independently of one another; C _3-7Cycloalkyl; Aryl; Het; Or C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

R ¹⁶Be hydrogen; C _2-6Alkenyl; C _3-7Cycloalkyl; Het; Or it is optional by C _3-7The C that cycloalkyl or Het replace _1-6Alkyl;

R ¹⁷Be hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl or aryl;

R ¹⁸Be hydrogen; Many halogen C _1-6Alkyl; C _3-7Cycloalkyl; Aryl; Het; Perhaps optional by C _3-7Cycloalkyl, the C that aryl or Het replace _1-6Alkyl;

Aryl as the part of group or group is phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydrochysene-naphthyl, and described each group can be chosen wantonly independently and be replaced by following group:

(a) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen-C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl; Perhaps

(b) the optional phenyl that is replaced by the substituent group of (a) definition above, two or three-or naphthyl-alkoxyl; Or

(c) the optional phenyl that is replaced by the substituent group of (a) definition above, two or three-or naphthyl-ketonic oxygen; And

As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl;

Aryl as the part of group or group ²Be phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydrochysene-naphthyl, described each group can be chosen wantonly independently and be replaced by following group:

(c) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen-C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; The optional phenyl that is replaced by halogen-or naphthyl-alkoxyl; The optional phenyl that is replaced by following groups-or naphthyl-ketonic oxygen: halogen, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Perhaps

(d) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n is 0 or 1, and X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²⁰-,-NR ²⁰-C _1-6Alkane two bases-,-NR ²⁰-CO-C _1-6Alkane two bases-,-CO-NR ²⁰-C _1-6Alkane two bases-,-O-,-O-C _1-6Alkane two bases-,-O-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6Alkane two bases-

R wherein ²⁰Be hydrogen, C _3-7Cycloalkyl, aryl, Het, C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

Het as the part of group or group ²Be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, oxo base, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Perhaps Het ²By formula-(X) _n-aryl or-(X) _n-Het replaces, and wherein n is 0 or 1, and

X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²¹-,-NR ²¹-C _1-6Alkane two bases-,-NR ²¹-CO-C _1-6Alkane two bases-,-CO-NR ²¹-C _1-6Alkane two bases-,-O-,-O-C _1-6Alkane two bases-,-O-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6Alkane two bases-

In other embodiments, the present invention relates to noval chemical compound itself with following formula (I),

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen, aryl, Het or C independently _1-6Alkyl;

R ²Be the optional C that is replaced by one or two substituent group that is selected from halogen and aryl independently _2-6Alkenyl;

Aryl ²Or

Het ²；

R ⁶Be hydrogen;

-C (=O)-C _1-7Alkyl, this C _1-7Alkyl is optional to be replaced by one, two or three substituent group that is selected from halogen, aryl and cyano group independently:

-C (=O)-C _2-6Alkenyl;

-C (=O)-aryl;

-C(＝O)-Het；

-C(＝O)-NR ^12aR ^12b，

R wherein ^12aAnd R ^12bBe hydrogen, aryl or C independently of one another _1-6Alkyl, this C _1-6Alkyl is optional to be replaced by one or two substituent group that is selected from aryl and Het independently;

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; Optional by halogen, hydroxyl, Het ,-OR ^14a, or-NR ^14aR ^14bThe C that replaces _1-6Alkyl; Optional by amino, hydroxyl, C _1-6The C that alkoxyl, hydroxycarbonyl group, aryl or Het replace _1-6Alkoxyl; Aryloxy group; Het-oxygen; Carboxyl; C _1-6Alkyl-carbonyl oxygen; C _1-6Alkoxy carbonyl;-NR ^14aR ^14bOr-C (=O)-NR ^14aR ^14b

R wherein ^14aAnd R ^14bBe hydrogen independently of one another; Perhaps C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from singly by one or two independently-or two C _1-6The substituent group of alkyl amino and Het replaces;

R ⁵Be hydrogen; Or the optional C that is replaced by aryl _1-6Alkyl;

Aryl as the part of group or group is phenyl and naphthyl, and described each group can be chosen wantonly independently and be replaced by following group:

(a) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, trifluoromethyl, C _1-6Alkoxyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, cyano group C _1-6Alkyl, nitro, list-or two C _1-6Alkyl amino; Perhaps

(b) the optional phenyl-alkoxyl that is replaced by the substituent group of (a) definition above, two or three; As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: C _1-6Alkyl and amino carbonyl;

Aryl as the part of group or group ²Be phenyl or naphthyl, described each group can be chosen wantonly independently and is selected from following substituent group replacement by one, two or three:

(a) halogen, C _1-6Alkyl, hydroxyl, trifluoromethyl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkyl-carbonyl oxygen, carboxyl, nitro, list-or two C _1-6Alkyl amino; Perhaps

(b) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n be 1 and X be-O-,-CO-NH-,-NH-CO-,-NH-SO ₂-,-SO ₂-NH-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-;

Het as the part of group or group ²Be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, aryl and nitro.

In one embodiment, the present invention relates to the purposes of formula (Ia) chemical compound in the active medicine of mammal inhibition HCV that preparation is used for being infected by HCV, described chemical compound is the benzodiazepine of the acidylate of formula (Ia)

And salt, heterogeneous type and racemic mixture, wherein

R ²Be hydrogen;

Aryl ²Perhaps

Het ²；

R ³Be C _1-7Alkyl, it is chosen wantonly independently and is selected from following substituent group replacement by one, two or three: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl, C _3-7Cycloalkyl or carboxyl substituted;

-C (=O)-C _2-6Alkenyl;

C _3-7Cycloalkyl, it is chosen wantonly independently and is selected from following substituent group replacement by one, two or three: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps cyano group, many halogen C _1-6Alkoxyl, C _3-7Cycloalkyl substituted,

Aryl;

Het；

-NR ^12aR ^12b、OR ^13a；

R ¹³Be hydrogen, C _2-6Alkenyl, C _3-7Cycloalkyl, Het or optional by C _3-7The C that cycloalkyl or Het replace _1-6Alkyl;

C _1-6Alkyl oxy carbonyl C _1-6Alkyl;

Het-sulfur C _1-6Alkyl; Perhaps

Het-oxygen C _1-6Alkyl; Perhaps

R ²And R ³Insertion group in the formula (I) of following inferior formula:

Form the ring of following formula:

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; Optional by halogen, hydroxyl, Het ,-OR ^14a, or-NR ^14aR ^14bThe C that replaces _1-6Alkyl; Optional by amino, hydroxyl, C _1-6The C that alkoxyl, hydroxycarbonyl group, aryl or Het replace _1-6Alkoxyl; Aryloxy group; Het-oxygen; Carboxyl; C _1-6Alkyl-carbonyl oxygen; C _1-6Alkoxy carbonyl; Aryl carbonyl;-NR ^14aR ^14bOr-C (=O)-NR ^14aR ^14b

R ⁵Be hydrogen; C _3-7Cycloalkyl; Or it is optional by the C of following replacement _1-6Alkyl: C _3-7Cycloalkyl, aryl, Het ,-C (=O) NR ^15aR ^15b,-NR ^15aR ^15b,-C (=O) R ¹⁷,-NR ^15aC (=O) R ¹⁷,-NR ^15aSO _pR ¹⁸,-SO _pR ¹⁸,-SO _pNR ^15aR ^15b,-C (=O) OR ¹⁶Or-NR ^15aC (=O) OR ^16a

Wherein

P is 0,1 or 2;

R ¹⁷Be hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl or aryl;

Aryl as the part of group or group is phenyl, naphthyl, indanyl or 1,2,3, the 4-tetralyl, and described each group can be chosen wantonly independently and be replaced by following group:

(a) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, cyano group C _1-6Alkyl, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl; Perhaps

(b) the optional phenyl that is replaced by the substituent group of (a) definition above, two or three-or naphthyl-alkoxyl; Perhaps

As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with the phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, amino carbonyl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl;

Aryl as the part of group or group ²Be phenyl, naphthyl, indanyl or 1,2,3,4-tetralyl, described each group can be chosen wantonly by one, two or three and be selected from following substituent group replacement: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, the optional phenyl that is replaced by halogen-or naphthyl-alkoxyl; Single-or two-alkyl amino; C _1-6Alkyl-carbonyl oxygen; Nitro; Many halogen C _1-6Alkoxyl; The optional phenyl that is replaced by following groups-or naphthyl-ketonic oxygen: halogen, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, list or dialkyl amido, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Perhaps aryl ²By formula-(X) _n-aryl-(X) _n-Het group replaces, and wherein n is 0 or 1, and

X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²⁰-,-NR ²⁰-C _1-6Alkane two bases-,-NR ²⁰-CO-C _1-6Alkane two bases-,-CO-NR ²⁰-C _1-6Alkane two bases-,-O-,-CO-NR ²⁰-,-NR ²⁰-CO-,-NR ²⁰-SO ₂-,-SO ₂-NR ²⁰-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6Alkane two bases-

Het as the part of group or group ²Be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with the phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Or Het ²By formula-(X) _n-aryl or-(X) _nThe group of-Het replaces, and wherein n is 0 or 1, and

X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²¹-,-NR ²¹-C _1-6Alkane two bases-,-NR ²¹-CO-C _1-6Alkane two bases-,-CO-NR ²¹-C _1-6Alkane two bases-,-O-,-O-C _1-6Alkane two bases-,-O-CO-,-O-CO-C _1-6Alkane two bases-,-S-,-S-C _1-6Alkane two bases-

And salt, heterogeneous type and racemic mixture, wherein

R ²Be hydrogen;

Aryl ²Perhaps

Het ²；

Aryl;

Het；

-NR ^12aR ^12b、OR ^13a；

C _1-6Alkyl oxy carbonyl C _1-6Alkyl;

Het-sulfur C _1-6Alkyl; Perhaps

Het-oxygen C _1-6Alkyl; Perhaps

R ²And R ³Insertion group in the formula (I) of following inferior formula:

Form the ring of following formula:

Wherein

P is 0,1 or 2;

R ^15aAnd R ^15bBe hydrogen independently of one another; C _3-7Cycloalkyl; Aryl; Het; Perhaps C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

R ¹⁷Be hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl or aryl;

(a) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl; Perhaps

As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with the phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl;

Aryl as the part of group or group ²Be phenyl, naphthyl, indanyl or 1,2,3,4-tetralyl, described each group can be chosen wantonly by one, two or three and be selected from following substituent group replacement: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, the optional phenyl that is replaced by halogen-or naphthyl-alkoxyl; Single-or two-alkyl amino; The optional phenyl that is replaced by following groups-or naphthyl-ketonic oxygen: halogen, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, list or dialkyl amido, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Perhaps aryl ²By formula-(X) _n-aryl or-(X) _nThe group of-Het replaces, and wherein n is 0 or 1, and

X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²⁰-,-NR ²⁰-C _1-6Alkane two bases-,-NR ²⁰-CO-C _1-6Alkane two bases-,-CO-NR ²⁰-C _1-6Alkane two bases-,-O-,-O-C _1-6Alkane two bases-,-O-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6Alkane two bases-

In further embodiment, the present invention relates to down the noval chemical compound itself of facial (Ia),

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen, aryl, Het or C independently _1-6Alkyl;

Aryl ²Perhaps

Het ²；

R ³Be optional independently by one, two or three C that is selected from the substituent group replacement of halogen, aryl and cyano group _1-7Alkyl;

C _2-6Alkenyl;

Aryl;

Het；

-NR ^12aR ^12b，

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; Optional by halogen, hydroxyl, Het ,-OR ^14aOr-NR ^14aR ^14bThe C that replaces _1-6Alkyl; Optional by amino, hydroxyl, C _1-6The C that alkoxyl, hydroxycarbonyl group, aryl or Het replace _1-6Alkoxyl; Aryloxy group; Het-oxygen; Carboxyl; C _1-6Alkyl-carbonyl oxygen; C _1-6Alkoxy carbonyl;-NR ^14aR ^14bOr-C (=O)-NR ^14aR ^14b

R ⁵Be hydrogen; Or the optional C that is replaced by aryl _1-6Alkyl;

Aryl as the part of group or group is a phenyl or naphthyl, and described each group can be chosen wantonly independently and be replaced by following group:

(c) halogen, C _1-6Alkyl, hydroxyl, trifluoromethyl, C _1-6Alkoxyl, C _1-6Alkyl-carbonyl oxygen, many halogen C _1-6Alkoxyl, nitro, list-or two C _1-6Alkyl amino; Perhaps

(d) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n is 1, and X be-O-,-CO-NH-,-NH-CO-,-NH-SO ₂-,-SO ₂-NH-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-;

In another embodiment, the present invention relates to down the noval chemical compound itself of facial (Ia), i.e. the compound N os.101,128,129,131,132,134,210 that is mentioned in the following table, 223 and 224, and salt, heterogeneous type and racemic mixture.

In one embodiment, the present invention relates to the purposes of formula (Ib) chemical compound in the active medicine of mammal inhibition HCV that preparation is used for being infected by HCV, described chemical compound is the benzodiazepine of formula (Ib)

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen independently; C _3-7Cycloalkyl; Aryl; Het; Or C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted;

R ²Be hydrogen;

Aryl ²Perhaps

Het ²；

R ³Be hydrogen; Or C _1-6Alkyl, this C _1-6Alkyl is optional by carboxyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl or Het-C _1-6Alkyl amino-carbonyl replaces;

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; Optional by halogen, hydroxyl or-NR ^14aR ^14bThe C that replaces _1-6Alkyl; C _1-6Alkoxyl; Carboxyl; C _1-6Alkoxy carbonyl; Aryl carbonyl; Or-NR ^14aR ^14b

Wherein

P is O, 1 or 2;

R ¹⁶Be hydrogen; C _2-6Alkenyl; C _3-7Cycloalkyl; Het; Perhaps by C _3-7The C that cycloalkyl or Het replace _1-6Alkyl;

R ¹⁷Be hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl or aryl;

(a) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl; Perhaps

Aryl as the part of group or group ²Be phenyl, naphthyl, indanyl or 1,2,3,4-tetralyl, described each group can be chosen wantonly independently and be selected from following substituent group replacement by one, two or three:

(e) halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen-C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl; Or

(f) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n is 0 or 1, and X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²⁰-,-NR ²⁰-C _1-6Alkane two bases-,-NR ²⁰-CO-C _1-6Alkane two bases-,-CO-NR ²⁰-C _1-6Alkane two bases-,-O-,-CO-NR ²⁰-,-SO ₂-NR ²⁰-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6Alkane two bases-

R wherein ²⁰Be hydrogen, C _3-7Cycloalkyl, aryl, Het, C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently:

Halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

Het as the part of group or group ²Be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, oxo base, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Perhaps Het ²By formula-(X) _n-aryl or-(X) _nThe group of-Het replaces, and wherein n is 0 or 1, and

And salt, heterogeneous type and racemic mixture, wherein

R ²Be hydrogen;

C _3-7Cycloalkyl, it is chosen wantonly independently and is selected from following substituent group replacement by one, two or three: halogen, C _1-6Alkoxyl, aryl and Het; Perhaps by cyano group, many halogen C _1-6Alkoxyl or C _3-7Cycloalkyl substituted,

Aryl ²Perhaps

Het ²；

R ³Be hydrogen or C _1-6Alkyl;

Wherein

P is 0,1 or 2;

R ^16aBe C _2-6Alkenyl; C _3-7Cycloalkyl; Het; Or it is optional by C _3-7The C that cycloalkyl or Het replace _1-6Alkyl;

R ¹⁷Be hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl or aryl;

Aryl as the part of group or group ²Be phenyl, naphthyl, indanyl or 1,2,3, the 4-tetralyl, described each group can be chosen wantonly independently and be replaced by following group:

(g) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen-C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl; Or

(h) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n is 0 or 1, and X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²⁰-,-NR ²⁰-C _1-6Alkane two bases-,-NR ²⁰-CO-C _1-6Alkane two bases-,-CO-NR ²⁰-C _1-6Alkane two bases-,-O-,-O-C _1-6Alkane two bases-,-O-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6The R of alkane two bases-wherein ²⁰Be hydrogen, C _3-7Cycloalkyl, aryl, Het, C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

In another embodiment, the present invention relates to down the noval chemical compound itself of facial (Ib),

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen, aryl or C independently _1-6Alkyl;

Aryl ²Or

Het ²；

R ³Be hydrogen;

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; Optional by halogen, hydroxyl or-NR ^14aR ^14bThe C that replaces _1-6Alkyl; Optional by C _1-6The C that alkoxyl replaces _1-6Alkoxyl; Carboxyl; Or-NR ^14aR ^14b

R wherein ^14aAnd R ^14bBe hydrogen independently of one another; Or C _1-6Alkyl;

R ⁵Be hydrogen;

(a) one, two or three is selected from following substituent group: halogen and C _1-6Alkoxyl; Perhaps

(b) the optional phenyl-alkoxyl that is replaced by the substituent group of (a) definition above, two or three; As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation;

A) halogen, hydroxyl, many halogen-C _1-6Alkoxyl, carboxyl, nitro; Perhaps

B) formula-(X) _nThe group of-aryl, wherein n is 1, and

X is-O-,-CO-NH-,-SO ₂-NH-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-; Het as the part of group or group ²Be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, optional and one or two phenyl ring condensation of described heterocycle, and wherein make as a whole group Het and can choose wantonly by one, two or three halogen replacement.

In another embodiment, the present invention relates to down the noval chemical compound itself of facial (Ib), be the compound N os.94,95,96,97,98,124,154,156,157,158 and 159 that mentions in the following table, and salt, heterogeneous type and racemic mixture.

Term " C as the part of group or group _1-6Alkyl " definition has the straight chain and the branched saturated hydrocarbon group of 1-6 carbon atom, for example methyl, ethyl, propyl group, butyl, 2-methyl-propyl group, amyl group, 2-methyl butyl, hexyl, 3-methyl amyl etc.

Term " C as the part of group or group _1-7Alkyl " definition has the straight chain and the branched saturated hydrocarbon group of 1-7 carbon atom, for example methyl, ethyl, propyl group, butyl, 2-methyl-propyl group, amyl group, 2-methyl butyl, hexyl, 3-methyl amyl, heptyl etc.

Term " C _1-6Alkoxyl " be meant wherein C _1-6Alkyl C as hereinbefore defined _1-6Alkyl oxy.

Term " C as the part of group or group _3-7Cycloalkyl " definition has the cyclic saturated hydrocarbon base of 3-7 carbon atom, for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and suberyl.

Term " C as the part of group or group _2-6Alkenyl " definition has the straight chain and the branched hydrocarbyl of at least one two key and 2-6 carbon atom, for example vinyl, third-1-thiazolinyl, but-1-ene base, but-2-ene base, penta-1-thiazolinyl, penta-2-thiazolinyl, oneself-the 1-thiazolinyl, oneself-2-thiazolinyl, own-the 3-thiazolinyl, 1-methyl-penta-2-thiazolinyl etc.The C that preferably has two keys _2-6Alkenyl.

Term " C as the part of group or group _4-8Cycloalkenyl group " definition has the cyclic hydrocarbon group of at least one two key and 4-8 carbon atom, for example cyclobutane base, cyclopentenyl, cyclohexenyl group or heptenyl etc., and comprise alkyl replacement on the described ring, for example 2,2-dimethyl-3-methyl-ring penta-3-thiazolinyl.The C that preferably has two keys _4-8Cycloalkenyl group.

Term " C as the part of group or group _1-6Alkane two bases " definition has the bivalence straight chain and the branched hydrocarbyl of 1-6 carbon atom, first two bases, 1 for example, 2-second two is basic or 1,1-second two bases, 1; 3-glyceryl, 1,3-fourth two bases, 1,4-fourth two bases, 1,3-penta 2 bases, 1; 5-penta 2 bases, 1,4-dihexyl, 1,6-dihexyl etc.

Term " halogen " is meant fluorine, chlorine, bromine or iodine.

As described above and hereinafter used, as term " many halogen C of the part of group or group _1-6Alkyl " be defined as single-or C of replacing of many halogen _1-6Alkyl, for example 1,1,1-trifluoroethyl, 1,1-two fluoro-ethyls, many halomethyls of mentioning hereinafter etc.Preferred many halogen C _1-6The subgroup of alkyl is many halomethyls, wherein is defined as single-or many halogen methyl, the especially methyl that is replaced by one or more fluorine atoms that replace, for example difluoromethyl or trifluoromethyl as the latter of the part of group or group.Be attached to many halomethyls or many halogen C at an above halogen atom _1-4Under the situation of the alkyl in the alkyl definition, described halogen atom can be identical or different.

