CN101516369A

CN101516369A - Pyridinone diketo acids: inhibitors of HIV replication in combination therapy

Info

Publication number: CN101516369A
Application number: CNA2007800346972A
Authority: CN
Inventors: 瓦瑟·奈尔; 徐炳益; 维诺德·R·尤奇尔; 迟国臣
Original assignee: University of Georgia Research Foundation Inc UGARF
Current assignee: University of Georgia Research Foundation Inc UGARF
Priority date: 2006-07-19
Filing date: 2007-07-13
Publication date: 2009-08-26

Abstract

A new class of diketo acids constructed on pyridinone scaffolds, designed as inhibitors of HTV replication through inhibition of HIV integrase, is described. These compounds are useful in the prevention or treatment of infection by HIV and in the treatment of AIDS and ARC, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with antivirals, immunomodulators, antibiotics, vaccines, and other therapeutic agents, especially other anti- HIV compounds (including other anti-HIV integrase agents), which can be used to create combination anti-HIV cocktails. Methods of treating AIDS and ARC and methods of treating or preventing infection by HIV are also described. Compounds of the present application include those of formula I and include tautomers, regioisomers, geometric isomers, and pharmaceutically acceptable salts thereof, wherein the pyridinone scaffold and R groups are as otherwise defined in the specification. These are combined, with any number of typical other anti-HIV agents (including other integrase-based anti-HIV agents) and other combination therapeutic agents described herein, to provide an effective treatment modality for HIV infections, including AIDS and ARC.

Description

Pyridinone diketo acids: the HIV replication inhibitors that is used for combined therapy

Invention field

The present invention relates to the antiviral therapy field, especially treat people HIV and infect, the preferred compositions treatment.

Related application and financial support

The provisional application US60/831 that submit to the 19 days July in 2006 that the application requires title to be " pyridinone diketo acids: HIV replication inhibitors ", 990, the provisional application US60/920 that submitted to March 27 in 2007,196, with the provisional application 60/920 of title for 27 submissions March in 2007 of " pyridinone diketo acids: the HIV replication inhibitors that is used for combined therapy ", 197 priority, described application is complete to be incorporated herein by reference.

The working portion of present patent application has obtained from the National Institutes of Health bonus number support for the fund of A143181.Therefore, U.S. government keeps certain right to this invention.

Background of invention

The human immunodeficiency virus is HIV, and the viral enzyme by three keys of its pol gene code and these enzymes are for duplicating of this virus very important [Fauci, Science, 239,617-622 (1988); Katz ﹠amp; Skalka, Annu.Rev.Biochem., 63,133-173 (1994); Frankel, Annu.Rev.Biochem., 67,1-25 (1998)].Therefore, in the exploitation HIV antiviral chemotherapeutics, these enzymes of pol gene are as the possible target spot [De Clercq, J.Med.Chem.38, the 2491-2517 (1995) that attack; Clin.Microbiol.Rev., 10,674-693 (1997); De Clercq, Nature Reviews:DrugDiscovery, 11,13-25 (2002); De Clercq, J.Med.Chem.48,1297-1313 (2005)].Relate to this two kinds of enzymes, the drug development of hiv reverse transcriptase (RT) and hiv protease (PR), and some the therapeutic agent combined therapies in these therapeutic agents are used for the follow-up clinical application of the treatment of the relevant complex with AIDS of acquired immune deficiency syndrome (AIDS) (AIDS) (complex) HAART (treatment of high activity retrovirus) (ARC), have illustrated that these class methods of targeting key enzyme have shown useful approach [the Johnson ﹠amp that is used for the antiviral chemotherapy; Gerber, " Advances in Internal Medicine, " vol.44.Mosby:St.Louis, 1-40 (2000); De Clercq, Nature Reviews:Drug Discovery, 11,13-25 (2002); Miller ﹠amp; Hazuda, Current Opinion in Microbiology, 4,535-539 (2001); Asante-Appiah ﹠amp; Skalka, Adv.Virus Res., 52,351-369 (1999); Nair, " RecentAdvances in Nucleosides:Chemistry and chemotherapy, " Elsevier Science:Netherlands, 149-166 (2002); DeClercq, Intl.J.Biochem.Cell Biol.36,1800-1822 (2004)].And for treatment, HIV RT and HIV PR have been widely studied, the 3rd enzyme of pol gene, hiv integrase (integrase), the much less of research [Miller ﹠amp; Hazuda, Current Opinion in Microbiology, 4,535-539 (2001); Nair, Rev.Med.Virol., 12,179-193 (2002); Nair, Current Pharmaceutical Design, 9,2553-2565 (2003); People such as Pommier, Nature Rev.Drug Discovery 4,236-248 (2005); Nair, Frontiersin Med.Chem.2,3-20 (2005)].