It should also be noted that unless otherwise instructed the described group position in definition on used any molecular moiety unless otherwise instructed, can be any position on the described part, as long as it is chemically stable.For example pyridine radicals comprises 2-pyridine radicals, 3-pyridine radicals and 4-pyridine radicals; Amyl group comprises 1-amyl group, 2-amyl group and 3-amyl group.

As any variable (for example halogen or C _1-4When alkyl) appearance was once above in any structure divides, each is self-defined to be independently.

The N-oxide form of The compounds of this invention means and comprises that one of them or several nitrogen-atoms are oxidized to any The compounds of this invention of so-called N-oxide.

For therapeutic use, the salt of The compounds of this invention is that wherein counter ion counterionsl gegenions are that pharmacy or physiology go up acceptable those salt.Yet the salt with unacceptable counter ion counterionsl gegenions pharmaceutically also can be for example finds purposes in the preparation of the pharmaceutically acceptable chemical compound of formula (I) or purification.No matter all salt is pharmaceutically useful or pharmaceutically unacceptable, all comprises within the scope of the present invention.

The addition salts form that the pharmaceutically acceptable or physiology that The compounds of this invention can form can tolerate can use suitable acid to prepare easily, described acid for example, mineral acid is for example hydrochloric acid or hydrobromic acid, sulphuric acid, hemisulfic acid, nitric acid, phosphoric acid etc. of halogen acids for example; Perhaps for example acetic acid, aspartic acid, lauryl sulphate acid, enanthic acid, caproic acid, benzoic acid, nicotinic acid, propanoic acid, hydroxyacetic acid, lactic acid, acetone acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, cyclohexane sulfamic acid, salicylic acid, para-aminosalicylic acid, pamoic acid etc. of organic acid.

On the contrary, can be by described acid-addition salts form being converted into free alkali form with suitable alkali treatment.

By handling, also formula (I) chemical compound that contains acid proton can be converted into its avirulent metal or amine addition base salt forms with suitable organic and inorganic base.Suitable base salt forms comprises, for example, and ammonium salt, alkali metal and alkali salt, for example, lithium, sodium, potassium, magnesium, calcium salt etc., the salt that forms with organic base, for example dibenzyl-ethylenediamin, N-methyl D-glycosamine, breathe out amine salt, and with the aminoacid salt that forms such as arginine, lysine for example.Perhaps, when carboxy moiety is present on formula (I) chemical compound, also The compounds of this invention can be provided as the salt with the acceptable cation formation of pharmacy.

On the contrary, by with suitable acid treatment, described base addition salts form can be converted into free acid form.

Term " salt " also comprises hydrate and the solvent addition form that The compounds of this invention can form.The example of form is for example hydrate, alcoholates etc. like this.

Any substituent group in formula (I) contains under the situation of chiral centre, as some really, formula (I) chemical compound comprises its all heterogeneous types, comprises the mixture of isolating stereoisomer and these heterogeneous types.

The spatial chemistry heterogeneous of term chemical compound of the present invention, used as mentioned, define that chemical compound of the present invention may have, by identical atom with identical key order bonding but have different three dimensional structures and not interchangeable all possible chemical compound.Unless otherwise mentioned or indicate, the chemical name of chemical compound comprises the mixture of all possible spatial chemistry heterogeneous that described chemical compound can have.Described mixture can contain all diastereomers and/or the enantiomer of the basic molecular structure of described chemical compound.All spatial chemistry heterogeneous of chemical compound of the present invention, no matter be to be pure type or to be the thing form that is mixed with each other, all expection is contained among the scope of the invention.

Referred in this pure heterogeneous type of chemical compound refer to be substantially free of described chemical compound or intermediate identical basic molecular structure other the enantiomerism type or the isomer of diastereo-isomerism type.Particularly, term " stereoisomerism is pure " refer to have tacticity excessive at least 80% (being a kind of isomer of minimum 90% and other possible isomers of maximum 10%) be 100% to being up to that tacticity the is excessive chemical compound or the intermediate of (i.e. a kind of isomer thing of 100% and do not contain other isomers), more to have tacticity excessive be 90% to being up to 100% for specific compound or intermediate, further specific for have tacticity excessive be 94% to be up to 100% and the most specific be 97% to being up to 100% for having tacticity excessive.Should understand term " enantiomerism is pure " and " diastereoisomerism is pure " in an identical manner, but excessive with the enantiomerism in the mixture that just is being studied respectively, diastereoisomerism is excessive considers.

The pure heterogeneous type of chemical compound of the present invention can be used program as known in the art and obtain.For example the selective crystallization of the enantiomer diastereoisomerism salt that can form by itself and optically active acid or alkali is separated from each other.Embodiment is tartaric acid, dibenzoyl tartaric acid, dimethylbenzene acyl group tartaric acid and camphorsulfonic acid.Perhaps, enantiomer can pass through chromatographic technique, uses chiral stationary phase to separate.Described pure spatial chemistry heterogeneous also can be derived from corresponding suitable raw-material pure spatial chemistry heterogeneous, and prerequisite is that this reaction Stereoselective ground takes place.Preferably, specific if desired stereoisomer will be by the synthetic described chemical compound of stereospecific preparation method.These methods will advantageously be used the raw material of enantiomer-pure.

The diastereo-isomerism racemic modification of formula (I) can obtain by conventional method individually.The suitable physical separation method that can advantageously use is, for example, and selective crystallization method and chromatography, for example column chromatography.

The compounds of this invention can also exist with its tautomerism type.Though these forms do not spell out in above-mentioned formula, are also included within the scope of the invention.For example, in the definition of Het, for example 1,2, the 4-oxadiazole can be replaced by hydroxyl in the 5-position, therefore keeps balance with its tautomerism type separately, and is as follows.

Run through term used herein " prodrug " and be meant pharmacology's acceptable derivates, for example ester, amide and phosphate, thus make that this derivant bioconversion product in vivo of gained is the active medicine that defines as in the chemical compound of formula (I).Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8 of prodrug are described prevailingly ^ThEd, McGraw-Hill, Int.Ed.1992, " Biotransformation of Drugs ", p 13-15) list of references shown is incorporated herein by reference.The prodrug of The compounds of this invention is to make by the functional group that exists in the modified compound by this way, thus modify by conventional treatment or in vivo cracking be converted into parent compound.For example, comprise sulfydryl substituent group can with the carrier coupling, described carrier makes chemical compound become non-activity biologically, until being removed by endogenous enzyme, perhaps for example is removed by the enzyme of targeting special receptor or position in the experimenter.

Prodrug is characterised in that the living body availability of splendid water-soluble, increase and is metabolised to activity inhibitor in vivo easily.

The present invention also expects all isotopes that comprise the atom that comes across on the chemical compound of the present invention.Isotope comprises those and has the same atoms ordinal number but the different atom of mass number.The unrestricted embodiment via generality, the isotope of hydrogen comprises tritium and deuterium.The isotope of carbon comprises C-13 and C-14.

When using hereinafter, term " formula (I) chemical compound " or similar terms mean and comprise general formula (I), (Ia), (Ib) chemical compound, its N-oxide, salt, heterogeneous type, racemic mixture, prodrug and ester.The significant subgroup of The compounds of this invention or its any subgroup are N-oxide, salt and all heterogeneous types thereof.

Formula (I) examples for compounds comprises wherein aryl or aryl ²Formula (I) chemical compound of the phenyl or naphthyl that group is replaced by following groups: halogen; Alkoxyl; The optional phenyl that is replaced by halogen-or naphthyl-oxygen; Single-or two C _1-6Alkyl amino; Nitro; Hydroxyl; The perhaps optional phenyl that is replaced by halogen-or naphthyl-ketonic oxygen.Particularly preferred substituent group comprises halogen for example fluorine, chlorine, bromine; Alkoxyl is methoxyl group, ethyoxyl, isopropoxy, n-butoxy or n-pentyloxy for example; And single-or two C _1-6Alkyl amino is dimethylamino or diethylamino for example.

Formula (I) examples for compounds comprises wherein Het or Het ²Be to contain 1,2 or 3 preferred 1 or 2 is selected from nitrogen, formula (I) chemical compound of heteroatomic 5 or 6 element heterocycles of oxygen and sulfur, furyl for example, thienyl, pyrrole radicals, pyrrolidinyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, pyrrole radicals, pyrazolyl, imidazole radicals oxazolyl isoxazolyl, thiazinyl (thiazinolyl), isothiazine base (isothiazinolyl), thiazolyl, isothiazolyl oxadiazole base, thiadiazolyl group, triazolyl (comprises 1,2, the 3-triazolyl, 1,2, the 4-triazolyl), tetrazole radical, pyridine radicals, pyrimidine radicals, pyridazinyl, pyrazolyl, triazine radical etc.Such Het or Het ²Group can be chosen wantonly by halogen, C _1-6Alkyl, nitro or the optional aryl that is replaced by halogen replace.In formula (Ib) chemical compound, such heterocyclic group can choose wantonly with one or two phenyl ring condensation to form for example carbazyl, indyl or chromenyl (cromenyl).

Can choose the above-mentioned group that is replaced by one, two or three substituent group wantonly is preferably usually and replaces or replaced by one or two substituent group.

Other embodiments of the present invention comprise formula (I) chemical compound or its any subgroup, wherein R ^1aAnd R ^1bIn at least one is hydrogen, halogen, C _1-6Alkyl, aryl or Het.In preferred embodiments, R ^1aAnd R ^1bIt all is methyl.In another embodiment preferred, R ^1aBe hydrogen and R ^1bBe selected from C by one or two _1-6Alkoxyl and phenyl C _1-6The aryl that the substituent group of alkoxyl replaces.Especially, R ^1aBe hydrogen and R ^1bBe selected from the phenyl that following substituent group replaces by one or two: methoxyl group, ethyoxyl and phenyl methoxyl group.

Other embodiments of the present invention comprise formula (I) chemical compound or its any subgroup, wherein R ²Be hydrogen; Optional by the C of aryl or halogen replacement _2-6Alkenyl; C _4-8Cycloalkenyl group C _1-6Alkyl; Aryl ²Or Het ²In preferred embodiments, R ²Be selected from the aryl that following substituent group replaces by one or two ²: halogen, C _1-6Alkoxyl and-(X) _n-aryl, wherein n be 1 and X be-O-C _1-6Alkane two bases.Especially, R ²Be selected from the phenyl that following substituent group replaces by two: halogen, methoxyl group, 1-methyl-propoxyl group and-(X) _n-phenyl, wherein n be 1 and X be-O-first two bases.In another embodiment preferred, R ²By the C of aryl and halogen replacement _2-6Alkenyl is especially by the vinyl of halogen and phenyl replacement.

Other embodiments of the present invention comprise formula (Ia) chemical compound or its any subgroup, wherein R ³Be optional by the C of halogen, aryl or carboxyl substituted _1-7Alkyl; C _3-7Cycloalkyl; Aryl; Het; Het-sulfur C _1-6Alkyl; Perhaps-NR ^12aR ^12bIn the embodiment preferred of formula (Ia) chemical compound or its any subgroup, R ³Be C _1-6Alkyl or many halogen C _1-6Alkyl, especially methyl, amyl group or trifluoromethyl.

Other embodiments of the present invention comprise formula (Ib) chemical compound or its any subgroup, wherein R ³Be hydrogen.In the embodiment preferred of formula (Ib) chemical compound or its any subgroup, R ³Be hydrogen or C _1-6Alkyl, especially propyl group.

Other embodiments of the present invention comprise formula (Ia) chemical compound or its any subgroup, wherein R ^4aAnd R ^4bIn at least one be hydrogen or aryl carbonyl.

Other embodiments of the present invention comprise formula (Ib) chemical compound or its any subgroup, wherein R ^4aAnd R ^4bIn at least one be hydrogen, halogen, C _1-6The alkyl or aryl carbonyl.In preferred embodiments, R ^4aAnd R ^4bAll be hydrogen.

Other embodiments of the present invention comprise formula (I) chemical compound or its any subgroup, wherein R ⁵Be hydrogen.

Other embodiments of the present invention comprise formula (Ia) chemical compound or its any subgroup, wherein R ^1aAnd R ^1bIn at least one be hydrogen, chlorine; Methyl; The optional phenyl that is replaced by following groups: halogen, C _1-6Alkoxyl (for example methoxyl group, ethyoxyl or positive propoxy), nitro or list-or two-C _1-6Alkyl amino; Perhaps R ^1aAnd R ^1bIn at least one be furyl or thienyl.

Other embodiments of the present invention comprise formula (Ib) chemical compound or its any subgroup, wherein R ^1aAnd R ^1bIn at least one be hydrogen, chlorine; Methyl; The optional phenyl that is replaced by following groups: halogen, alkylenedioxy group, C _1-6Alkoxyl (for example methoxyl group, ethyoxyl or positive propoxy), nitro, list-or two-C _1-6Alkyl amino or benzyloxy; Perhaps R ^1aAnd R ^1bIn at least one be furyl or thienyl.

Other embodiments of the present invention comprise formula (Ia) chemical compound or its any subgroup, wherein R ^1aAnd R ^1bAll be hydrogen.

Other embodiments of the present invention comprise formula (Ib) chemical compound or its any subgroup, wherein R ^1aAnd R ^1bAll be hydrogen or all be methyl.

Other embodiments of the present invention comprise formula (Ia) chemical compound or its any subgroup, wherein R ²Be hydrogen, the optional phenyl that is replaced by following groups: halogen, C _1-6Alkyl, many halogen-C _1-6Alkyl, C _1-6Alkoxyl, alkylenedioxy group, nitro, hydroxyl, list-or two C _1-6Alkyl amino or the optional benzyloxy that is replaced by halogen (for example fluorine), perhaps R ²Be the optional phenyl that is replaced by benzoyl oxygen base, this benzoyl oxygen base is optional to be replaced by halogen (for example chlorine), perhaps R ²Be optional furyl, thienyl or the pyrrole radicals that is replaced by following groups: halogen, C _1-6Alkyl, nitro, perhaps R ²Be C _2-6Alkenyl, described C _2-6Alkenyl is optional to be replaced by aryl especially phenyl, perhaps by aryl especially phenyl and especially bromine replacement of halogen; Perhaps R ²Be to choose wantonly on the cyclopentenes basic ring by C _1-6The for example methyl substituted cyclopentenyl methyl of alkyl is especially by 1,2 or 3 methyl for example especially 2,2, ring penta-3-thiazolinyl that the 3-trimethyl replaces.

Other embodiments of the present invention comprise formula (Ib) chemical compound or its any subgroup, wherein R ²Be hydrogen, the optional phenyl that is replaced by following groups: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, C _1-6Alkoxyl, C _1-6Alkyl sulfide, alkylenedioxy group, nitro, hydroxyl, list-or two-C _1-6Alkyl amino or the benzyloxy that is replaced by halogen (for example fluorine), perhaps R ²Be the optional separately phenyl or naphthyl that is replaced by benzoyl oxygen base, this benzoyl oxygen base is optional to be replaced by halogen (for example chlorine), perhaps R ²Be optional separately by C _1-6Pyridine radicals, thienyl, carbazyl, indyl or chromenyl that alkyl replaces; Perhaps R ²Be C _2-6Alkenyl, described C _2-6Alkenyl is optional to be replaced by aryl especially phenyl, perhaps by aryl especially phenyl and especially bromine replacement of halogen.

Other embodiments of the present invention comprise formula (Ia) chemical compound or its any subgroup, wherein R ³Be methyl, ethyl, isopropyl, normal-butyl, sec-butyl, amyl group, heptyl; Many halomethyls; Cyclopropyl; Optional by halogen fluorine or for example by the phenyl of carboxyl substituted; Optional by the halogen benzyl that replaces of fluorine for example; Perhaps R ³Arylamino is Dichlorobenzene base amino for example; Perhaps optional by C _1-6Alkoxyl is benzothiazolyl sulfur-alkyl of replacing of methoxyl group (for example-methyl) for example.

Other embodiments of the present invention comprise formula (I) chemical compound or its any subgroup, wherein R ^4aAnd R ^4bIn at least one be hydrogen, R wherein for example ^4aAnd R ^4bAll be hydrogen.

Other embodiments of the present invention comprise one formula (Ia) chemical compound or its any subgroup that contains a plurality of following groups:

R ^1aAnd R ^1bIt all is methyl;

R ²Be 2,4-Dichlorobenzene base, 3-methoxyl group-4-benzyloxy-phenyl or 1-bromo-2-phenyl vinyl;

R ³Be methyl, phenyl, trifluoromethyl or cyclopropyl;

R ^4aAnd R ^4bAll be hydrogen; And

R ⁵Be hydrogen.

Other embodiments of the present invention comprise one formula (Ib) chemical compound or its any subgroup that contains a plurality of following groups:

R ^1aAnd R ^1bAll be methyl, perhaps R ^1aAnd R ^1bIn one be hydrogen, and another is a phenyl, described phenyl is by one or two C _1-6Alkoxy substituent replaces or is replaced by the benzyloxy substituent group;

R ²Be phenyl, described phenyl is by one or two halogen or C _1-6Alkoxy substituent replaces, and is perhaps replaced by nitro or benzyloxy substituent group;

R ³Be hydrogen;

R ^4aAnd R ^4bAll be hydrogen, perhaps R ^4aAnd R ^4bIn one be hydrogen, and another is a benzoyl; And

R ⁵Be hydrogen.

Concrete formula (Ia) examples for compounds of the present invention comprises the compound N os.35,38,42,45,48,51 shown in the following table, 53 and 193 and salt, heterogeneous type and racemic mixture.

Concrete formula (Ib) examples for compounds of the present invention comprises the compound N os.78,97,108,116 shown in the following table, 156 and 157 and salt, heterogeneous type and racemic mixture.

The pharmacology

Because they have good antiviral properties, as can obviously finding out from embodiment, chemical compound of the present invention can be used for treating the individuality that is infected by HCV and preventing these individualities infected.Usually, The compounds of this invention can be used for treating the homoiothermic animal that has infected banzi virus.Can use the situation of The compounds of this invention prevention or treatment, particularly relevant with other pathogenic banzi virus with HCV situation for example is yellow fever, dengue fever (Class1-4), St. Louis encephalitis, Japanese encephalitis, Murray valley encephalitis, west nile virus and hole wise man's virus (Kunjin virus).The situation relevant with HCV comprise the hepatic fibrosis of carrying out property, cause cirrhotic inflammation and necrosis, latter stage hepatopathy and HCC; And about other pathogenic banzi virus, described situation comprises yellow fever, dengue fever, hemorrhagic heating and encephalitis.

Therefore, The compounds of this invention or its any subgroup can be used as the medicine that resists above-mentioned condition.Described purposes or Therapeutic Method as medicine comprises experimenter's systemic administration effective dose that HCV-is infected, with the resistance situation relevant with other pathogenic banzi virus with HCV.Therefore, The compounds of this invention can be used for preparing the medicine that is used for the treatment of the situation relevant with other pathogenic banzi virus with HCV.

In one embodiment, the present invention relates to formula defined herein (I) chemical compound or its any subgroup purposes in preparing the medicine for the treatment of or resist infection relevant in the mammal or disease with the HCV infection.The invention still further relates to a kind of treat flaviviridae infections particularly HCV infect or the method for the disease relevant with flaviviridae infections, this method comprises formula defined herein (I) chemical compound or its subgroup to the administration effective dose that the treatment needs are arranged.

In another embodiment, the present invention relates to the formula (I) or the purposes of its any subgroup in the active medicine of mammal inhibition HCV that preparation is used for being infected by banzi virus especially HCV of this paper definition.

In another embodiment, the formula (I) or its any subgroup that the present invention relates to this paper definition are used in the purposes that is suppressed by the mammal of flaviviridae infections in the active medicine of HCV in preparation, and wherein said HCV is suppressed in it duplicates.

On the other hand, the present invention relates to pharmaceutical composition, this pharmaceutical composition comprises noval chemical compound and pharmaceutically suitable carrier of the formula (I) of this paper definition for the treatment of effective dose.In the present context, the treatment effective dose is the experimenter who infects or has among the experimenter of infected danger, is enough to provide preventive effect, with stable or reduce viral infection and the especially amount of HCV viral infection.Also on the other hand, the present invention relates to prepare the method for the pharmaceutical composition of this paper definition, this method comprises described formula (I) chemical compound of pharmaceutically suitable carrier with this paper definition of treatment effective dose is mixed closely.

Therefore, The compounds of this invention can be mixed with and be applicable to the various medicament forms of using purpose.As suitable compositions, can enumerate all compositionss that are generally used for the systemic administration medicine.In order to prepare pharmaceutical composition of the present invention, the specific compound (optional with addition salts form or metal complex form) of effective dose is mixed closely as active component and pharmaceutically suitable carrier, and described carrier can depend on the form of using required preparation and take multiple different form.The unit dosage forms that these pharmaceutical compositions need be suitable for particularly per os, rectum, percutaneous or use by parenteral injection.For example, in the compositions of preparation per os dosage form, optional common drug media be can use, for example, for example under the situation of suspension, syrup, elixir, Emulsion and solution, water, ethylene glycol, oil, alcohol etc. made at the per os liquid preparation; Perhaps under the situation of powder, pill, capsule and tablet, use solid carrier for example starch, sugar, Kaolin, lubricant, binding agent, disintegrating agent etc.Because it is easy to use, so tablet and capsule are represented best per os unit dosage forms, obviously uses solid pharmaceutical carriers in this case.For parenteral composition, though can comprise and for example help deliquescent other composition, carrier will be usually at least major part comprise sterilized water.For example, can prepare injection, wherein carrier comprises the mixture of saline solution, glucose solution or saline and glucose solution.Also injectable suspensions can be prepared, under described situation, appropriate liquid carrier, suspending agent etc. can be adopted.Also comprise the solid form preparation, described solid preparation is expected to face to use and changes liquid form preparation before into.In being suitable for the compositions of applied dermally, optional penetration enhancer and/or the suitable wetting agent of comprising of carrier chosen the additive combination with suitable any character of less ratio wantonly, and described additive can not introduced significant illeffects to skin.

Suck or be blown into the method and formulation of using by means of being used in this area via per os, also The compounds of this invention can be sucked and is blown into via per os and use.Therefore, generally speaking, can adopt the form of solution, suspension or dried powder that The compounds of this invention is applied to lung, and solution is preferred.Being used for sucking or being blown into any system of sending solution, suspension or dried powder via per os of exploitation suits for using of The compounds of this invention.

Therefore, the present invention also provides and is suitable for sucking or being blown into the pharmaceutical composition of using via mouth, and described pharmaceutical composition comprises formula (I) chemical compound and pharmaceutically suitable carrier.Preferably, use The compounds of this invention via the solution that sucks atomizing or aerosolized dosage.

To be easy to the using unit dosage forms preparation aforementioned pharmaceutical compositions consistent with dosage is particularly advantageous.Unit dosage forms used herein is meant the discrete unit of physics that is suitable as unit dose, and per unit contains the active component that produces required therapeutic effect as calculated of the amount of pre-determining, and itself and required pharmaceutically suitable carrier make up.The example of such unit dosage forms is tablet (comprising indentation and coated tablet), capsule, pill, suppository, powder packets, thin slice (wafer), injection or suspension etc., and link in groups (multiple) that separate.

The dosage of The compounds of this invention will depend on many factors, and described factor is different between the patient.Yet, it is believed that generally speaking day per os dosage will utilize the 0.001-100mg/kg TBW, preferred 0.01-50mg/kg and 0.01mg/kg-10mg/kg more preferably from about.Dosage will depend on the situation of being treated and practitioner's judgement is changed.

Should be noted that The compounds of this invention can be used as indivedual active component or uses as the mixture of several embodiments of described formula.In addition, The compounds of this invention can be used as the single therapy agent or unites use with other therapeutic agent.

Equally, can with previously known anti-HCV chemical compound for example the combination of the interferon-' alpha ' of interferon-' alpha ' (IFN-α), Pegylation and/or ribavirin and The compounds of this invention as the medicine in the therapeutic alliance.Term " therapeutic alliance " relates to the product that must comprise following compositions: (a) The compounds of this invention, (b) optional other anti-HCV chemical compounds, it is used for the treatment of the HCV infection simultaneously, respectively or successively as combination formulations, especially for the infection of treatment 1 type HCV.Therefore, infect in order to resist or treat HCV, can make up with the interferon-' alpha ' of The compounds of this invention and for example interferon-' alpha ' (IFN-α), Pegylation and/or ribavirin and based on the therapy of the antibody of targeting HCV epi-position, siRNA (Si RNA), ribozyme, DNA ribozyme, antisense RNA, micromolecule antagonist (at for example NS3 protease, NS3 unwindase and NS5B polymerase) and use altogether.

Therefore, the present invention relates to formula defined above (I) chemical compound or its any subgroup is used in the application that is suppressed by the mammal of HCV viral infection in the active medicine of HCV in preparation, wherein said medicine uses in therapeutic alliance, and described therapeutic alliance preferably comprises formula (I) chemical compound and (Pegylation) IFN-α and/or ribavirin.

Preparation

The compounds of this invention can commercial have been bought, and perhaps the program that can for example describe in patent of above determining and list of references according to conventional program perhaps prepares according to route of synthesis described below.

R wherein ⁵Be hydrogen, by formula (Ia) of following formula (Ia ') and (Ib ') expression and (Ib) chemical compound, can prepare according to route of synthesis shown in the following scheme 1:

Scheme 1

Step (a): make formula (II) cyclohexane extraction-1, the reaction of 3-diketone and formula (III) ortho-phenylene diamine is with production (IV) adduct; This reaction, is for example carried out under refluxing for example in the toluene at organic solvent usually.

Step (b): formula (IV) adduct and formula V aldehyde were for example reacted about 5 hours under the following conditions: at anhydrous organic solvent for example in the ethanol, under acid condition for example in the presence of acetic acid, advantageously at high temperature, for example at 40 ℃-130 ℃, preferably at 75 ℃.

Step (c): making formula (Ib ') chemical compound and formula (VI) acylating agent is R ³-C (=O)-LG (wherein LG represents leaving group) reaction; The example of described acylating agent comprises carboxylic acid halides for example acyl chlorides and acyl anhydrides, and acylation reaction is in alkali organic solvent for example in the pyridine, for example carries out to 50 ℃ preferred about 0 ℃ in temperature-20 ℃.

For R wherein ⁵Not formula (the Ia ') chemical compound of hydrogen, can be by making corresponding formula (Ia ') chemical compound (R wherein ⁵Be hydrogen) and formula R ^5a-LG ¹Chemical compound (R wherein ^5aExcept that not being the hydrogen as for R ⁵Define and LG ¹Being for example halogen atom of leaving group) reaction prepares, and reaction is normally at alkali for example in the presence of the sodium hydride, and for example carry out in oxolane or the dimethyl formamide at the organic solvent that suits.

For R wherein ³Be C _1-6The formula of alkyl (Ib) chemical compound can be by R wherein ³Be corresponding formula (Ib) chemical compound of hydrogen, by with alkylating agent C for example _1-6Alkyl halide for example iodide is handled and is prepared, and reaction is usually at alkali for example in the presence of the potassium carbonate,, carries out in room temperature easily for example in the acetone in The suitable solvent.

R wherein ⁵Formula (I) chemical compound that is not hydrogen can prepare like this: make wherein R ⁵Be the corresponding formula (I), (Ia) of hydrogen or (Ib) chemical compound, with R wherein ^5aExcept that not being the hydrogen as for R ⁵Define and LG ¹Be for example formula R of halogen atom of leaving group ^5a-LG ¹Chemical compound reacts, and reaction is usually at alkali for example in the presence of the sodium hydride, for example carries out in oxolane and the dimethyl formamide at the organic solvent that suits.

The raw material of formula (II) can commercial have been bought, and perhaps can prepare according to conventional program.For example by the wherein R of following formula (IIa) expression ^1bBe formula (II) chemical compound of H, can prepare according to route of synthesis shown in the scheme 2:

Scheme 2

Step a): formula (VII) aldehyde and acetone are for example reacted, with the ketone of production (VIII) in the presence of the sodium hydrate aqueous solution at alkali;

Step b): by at alkali for example in the presence of the potassium tert-butoxide, for example in the ethanol,, be corresponding formula (IIa) cyclohexane extraction-1 with the cyclisation of formula (VIII) ketone with the diethyl malonate reaction in The suitable solvent, the 3-diketone.

The raw material of other formula (II) can commercial have been bought, for example R wherein ^1aAnd R ^1bThe formula (II) that all is methyl is available under the title of 1,1-Dimethyl-3,5-diketocyclohexane at large.

Perhaps, formula (II) chemical compound can be according to following scheme 3, by with the diethyl malonate condensation, make by the α alkenone of formula (IX):

Scheme 3

Therefore, formula (IX) ketone can with monovalent or excessive diethyl malonate, choose wantonly at solvent and for example in the presence of ethanol or the isopropyl alcohol, react.

The present invention also comprises the noval chemical compound of formula (IV) and (Ib '), for example is used as intermediate in the preparation of formula (Ia) chemical compound.The present invention also comprises the noval chemical compound of formula (IV), for example is used as intermediate in the preparation of the chemical compound of formula (Ib).

Embodiment

Following examples meant for illustration, rather than restriction, the present invention.

Zhi Bei some chemical compounds are being analyzed by LC/MS on a kind of following instrument in an embodiment.

LCT: method XterragradPOS@V1002V1003.olp

The electrospray ionization of holotype, the scan pattern from 100 to 900amu

Xterra MS C18 (Waters, Milford, MA) 5 μ m, 3.9 * 150mm); Flow velocity 1ml/ minute.Adopt two kinds of mobile phases (mobile phase A: 85%6.5mM ammonium acetate+15% acetonitrile; Mobile phase B: 20%6.5mM ammonium acetate+80% acetonitrile) move following gradient: 100%A and kept 3 minutes, reach 100%B via 5 minutes, 100%B kept 6 minutes, reached 100%A via 3 minutes, and used the 100%A balance once more 3 minutes).

ZQ: method Xterra_15cm@V2001V2001.olp

The electrospray ionization of positive and negative (pulse) pattern, the scanning from 100 to 1000amu

Xterra RP C18 (Waters, Milford, MA) 5 μ m, 3.9 * 150mm); Flow velocity 1ml/ minute.Adopt two kinds of mobile phases (mobile phase A: 85%6.5mM ammonium acetate+15% acetonitrile; Mobile phase B: 20%6.5mM ammonium acetate+80% acetonitrile) move following gradient condition: 100%A and kept 3 minutes, reach 100%B via 5 minutes, 100%B kept 6 minutes, reached 100%A via 3 minutes, and used the 100%A balance once more 3 minutes).

Use following abbreviation in an embodiment:

(M+H) ⁺: molecular ion; : dust (10 ^-10M); Ac ₂O: acetic anhydride; AcOH: acetic acid; Et ₂O: ether; EtOAc: ethyl acetate; EtOH: ethanol; I-Pr ₂O: diisopropyl ether; M: molar concentration, i.e. molL ^-1M/z: mass-to-charge ratio; MeOH: methanol; N: equivalent; TLC: thin layer chromatography; DIPE: diisopropyl ether; THF: oxolane; The DMAP:4-dimethyl aminopyridine; DMF: dimethyl formamide; EDCI:1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; The HOBT:1-hydroxybenzotriazole; DMA:N, accelerine.

Embodiment 1:

10-acetyl group-3-(2-benzyloxy phenyl)-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-hexichol And [b, e] [1,4] diaza

-1-ketonic compound No.186 diastereomer A

Steps A

(30g, 141.3mmol) (intermediate (1-1)) stirred for 1 week in the mixture of 80mL acetone and 500mL NaOH 5% aqueous solution with 2-benzyloxy benzaldehyde.Leach white precipitate, water is washing and dry thoroughly, thereby obtains 35.2 gram (98.9%) intermediate (1-2): m/z=253 (M+H) ⁺

Step B

Potassium tert-butoxide (2.22g, 19.8mmol) and diethyl malonate (3.01mL 19.8mmol) is added to 50mL EtOH (3 Exsiccant on the molecular sieve) in.In this mixture, (5g is 19.8mmol) with the other anhydrous EtOH of 10mL to add intermediate (1-2).This reaction mixture refluxed is spent the night.EtOH is evaporated, and residue was refluxed 2 hours in 100mL 2M NaOH.This solution cools off in ice bath, adds 100mL 5M H ₂SO ₄, and with this mixture backflow 4 hours.Form two layers, and from oil reservoir the decant water layer.Oil solidifies after being cooled to room temperature, and it is used Et ₂The O extraction.With Et ₂O layer drying (Na ₂SO ₄) and evaporation, to obtain 4.21g (72.2%) intermediate (1-3): m/z=295 (M+H) ⁺

Step C

With intermediate (1-3) (3.47g, 11.78mmol) and o-phenylenediamine (1.27g, 11.74mmol) mixture in the 100mL dry toluene reacts in Dean and Stark apparatus and spends the night.Reaction is cooled to room temperature, and with toluene evaporates.With residue at i-Pr ₂Stir among the O and leach, to obtain 4.26g (77.6%) intermediate (1-4).

Step D

(200mg, 0.520mmol) with 2, (91mg, 0.520mmol) solution that is dissolved among anhydrous EtOH of 10mL and the 1mL AcOH heated 5 hours at 75 ℃ the 4-dichlorobenzaldehyde with intermediate (1-4).With solvent evaporation.Residue is dissolved among the EtOAc and with saturated NaHCO ₃Aqueous solution stirred 1.5 hours together, and dry (Na ₂SO ₄).Obtained two diastereomers, and by the hurried column chromatography purification of silica gel (silica) (gradient elution is from heptane/EtOAc 4: 1-2: 1), to obtain intermediate (1-5) diastereomer A, (yield: 118mg, 41.1%): m/z=542 (M+H) ⁺, and intermediate (1-5) diastereomer B (yield: 57mg, 20.2%): m/z=542 (M+H) ⁺

Step e

Acetic anhydride (211 μ L) is added to intermediate (1-5) diastereomer A in 0 ℃, and (52mg 0.096mmo1) is dissolved in the solution in the pyridine (3mL).Mixture was stirred 3 days at 0 ℃.Then water is added in the reactant mixture, and solid is leached and washes with water.By preparation type TLC purification (gradient EtOAc/ heptane 2: 1-3: 1; The CH that continues ₂Cl ₂/ MeOH 9: 1), obtained the final compound N of 41mg (73.2%) o.186:m/z=583 (M+H) ⁺

Embodiment 2:

-1-ketonic compound No.187 diastereomer B

According to the program of describing among the embodiment 1, (52mg 0.096mmol) makes this title product by intermediate (1-5) diastereomer B.

Embodiment 3

10-acetyl group-3,11-pair-(2-benzyloxy phenyl)-11-(3-benzyloxy phenyl)-2,3,4,5,10,11 ,-six hydrogen -dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.189 diastereomer A

According to the program of describing among the embodiment 1, (300mg, 0.780mmol) (199mg 0.938mmol) makes this title product with 3-benzyloxy benzaldehyde by intermediate (1-4).

Embodiment 4

10-acetyl group-3,11-pair-(2-benzyloxy phenyl)-11-(3-benzyloxy phenyl)-2,3,4,5,10,11-six hydrogen -dibenzo [b, e] [1,4] diaza

-1-ketonic compound 190 diastereomer B.

Method according to describing among the embodiment 1 makes this title product by intermediate (1-4) and 3-benzyloxy benzaldehyde.

Embodiment 5

10-acetyl group-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

O.36 and enantiomer-1-ketonic compound No.38 and mapping A compound N The B compound N o.35

Steps A

With 1,1-Dimethyl-3,5-diketocyclohexane (intermediate (5-1)), 5.0g, 35.67mmol) and ortho-phenylene diamine (3.86g 35.69mmol) is dissolved in solution in the 150mL dry toluene and refluxes in Dean-Rodney Stark catcher and spend the night.After 24 hours,,, be orange foam, it is used for next step under situation about not being further purified to obtain intermediate (5-2) with solvent evaporation.

Step B

Intermediate (5-2) (35.7mmol) and 2, (6.24g 35.65mmol) is dissolved in solution in anhydrous EtOH of 100mL and the 10mL AcOH mixture 75 ℃ of heated overnight to the 4-dichlorobenzaldehyde.Reactant mixture is cooled to room temperature, and with solvent evaporation.Residue is dissolved among the EtOAc, and with saturated NaHCO ₃Aqueous solution stirred 1.5 hours together.Then, in separatory funnel, remove water layer, and organic layer is leached, filtrate is used the EtOAc washed twice.With organic layer drying (Na ₂SO ₄), evaporation and residue is dry under fine vacuum, obtained 9.45g (68.4%) intermediate (5-3): m/z=387 (M+H) ⁺

Step C

(1.0g 2.582mmol) is dissolved in the 25mL pyridine, is cooled to 0 ℃, and adds the 1mL acetic anhydride intermediate (5-3).Allowable temperature is increased to room temperature.After 12 hours, reactant mixture is cooled to 0 ℃, and adds other 1mL acetic anhydride.After 12 hours, reactant mixture is leached, washes with water, and under fine vacuum in 40 ℃ of dried overnight.Then, with this material at 0.5N KHSO ₄The middle stirring 1 hour, and use CH ₂Cl ₂Extraction.With organic layer 0.5N KHSO ₄Washing, dry (Na ₂SO ₄) and evaporation.At last with product at i-Pr ₂Supersound process among the O leaches and dry, obtaining 834mg (75.2%) compound N o.38, is compound N enantiomer A and the compound N mixture of enantiomer B o.35 o.36.

Step D: separating compound No.36 enantiomer A and compound N be enantiomer B. o.35

With the compound N that obtains in the said mixture o.36 enantiomer A and compound N o.35 enantiomer B use to be equipped with and separate by chirality HPLC with BergerMinigram SFC, the Knauer K2501 UV detector means of Daicel AD-H 4.6x250mm post.Mobile phase is 80%CO ₂/ 20%MeOH, flow velocity 5mL/ minute, and pressure 100 crust.Detection is carried out at 220nm.Carry out the 100 microlitres injection of 5mg/mL solution several times.Compound N o.36 enantiomer A or " preceding enantiomer " is the enantiomer of eluting from the post at first, is o.35 enantiomer B or " back enantiomer " of compound N afterwards, and it is the enantiomer of second eluting from the post: m/z=430 (M+H) ⁺

Embodiment 6:

10-acetyl group-11-(1-bromo-2-phenyl vinyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-dibenzo [b, e] [1,4] diaza -1-ketonic compound No 274.

Program according to describing among the embodiment 5 makes this title compound by intermediate (5-2) and 2-bromo-3-phenylacrolein.m/z＝466(M+H) ⁺.

Embodiment 7

10-acetyl group-11-(1-chloro-2-phenyl vinyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.273

Program according to describing among the embodiment 5 makes this title compound, m/z=421 (M+H) by intermediate (5-2) and 2-chloro-3-phenyl-acrylic aldehyde ⁺

Embodiment 8

10-acetyl group-3,3-dimethyl-11-[3-(4-chlorobenzene formacyl oxygen) phenyl]-2,3,4,5,10,11-six hydrogen- Dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.101

According to the program of describing among the embodiment 5, by intermediate (5-2) and 3-[(4-chlorobenzene formacyl) oxygen] benzaldehyde makes this title compound: m/z=515 (M+H) ⁺

Embodiment 9

10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3,7,8-tetramethyl-2,3,4,5,10,11-six hydrogen-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.308.

According to the program of describing among the embodiment 5, by 4,5-dimethyl-ortho-phenylene diamine and 2,4-dichlorobenzaldehyde make this title compound m/z=457 (M+H) ⁺

Embodiment 10

10-acetyl group-3-(2-benzyloxy phenyl)-11-[3-(4-chlorobenzene formacyl oxygen) phenyl]-2,3,4,5,10,11- Six hydrogen-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.192 diastereomer A

According to the program of describing among the embodiment 1, by intermediate (1-4) and 3-[(4-chlorobenzene formacyl) oxygen] benzaldehyde makes this title compound: m/z=669 (M+H)+.

Embodiment 11

-1-ketone-compound N is diastereomer B o.191

According to the program of describing among the embodiment 2, by intermediate (1-4) and 3-[(4-chlorobenzene formacyl) oxygen]-benzaldehyde makes this title compound m/z=669 (M+H) ⁺.

Embodiment 12

10-acetyl group-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] phenodiazine Assorted

-1-ketonic compound No.291.

According to the program of describing among the embodiment 5, by cyclohexane extraction-1,3-dioxane ketone (dianone), ortho-phenylene diamine and 2, the 4-dichlorobenzaldehyde makes this title compound: m/z=401 (M+H) ⁺

Embodiment 13:

10-acetyl group-7,8-two chloro-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H- Dibenzo [b, e] [1,4] diaza -1-ketonic compound No.307.