Mechanism of action is the HIV/AIDS of inhibition hiv integrase not have at present medicine to be used for wherein clinically.The HIV-1 intergrase be pol gene 3 '-albumen [the Asante-Appiah ﹠amp of the 32kDa of terminal coding; Skalka, Adv.Virus Res., 52,351-369 (1999); Esposito ﹠amp; Craigie, Adv.Virus Res., 52,319-333 (1999)].It relates to the integration (integration) of HIV DNA to host cell chromosome.Because intergrase nobody homologue (counterpart), and in finishing HIV intrusion people cell, play an important role, it is the attack target spot of the inhibitor of exploitation treatment effect.

HIV DNA be incorporated into host cell nuclear staining body DNA obviously by by specific sequence 3 '-processing or shear and be connected enzyme catalysis [the Asante-Appiah ﹠amp that (strand) conversion/integrating remark produces; Skalka, Adv.Virus Res., 52,351-369 (1999); Esposito ﹠amp; Craigie Adv.Virus Res., 52,319-333 (1999)].Before the beginning integration process, the viral DNA that assembling produces through reverse transcription in advance on intergrase.Distinguished sequence among the LTRs of hiv integrase identification viral DNA.Behind assembling viral DNA on the intergrase, wherein has the processing of the active place's generation of locus specificity endonuclease viral DNA, and two nucleotidases from the Double helix viral DNA each 3 '-end is cut out producing specific viral DNA, described specific viral DNA embeds and has a terminal CAOH-3 ' through two nucleotidases.For initial 3 '-procedure of processing, intergrase has obviously activated the phosphodiester bond for cutting.So the viral DNA of the embedding that produces is connected to host cell nuclear DNA through trans-esterification in next step.In this step, intergrase be positioned at 3 of viral DNA '-the OH end, be used for the phosphodiester bond of nucleophillic attack host DNA.In subsequent step, in host DNA, produce the cutting of 4-6bp, and this coupling relates to after the processing CAOH-3 ' viral DNA end to 5 of host DNA '-connection of phosphate terminal.At last, repair resulting intermediate through host cell enzymes (although intergrase also may have this effect) mediation jaggy.

A large amount of chemical compounds are hiv integrase inhibitor, but some chemical compounds in these chemical compounds are non--specific inhibitors of enzyme, evidence show that then other chemical compound can have specificity.The different classes of nucleotidase that comprises, the oligonucleotide enzyme, dinucleotide enzyme and various micromolecule (comprise heterocyclic system, natural product, two keto acids, sulfone and other [Nair, Rev.Med.Virol., 12,179-193 (2002); Nair, Current Pharmaceutical Design, 9,2553-2565 (2003); Chi and and Nair, Bioorg.Med.Chem.Lett.14,4815-4817 (2004); Nair and coworkers, J.Am.Chem.Soc., 122,5671-5677 (2000)].