According to the program of describing among the embodiment 5, by 4,5-two chloro-ortho-phenylene diamines and 2, the 4-dichlorobenzaldehyde makes this title compound m/z=497 (M+H) ⁺

Embodiment 14:3,3-dimethyl-11-(4-hydroxy phenyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound No.440.

According to for 11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

The described program of-1-ketone 5-3 makes this title compound by intermediate 5-2 and 4-hydroxy benzaldehyde: m/z=335 (M+H) ⁺

Embodiment 15:11-(4-acetoxyl group phenyl)-10-acetyl group-3,3-dimethyl-2,3,4,5,10,11-six Hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.1001.

Ac ₂O (5mL) is added to 3,3-dimethyl-11-(4-hydroxy phenyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza in 0 ℃

-1-ketone 440 is dissolved in the solution in the pyridine (50mL).After 7 days, this reactant mixture of water (250mL) quencher.Then solid is leached and washes with water.In succession solid is dissolved in CH again ₂Cl ₂In, use 0.5N KHSO ₄Washing (twice), dry (Na ₂SO ₄) and evaporation.Residue at Et ₂Supersound process and leaching among the O, with obtain 4.36g (71%) target compound 1001:m/z=419 (M+H)+.

Embodiment 16:10-acetyl group-11-(4-hydroxy phenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H- Dibenzo [b, e] [1,4] diaza -1-ketonic compound No.137.

Solution in the lithium hydroxide monohydrate (672mg) water-soluble (5mL) is added to 11-(4-acetoxyl group the phenyl)-10-acetyl group-3 of stirring, 3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

(4.26g is 10.2mmol) at MeOH/THF/H for-1-ketone 1001 ₂O2.5: in the suspension in 0.5: 1 (70mL).After 30 minutes, add 1N HCl (20mL).Then, with reactant mixture water (100mL) dilution and concentrating under reduced pressure.In succession precipitation is leached then, washes with water and dry, to obtain this title product of 3.70g (97%) 137, be white powder: m/z=377 (M+H)+.

Embodiment 17:10-acetyl group-3,3-dimethyl-11-[4-(2-pyridine radicals methoxyl group) benzene Base]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.141.

With 10-acetyl group-3,3-dimethyl-11-(4-hydroxy phenyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 137 (250mg, 0.664mmol), 2-chloromethyl pyridine hydrochloride (109mg, 1 equivalent), the mixture of cesium carbonate (476mg, 2.2 equivalents) in dry DMF (10mL) be in stirring at room 78 hours.Then, water (300mL) dilutes this reactant mixture, and in succession precipitation is leached, and washes with water, and drying is also developed in diisopropyl ether, to obtain 79mg target product 141:m/z=468 (M+H) ⁺

Embodiment 18:10-acetyl group-11-[4-(2-chlorine benzyloxy) phenyl]-3,3-dimethyl-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound No.148

According to embodiment 17 described programs, by 10-acetyl group-11-(4-hydroxy phenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 137 and 2-chlorine benzyl bromide a-bromotoluene make this title compound: m/z=501 (M+H) ⁺

Embodiment 19:10-acetyl group-3,3-dimethyl-11-[4-(4-pyridine radicals methoxyl group) benzene Base]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.145.

-1-ketone 137 and 4-chloromethyl pyridine hydrochloride make this title compound: m/z=468 (M+H) ⁺

Embodiment 20:10-acetyl group-3,3-dimethyl-11-[4-(3-pyridine radicals methoxyl group) benzene Base]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.140

-1-ketone 137 and 3-chloromethyl pyridine hydrochloride make this title compound: m/z=468 (M+H) ⁺

Embodiment 21:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylate methyl ester chemical compound no.520

Steps A.

(16.0mL 220mmol) is added to 3, and (16.8g is 110mmol) in the suspension in anhydrous MeOH (200mL) for the 4-diaminobenzoic acid thionyl chloride.The gained mixture is heated down in refluxing.After 12 hours, in succession this solution is cooled to room temperature, and concentrating under reduced pressure.With the NaHCO of residue in dilution ₃Middle development.Then, precipitation is leached and drying, to obtain 10.1g (55%) target compound 1007.

Step B.

According to synthetic 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza -1-ketone (compound N o.38) described program (steps A), by 3,4-diamino-methyl benzoate 1007 and 1,1-Dimethyl-3,5-diketocyclohexane 1000 make intermediate 1008 and 1009.

Step C.

According to for 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

The described program of-1-ketone (compound N o.38), by 1008 and 2, the 4-dichlorobenzaldehyde makes this title compound 520:m/z=487 (M+H) ⁺

Embodiment 22:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-8-carboxylate methyl ester chemical compound no.521

According to about 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

The described program of-1-ketone (compound N o.38), by 1009 and 2, the 4-dichlorobenzaldehyde makes this title compound 521:m/z=487 (M+H) ⁺

Embodiment 23:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylic acid compound no.1012.

(354mg, 8.2mmol) solution is added to 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza lithium hydroxide monohydrate

(2.0g is 4.10mmol) in the suspension in water (25mL) and THF (25mL) for-7-carboxylate methyl ester 520.After 12 hours, the PH of reactant mixture is adjusted to 3 with 1N HCl.To precipitate by filtering and collect, wash with water and drying, to obtain 1.87g (96.4%) this title product 1012:m/z=473 (M+H) ⁺

Embodiment 24:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-8-carboxylic acid compound no.522

According to preparation 10 acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylic acid 1012 described programs, by 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-8-carboxylate methyl ester 521 has made this title compound 522:m/z=473 (M+H) ⁺

Embodiment 25:10-acetyl group-N-(morpholine-4-base ethyl)-11-(2, the 4-Dichlorobenzene base)-3, the 3-dimethyl -1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxamide compounds No.321

With 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylic acid 1012 (250mg, 0.53mmol), 4-(2-amino-ethyl) morpholine, EDCI.HCl (203mg, 1.06mmol), HOAT (144mg, 1.06mmol) and DIPEA (185 μ L 1.06mmol) are dissolved in solution in the dry DMF (5mL) in stirred overnight at room temperature.Then, water (75mL) dilutes this reactant mixture, and passes through to filter and collect the precipitation that forms, and washes with water then and drying, to obtain 120mg (39%) this title product 321:m/z=585 (M+H) ⁺

Embodiment 26:10-acetyl group-N-(N, N-dimethylaminopropyl)-11-(2, the 4-Dichlorobenzene base)-3,3-two Methyl isophthalic acid-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -7-carboxylic acid amidesization Compound no.1015.

According to preparation N-(morpholine-4-base ethyl)-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylic acid amides 321 described programs, by 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylic acid 1012 and 3-(N, N-dimethylamino) propylamine has made this title compound 1015, yield 73%:m/z=557 (M+H) ⁺

Embodiment 27:10-acetyl group-N-(4-pyridine radicals ethyl)-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1- Oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxamide compounds no. 1016.

According to preparation 10-acetyl group-N-(morpholine-4-base ethyl)-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylic acid 1012 and 4-pyridine radicals ethamine have made this title compound 1016, yield 53%:m/z=577 (M+H) ⁺

Embodiment 28:10-acetyl group-N-(N, N-dimethyl aminoethyl)-11-(2, the 4-Dichlorobenzene base)-3,3-two Methyl isophthalic acid-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylic acid amidesization Compound no.1018.

According to preparation 10-acetyl group-N-(morpholine-4-base ethyl)-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -7-carboxylic acid amides 321 described programs, by 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxylic acid 1012 and 2-(N, N-dimethylamino) ethamine has made this title compound 1018:m/z=543 (M+H) ⁺

Embodiment 29:10-acetyl group-N-(2-piperidines-1-base ethyl)-11-(2, the 4-Dichlorobenzene base)-3, the 3-dimethyl -1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxamide compounds No.1019.

-7-carboxylic acid 1012 and 2-(piperidines-1-yl) ethamine makes this title compound 1019:m/z=583 (M+H) ⁺

Embodiment 30:10-acetyl group-N-(2-cyano ethyl)-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxygen Generation-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-carboxamide compounds no. 1020.

-7-carboxylic acid 1012 and 2-cyano group ethamine make this title compound 1020:m/z=525 (M+H) ⁺

Embodiment 31:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-7-hydroxymethyl-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.523

(824mg 21.8mmol) is added to 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3 in batches, 3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza sodium borohydride

(5.3g 10.9mmol) is dissolved in the solution in the dehydrated alcohol (100mL)-7-carboxylate methyl ester 520.After 24 hours, (824mg 21.8mmol) is added in the reactant mixture sodium borohydride.Should operate and repeat 3 times (altogether: use 14 equivalent NaBH ₄).Reactant mixture is added drop-wise in the 2N HCl solution (500mL).By filtering collecting precipitation, wash with water and drying, to obtain this title product of 3.83g (77%) 523, be white powder: m/z=459 (M+H) ⁺

Embodiment 32:10-acetyl group-7-bromomethyl-11-(2, the 4-Dichlorobenzene base)-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.1022.

(118 μ L 1.25mmol) are added to 10-acetyl group-11-(2, the 4-the Dichlorobenzene base)-7-hydroxymethyl-3 of stirring, 3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza gradually phosphorus tribromide in 0 ℃ under nitrogen

-1-ketone 523 is dissolved in the solution among the DCE (2mL).Gained solution was in stirring at room 1 hour.Then, the sodium bicarbonate aqueous solution that adds dilution.Reactant mixture is extracted dry (Na with AcOEt ₂SO ₄) and evaporation, to obtain 157mg (68%) this title product 1022:m/z=522 (M+H) ⁺

Embodiment 33:10-acetyl group-7-chloromethyl-11-(2, the 4-Dichlorobenzene base)-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.1023.

(238 μ L 3.26mmol) are added drop-wise to 10-acetyl group-11-(2, the 4-the Dichlorobenzene base)-7-hydroxymethyl-3 of stirring, 3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza thionyl chloride in 0 ℃ under nitrogen (500mg 1.09mmol) is dissolved in the solution among the DCE (10mL)-1-ketone 523.Gained solution was in stirring at room 2 hours.Then, add icy water.With reactant mixture with DCM extraction, dry (Na ₂SO ₄) and evaporation, to obtain 410mg (79%) this title product 1023:m/z=477 (M+H) ⁺

Embodiment 34:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-formaldehyde (carboxaldehyde) chemical compound no. 1024.

Manganese oxide (IV) is added to 10-acetyl group-11-(2, the 4-the Dichlorobenzene base)-7-hydroxymethyl-3 of stirring, 3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 523 is dissolved in the solution in the acetone (10mL).Gained solution is heated to backflow.After 2 days, reactant mixture is cooled to room temperature, through diatomite filtration, and evaporation, to obtain 400mg (40%) this title product 1024:m/z=457 (M+H) ⁺

Embodiment 35:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-(2-morpholine-4-base ethyl Amino methyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.1025.

-7-formaldehyde 1024 (200mg, 0.44mmol) and 4-(2-amino-ethyl) morpholine (53 μ L 0.40mmol) are dissolved in solution among the DCM (5mL) in stirring at room 30 minutes.Then, add NaBH (OAc) ₃(122mg, 0.57mmol) and acetic acid (26.3 μ L, 1.2 equivalents).The gained reactant mixture in stirred overnight at room temperature, is used the saturated sodium bicarbonate solution quencher then, with the AcOEt extraction, dry (Na ₂SO ₄) and evaporation, to obtain 190mg (87%) this title product 1025:m/z=571 (M+H) ⁺

Embodiment 36:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-[3-(N, N-dimethylamino Base) propyl group amino methyl]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketone Chemical compound no.1026.

According to preparation 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-(2-morpholine-4-base ethylamino methyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 1025 described programs, by 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

(N, N-dimethylamino propylamine make this title compound 1026:m/z=543 (M+H) for-7-formaldehyde 1024 and 3- ⁺

Embodiment 37:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-[2-(4-pyridine radicals) second The base amino methyl]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonize is closed Thing no.1027.

-7-formaldehyde 1024 and 4-pyridine radicals ethamine make this title compound 1027:m/z=563 (M+H) ⁺

Embodiment 38:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-[2-(N, N-dimethylamino Base) ethylamino methyl]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone Chemical compound no.1028.

-7-formaldehyde 1024 and 2-(N, N-dimethylamino) ethamine makes this title compound 1028:m/z=529 (M+H) ⁺

Embodiment 39:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-[2-(piperidines-1-yl) second The base amino methyl]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonize is closed Thing no.1030.

-7-formaldehyde 1024 and 2-(piperidines-1-yl) ethamine makes this title compound 1030:m/z=569 (M+H) ⁺

Embodiment 40:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-(2-cyano ethyl amino- Methyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no. 1031.

-7-formaldehyde 1024 and 2-cyano group ethamine make this title compound 1031:m/z=511 (M+H) ⁺

Embodiment 41:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-(morpholine-4-Ji Jia Base)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no. 1032.

-7-formaldehyde 1024 and morpholine make this title compound 1032:m/z=528 (M+H) ⁺

Embodiment 42:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-(N-methyl-N-propyl group ammonia Ylmethyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no. 1033.

-7-formaldehyde 1024 and N methyl pmpyl amine make this title compound 1033:m/z=514 (M+H) ⁺

Embodiment 43:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-[4-(amino carbonyl)-piperazine Pyridine-1-ylmethyl]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonize is closed Thing no.1034.

-7-formaldehyde 1024 and 4-(amino carbonyl) piperidines makes this title compound 1034:m/z=569 (M+H) ⁺

Embodiment 44:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-(4-methyl piperazine-1-base Methyl)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no. 1035.

-1-ketone 1025 described programs, by 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -7-formaldehyde 1024 and 4-methyl piperazine make this title compound 1035:m/z=541 (M+H) ⁺

Embodiment 45:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-(piperidines-1-Ji Jia Base)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.1037.

The program that-1-ketone 1025 is described, by 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-1-oxo-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-7-formaldehyde 1024 and piperidines make this title compound 1037:m/z=526 (M+H) ⁺.

Embodiment 46:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-(pyrrolidine-1-Ji Jia Base)-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no.1038.

-7-formaldehyde 1024 and pyrrolidine make this title compound 1038:m/z=512 (M+H) ⁺

Embodiment 47:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-[2-(piperidines-1-yl) ethoxy Ylmethyl]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no. 1039.

In 0 ℃ the following sodium hydride of argon (17mg, 60% in mineral oil, (53 μ L 0.4mmol) are dissolved in the solution in the dry DMF (4mL) 0.42mmol) to be added to N-piperidines ethanol.Be added to 10-acetyl group-7-bromomethyl-11-(2, the 4-Dichlorobenzene base)-3 in 0 ℃ at following gained solution of argon, 3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

(200mg 0.38mmol) is dissolved in the solution in the dry DMF (2mL)-1-ketone 1022.After 2 hours, with icy water (70mL) diluted reaction mixture.With 2N NaOH aqueous solution the pH regulator to 7 of gained solution.Then, reactant mixture is used in succession AcOEt (3 times), THF (3 times) extraction.With the organic extract liquid salt water washing that merges, dry (Na ₂SO ₄) and evaporation.Residue is developed in toluene, and evaporation.The gained residue is developed in DCM and methanol, filtered and under vacuum, concentrate.Residue is by column chromatography purification (CH on Alumina ₂Cl ₂/ MeOH, gradient 1: 0-92: 8), to obtain 85mg (39%) target compound 1039:m/z=570 (M+H) ⁺

Embodiment 48:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-[3-(N, N-dimethylamino Base) propoxyl group methyl]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonize Compound no.1040.

According to preparation 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-7-[2-(piperidines-1-yl) ethoxyl methyl]-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketone 1039 described programs, by 10-acetyl group-7-bromomethyl-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 1022 and 3-(N, N-dimethylamino) propanol makes this title compound 1040:m/z=544 (M+H) ⁺

Embodiment 49:10-acetyl group-11-[4-(phenyl amino carbonyl) phenyl]-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no.1041.

According to synthetic 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

The described program of-1-ketone (chemical compound no.38) makes this title compound 1041:m/z=480 (M+H) by 4-(phenyl amino carbonyl) benzaldehyde ⁺

Embodiment 50:10-acetyl group-11-[4-(N-acetyl group-N-phenyl amino sulfonyl) phenyl]-3,3-two Methyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no. 1042.

The described program of-1-ketone (chemical compound no.38) makes this title compound 1042:m/z=558 (M+H) by 4-(N-phenyl amino sulfonyl) benzaldehyde ⁺

Embodiment 51:10-acetyl group-11-[4-(N-phenyl amino sulfonyl) phenyl]-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.1043.

In 0 ℃ lithium hydroxide monohydrate (11mg, 0.26mmol) solution in water-soluble (0.5mL) is added to 10-acetyl group-11-[4-(N-acetyl group-N-phenyl amino sulfonyl) phenyl of stirring]-3,3-dimethyl-2,3; 4,5,10; 11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

(133mg is 0.26mmol) in the solution for-1-ketone 1042., after 12 hours reactant mixture is diluted with saturated ammonium chloride solution in room temperature, use the AcOEt extracting twice, use the salt water washing, dry (Na ₂SO ₄) and evaporation, to obtain this title product of 100mg: m/z=516 (M+H) ⁺

Embodiment 52:10-acetyl group-11-(4-nitrobenzophenone)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H- Dibenzo [b, e] [1,4] diaza -1-ketonic compound no.1044.

The described program of-1-ketone (chemical compound no.38) makes this title compound 1044:m/z=406 (M+H) by intermediate 5-2 and 4-nitrobenzaldehyde ⁺

Embodiment 53:10-acetyl group-11-(4-aminophenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H- Dibenzo [b, e] [1,4] diaza -1-ketonic compound no.1045.

10-acetyl group-11-(4-nitrobenzophenone)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 1044 (862mg, 2.13mmol) be dissolved in solution among MeOH (3mL) and the THF (3mL) be added to ferrum (476mg, 8.52mmol) and ammonium chloride (460mg is 8.52mmol) in the suspension in water (3mL).With the gained mixture in 70 ℃ of heating.After 2 hours, reactant mixture is filtered on kieselguhr, and thoroughly wash with AcOEt.With the organic extract liquid salt water washing that merges, dry (Na ₂SO ₄) and evaporation, to obtain 272mg (35%) this title product 1045:m/z=376 (M+H) ⁺

Embodiment 54:10-acetyl group-11-[4-(phenyl sulfonyl amino) phenyl]-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no.1046.

With 10-acetyl group-11-(4-aminophenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 1045 (127mg, 0.34mmol), (45.5 μ L 0.36mmol) are dissolved in solution in the pyridine (2mL) in stirring at room 12 hours to benzene sulfonyl chloride.Reactant mixture is added drop-wise to 10mL water successively, with the AcOEt extraction, dry (Na ₂SO ₄) and evaporation, to obtain 78mg this title product 1046:m/z=516 (M+H) ⁺

Embodiment 55:10-acetyl group-11-[4-(phenylcarbonyl group amino) phenyl]-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.1047.

According to 10-acetyl group-11-[4-(phenyl sulfonyl amino) phenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 1046 described programs, by 10-acetyl group-11-(4-aminophenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 1045 and Benzenecarbonyl chloride. make this title compound 1047:m/z=480 (M+H) ⁺

Embodiment 56:11-[4-(phenylcarbonyl group) phenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-hexichol And [b, e] [1,4] diaza

-1-ketonic compound no.1048.

The described program of-1-ketone 5-3 makes this title compound by intermediate 5-2 and 4-(phenylcarbonyl group) benzaldehyde: m/z=423 (M+H) ⁺

Embodiment 57:10-acetyl group-11-[4-(phenylcarbonyl group) phenyl]-33-dimethyl-2,3,4,5,10,11-six Hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.1049.

The described program of-1-ketone (chemical compound no.38) is by 11-[4-(phenylcarbonyl group) phenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 1048 makes this title compound 1049:m/z=465 (M+H) ⁺

Embodiment 58:11-[4 benzyloxycarbonyl-2-chlorphenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen -1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.443.

According to about 11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

The described program of-1-ketone 5-3 makes this title compound 443:m/z=459 (M+H) by intermediate 5-2 and 4-benzyloxy-2-chlorobenzaldehyde ⁺

Embodiment 59:10-acetyl group-11-[4-benzyloxycarbonyl-2-chlorphenyl]-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.142.

The described program of-1-ketone (chemical compound no.38) is by 11-[4-benzyloxycarbonyl-2-chlorphenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 443 makes this title compound 142:m/z=501 (M+H) ⁺

Embodiment 60:11-[3, the 5-Dichlorobenzene base]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.436.

The described program of-1-ketone 5-3, by intermediate 5-2 and 2, the 5-dichlorobenzaldehyde makes this title compound 436:m/z=387 (M+H) ⁺

Embodiment 61:10-acetyl group-11-[3, the 5-Dichlorobenzene base]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen -1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.133.

The described program of-1-ketone (chemical compound no.38), by 11-[3, the 5-Dichlorobenzene base]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 436 makes this title compound 133:m/z=429 (M+H) ⁺

Embodiment 62:11-[4-benzyloxy-3-chlorphenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-two Benzo [b, e] [1,4] diaza -1-ketonic compound no.439.

According to for 11-(2, the 4-Dichlorobenzene base)-23,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

The described program of-1-ketone 5-3 makes this title compound 439:m/z=459 (M+H) by intermediate 5-2 and 3-chloro-4-benzyloxy benzaldehyde ⁺

Embodiment 63:10-acetyl group-11-[4-benzyloxy-3-chlorphenyl]-3,3-dimethyl-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.139

According to for 10-acetyl group-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza The described program of-1-ketone (chemical compound no.38) is by 11-[4-benzyloxy-3-chlorphenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 439 makes this title compound 139:m/z=501 (M+H) ⁺

Embodiment 64:11-[4-benzyloxy-3, the 5-Dichlorobenzene base]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen -1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.444

The described program of-1-ketone 5-3, by intermediate 5-2 and 3,5-two chloro-4-benzyloxy benzaldehydes make this title compound 444:m/z=493 (M+H) ⁺

Embodiment 65:10-acetyl group-11-[4-benzyloxy-3, the 5-Dichlorobenzene base]-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.143

The described program of-1-ketone (chemical compound no.38), by 11-[4-benzyloxy-3, the 5-Dichlorobenzene base]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 444 makes this title compound 143:m/z=535 (M+H) ⁺

Embodiment 66:11-[2, the 5-Dichlorobenzene base]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.438

The described program of-1-ketone 5-3, by intermediate 5-2 and 2, the 5-dichlorobenzaldehyde makes this title compound 438:m/z=387 (M+H) ⁺

Embodiment 67:10-acetyl group-11-[2, the 5-Dichlorobenzene base]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen -1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.138

The described program of-1-ketone (chemical compound no.38), by 11-[2, the 5-Dichlorobenzene base]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 438 makes this title compound 138:m/z=429 (M+H) ⁺

Embodiment 68:11-[2, the 4-benzyloxy phenenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-two Benzo [b, e] [1,4] diaza

-1-ketonic compound no.445

The described program of-1-ketone 5-3, by intermediate 5-2 and 2,4-benzyloxy benzaldehyde makes this title compound 445:m/z=531 (M+H) ⁺

Embodiment 69:10-acetyl group-11-[2, the 4-benzyloxy phenenyl]-3,3-dimethyl-2,3,4,5,10,11-six Hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no.144

The described program of-1-ketone (chemical compound no.38), by 11-[2, the 4-benzyloxy phenenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketone 445 makes this title compound 144:m/z=573 (M+H) ⁺

Embodiment 70:11-(2,4 difluorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.441.

The described program of-1-ketone 5-3 makes this title compound 441:m/z=355 (M+H) by intermediate 5-2 and 2,4 difluorobenzene formaldehyde ⁺

Embodiment 71:10-acetyl group-11-(2,4 difluorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen -1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.146.

The described program of-1-ketone (chemical compound no.38), by 11-(2,4 difluorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 441 makes this title compound 146:m/z=397 (M+H) ⁺

Embodiment 72:11-(4-trifluoromethyl oxygen base phenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H- Dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.434.

According to for 11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza The described program of-1-ketone 5-3 makes this title compound 434:m/z=403 (M+H) by intermediate 5-2 and 4-trifluoromethyl oxygen benzaldehyde ⁺

Embodiment 73:10-acetyl group-11-(4-trifluoromethyl oxygen base phenyl)-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.1064.

The described program of-1-ketone (chemical compound no.38) is by 11-(4-trifluoromethyl oxygen base phenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 434 makes this title compound 1064:m/z=445 (M+H) ⁺

Embodiment 74:11-(4-benzyloxy-2,6-Dichlorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen -1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.447.

The described program of-1-ketone 5-3, by intermediate 5-2 and 4-benzyloxy-2, the 6-dichlorobenzaldehyde makes this title compound 447:m/z=493 (M+H) ⁺

Embodiment 75:10-acetyl group-11-(4-benzyloxy-2,6-Dichlorobenzene base)-3, the 3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.150

The described program of-1-ketone (chemical compound no.38), by 11-(4-benzyloxy-2,6-Dichlorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 447 makes this title compound 150:m/z=535 (M+H) ⁺

Embodiment 76:11-(3-benzyloxy phenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no.437.

According to for 11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza The described program of-1-ketone 5-3 makes this title compound 437:m/z=425 (M+H) by intermediate 5-2 and 3-benzyloxy benzaldehyde ⁺.

Embodiment 77:10-acetyl group-11-(3-benzyloxy phenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen -1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.136.

The described program of-1-ketone (chemical compound no.38), by 11-(3-benzyloxy phenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 437 makes this title compound 136:m/z=467 (M+H) ⁺

Embodiment 78:11-(4-Phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.435.

According to for 11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza The described program of-1-ketone 5-3 makes this title compound 435:m/z=411 (M+H) by intermediate 5-2 and 4-phenoxy benzaldehyde ⁺

Embodiment 79:10-acetyl group-11-(4-Phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen -1H-dibenzo [b, e] [1,4] diaza -1-ketonic compound no.134.

The described program of-1-ketone (chemical compound no.38), by 11-(4-Phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 435 makes this title compound 134:m/z=453 (M+H) ⁺.

Embodiment 80:11-[4-(2-bromine phenoxy group) phenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-two Benzo [b, e] [1,4] diaza

-1-ketonic compound no.442.

The described program of-1-ketone 5-3 makes this title compound 442:m/z=490 (M+H) by intermediate 5-2 and 4-(2-bromine phenoxy group) benzaldehyde ⁺

Embodiment 81:10-acetyl group-11-[4-(2-bromine phenoxy group) phenyl]-3,3-dimethyl-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.147.

The described program of-1-ketone (chemical compound no.38) is by 11-[4-(2-bromine phenoxy group) phenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketone 442 makes this title compound 147:m/z=532 (M+H) ⁺

Embodiment 82:11-(3-Phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.433.

According to for 11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza The described program of-1-ketone 5-3 makes this title compound 433:m/z=411 (M+H) by intermediate 5-2 and 3-phenoxy benzaldehyde ⁺

Embodiment 83:11-(3-Phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.135.

The described program of-1-ketone (chemical compound no.38), by 11-(3-Phenoxyphenyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza -1-ketone 433 makes this title compound 135:m/z=453 (M+H) ⁺

Embodiment 84:11-[3-(2-bromine phenoxy group) phenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-two Benzo [b, e] [1,4] diaza

-1-ketonic compound no.446.

The described program of-1-ketone 5-3 makes this title compound 446:m/z=490 (M+H) by intermediate 5-2 and 3-(2-bromine phenoxy group) benzaldehyde ⁺

Embodiment 85:10-acetyl group-11-[3-(2-bromine phenoxy group) phenyl]-3,3-dimethyl-2,3,4,5,10,11- Six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.149

The described program of-1-ketone (chemical compound no.38) is by 11-[3-(2-bromine phenoxy group) phenyl]-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 446 makes this title compound 149:m/z=532 (M+H) ⁺

Embodiment 86:7,8-dimethoxy-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six Hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.467

The described program of-1-ketone 5-3, by 2, the 4-dichlorobenzaldehyde makes this title compound 467:m/z=447 (M+H) ⁺

Embodiment 87:10-acetyl group-7,8-dimethoxy-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.309

The described program of-1-ketone (chemical compound no.38), by 7,8-dimethoxy-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 467 makes this title compound 309:m/z=489 (M+H) ⁺

Embodiment 88:7,8-two fluoro-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H- Dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.466

The described program of-1-ketone 5-3, by 2, the 4-dichlorobenzaldehyde makes this title compound 466:m/z=423 (M+H) ⁺

Embodiment 89:10-acetyl group-7,8-two fluoro-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl -2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.310

The described program of-1-ketone (chemical compound no.38), by 7,8-two fluoro-11-(2, the 4-Dichlorobenzene base)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 466 makes this title compound 310:m/z=465 (M+H) ⁺

Embodiment 90:11-(2, the 4-Dichlorobenzene base)-3-methyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound no.422

The described program of-1-ketone 5-3, by 2, the 4-dichlorobenzaldehyde makes this title compound 422:m/z=373 (M+H) ⁺

Embodiment 91:10-acetyl group-11-(2, the 4-Dichlorobenzene base)-3-methyl-2,3,4,5,10,11-six hydrogen-1H-two Benzo [b, e] [1,4] diaza

-1-ketonic compound no.294

The described program of-1-ketone (chemical compound no.38), by 11-(2, the 4-Dichlorobenzene base)-3-methyl-2,3,4,5,10,11-six hydrogen-1H-dibenzo [b, e] [1,4] diaza

-1-ketone 442 makes this title compound 294:m/z=415 (M+H) ⁺

Embodiment 92

Option A

With a-1 (0.0022mol) at Ac ₂Mixture among the O (10mL) stirs and refluxed 1 hour.The DMAP that adds the most advanced and sophisticated amount of spoon (tip spat).Mixture was stirred 1 hour.Add H ₂O.With mixture CH ₂Cl ₂Extraction.Organic layer is separated, dry (through MgSO ₄), filtration is also extremely dry with solvent evaporation.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 99/1/0.05).Collect pure fraction, and with solvent evaporation.With residue crystallization from 2-acetone (on a small quantity)/ether/EtOH.Precipitation is leached and drying, obtain 0.352g chemical compound no.48 (fusing point: 216 ℃).

Option b

(0.024mol 0.54g) is added to b-1 (0.0006mol) and is dissolved in the solution in the pyridine (6mL) b-2 in 0 ℃.With mixture in stirring at room 12 hours.In 0 ℃ add again b-2 (0.0024mol, 0.54g).Mixture was stirred 24 hours, be evaporated to drying then.Residue is dissolved in CH ₂Cl ₂In.With organic layer H ₂The O washing, dry (through MgSO ₄), filter and with solvent evaporation.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH 98/2).Collect pure fraction, and with solvent evaporation.With residue crystallization from the 2-acetone.Precipitation leached and dry, obtained 0.089g chemical compound no.45 (fusing point＞250 ℃).

Scheme C

The mixture of c-1 (0.0003mol) in c-2 (5mL) in stirring at room 12 hours, cooled off in ice bath then.Drip H ₂O.Mixture is dissolved in CH ₂Cl ₂In.Organic layer is separated, dry (through MgSO4), filtration is also extremely dry with solvent evaporation.With residue (0.165g) from CH ₃Crystallization among the CN.Precipitation leached and dry, obtain 0.089g chemical compound no.107 (74%) (fusing point＞260 ℃).

Scheme D

In 0 ℃ Ac ₂O (2mL) is added drop-wise to d-1 (0.0052mol) and is dissolved in the solution in the pyridine (50mL).With mixture in stirring at room 12 hours.Add Ac again in 0 ℃ ₂O (2mL).With mixture in stirring at room 12 hours.With sedimentation and filtration, use H ₂O washing is also dry, obtains: 1.67g chemical compound no.38 (75%) (fusing point＞260 ℃).

Scheme E

Mixture in DMF (2mL) stirred 10 minutes with e-1 (0.0004mol) and NaH (0.0004mol).Add CH then ₃I (0.0004mol).Mixture in stirring at room 12 hours, and is evaporated to drying.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH99/1; 10 μ m).Collect pure fraction, and with solvent evaporation.With residue crystallization from the 2-acetone.Precipitation is leached and drying, obtain 0.037g chemical compound no.322 (20%) (fusing point: 145 ℃).

Scheme F

Mixture in toluene (20mL) stirs and refluxed 12 hours with f-1 (0.0057mol) and f-2 (0.0057mol), then concentrating under reduced pressure.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 96/4/0.2).Collect two fraction and solvent evaporation is extremely dry, obtain the mixture (71%) of f-3 and f-4.

Mixture in EtOH (10mL) and AcOH (10mL) is evaporated to drying then in 75 ℃ of stirrings 12 hours with f-3+f-4 (0.004mol) and f-5 (0.004mol).Residue is dissolved among the EtOAc.Add saturated NaHCO ₃Residue was stirred 1 hour 30 minutes, filter then and extract with EtOAc.Organic layer is separated, dry (through MgSO ₄), filtration is also extremely dry with solvent evaporation.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH99.5/0.5).Collect three fraction and with solvent evaporation, obtain: the mixture of 0.2g f-7,1g f-6+f-7 and 0.1g f-6 (fusing point: 170 ℃).

With f-6+f-7 (0.0004mol) at Ac ₂Mixture among the O (5mL) stirs and refluxed 4 hours, then concentrating under reduced pressure.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 97/3/0.1).Collect two fraction and with solvent evaporation, obtain: 0.065g f-9 and 0.09g f-8.With part f-8 crystallization from ether/2-acetone.Precipitation leached and dry, obtain 0.03g (fusing point＞260 ℃).

Scheme G

Program according to describing among the embodiment 5 makes this title compound 139:m/z=501 (M+H) by intermediate (5-2) and 4-benzyloxy-3-chlorobenzaldehyde ⁺

(R) of separating compound no.139-and (S)-enantiomer.

Described two enantiomer are used chiral column (eluant: CO by SFC ₂/ CH ₃OH 40/60) separate.Collect two fraction and with solvent evaporation, obtain: 0.085g enantiomer A and 0.085g enantiomer B.With two fraction crystallizations from DIPE/2-acetone.Precipitation is leached and drying, obtain 0.042g chemical compound no.303 (enantiomer A) (fusing point: 130 ℃) and 0.055g chemical compound no.304 (enantiomer B) (fusing point: 130 ℃).

Scheme H

With h-1 (0.0004mol), Zn (CN) ₂(0.0007mol), Pd ₂Dba ₃(0.022g), dppf (0.033g), Zn (0.0002mol) and Zn (OAc) ₂(0.0002mol) mixture in DMA (2mL) in 130 ℃ of stirrings 30 minutes, is poured H into then in microwave oven ₂Extract among the O and with EtOAc.With organic layer H ₂The O washing, dry (through MgSO ₄), filtration is also extremely dry with solvent evaporation.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ EtOAc 95/5).Collect pure fraction, and with solvent evaporation.With residue (0.14g) from CH ₃Crystallization among the CN.Precipitation is leached and drying, obtain 0.06g h-2 (fusing point: 225 ℃).

With h-2 (0.0002mol) at Ac ₂Mixture among the O (4mL) stirs and refluxed 12 hours, is evaporated to drying then.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH98/2).Collect pure fraction, and with solvent evaporation.With residue (0.07g) crystallization from the 2-acetone.Precipitation is leached and drying.Obtain: 0.025g chemical compound 313 (fusing point: 248 ℃).

Scheme I

Mixture in toluene (50mL) stirs in Dean and Stark apparatus and refluxed 12 hours with i-1 (0.0094mol) and i-2 (0.0094mol), is cooled to room temperature then.Precipitation is leached and drying, obtain 2.3g i-3 (76%).

Mixture in EtOH (12.44mL) and AcOH (1.23mL) is evaporated to drying then in 75 ℃ of stirrings 12 hours with i-3 (0.0044mol) and i-4 (0.0044mol).Residue is dissolved in EtOAc/NaHCO3 10% aqueous solution (aq).Mixture in stirring at room 1 hour 30 minutes, is leached and dry then.Residue (0.4g) is washed with EtOAc, and dry (through MgSO4) filters also that solvent evaporation is extremely dry.Residue (1.77g) is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 98.5/1.5/0.1).Collect pure fraction and with solvent evaporation, obtain: 1g I-5 (52%).With the crystallization from CH3CN/DIPE (fusing point: 208 ℃) of a small amount of fraction.The residue fraction of i-5 is used for next reactions steps.

With i-5 (0.0008mol) at Ac ₂Mixture among the O (60mL) stirs and refluxed 4 hours, is evaporated to drying then, obtains: the i-6 of 0.46g (100%).

In 0 ℃ at N ₂Flow down an i-6 (0.0059mol) and be added to LiAlH ₄(0.0018mol) in the suspension in THF (4mL).Mixture was stirred 3 hours in 0 ℃.Add EtOAc and ice successively.Mixture is extracted with EtOAc.Organic layer is separated, dry (through MgSO4), filtration is also extremely dry with solvent evaporation.Residue (0.175g) is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 95/5/0.5 to 93/7/0.7).Collect pure fraction and with solvent evaporation, obtain: 0.032g i-7 (12%) (200 ℃ of fusing points).

With i-7 (0.0005mol) and MnO ₂(1.5g) at CH ₂Cl ₂Mixture (10mL) filters and uses CH through Yin Shi salt then in stirring at room 3 hours ₂Cl ₂Washing.Filtrate is evaporated to drying.With residue from CH ₃Crystallization among the CN/DIPE.Precipitation is leached and drying, obtain 0.12g i-8 (48%).

With the BH on i-8 (0.0001mol), i-9 (0.0001mol), the solid support ₃CN (0.0001mol) and AcOH (5) are at CH ₃Mixture among the OH (5mL) was in stirring at room 5 hours.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH94/6/0.6 to 82/18/1.8).Collect pure fraction, and with solvent evaporation.With residue (0.035g) from CH ₃Crystallization among the CN.Precipitation is leached and drying.Obtain: 0.022g chemical compound no.514 (31%) (fusing point: 258 ℃).

Scheme J

With j-1 (0.0004mol) and LiOH (0.0009mol) at THF (20mL) and H ₂Mixture among the O (20mL) stirred 36 hours in 50 ℃.THF is evaporated.It is 7 that mixture is acidified to pH with 1N HCl.With sedimentation and filtration.Filtrate is used 10%K ₂CO ₃Alkalization.With water layer 1NHCl acidify.Precipitation is leached and drying, obtain 0.092gj-2 (60%).

With j-2 (0.0001mol), j-3 (0.0003mol), EDCI (0.0003mol) and HOBT (0.0003mol) at CH ₂Cl ₂(4mL) and the mixture among the THF (2mL) in stirring at room 6 hours, pour H into ₂Among the O and use CH ₂Cl ₂Extraction.Organic layer is separated, dry (through MgSO ₄), filtration is also extremely dry with solvent evaporation.Residue (0.1g) is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 92/8/0.8 to 78/20/2).Collect pure fraction, and with solvent evaporation.With residue (0.054g) from CH ₃Crystallization among the CN/DIPE.Precipitation is leached and drying, obtain 0.048g chemical compound no.515 (fusing point: 226 ℃).

Scheme K

NaH (0.0001mol) is added to k-1 (0.0005mol) to be dissolved in the solution among the DMF (2.5mL).Mixture was stirred 10 minutes.Add k-2 (0.0001mol).Mixture in stirring at room 12 hours, is evaporated to drying then.Residue (0.45g) is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH 98/2).Collect pure fraction, and with solvent evaporation.With residue (0.2g) crystallization from 2-acetone.Precipitation is leached and drying, obtain 0.043g chemical compound no.323 (fusing point: 235 ℃).

Scheme L

With 1-1 (0.0003mol), 1-2 (0.0004mol) and NEt ₃(0.065mL) at CH ₂Cl ₂Mixture (4mL) was in stirring at room 48 hours.In stirring at room 12 hours, pour mixture into H then ₂O/CH ₂Cl ₂In.Organic layer is separated, dry (through MgSO ₄), filter and with solvent evaporation.Residue (0.13g) is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 99/1/0.1 to 94/6/0.6).Collect pure fraction, and with solvent evaporation.With residue (0.05g) from CH ₃Crystallization among the CN/DIPE.Precipitation leached and dry, obtain 0.041g chemical compound no.151 (23%) (fusing point＞260 ℃).