This compounds the most directly related with this patent of previous research is for having the substituent diketone of aryl or heteroaryl.Some these compounds are hiv integrase inhibitor, but the most common only be chain transfer step (strand transfer step).Intergrase suppresses data report [Wai in some scientific publication things, Deng the people, " 4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viralreplication in cells; " J.Med.Chem.43,4923-4926 (2000); Pais, G.C.G. waits the people, " Structure activity of 3-aryl-1,3-diketo-containing compounds as HIV-1 integraseinhibitors, " J.Med.Chem.45,3184-3194 (2002); Marchand, C. waits the people, " Structural determinants for HIV-1 integrase inhibition by β-diketo acids, " J.Biol.Chem.277,12596-12603 (2002); Sechi, M. waits the people, " Design and synthesisof novel indole beta-diketo acid derivatives as HIV-1 integrase inhibitors, " J.Med.Chem.47,5298-5310 (2004); Zhang, Deng the people, " Azido-containing aryl β-ketoacid HIV-1 integrase inhibitors; " Bioorg.Med.Chem.Lett.13,1215-1219 (2003), Nair, Deng the people, " HIV integrase inhibitors with nucleobase scaffolds:discovery of ahighly potent anti-HIV agent, " J.Med.Chem.49,445-447 (2006); Nair waits the people, " Conceptually novel HIV integrase inhibitors with nucleobase scaffolds:discovery of a highly potent anti-HIV agent, " Antiviral Res.70, A26 (2006); Sato waits the people, " Novel HIV-1 integrase inhibitors derived from quinolone antibiotics, " J.Med.Chem.49,1506-1508 (2006); People such as Nair, " Beta-diketo acids with purinenucleobase scaffolds:novel selective inhibitors of the strand transfer step of HIVintegrase; " Bioorg.Med.Chem.Lett.16,1920-1923 (2006), people such as Chi, " A noveldiketo phosphonic acid that exhibits specific; strand-transfer inhibition of HIVintegrase and anti-HIV activity; " Bioorg.Med.Chem.Lett.17,1266-1269 (2007)].The publication in other this field is a surround relationship for the application.

The mechanism of action of hiv integrase inhibitor by diketone may be the results of interaction of the avtive spot metal ion of functional group on these chemical compounds and intergrase, caused the functionality of these crucial metal common factors to isolate (functional sequestration) [Grobler, J.A., Deng the people, Proc.Natl.Acad.Sci.U.S.A.99,6661-6666 (2002)].

The patent relevant with the application is: Selnick, people such as H.G., (Merck ﹠amp; Co.Inc.), and " Preparation of nitrogen-containing 4-heteroaryl-2,4-dioxobutyric acids useful asHIV integrase inhibitors, " WO 9962513; Young, S.D. waits the people, (Merck ﹠amp; Co.Inc.), and " Preparation of aromatic and heteroaromatic 4-aryl-2,4-dioxobutyric acidderivatives useful as HIV integrase inhibitors, " WO 9962897; Fujishita, T. waits the people, Yoshinaga, T. waits people (Shionogi ﹠amp; Co.Ltd.), " Preparation of aromatic heterocyclecompounds having HIV integrase inhibiting activities, " WO 0039086; Akihiko, S., (Shionogi ﹠amp; Co.Ltd.), " Medicinal compositions containing propenonederivatives, " WO 0196329; Payne, L.S. waits the people, (Merck ﹠amp; Co.Inc.; Tularik, Inc.), " Preparation of 1,3-diaryl-1,3-propanediones as HIV integrase inhibitors, " WO0100578; Egbertson, M. waits the people, (Merck ﹠amp; Co.Ltd.), " HIV integrase inhibitors, " WO 9962520.Above-mentioned some patents of quoting are closely related.Yet these patents or publication are not all described this compounds of the present invention.With the application other patent of surround relationship: Anthony is arranged, wait the people, (Merck ﹠amp; Co.Inc.), " Aza and polyaza-napthalenyl-carboxamides useful asHIV integrase inhibitors, " WO 02/30426; Sato waits the people, (Japan Tobacco Inc.), " Preparation of 4-oxoquinoline derivatives as HIV integrase inhibitors, " WO2004046115; Sato waits the people, (Japan Tobacco Inc.), " Novel 4-oxoquinolinecompounds and use thereof as HIV integrase inhibitors, " WO 2005113509; Crescenzi, Deng the people, (Instituto Di Richerche Di Biologia Molecolare P.AngelettiSPA) " Preparation of N-substituted hydroxypyrimidinone carboxamide inhibitorsof HIV integrase, " WO 2003035077; Belyk waits the people, (Merck ﹠amp; Co.Inc., InstitutoDi Richerche Di Biologia Molecolare P.Angeletti SPA), " Preparation ofN-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1; 3; 4-oxadiazol-2-yl) carbonyl] amino}ethyl)-6-oxo-1; 6-dihydropyrimidine-4-carboxamidepotassium salts as HIV integrase inhibitors, " WO 2006060712; Sato waits the people, (Japan Tobacco Inc.), " Preparation of quinolizinone compounds as HIV integraseinhibitors, " WO 2006033422; Yoshida, H. waits the people, (Shionogi ﹠amp; Co.Ltd.), " Preparation of carbamoyl-pyridinone derivative having HIV integrase inhibitoryactivity, " WO 2006030807; Dress waits the people, (Pfizer, Inc.), " Preparation ofN-hydroxy pyrrolopyridinecarboxamides as inhibitors of HIV integrase, " WO2006027694; Naidu waits the people, (Bristol-Myers Squibb Co.), " HIV integraseinhibitors, " US 2005/0261322; Naidu waits the people, (Bristol-Myers Squibb Co.), " Bicyclic heterocycles as HIV integrase inhibitors, " US 2005/0267105; Naidu waits the people, (Bristol-Myers Squibb Co.), " Bicyclic heterocycles as HIV integraseinhibitors, " US 2006/0199956.Above-mentioned some patents of quoting are more relevant than other patent, but described patent or publication are not all described this compounds of the present invention.