Scheme M

Mixture in THF (5mL) stirs and refluxed 1 hour 30 minutes with m-1 (0.0002mol) and m-2 (0.0003mol), is dissolved in H then ₂O/CH ₂Cl ₂In, and use CH ₂Cl ₂Extraction.Organic layer is separated, dry (through MgSO ₄), filtration is also extremely dry with solvent evaporation.With residue from CH ₃Crystallization among the CN/DIPE (on a small quantity).Precipitation leached and dry, obtains 0.064g chemical compound no.156 (53%) (fusing point＞260 ℃).

Scheme N

Mixture in toluene (20mL) stirs in Dean and Stark apparatus and refluxed 12 hours with n-1 (0.01mol) and n-2 (0.01mol), is evaporated to drying then, obtains: 3g n-3+n-4.This mixture of product is directly used in next reactions steps.

Mixture in EtOH (25mL) and AcOH (25mL) is evaporated to drying then in 75 ℃ of stirrings 12 hours with n-3+n-4 (0.01mol) and n-5 (0.01mol).Residue is dissolved in EtOAc and saturated NaHCO ₃In the solution.Mixture was stirred 1 hour 30 minutes, filter then.Water layer is extracted with EtOAc.Organic layer is separated, dry (through MgSO ₄), filter and with solvent evaporation.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂100).Collect pure fraction and with solvent evaporation, obtain: 1.25g n-6+n-7.

Ac ₂O (1mL) is added to n-6+n-7 (0.0012mol) and is dissolved in the solution in the pyridine (10mL).Mixture in stirring at room 12 hours, is evaporated to drying then.Residue (0.54g) is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 98/2/0.2-92/8/0.8).Collect two fraction and with solvent evaporation, obtain: 0.14g F1 (24%) and 0.15gF2 (25%).With the crystallization from the 2-acetone of each fraction.Precipitation is leached and drying.Obtain: n-8 (fusing point＞250 ℃) and n-9 (fusing point＞250 ℃).

Scheme O

With o-1 (0.003mol) and LiAlH ₄(0.012mol) mixture in THF (60mL) was in stirring at room 2 hours.Add H carefully ₂O and NaOH 3M.Mixture was stirred 1 hour.With mixture CH ₂Cl ₂/ CH ₃OH (on a small quantity) extraction.Organic layer is separated, dry (through MgSO ₄), filtration is also extremely dry with solvent evaporation.With residue H ₂The O washing is also dry, obtains: 1.54g o-2 (100%).Small part (0.07g) is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 98/2/0.2 to 92/8/0.8).Collect pure fraction and with solvent evaporation, obtain: 0.022g.Resultant product is used for next reactions steps.

Dess Martin reagent (13.34mL) is added to o-2 (0.0031mol) in room temperature is dissolved in CH ₂Cl ₂In the solution (11.6mL).With mixture in stirring at room 1 hour.Add saturated NaHCO ₃And Na ₂S ₂O ₄With mixture CH ₂Cl ₂Extraction.Organic layer is separated, dry (through MgSO ₄), filtration is also extremely dry with solvent evaporation.With residue from CH ₃Crystallization among the CN.Precipitation is leached and drying, obtain the o-3 of 1.3g.

With o-3 (0.0002mol), dimethylamine (0.0006mol), BH on solid support ₃CN (0.0006mol) and AcOH (4) are at CH ₃Mixture among the OH (5mL) was in stirring at room 12 hours.Add the BH on dimethylamine (0.5 equivalent) and the solid support again ₃CN (0.5 equivalent).Mixture in stirring at room 12 hours, is filtered then.Filtrate is evaporated.Mixture is dissolved in CH ₂Cl ₂/ H ₂Among the O.Organic layer is separated, and dry (through MgSO4) filters and with solvent evaporation.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH97/3/0.5).Collect pure fraction, and with solvent evaporation.With residue (0.085g) from CH ₃Crystallization among the CN/DIPE.Precipitation leached and dry, obtain 0.056g chemical compound no.516 (52%) (fusing point＞260 ℃).

Scheme P

With p-1 (0.0001mol) and LiOH/H ₂O (0.0004mol) is at THF/H ₂The mixture of O (1/1) in (10mL) is in stirring at room 12 hours, concentrating under reduced pressure then.Water layer is washed acid and filtration with 1N HCl furnishing with ether.To precipitate dryly, obtain: 0.045g chemical compound no.517 (fusing point＞250 ℃).

Scheme Q

Q-2 (0.0012mol) is added drop-wise to q-1 (0.001mol) and NEt ₃(0.0012mol) in the mixture in THF (5mL).Mixture is stirred and refluxed 12 hours, be cooled to room temperature then.With sedimentation and filtration, wash with THF.Filtrate is evaporated.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 98/2/0.2,93/7/0.7 then 94/6/0.6).Collect pure fraction, and with solvent evaporation.With residue (0.09g, 18%) crystallization from 2-acetone.Precipitation is leached and drying.Obtain: q-3 (fusing point: 190 ℃).

With q-3 (0.0001mol) and LiOH/H ₂O (0.0002mol) is at THF (5mL) and H ₂Mixture among the O (5mL) was in stirring at room 3 hours.THF is evaporated.With residue CH ₂Cl ₂Extraction.With water layer 3N HCl furnishing acidity.Mixture is leached and drying, obtain: 0.055g chemical compound no.518 (83%) (fusing point: 200 ℃).

Scheme R

Mixture in toluene (100mL) stirs in the Rodney Stark device of Dean and refluxed 12 hours with r-1 (0.02mol) and r-2 (0.02mol).Solution decompression is concentrated, and residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 95/5/0.5).Collect pure fraction and, obtain the mixture of 2.04g r-3+r-4 solvent evaporation.

Mixture in EtOH (30mL) and AcOH (3mL) is evaporated to drying then in 75 ℃ of stirrings 12 hours with r-3+r-4 (0.0063mol) and r-5 (0.0035mol).Residue is dissolved in EtOAc and saturated NaHCO ₃In the solution.Mixture was stirred 1 hour 30 minutes, filter and extract with EtOAc.Organic layer is separated, dry (through MgSO ₄), filter and with solvent evaporation.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH98.5/1.5/0.1).Collect pure fraction and, obtained the mixture of 0.072g r-6+r-7 solvent evaporation.

The mixture of r-6+r-7 (0.0004mol) in C (5mL) stirred and refluxed 2 hours, be evaporated to drying then.Residue (0.2g) is passed through purification by silica gel column chromatography (eluant: toluene/iPrOH/NH ₄OH 90/10/0.5).Collect two fraction and with solvent evaporation.Obtain: 0.125g F1 and 0.037g F2.With fraction crystallization from the 2-acetone separately.Precipitation leached and dry, obtain 0.034g chemical compound no.319 (r-8) (fusing point＞250 ℃) and 0.008g chemical compound no.318 (r-9) (fusing point＞250 ℃).

Scheme S

S-1 (0.0001mol) is carried out purification (eluant: CO by SFC with chiral column ₂/ iPrOH65/35).Collect two fraction and with solvent evaporation, obtain: 0.02g chemical compound no.306 (enantiomer A) and 0.018g chemical compound no.305 (enantiomer B).

Scheme T

T-1 (0.1g) is carried out purification (eluant: EtOH/2-propanol 50/50), obtain 0.054g chemical compound no.302 (enantiomer A) and 0.044g chemical compound no.301 (enantiomer B) through Chiracel pack OD by column chromatography.

Scheme U

TBuOK (0.00044mol) is added to u-2 (0.00044mol) in 0 ℃ in batches to be dissolved in the solution among the THF (5mL).Mixture was stirred 15 minutes in this temperature, add u-1 (0.00022mol) then.To react on stirring at room 2 hours, pour in the water then.With solution 3NHCl acidify, and use CH ₂Cl ₂Extraction.With the organic layer drying (through MgSO ₄), filter and concentrating under reduced pressure.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH95/5/0.5).Collect pure fraction and, obtained the u-3 (95%) of 0.1g solvent evaporation.

With u-3 (0.1g), Raney nickel (0.1g) at NH ₃Mixture in the solution of/MeOH 7N (10mL) under 3 bar pressures in room temperature hydrogenation 8 hours.Then solution is filtered with MeOH by Yin Shi salt pad, and concentrating under reduced pressure.Residue is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 85/15/1).Collect pure fraction and, obtain 0.024g solvent evaporation.With residue from CH ₃Crystallization among the CN/DIPE has obtained 0.013g chemical compound no.519 (TMC533774) (13%) (242 ℃ of fusing points).

Embodiment 93:3-(2-benzyloxy phenyl)-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-hexichol And [b, e] [1,4] diaza

-1-ketone: chemical compound 417 (diastereomer A) and chemical compound 419 are (non-right Reflect body B)

(200mg, 0.520mmol) with 2, (91mg, 0.520mmol) solution that is dissolved among anhydrous EtOH of 10mL and the 1mL AcOH heated 5 hours in 75 ℃ the 4-dichlorobenzaldehyde with intermediate (1-4).With solvent evaporation.Residue is dissolved among the EtOAc, and with saturated NaHCO ₃Aqueous solution stirred 1.5 hours together, and dry (Na ₂SO ₄).Obtained two diastereomers, and (gradient elution is from heptane/EtOAc 4: 1-2: 1) to obtain o.417 diastereomer A of final compound N, (yield: 118mg, 41.1%): m/z=542 (M+H) by the hurried column chromatography purification of silica gel with it ⁺And final compound N diastereomer B (yield: 57mg, 20.2%): m/z=542 (M+H) o.419 ⁺

Embodiment 94:3-(2-benzyloxy phenyl)-11-(3-benzyloxy phenyl)-2,3,4,5,10,11-six hydrogen-hexichol And [b, e] [1,4] diaza

-1-ketonic compound No.418 (diastereomer A) and compound N o.420

(diastereomer B.

According to for compound N os.417 and 419 described programs, by intermediate (1-4) and the preparation of 3-benzyloxy benzaldehyde and isolate this title compound: m/z=580 (M+H) ⁺

Embodiment 95:11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.423.

Steps A.

With 1,1-Dimethyl-3,5-diketocyclohexane (95-7,5.0g, 35.67mmol) and ortho-phenylene diamine (3.86g 35.69mmol) is dissolved in solution in the 150mL dry toluene and refluxes in Dean-Rodney Stark catcher and spend the night.After 24 hours,,, be orange foam, it is used for next step under situation about not being further purified to obtain intermediate (95-8) with solvent evaporation.

Step B.

With intermediate (95-8) (35.7mmol) and 2, (6.24g 35.65mmol) is dissolved in solution in the mixture of anhydrous EtOH of 100mL and 10mL AcOH in 75 ℃ of heated overnight to the 4-dichlorobenzaldehyde.Reactant mixture is cooled to room temperature, and with solvent evaporation.Residue is dissolved among the EtOAc, and with saturated NaHCO ₃Aqueous solution stirred 1.5 hours together.Then, in separatory funnel, take out water layer, and organic layer is leached, filtrate is used the EtOAc washed twice.With organic layer drying (Na ₂SO ₄), evaporation, and residue is dry under fine vacuum, obtain the final compound N of 9.45g (68.4%) o.423:m/z=387 (M+H) ⁺

Embodiment 96:11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3,10-trimethyl-1H-hexichol And [b, e] [1,4] diaza

-1-ketonic compound No.507.

Methyl iodide (97 μ L, 1.555mmol) be added to compound N o.423 (0.50g, 1.291mmol) and K ₂CO ₃(214mg 1.55mmol) is dissolved in the solution in the acetone.With the seal of tube and in stirred overnight at room temperature.(146 μ L, 2.34mmol), and the pipe that will seal stirred 2 days to add methyl iodide again.Reactant mixture is added drop-wise in the water, and solid is leached and drying.By preparation type TLC purification (EtOAc/ heptane 1: 1), then at i-Pr ₂Carry out supersound process and filtration among the O, obtain final compound N o.507:m/z=401 (M+H) ⁺

Embodiment 97:11-(2, the 4-Dichlorobenzene base)-10-ethyl-2,3,4,5,10,11-six hydrogen-3,3-dimethyl 1H- Dibenzo [b, e] [1,4] diaza -1-ketonic compound No.508

According to for the o.507 described program of compound N, by compound N o.423 and ethyl iodide (1mL 12.5mmol) makes this title compound m/z=415 (M+H) ⁺

Embodiment 98:11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl-10-propyl group-1H- Dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.509

According to for the o.507 described program of compound N, by compound N o.423 and propyl iodide (1.26mL 12.9mmol) makes this title compound m/z=429 (M+H) ⁺

Embodiment 99:11-(1-bromo-2-phenyl vinyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.500

According to for the o.423 described program of compound N, (11.9mmol) (2.51g 11.9mmol) makes this title compound: m/z=424 (M+H) with 2-bromo-3-phenylacrolein by intermediate (95-8) ⁺

Embodiment 100:11-(1-chloro-2-phenyl vinyl)-3,3-dimethyl-2,3,4,5,10,11-six hydrogen-hexichol And [b, e] [1,4] diaza

-1-ketonic compound No.506

According to for the o.423 described program of compound N, by intermediate (95-8) (11.9mmol) and 2-chloro-3-phenylacrolein (1.98g, 11,88mmol) make this title compound: m/z=380 (M+H) ⁺

Embodiment 101:11-[3-(4-chlorobenzene formacyl oxygen base) phenyl]-3,3-dimethyl-2,3,4,5,10,11-six Hydrogen-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.431.

According to for the o.423 described program of compound N, by intermediate (95-8) (3.9mmol) and the 3-[(4-chlorobenzene formacyl) the oxygen base] (1.03g 3.95mmol) makes this title compound to benzaldehyde: m/z=474 (M+H) ⁺

Embodiment 102:11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3,7,8-tetramethyl-1H-two Benzo [b, e] [1,4] diaza

-1-ketonic compound No.464.

According to for the o.423 described program of compound N, by 4, (2.48g, 18.21mmol) with 2, (3.19g 18.23mmol) makes this title compound to the 4-dichlorobenzaldehyde to 5-dimethyl-ortho-phenylene diamine: m/z=416 (M+H) ⁺

Embodiment 103:11-[3-(4-chlorobenzene formacyl oxygen base) phenyl]-3-(2-benzyloxy phenyl)- 2,3,4,5,10,11-six hydrogen-dibenzo [b, e] [1,4] diaza The non-mapping of-1-ketonic compound No.512 Body A

According to for the o.417 described program of compound N, by intermediate (93-4) (300mg, 0.780mmol) and 3-[(4-chlorobenzene formacyl) oxygen base] (244mg 0.936mmol) makes this title compound to benzaldehyde: m/z=628 (M+H) ⁺

Embodiment 104:3-(2-benzyloxy phenyl)-11-[3-(4-chlorobenzene formacyl oxygen base) benzene Base]-2,3,4,5,10,11-six hydrogen-dibenzo [b, e] [1,4] diaza

-1-ketone-compound N is o.513 non- Enantiomer B

According to for the o.419 described program of compound N, by intermediate (93-4) (300mg, 0.780mmol) and 3-[(4-chlorobenzene formacyl) oxygen base] (244mg 0.936mmol) makes this title compound to benzaldehyde: m/z=628 (M+H) ⁺

Embodiment 105:7,8-two chloro-11-(2, the 4-Dichlorobenzene base)-2,3,4,5,10,11-six hydrogen-3,3-dimethyl -1H-dibenzo [b, e] [1,4] diaza

-1-ketonic compound No.465

According to for the o.423 described program of compound N, by 4,5-two chloro-ortho-phenylene diamines and 2, the 4-dichlorobenzaldehyde makes this title compound: m/z=455 (M+H)+.

Embodiment 106

Plan V

Mixture in toluene (50mL) stirs in Dean and Stark apparatus and refluxed 12 hours with v-1 (0.0089mol) and v-2 (0.0089mol), is cooled to room temperature then.With sedimentation and filtration,, obtain: 2g v-3 (100%) with ether washing and dry.

Mixture in AcOH (2.6mL) and EtOH (50mL) is cooled to room temperature and concentrating under reduced pressure then in 75 ℃ of stirrings 24 hours with v-3 (0.0106mol) and v-4 (0.0106mol).Residue is dissolved in CH ₂Cl ₂In.With organic layer K ₂CO ₃10% washing, dry (through MgSO ₄), filter and with solvent evaporation.Residue (5.7g) is passed through purification by silica gel column chromatography (eluant: CH ₂Cl ₂/ CH ₃OH/NH ₄OH 100/0/0-99/1/0.1).Collect three fraction, and with solvent evaporation, obtain: 0.27g v-5 (4.5%) (fusing point＞260 ℃), 0.4g v-6 (6.7%) and 0.34g v-7 (5.7%) (fusing point＞260 ℃).

With v-6 (0.0006mol) and NH ₂-NH ₂/ H ₂The mixture of O (0.003mol) in EtOH (20mL) stirs and refluxed 6 hours, then concentrating under reduced pressure.With residue from CH ₃Crystallization among the CN.Precipitation is leached and drying, obtain 0.12g (50%).Partly this fraction (0.04g) is from CH ₃Crystallization among the CN.Precipitation is leached and drying, obtain 0.03g v-8 (fusing point: 248 ℃).

Scheme W

W-2 (0.0024mol) is added to w-1 (0.0021mol) and NEt in 5 ℃ ₃(0.0032mol) be dissolved in CH ₂Cl ₂In the solution (15mL).Mixture was stirred 2 hours in 5 ℃, then in stirring at room 2 hours.With sedimentation and filtration, use CH ₂Cl ₂Washing is also dry, obtains: 0.15g w-3 (17%) (fusing point: 240 ℃).

The mixture of w-3 (0.0001mol) and PPA (1.4g) was stirred 3 hours in 130 ℃, be cooled to room temperature then, and be dissolved in K ₂CO ₃In 10%.With sedimentation and filtration, use H ₂The O washing also is dissolved in CH ₂Cl ₂In.Organic layer is separated, dry (through MgSO ₄), filter, use H ₂The O washing, and solvent evaporation is extremely dry.With residue from CH ₃Crystallization among the CN/DIPE.Precipitation is leached and drying, obtain 0.032g w-4 (44%) (fusing point: 252 ℃).

The compounds of this invention is listed in the following table, comprises chemical compound according to the preparation of embodiment 1-106 above.All the other listed chemical compounds can adopt with similar method described in the embodiment and prepare in the table.In these tables, compound number suffix A represents diastereomer A, i.e. the diastereomer of eluting at first from tomographic system; Compound number suffix B represents diastereomer B, i.e. the diastereomer of next eluting from tomographic system.Chemical compound is the mixture of heterogeneous type under other situation.

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

Table 17

Antivirus test

In the mensuration of measuring its anti-NS5b polymerase activity with in the HCV replicon is measured, the anti-HCV activity of formula (I) chemical compound is tested.

A) the NS5b polymerase is measured

A) protein purification

To encode the cDNA sub-clone of NS5B amino acid/11-570 (pCV-J4L6S, genebank numbers AF054247 for HC-J4, genotype 1b) in the restriction site of the Nhe I of pET-21b and Xho I.The expression of the NS5B of terminal 21 aminoacid deletion of C-that carry out His-labelling subsequently as described below:

After in BL21 (DE3) competent cell, transforming, bacterial cell is grown very to reaching OD in 22 liters of LB/Amp culture medium ₆₀₀=0.4-0.6.Add with 10 μ M MgCl by interpolation ₂IPTG 0.4mM come induced protein to express, and in 20 ℃ of incubation 14-16 hours.Harvesting is resuspended in lysis buffer (20mM Tris-HCl pH=7.5,0.3M NaCl, 10% glycerol, 0.1%NP40,4mM MgCl with it ₂, the 14mM beta-mercaptoethanol has the tablet of the protease mixed inhibitor that does not contain EDTA) in, and come cracking by supersound process.Cell lysate by supercentrifugal process clarification (20K * g, 30 minutes), was caught on the Ni-NTA pearl 70 minutes in 4 ℃, and with 25mM Hepes pH7.5,0.5M NaCl, 10% glycerol, 14mM BME, 500mM imidazoles eluting.With eluant to 25mM Hepes pH7.5,10% glycerol, 50mMNaCl, after this 14mM BME dialysis is further purified protein by the heparin chromatography, wherein use the same buffer solution elution that contains 1M NaCl.Collection contains the fraction of true protein, to storage buffer 25mM Hepes pH=7.5,300mM NaCl, 10% glycerol, 14mMBME) dialysis, and in liquid nitrogen moment freeze.Described program obtains about 40mg protein.By the dyeing of SDS PAGE coomassie, judge that lipidated protein is at least 90%.

B) protein sequence

PDB:1nb4, apoenzyme (Apo) form

M A S S M S Y T W T G A L I T P C A A E E S K L P I N P L S N S L L R H H N M

V Y A T T S R S A S L R Q K K V T F D R L Q V L D D H Y R D V L K E M K A K

A S T V K A K L L S I E E A C K L T P P H S A K S K F G Y G A K D V R N L S S

R A V N H I R S V W E D L L E D T E T P I D T T I M A K S E V F C V Q P E K G

G R K P A R L I V F P D L G V R V C E K M A L Y D V V S T L P Q A V M G S S

Y G F Q Y S P K Q R V E F L V N T W K S K K C P M G F S Y D T R C P D S T V

T E S D I R V E E S I Y Q C C D L A P E A R Q A I R S L T E R L Y I G G P L T N

S K G Q N C G Y R R C R A S G V L T T S C G N T L T C Y L K A T A A C R A A

K L Q D C T M L V N G D D L V V I C E S A G T Q E D A A A L R A F T E A M T

R Y S A P P G D P p Q P E Y D L E L I T S C S S N V S V A H D A S G K R V Y Y

L T R D P T T P L A R A A W E T A R H T P I N S W L G N I I M Y A P T L W A R

M I L M T H F F S I L L A Q E Q L E K A L D C Q I Y G A C Y S I E P L D L P Q I

I E R L H G L S A F T L H S Y S P G E I N R V A S C L R K L G V P P L R T W R

H R A R S V R A K L L S Q G G R A A T C G R Y L F N W A V R T K L K L T P I

P A A S Q L D L S G W F V A G Y S G G D I Y H S L S R A R P R A A A L E H H

H H H H

Calculate molecular weight character (Calc.mol.Properties) 64941.4g/mol

C) biochemistry RdRD measures

Measure HCV NS5B polymerization activity by the following method: the amount of in using the assorted poly-new synthetic RNA of RNA template/primer, assessing the radiolabeled GTP that is mixed by enzyme.It is in the flat board of 384-hole that this high flux RdRp measures, and is used in 20mM Tris pH7.5,21mM KCl, 2.5mM DTT, the 200nM enzyme among 16.7mM NaCl and the 0.17mM EDTA, 0.1 μ Ci ³H GTP, 5mM MgCl ₂, 600nM GTP, 30nM PolyC, 300nM 5 '-biotinylated widow (rG13)/poly-(rC) carries out.Test compound is dissolved in the dimethyl sulfoxide.Test compound is added in the polymerase-template composite of carrying out, and, adds NTPs then room temperature (RT) incubation 15 minutes.After 2 hours, stop 30 μ l reaction 25 ℃ of reactions by adding 30-μ l PVT-SPA pearl (Amersham Biosciences RPNQ0009,5mg/ml is in 0.5M EDTA).After 25 ℃ of incubations 30 minutes, use Packard TopCount microtitration plate reader (30 seconds/hole, 1 minute count delay) to count flat board, and calculate the EC50 value.

B) replicon is measured

A) the fixed replicon cell reporter assay of urgency:

Checked chemical compound of the present invention activity aspect inhibition HCV rna replicon in raji cell assay Raji.This mensuration has proved that chemical compound of the present invention shows the activity of anti-HCV replicon function in cell culture.The basis of raji cell assay Raji is the bicistronic mRNA expression construct, describe as people such as Lohmann (1999) Science vol.285pp.110-113, doing improvement aspect many targets screening strategy by people such as Krieger (2001) Journal of Virology 75:4614-4624.In itself, this method is as mentioned below.

This mensuration has been utilized the cell line Huh-7 luc/neo (after this being known as Huh-Luc) of stable transfection.This cell line comprises the RNA of coding bicistronic mRNA expression construct, described expression construct comprises the wild type NS3-NS5B zone of HCV 1b type, its internal ribosome entry site by encephalomyocarditis virus (EMCV) (IRES) translation, its front are reporter molecule part (FfL-luciferase) and selected marker part (neo ^R, neomycin phosphotransferase) afterwards.This construct with 5 of HCV 1b type ' and 3 ' NTRs (untranslated region) be the border.At G418 (neo ^R) existence under, the continuous culture of replicon cell depends on duplicating of HCV RNA.The replicon cell of the stable transfection of expression of HCV RNA is used to screen antiviral compound, and described HCV RNA self-replicating also reaches high level, its luciferase of especially encoding.

B) raji cell assay Raji experimental technique:

The replicon cell is paved plate in 384 orifice plates of test that is added with various concentration and control compound existence.Behind the incubation 3 days, (use standard luciferase assay substrate and reagent, reach Perkin Elmer ViewLux by the activity of measuring luciferase ^TmUltraHTS microtest plate imager), measure duplicating of HCV.Replicon cell in control cultures has high luciferase expression under the situation that does not have any inhibitor.The monitoring chemical compound is for the inhibition activity of luciferase activity on the Huh-Luc cell, thereby makes and can access dose-response curve for each test compound.Calculate the IC50 value then, on behalf of the activity level that makes detected luciferase, this value reduce the amount of 50% needed chemical compound, perhaps more specifically is the replication capacity of the HCV replicon rna that is associated in heredity.

The activity of the chemical compound of test in measuring above being given in below.Band, promptly-, expression does not obtain the result.

Table 18

Table 19

Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)
Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)	324	＞42.612	＝18.527
325	＞42.612	＝16.290	324	＞42.612	＝18.527
325	＞42.612	＝16.290	326	＞33.333	＝4.692
327	＞33.333	＝12.494	326	＞33.333	＝4.692
327	＞33.333	＝12.494	328	＞42.670	＝22.713
329	＞33.333	＝11.085	328	＞42.670	＝22.713
329	＞33.333	＝11.085	330	＞42.680	＝23.202
331	＞42.663	＝7.441	330	＞42.680	＝23.202
331	＞42.663	＝7.441	332	＞42.675	＝9.740
333	＞42.678	-	332	＞42.675	＝9.740
333	＞42.678	-	334	＞42.670	-
335	＞42.672	＝11.929	334	＞42.670	-
335	＞42.672	＝11.929	336	＞42.664	＝13.762
337	＞42.660	＝17.547	336	＞42.664	＝13.762
337	＞42.660	＝17.547	338	＞42.664	＝16.895
339	＞42.664	＝9.154	338	＞42.664	＝16.895
339	＞42.664	＝9.154	340	＞42.673	＝5.094
341	＞42.667	＝3.926	340	＞42.673	＝5.094
341	＞42.667	＝3.926	342	＞42.663	＝4.193
343	＞42.658	＝10.962	342	＞42.663	＝4.193
343	＞42.658	＝10.962	344	＞42.664	＝21.600
345	＞42.662	＝21.008	344	＞42.664	＝21.600
345	＞42.662	＝21.008	346	＞42.666	＝24.584
347	＞42.672	＝20.700	346	＞42.666	＝24.584
347	＞42.672	＝20.700	348	＝29.574	＝4.476
349	＞42.677	＝2.863	348	＝29.574	＝4.476
349	＞42.677	＝2.863	350	＝25.136	＝5.213
351	＞42.672	-	350	＝25.136	＝5.213
351	＞42.672	-	352	＞42.665	＝9.608
353	＞42.667	＝5.304	352	＞42.665	＝9.608
353	＞42.667	＝5.304	354	＞42.664	＝20.534
355	＞42.666	＝5.483	354	＞42.664	＝20.534
355	＞42.666	＝5.483	356	＞42.665	＝16.095

Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)
Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)	357	＞42.666	＝7.006
358	＞42.670	＝20.435	357	＞42.666	＝7.006
358	＞42.670	＝20.435	359	＞42.663	＝7.332
360	＞42.667	＝11.225	359	＞42.663	＝7.332
360	＞42.667	＝11.225	361	＞42.667	＝6.650
362	＝30.574	＝19.271	361	＞42.667	＝6.650
362	＝30.574	＝19.271	363	＞42.667	＝25.826
364	＞42.667	＝20.793	363	＞42.667	＝25.826
364	＞42.667	＝20.793	365	＝27.340	＝5.240
366	＞42.667	＝5.308	365	＝27.340	＝5.240
366	＞42.667	＝5.308	367	＞42.667	＝24.606
368	＞42.667	＝14.940	367	＞42.667	＝24.606
368	＞42.667	＝14.940	369	＞42.667	＝10.001
370	＞42.667	＝3.425	369	＞42.667	＝10.001
370	＞42.667	＝3.425	371	＞42.667	＝3.737
372	＞42.667	＝1.944	371	＞42.667	＝3.737
372	＞42.667	＝1.944	373	＞42.667	＝9.415
374	＞42.667	＝10.106	373	＞42.667	＝9.415
374	＞42.667	＝10.106	375	＞42.667	＝19.933
376	＞42.667	＝9.450	375	＞42.667	＝19.933
376	＞42.667	＝9.450	377	＞42.667	＝4.463
378	＞42.667	＝5.944	377	＞42.667	＝4.463
378	＞42.667	＝5.944	379	＞42.667	＝6.789
380	＞42.667	＝8.626	379	＞42.667	＝6.789
380	＞42.667	＝8.626	381	＞42.667	＝4.766
382	＞42.667	＝16.660	381	＞42.667	＝4.766
382	＞42.667	＝16.660	383	＞42.667	＝17.252
384	＝4.582	＝15.911	383	＞42.667	＝17.252
384	＝4.582	＝15.911	385	＞42.667	＝3.535
386	＞42.667	＞29.590	385	＞42.667	＝3.535
386	＞42.667	＞29.590	387	＞42.667	＝5.558
388	＞42.667	＝6.350	387	＞42.667	＝5.558
388	＞42.667	＝6.350	389	＞42.667	＝5.577
390	＞42.667	＝9.067	389	＞42.667	＝5.577
390	＞42.667	＝9.067	391	＞42.667	＝18.488

Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)
Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)	392	＞42.667	＝22.649
393	＞33.333	＝6.844	392	＞42.667	＝22.649
393	＞33.333	＝6.844	394	＞42.667	＝14.075
395	＞42.667	＝9.906	394	＞42.667	＝14.075
395	＞42.667	＝9.906	396	＞42.667	＝11.306
397	＞42.667	＝6.131	396	＞42.667	＝11.306
397	＞42.667	＝6.131	398	＞42.667	＝10.911
399	＞42.667	＝19.434	398	＞42.667	＝10.911
399	＞42.667	＝19.434	400	＞42.667	＝3.278
401	＞42.667	＝2.880	400	＞42.667	＝3.278
401	＞42.667	＝2.880	402	＞42.667	＝8.593
403	＞42.667	＝7.115	402	＞42.667	＝8.593
403	＞42.667	＝7.115	404	＞42.667	＝3.242
405	＞42.667	＝5.344	404	＞42.667	＝3.242
405	＞42.667	＝5.344	406	＞42.667	＝7.290
407	＞33.333	＝15.646	406	＞42.667	＝7.290
407	＞33.333	＝15.646	408	＞33.333	＝14.159
409	＞33.333	＝14.892	408	＞33.333	＝14.159
409	＞33.333	＝14.892	410	＞33.333	＝22.575
411	＞33.333	＝17.869	410	＞33.333	＝22.575
411	＞33.333	＝17.869	412	＞33.333	＝16.678
413	＞33.333	＝12.031	412	＞33.333	＝16.678
413	＞33.333	＝12.031	414	＞33.333	＝13.640
415	＞33.333	＝14.666	414	＞33.333	＝13.640
415	＞33.333	＝14.666	416	＞33.333	＝11.166
417	＞42.667	＝8.328	416	＞33.333	＝11.166
417	＞42.667	＝8.328	418	＞42.667	＝2.162
419	＞42.667	＝4.815	418	＞42.667	＝2.162
419	＞42.667	＝4.815	420	＞42.667	＝3.235
421	＞133.334	＝51.929	420	＞42.667	＝3.235
421	＞133.334	＝51.929	423	＝37.863	＝26.399
424	＝11.606	＝12.534	423	＝37.863	＝26.399
424	＝11.606	＝12.534	425	＞42.674	＝13.245
426	＝30.781	＝7.306	425	＞42.674	＝13.245
426	＝30.781	＝7.306	427	＞42.667	＝20.672

Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)
Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)	428	＞42.667	＝15.991
429	＞42.667	＞30.966	428	＞42.667	＝15.991
429	＞42.667	＞30.966	430	＞33.333	＝10.832
431	＝82.880	＞100	430	＞33.333	＝10.832
431	＝82.880	＞100	449	＞42.667	＝1.211
450	＞42.667	＝4.517	449	＞42.667	＝1.211
450	＞42.667	＝4.517	451	＞33.333	＝11.324
452	＞42.680	＝19.688	451	＞33.333	＝11.324
452	＞42.680	＝19.688	453	＞42.664	＝19.174
454	＞42.667	＝3.435	453	＞42.664	＝19.174
454	＞42.667	＝3.435	455	＞42.667	＝5.070
456	＞42.667	＝17.759	455	＞42.667	＝5.070
456	＞42.667	＝17.759	457	＞42.667	＝2.636
458	＞42.667	＝22.916	457	＞42.667	＝2.636
458	＞42.667	＝22.916	459	＞42.667	-
460	＞42.667	＝15.648	459	＞42.667	-
460	＞42.667	＝15.648	461	＞42.667	＝24.525
462	＝30.855	＞25.000	461	＞42.667	＝24.525
462	＝30.855	＞25.000	463	＞33.333	＝7.432
464	＞133.334	＝82.697	463	＞33.333	＝7.432
464	＞133.334	＝82.697	475	＞42.661	-
465	＝59.958	＝3.838	475	＞42.661	-
465	＝59.958	＝3.838	476	＞42.667	＝22.889
477	＞42.667	＝4.492	476	＞42.667	＝22.889
477	＞42.667	＝4.492	478	＞42.667	＝2.405
479	＞42.667	-	478	＞42.667	＝2.405
479	＞42.667	-	480	＞42.667	＝5.695
481	＞42.667	＝1.609	480	＞42.667	＝5.695
481	＞42.667	＝1.609	482	＞42.667	＝27.029
483	＞42.667	＝15.517	482	＞42.667	＝27.029
483	＞42.667	＝15.517	484	＞42.667	＝6.647
485	＞42.667	＝3.388	484	＞42.667	＝6.647
485	＞42.667	＝3.388	486	＞42.667	＝3.305
487	＞42.667	＝3.149	486	＞42.667	＝3.305
487	＞42.667	＝3.149	488	＞42.667	＝17.821

Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)
Compound N o.	The NS5B polymerase is measured IC ₅₀(μM)	Replicon is measured EC ₅₀(μM)	489	＞42.667	＝5.905
490	＞42.667	＝24.862	489	＞42.667	＝5.905
490	＞42.667	＝24.862	491	＞42.667	＝12.070
492	＞42.667	＝11.024	491	＞42.667	＝12.070
492	＞42.667	＝11.024	493	＞42.667	＝1.302
494	＞42.667	＝21.678	493	＞42.667	＝1.302
494	＞42.667	＝21.678	495	＞42.667	＝3.692
496	＞42.667	＝22.875	495	＞42.667	＝3.692
496	＞42.667	＝22.875	499	＞42.667	＞31.959
500	＞133.334	＝26.452	499	＞42.667	＞31.959
500	＞133.334	＝26.452	501	＞42.678	＝19.781
502	＞42.678	＝13.195	501	＞42.678	＝19.781
502	＞42.678	＝13.195	503	＞42.668	＝22.390
504	＝39.062	＝17.106	503	＞42.668	＝22.390
504	＝39.062	＝17.106	505	＞42.667	＝13.457
506	＞42.667	＝56.654	505	＞42.667	＝13.457
506	＞42.667	＝56.654	507	＞42.667	＝4.632
508	＞42.667	＝1.366	507	＞42.667	＝4.632
508	＞42.667	＝1.366	509	＞42.667	＝0.894
512	＝84.493	＝8.418	509	＞42.667	＝0.894
512	＝84.493	＝8.418	513	＝70.082	＝3.672
422	＞133.334	＞100	513	＝70.082	＝3.672
422	＞133.334	＞100	432	＞42.667	＝17.691
433	＞133.334	＝3.811	432	＞42.667	＝17.691
433	＞133.334	＝3.811	434	＞133.334	＝22.924
435	＞133.334	＝6.699	434	＞133.334	＝22.924
435	＞133.334	＝6.699	436	＞133.334	＝19.689
437	＝32.922	＝6.350	436	＞133.334	＝19.689
437	＝32.922	＝6.350	438	＞133.334	＝15.402
439	＝3.631	＝4.332	438	＞133.334	＝15.402
439	＝3.631	＝4.332	440	＞133.334	＞100
441	＞133.334	＞100	440	＞133.334	＞100
441	＞133.334	＞100	442	＞133.334	＝2.706
443	＝0.312	＝1.778	442	＞133.334	＝2.706
443	＝0.312	＝1.778	444	＝33.230	＝4.449

Compound N o.	The NS5B polymerase is measured 1C ₅₀(μM)	Replicon is measured EC ₅₀(μM)
Compound N o.	The NS5B polymerase is measured 1C ₅₀(μM)	Replicon is measured EC ₅₀(μM)	445	＞133.334	＝1.984
446	＞133.334	＝4.125	445	＞133.334	＝1.984
446	＞133.334	＝4.125	447	＞133.334	＝2.518
448	＞133.334	＞100	447	＞133.334	＝2.518
448	＞133.334	＞100	466	＝68.053	＝6.808
467	＞133.334	＝30.030	466	＝68.053	＝6.808
467	＞133.334	＝30.030	468	＝25.627	＝5.175
469	＝32.310	＝8.242	468	＝25.627	＝5.175
469	＝32.310	＝8.242	470	＝23.314	＝16.518
471	＞133.334	＝14.691	470	＝23.314	＝16.518
471	＞133.334	＝14.691	472	＝9.354	＝16.965
473	＝49.962	＝19.998	472	＝9.354	＝16.965
473	＝49.962	＝19.998	474	＝1.721	＝34.082
497	＞133.334	＝3.786	474	＝1.721	＝34.082
497	＞133.334	＝3.786	498	＞133.334	＝2.922
510	＞133.334	＝4.563	498	＞133.334	＝2.922
510	＞133.334	＝4.563	511	＝1.902	＞100

In the table 20 below, listed the mass spectral analysis (MH+) and the melting point values of some The compounds of this invention.The indication for preparing the employed program of these chemical compounds also is provided.