This compounds that we describe in the present invention is the HIV-1 integrase inhibitor, and also has external anti-HIV activity.Be used for clinical isolating PBMC, HIV _NL4-3In the example (in PBMC our chemical compound 4-(1,5-dibenzyl-1,2-dihydro-2-oxo-pyridin-3-yl)-2-hydroxyl-4-oxo fourth-2 olefin(e) acid (8) of research and in same research, studying AZT) of anti-HIV data as follows.

Chemical compound 8 EC ₉₅0.61 μ M, CC ₉₅＞200 μ M, therapeutic index (TI)＞330

AZT EC ₉₅9.42nM, CC ₉₅＞1 μ M, therapeutic index (TI)＞106

PH 7.4,8 half-life of chemical compound (t _1/2) be＞41 hours.The t of chemical compound 8 in people's hepatomicrosome of collecting _1/2Be＞6 hours.

Summary of the invention

The present invention put down in writing a class novelty with the pyridone framework construction and by suppressing two keto acids of hiv integrase as the HIV replication inhibitors.These chemical compounds can be expressed as general formula I and (and comprise its tautomer, regional isomer (regioisomers) and geometric isomer, and the acceptable salt of pharmacy, when applicable), wherein the part in the block diagram (moiety) is the molecular skeleton that constitutes with Pyridione derivatives.These chemical compounds are used for prevention or treatment HIV infects and treatment AIDS and ARC, with chemical compound or the acceptable salt of its pharmacy, with pharmaceutically acceptable carrier, use separately or be used in combination with antiviral agent, immunomodulator, antibiotic, vaccine and other therapeutic agent especially other anti-HIV chemical compound (comprising other anti-HIV intergrase medicine) (they can be used for producing the combination of combination anti-HIV HAART).The method of treatment AIDS and ARC and the method for treatment or prevention HIV infection are also disclosed.

The preferred aspect of the purposes of other anti-hiv agent combination that also relates at least a above-claimed cpd and at least a this paper and put down in writing of the present invention.

Detailed Description Of The Invention

In whole description, use following term description the present invention.Except as otherwise noted, being used for term of the present invention explains by the meaning of those skilled in the art's common sense.

Term herein " chemical compound " except as otherwise noted, is meant any concrete chemical compound disclosed herein, comprises its tautomer, regional isomer, geometric isomer and if desired, optical isomer, with and the acceptable salt of pharmacy.In the context of this article, the term chemical compound is often referred to individualized compound, but also can comprise other chemical compound for example stereoisomer, regional isomer and/or the optical isomer (comprising racemic mixture) of disclosed chemical compound and the mixture of special enantiomer or enantiomer enrichment.Term " chemical compound " scope should be used for explaining according to this term making in context.

Term " patient " or " experimenter " of running through description are meant animal, and normally mammal people preferably uses compositions provided by the invention that they are treated and comprises prophylactic treatment.For the treatment of those infection, disease or morbid state, its for concrete animal for example people patient be specific, the term patient is meant the animal that this is concrete.

Term herein " effectively ", except as otherwise noted, a certain amount of chemical compound or compositions or composition are described, it is used for producing or influencing desired result in context, if this result relates in particular to virus, microorganism or other morbid state, disease or the disease relevant with HIV, ARC or AIDS; Perhaps be used to prepare other chemical compound, medicine or compositions.This term comprises all other effective doses or valid density term, and it is described in this application in addition.

The term " skeleton (scaffold) " that runs through description is meant the pyridone chemical constitution, can contain at least 4 substituent groups in substituted position at this skeleton at 5, and one of them is the keto acid (ketoacid) that defines in addition herein, other 4, and R ¹, R ², R ³And R ⁴As definition herein.

Term " heteroaryl " is meant 5 or 6-unit hetero-aromatic ring, and it contains 1～2 hetero atom that is selected from oxygen, nitrogen and sulfur, and this hetero-aromatic ring is optional to be replaced by 1～3 substituent group, and described substituent group is halogen, hydroxyl, C for example _1-3Alkyl, C _1-3Alkoxyl and CF ₃Term heteroaryl and " hetero-aromatic ring " can exchange use in this article.

Term " human immunodeficiency virus " or " HIV " can be used for describing human immunodeficiency virus 1 and 2 (HIV-1 and HIV-2).

Term " ARC " and " AIDS " are meant the immune system syndrome that the human immunodeficiency virus causes, and it is characterized in that the susceptibility to some disease, and compare the decline of T cell counting with normal counting.HIV from 1 class (asymptomatic HIV disease) be developed to 2 classes (ARC), to 3 classes (AIDS), severity of disease increases.

1 class HIV infection characteristic is that patient or experimenter are the HIV positives, and is asymptomatic but also do not have and be less than 500 cd4 cell.If the patient has the disease that the listed AIDS-to 2 classes (ARC) or 3 classes (AIDS) of any following table defines, then the patient does not belong to such.Be lower than 500 if patient's t-cell counting has dropped to, then the patient is considered to 2 classes (ARC) or 3 classes (AIDS).

2 classes (ARC) infection characteristic is following standard: patient's T-cell has dropped to and has been lower than 500, but also is not lower than 200, and the patient does not also have 3 class diseases (as follows) but the disease of at least a following qualification has been arranged--

The ο BA

The ο candidiasis, (thrush) of oropharynx

The ο candidiasis, vulvoaginal; Lasting to treating, often or seldom reply

ο cervical atypical hyperplasia (moderate or serious)/carcinoma in situs of cervix

ο General Symptoms, for example heating (38.5C) or lasting above 1 month diarrhoea

The ο hairy leukoplakia, the oral cavity

ο herpes zoster (shingles) relates at least two kinds of different outbreaks or more than a kind of dermatotome

The ο idiopathic thrombocytopenic purpura

The ο listeriosis

If the ο inflammatory pelvic disease is concurrent especially tubo-ovarian abscess

The ο peripheral neuropathy

According to U.S. government, in 2 class ARC, immune system has shown the signal of damage but has not been life-threatening.

3 classes (AIDS) infection characteristic is following standard:

The T-cell dropped to be lower than 200 or

The disease that has had at least a following qualification--

The candidiasis of ο bronchus, trachea or lung

The candidiasis of ο esophagus

ο invasive cervical cancer ^*

Outside the ο coccidioidomycosis, dispersivity or lung

Outside the ο cryptococcosis, lung

The ο cryptosporidiosis, (being longer than one month persistent period) of chronic enteral

ο cytomegalovirus disease (not comprising liver, spleen or lymph node)

ο cytomegalovirus retinitis (with visual deprivation)

The ο encephalopathy, HIV-is correlated with

ο herpes simplex: chronic ulcer (being longer than one month persistent period); Or bronchitis, pneumonia, or esophagitis

Outside the ο histoplasmosis, dispersivity or lung

The ο isosporiasis, (being longer than one month persistent period) of chronic enteral

The ο Kaposi sarcoma

ο Burkitt lymphomas (or suitable term)

ο lymphoblast lymphoma (or suitable term)

ο lymphoma former, brain

Outside ο bird-mycobacteria compound bacteria group (Mycobacterium avium complex) or the Kansasiin (M.kansasii), dispersivity or lung