Table 20

Compound N o.	MH+	Fusing point	According to following preparation
Compound N o.	MH+	Fusing point	According to following preparation	48	497	216	Embodiment 92 option As
45	491-495	＞250	Embodiment 92 option bs	48	497	216	Embodiment 92 option As
45	491-495	＞250	Embodiment 92 option bs	107	483-487	＞260	Embodiment 92 scheme C
38	429-433	＞250	Embodiment 92 scheme D	107	483-487	＞260	Embodiment 92 scheme C
38	429-433	＞250	Embodiment 92 scheme D	120	429	＞250	Embodiment 92 scheme D
124	497	215	Embodiment 92 scheme D	120	429	＞250	Embodiment 92 scheme D
124	497	215	Embodiment 92 scheme D	42	467	170	Embodiment 92 scheme D
273	421-423	258	-	42	467	170	Embodiment 92 scheme D
273	421-423	258	-	322	443-447	145	Embodiment 92 scheme E
302	467	-	Embodiment 92 scheme T	322	443-447	145	Embodiment 92 scheme E

301	467	-	Embodiment 92 scheme T
301	467	-	Embodiment 92 scheme T	311	507-513	＞260	Embodiment 92 scheme F
312	507-513	-	Embodiment 92 scheme F	311	507-513	＞260	Embodiment 92 scheme F
312	507-513	-	Embodiment 92 scheme F	139	501-503	197	Embodiment 92 scheme G
313	454-458	248	Embodiment 92 scheme H	139	501-503	197	Embodiment 92 scheme G
313	454-458	248	Embodiment 92 scheme H	314	443-447	-	Embodiment 92 scheme F
315	443-447	＞260	Embodiment 92 scheme F	314	443-447	-	Embodiment 92 scheme F
315	443-447	＞260	Embodiment 92 scheme F	316	454-458	-	Embodiment 92 scheme H
520	487-491	＞250	Embodiment 92 scheme N	316	454-458	-	Embodiment 92 scheme H
520	487-491	＞250	Embodiment 92 scheme N	521	487-491	＞250	Embodiment 92 scheme N
517	473-477	＞250	Embodiment 92 scheme P	521	487-491	＞250	Embodiment 92 scheme N
517	473-477	＞250	Embodiment 92 scheme P	522	473-477	-	Embodiment 92 scheme P
523	459-463	-	Embodiment 92 scheme O	522	473-477	-	Embodiment 92 scheme P
523	459-463	-	Embodiment 92 scheme O	524	459-463	-	Embodiment 92 scheme O
518	473-477	200	Embodiment 92 scheme Q	524	459-463	-	Embodiment 92 scheme O
518	473-477	200	Embodiment 92 scheme Q	525	473-477	＞260	Embodiment 92 scheme P
526	459-463	200	Embodiment 92 scheme O	525	473-477	＞260	Embodiment 92 scheme P
526	459-463	200	Embodiment 92 scheme O	304	501-503	130	Embodiment 92 scheme G
303	501-503	130	Embodiment 92 scheme G	304	501-503	130	Embodiment 92 scheme G
303	501-503	130	Embodiment 92 scheme G	318	454-458	＞250	Embodiment 92 scheme R
319	454-458	＞250	Embodiment 92 scheme R	318	454-458	＞250	Embodiment 92 scheme R
319	454-458	＞250	Embodiment 92 scheme R	527	571-575	236	Embodiment 92 scheme I
306	501-503	-	Embodiment 92 scheme S	527	571-575	236	Embodiment 92 scheme I
306	501-503	-	Embodiment 92 scheme S	305	501-503	-	Embodiment 92 scheme S
515	557-561	226	Embodiment 92 scheme J	305	501-503	-	Embodiment 92 scheme S
515	557-561	226	Embodiment 92 scheme J	321	585-589	＞260	Embodiment 92 scheme J
528	577-581	＞260	Embodiment 92 scheme J	321	585-589	＞260	Embodiment 92 scheme J
528	577-581	＞260	Embodiment 92 scheme J	514	543-547	258	Embodiment 92 scheme I
529	563-567	212	Embodiment 92 scheme I	514	543-547	258	Embodiment 92 scheme I
529	563-567	212	Embodiment 92 scheme I	323	519-523	235	Embodiment 92 scheme K
530	514-518	＞260	Embodiment 92 scheme I	323	519-523	235	Embodiment 92 scheme K

531	458-462	＞260	Embodiment 92 scheme O
531	458-462	＞260	Embodiment 92 scheme O	532	528-532	＞260	Embodiment 92 scheme I
151	454-458	＞260	Embodiment 92 scheme L	532	528-532	＞260	Embodiment 92 scheme I
151	454-458	＞260	Embodiment 92 scheme L	152	519-523	242	Embodiment 92 scheme L
153	481-485	＞260	Embodiment 92 scheme L	152	519-523	242	Embodiment 92 scheme L
153	481-485	＞260	Embodiment 92 scheme L	533	469-473	200	Embodiment 92 scheme L
154	505-509	＞260	Embodiment 92 scheme L	533	469-473	200	Embodiment 92 scheme L
154	505-509	＞260	Embodiment 92 scheme L	155	498-502	＞260	Embodiment 92 scheme L
156	472-476	＞260	Embodiment 92 scheme M	155	498-502	＞260	Embodiment 92 scheme L
156	472-476	＞260	Embodiment 92 scheme M	516	486-490	＞260	Embodiment 92 scheme O
534	546-550	220	Embodiment 92 scheme M	516	486-490	＞260	Embodiment 92 scheme O
534	546-550	220	Embodiment 92 scheme M	535	472-476	＞260	Embodiment 92 scheme O
157	549-553	238	Embodiment 92 scheme M	535	472-476	＞260	Embodiment 92 scheme O
157	549-553	238	Embodiment 92 scheme M	158	510-514	＞260	Embodiment 92 scheme M
159	520-524	＞260	Embodiment 92 scheme O	158	510-514	＞260	Embodiment 92 scheme M
159	520-524	＞260	Embodiment 92 scheme O	519	486-490	242	Embodiment 92 scheme U
468	465-471	170	Embodiment 92 scheme F	519	486-490	242	Embodiment 92 scheme U
468	465-471	170	Embodiment 92 scheme F	469	401-405	235	Embodiment 92 scheme F
470	412-416	225	Embodiment 92 scheme H	469	401-405	235	Embodiment 92 scheme F
470	412-416	225	Embodiment 92 scheme H	471	401-405	225	Embodiment 92 scheme F
536	431-434	＞250	Embodiment 92 scheme P	471	401-405	225	Embodiment 92 scheme F
536	431-434	＞250	Embodiment 92 scheme P	537	444-448	-	Embodiment 92 scheme I
538	417-421	160	Embodiment 92 scheme O	537	444-448	-	Embodiment 92 scheme I
538	417-421	160	Embodiment 92 scheme O	539	417-421	168	Embodiment 92 scheme O
472	412-416	＞250	Embodiment 92 scheme R	539	417-421	168	Embodiment 92 scheme O
472	412-416	＞250	Embodiment 92 scheme R	473	412-416	-	Embodiment 92 scheme R
474	402-406	248	Embodiment 106 plan V	473	412-416	-	Embodiment 92 scheme R
474	402-406	248	Embodiment 106 plan V	540	459-463	208	Embodiment 92 scheme I
541	417-421	＞260	Embodiment 92 scheme I	540	459-463	208	Embodiment 92 scheme I

Sequence table

<110>Tibotec Pharmaceuticals Ltd.

＜120〉as the benzodiazepine of HCV inhibitor

<130>TIP 114 PCT

<150>EP 05108058.8

<151>2005-09-02

<150>EP 05110606.0

<151>2005-11-10

<160>1

<170>PatentIn version 3.3

<210>1

<211>584

<212>PRT

＜213〉hepatitis C virus

<400>1

Met Ala Ser Ser Met Ser Tyr Thr Trp Thr Gly Ala Leu Ile Thr Pro

1 5 10 15

Cys Ala Ala Glu Glu Ser Lys Leu Pro Ile Asn Pro Leu Ser Asn Ser

20 25 30

Leu Leu Arg His His Asn Met Val Tyr Ala Thr Thr Ser Arg Ser Ala

35 40 45

Ser Leu Arg Gln Lys Lys Val Thr Phe Asp Arg Leu Gln Val Leu Asp

50 55 60

Asp His Tyr Arg Asp Val Leu Lys Glu Met Lys Ala Lys Ala Ser Thr

65 70 75 80

Val Lys Ala Lys Leu Leu Ser Ile Glu Glu Ala Cys Lys Leu Thr Pro

85 90 95

Pro His Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Lys Asp Val Arg

100 105 110

Asn Leu Ser Ser Arg Ala Val Asn His Ile Arg Ser Val Trp Glu Asp

115 120 125

Leu Leu Glu Asp Thr Glu Thr Pro Ile Asp Thr Thr Ile Met Ala Lys

130 135 140

Ser Glu Val Phe Cys Val Gln Pro Glu Lys Gly Gly Arg Lys Pro Ala

145 150 155 160

Arg Leu Ile Val Phe Pro Asp Leu Gly Val Arg Val Cys Glu Lys Met

165 170 175

Ala Leu Tyr Asp Val Val Ser Thr Leu Pro Gln Ala Val Met Gly Ser

180 185 190

Ser Tyr Gly Phe Gln Tyr Ser Pro Lys Gln Arg Val Glu Phe Leu Val

195 200 205

Asn Thr Trp Lys Ser Lys Lys Cys Pro Met Gly Phe Ser Tyr Asp Thr

210 215 220

Arg Cys Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Arg Val Glu Glu

225 230 235 240

Ser Ile Tyr Gln Cys Cys Asp Leu Ala Pro Glu Ala Arg Gln Ala Ile

245 250 255

Arg Ser Leu Thr Glu Arg Leu Tyr Ile Gly Gly Pro Leu Thr Asn Ser

260 265 270

Lys Gly Gln Asn Cys Gly Tyr Arg Arg Cys Arg Ala Ser Gly Val Leu

275 280 285

Thr Thr Ser Cys Gly Asn Thr Leu Thr Cys Tyr Leu Lys Ala Thr Ala

290 295 300

Ala Cys Arg Ala Ala Lys Leu Gln Asp Cys Thr Met Leu Val Asn Gly

305 310 315 320

Asp Asp Leu Val Val Ile Cys Glu Ser Ala Gly Thr Gln Glu Asp Ala

325 330 335

Ala Ala Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Tyr Ser Ala Pro

340 345 350

Pro Gly Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Leu Ile Thr Ser

355 360 365

Cys Ser Ser Asn Val Ser Val Ala His Asp Ala Ser Gly Lys Arg Val

370 375 380

Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Arg Ala Ala Trp

385 390 395 400

Glu Thr Ala Arg His Thr Pro Ile Asn Ser Trp Leu Gly Asn Ile Ile

405 410 415

Met Tyr Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Met Thr His Phe

420 425 430

Phe Ser Ile Leu Leu Ala Gln Glu Gln Leu Glu Lys Ala Leu Asp Cys

435 440 445

Gln Ile Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu Asp Leu Pro Gln

450 455 460

Ile Ile Glu Arg Leu His Gly Leu Ser Ala Phe Thr Leu His Ser Tyr

465 470 475 480

Ser Pro Gly Glu Ile Asn Arg Val Ala Ser Cys Leu Arg Lys Leu Gly

485 490 495

Val Pro Pro Leu Arg Thr Trp Arg His Arg Ala Arg Ser Val Arg Ala

500 505 510

Lys Leu Leu Ser Gln Gly Gly Arg Ala Ala Thr Cys Gly Arg Tyr Leu

515 520 525

Phe Asn Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pro Ile Pro Ala

530 535 540

Ala Ser Gln Leu Asp Leu Ser Gly Trp Phe Val Ala Gly Tyr Ser Gly

545 550 555 560

Gly Asp Ile Tyr His Ser Leu Ser Arg Ala Arg Pro Arg Ala Ala Ala

565 570 575

Leu Glu His His His His His His

580

Claims

1. formula (I) chemical compound is used for the mammal that infected by HCV in preparation and suppresses purposes in the active medicine of HCV, and described chemical compound is the benzodiazepine of the acidylate of formula (I)

:

And salt, heterogeneous type and racemic mixture, wherein

R ²Be hydrogen;

Aryl ²Perhaps

Het ²；

R ⁶Be hydrogen;

C _1-6Alkyl, this C _1-6Alkyl is optional to be replaced by following groups: carboxyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, Het-C _1-6Alkyl amino-carbonyl;

-C (=O)-C _2-6Alkenyl;

-C (=O)-aryl;

-C(＝O)-Het；

-C(＝O)-NR ^12aR ^12b，

-C(＝O)-OR ^13a，

-C (=O)-C _1-6Alkoxy carbonyl C _1-6Alkyl;

-C (=O)-Het-sulfur C _1-6Alkyl; Perhaps

-C (=O)-Het-oxygen C _1-6Alkyl; Perhaps

R ²And R ⁶Insertion group in the formula (I) of following inferior formula:

Form the ring of following formula:

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; Optional by halogen, hydroxyl, Het ,-OR ^14aOr-NR ^14aR ^14bThe C that replaces _1-6Alkyl; Optional by amino, hydroxyl, C _1-6The C that alkoxyl, hydroxycarbonyl group, aryl or Het replace _1-6Alkoxyl; Aryloxy group; Het-oxygen; Carboxyl; C _1-6Alkyl-carbonyl oxygen; C _1-6Alkoxy carbonyl; Aryl carbonyl;-NR ^14aR ^14bPerhaps-C (=O)-NR ^14aR ^14b

R wherein ^14aAnd R ^14bBe hydrogen independently of one another; C _3-7Cycloalkyl; Aryl; Het; Perhaps C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, list-or two C _1-6Alkyl amino, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

Wherein

P is 0,1 or 2;

R ¹⁷Be hydrogen, C _1-6Alkyl, C _3-7Cycloalkyl or aryl;

(a) one, two or three is selected from following substituent group: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen-C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, cyano group C _1-6Alkyl, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl; Perhaps

As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, amino carbonyl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl and morpholinyl;

Aryl as the part of group or group ²Be phenyl, naphthyl, indanyl or 1,2,3,4-tetrahydrochysene-naphthyl, described each group can be chosen wantonly independently and be selected from following substituent group replacement by one, two or three:

(a) halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, trifluoromethyl, alkylenedioxy group, C _1-6Alkoxyl, C _1-6Alkyl sulfide, many halogen-C _1-6Alkoxyl, C _1-6Alkyl-carbonyl oxygen, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; The optional phenyl that is replaced by halogen-or naphthyl-alkoxyl; The optional phenyl that is replaced by following groups-or naphthyl-ketonic oxygen: halogen, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, azido, sulfydryl, C _3-7Cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Perhaps

(b) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n is 0 or 1, and X is-C _1-6Alkane two bases-, C _1-6Alkene two bases-,-NR ²⁰-,-NR ²⁰-C _1-6Alkane two bases-,-NR ²⁰-CO-C _1-6Alkane two bases-,-CO-NR ²⁰-C _1-6Alkane two bases-,-O-,-CO-NR ²⁰-,-NR ²⁰-CO-,-NR ²⁰-SO ₂-,-SO ₂-NR ²⁰-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-,-O-CO-C _1-6Alkane two bases-,-S-or-S-C _1-6Alkane two bases-, R wherein ²⁰Be hydrogen, C _3-7Cycloalkyl, aryl, Het, C _1-6Alkyl, this C _1-6Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, C _1-6Alkoxyl, aryl, Het, cyano group, many halogen C _1-6Alkoxyl and C _3-7Cycloalkyl;

Het as the part of group or group ²Be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: halogen, C _1-6Alkyl, many halogen C _1-6Alkyl, hydroxyl, oxo base, aryl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkoxy C _1-6Alkyl, carboxyl, C _1-6Alkyl-carbonyl, cyano group, nitro, amino, list-or two C _1-6Alkyl amino, cycloalkyl, pyrrolidinyl, piperidyl, piperazinyl, 4-C _1-6Alkyl piperazine base, 4-C _1-6Alkyl-carbonyl-piperazinyl, morpholinyl; Or Het ²By formula-(X) _n-aryl or-(X) _nThe group of-Het replaces, and wherein n is 0 or 1, and

2. formula (I) chemical compound

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen, aryl, Het or C independently _1-6Alkyl;

Aryl ²Perhaps

Het ²；

R ⁶Be hydrogen;

C _1-6Alkyl, this C _1-6Alkyl is optional by carboxyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, Het-C _1-6Alkyl amino-carbonyl replaces;

-C (=O)-C _1-7Alkyl, this C _1-7Alkyl is optional to be selected from following substituent group replacement by one, two or three independently: halogen, aryl and cyano group;

-C (=O)-C _2-6Alkenyl;

-C (=O)-aryl;

-C(＝O)-Het；

-C(＝O)-NR ^12aR ^12b，

R wherein ^12aAnd R ^12bBe hydrogen, aryl or the optional C that is replaced by one or two substituent group that is selected from aryl and Het independently independently of one another _1-6Alkyl;

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; The optional C that is replaced by following groups _1-6Alkyl: halogen, hydroxyl, Het ,-OR ^14aOr-NR ^14aR ^14bThe optional C that is replaced by following groups _1-6Alkoxyl: amino, hydroxyl, C _1-6Alkoxyl, hydroxycarbonyl group, aryl or Het; Aryloxy group; Het-oxygen; Carboxyl; C _1-6Alkyl-carbonyl oxygen; C _1-6Alkoxy carbonyl;-NR ^14aR ^14bPerhaps-C (=O)-NR ^14aR ^14b

R wherein ^14aAnd R ^14bBe hydrogen independently of one another; Perhaps optionally be selected from single-or two C independently by one or two _1-6The C that the substituent group of alkyl amino and Het replaces _1-6Alkyl;

R ⁵Be hydrogen; The C that perhaps optional aryl replaces _1-6Alkyl;

(e) halogen, C _1-6Alkyl, hydroxyl, trifluoromethyl, C _1-6Alkoxyl, many halogen C _1-6Alkoxyl, C _1-6Alkyl-carbonyl oxygen, carboxyl, nitro, list-or two C _1-6Alkyl amino; Perhaps

(f) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n be 1 and X be-O-,-CO-NH-,-NH-CO-,-NH-SO ₂-,-SO ₂-NH-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-;

3. formula (Ia) chemical compound

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen, aryl, Het or C independently _1-6Alkyl;

Aryl ²Perhaps

Het ²；

R ³Be C _1-7Alkyl, it is chosen wantonly independently and is selected from following substituent group replacement by one, two or three: halogen, aryl and cyano group;

C _2-6Alkenyl;

Aryl;

Het；

-NR ^12aR ^12b，

R ⁵Be hydrogen; The perhaps optional C that is replaced by aryl _1-6Alkyl;

(b) the optional phenyl-alkoxyl that is replaced by the substituent group of (a) definition above, two or three;

As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation, and wherein make as a whole group Het and can choose wantonly and be selected from following substituent group independently of one another by one, two or three and replace: C _1-6Alkyl and amino carbonyl;

(g) halogen, C _1-6Alkyl, hydroxyl, trifluoromethyl, C _1-6Alkoxyl, C _1-6Alkyl-carbonyl oxygen, many halogen C _1-6Alkoxyl, nitro, list-or two C _1-6Alkyl amino; Perhaps

(h) formula-(X) _n-aryl or-(X) _nThe group of-Het, wherein n be 1 and X be-O-,-CO-NH-,-NH-CO-,-NH-SO ₂-,-SO ₂-NH-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-;

4. formula (Ib) chemical compound

And salt, heterogeneous type and racemic mixture, wherein

R ^1aAnd R ^1bBe hydrogen, aryl or C independently _1-6Alkyl;

Aryl ²Perhaps

Het ²；

R ³Be hydrogen;

The optional C that is replaced by following groups _1-6Alkyl: carboxyl, C _1-6Alkyl-carbonyl, C _1-6Alkoxy carbonyl, Het-C _1-6Alkyl amino-carbonyl;

R ^4aAnd R ^4bBe hydrogen independently; Halogen; Cyano group; Optional by halogen, hydroxyl or-NR ^14aR ^14bThe C that replaces _1-6Alkyl; Optional by C _1-6The C that alkoxyl replaces _1-6Alkoxyl; Carboxyl; Perhaps-NR ^14aR ^14b

R wherein ^14aAnd R ^14bBe hydrogen independently of one another; Perhaps C _1-6Alkyl;

R ⁵Be hydrogen;

As the Het of the part of group or group be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, described heterocycle optional with one or two phenyl ring condensation;

C) halogen, hydroxyl, many halogen-C _1-6Alkoxyl, carboxyl, nitro; Perhaps

D) formula-(X) _nThe group of-aryl, wherein n be 1 and X be-O-,-CO-NH-,-SO ₂-NH-,-O-C _1-6Alkane two bases-,-O-CO-,-CO-;

Het as the part of group or group ²Be 5 or 6 Yuans saturated, part is unsaturated or complete unsaturated heterocycle, described heterocycle contains 1-4 hetero atom that is selected from nitrogen, oxygen and sulfur independently of one another, optional and one or two phenyl ring condensation of described heterocycle, and wherein make as a whole group Het and can choose wantonly by one, two or three halogen replacement.

5. the chemical compound of any one among claimed purposes or the claim 2-4 in the claim 1, wherein

R ^1aAnd R ^1bIn at least one be hydrogen, halogen, C _1-6Alkyl, aryl or Het.

R ²Be hydrogen; Optional by the C of aryl or halogen replacement _2-6Alkenyl; C _4-8Cycloalkenyl group C _1-6Alkyl; Aryl ²Or Het ²

R ^4aAnd R ^4bIn at least one be hydrogen or aryl carbonyl.

R ⁵Be hydrogen.

6. the chemical compound of any one, wherein R among claimed purposes or the claim 2-3 in the power medicine 1 ³Or R ⁶Be C _1-6Alkyl or many halogen C _1-6Alkyl.

7. the chemical compound of any one, wherein R in claimed purposes or claim 2 and 4 in the claim 1 ³Or R ⁶Be hydrogen or C _1-6Alkyl.

8. treat the method that HCV infects, described method comprises formula (I) compound or its salt, heterogeneous type or the racemic mixture of definition in the claim 1 of the administration effective dose that these needs are arranged.

9. pharmaceutical composition, described pharmaceutical composition comprise among the claim 2-4 that treats effective dose formula (I) noval chemical compound and the pharmaceutically suitable carrier of any one.

10. the method for preparation claimed pharmaceutical composition in the claim 9, described method comprise mixes formula (I) chemical compound of any one among pharmaceutically suitable carrier and the claim 2-4 that treats effective dose closely.