The ο Mycobacterium tuberculosis, any site be (lung ^*Or outside the lung)

The ο mycobacteria, other class or unidentified classification, outside dispersivity or the lung

The ο pneumocystis carinii pneumonia

The ο pneumonia, recurrence ^*

The ο progressive multifocal leukoencephalopathy

The ο salmonella septicemia, recurrence

ο cerebral toxoplasmosis disease

The exhaustion syndrome that ο HIV brings out

Term " altogether administration (coadministration) " or " combined therapy " be meant simultaneously to two kinds of chemical compounds of patient's administration or compositions at least, so that each in two or more chemical compounds of given time point visible effective dose or valid density in patient's body.Although chemical compound of the present invention can be simultaneously to patient's administration altogether, this term comprises simultaneously or at two or more medicines of different time administrations, condition is chemical compound or the compositions in all the common administrations of visible valid density in subject of given time.More of the present invention preferred aspect, above-mentioned one or more diketone acid compounds, with herein in addition at least a other the inverase form of record be used for the treatment of HIV and infect with HAART (cocktail) combination administration altogether.The present invention especially preferred aspect, the common administration of chemical compound produces collaborative anti-HIV therapeutic activity.

Term herein " independently " is meant this variable (it uses independently), changes independently between using.

The present invention relates to chemical compound, its combination or the acceptable salt of its pharmacy of general formula I, be used to suppress hiv integrase, the treatment of prevention or treatment HIV infection and AIDS and ARC.Formula I chemical compound is as giving a definition:

Comprise its tautomer, regional isomer, and the acceptable salt of pharmacy, wherein two representative pyridone skeletons and R base as give a definition:

Two keto acids with following two pyridone skeletons;

R ¹And R ²Be independently:

a)H，

B) C _1-6Alkyl,

C) C _1-6Fluoro-alkyl,

D) C _1-6Alkyl S (O) _nR, wherein n is selected from 0-2, and R is selected from C _1-3The phenyl of alkyl, phenyl and replacement, substituent group is selected from:

1) halogen,

2) hydroxyl,

3) C _1-3Alkyl,

4) C _1-3Alkoxyl,

5)CF ₃，

E) have and be selected from 1～3 following substituent C _5-6Cycloalkyl:

1) halogen,

2) hydroxyl,

3) C _1-3Alkyl,

4) C _1-3Alkoxyl,

5)CF ₃，

F) C _2-6Thiazolinyl,

G) C _1-6Alkyl CO _nR ^a, wherein n is selected from 1 and 2, R ^aBe selected from:

1) C _1-6Alkyl,

2)H，

H) phenyl,

I) be selected from the phenyl that following substituent group replaces by 1～3:

1) halogen,

2) hydroxyl,

3) C _1-3Alkyl,

4) C _1-3Alkoxyl,

5)CF ₃，

J) benzyl,

K) have 1～3 and be selected from following substituent substituted benzyl:

1) halogen,

2) hydroxyl,

3) C _1-3Alkyl,

4) C _1-3Alkoxyl,

5)CF ₃，

L) C that is replaced by phenyl _2-6Alkyl,

M) C that is replaced by phenyl _2-6Alkyl, this phenyl can be selected from following substituent group by 1～3 and replace:

1) halogen,

2) hydroxyl,

3) C _1-3Alkyl,

4) C _1-3Alkoxyl,

5)CF ₃，

n)R ^b，

O) by R ^bThe C that replaces _1-6Alkyl,

Each R wherein ^bBe 5 or 6 yuan of hetero-aromatic rings, it contains 1～2 hetero atom that is selected from oxygen, nitrogen and sulfur, and this ring can be selected from following substituent group replacement by 1～3 or not be substituted on carbon or nitrogen:

1) halogen,

2) hydroxyl,

3) C _1-3Alkyl,

4) C _1-3Alkoxyl,

5)CF ₃，

R ³And R ⁴Be independently selected from:

a)H，

B) C _1-6Alkyl,

C) halogen,

D) hydroxyl,

E) thiophenyl (phenylthio),

F) have 1～3 and be selected from following substituent substituted thiophenyl:

1) halogen,

2) hydroxyl,

3) C _1-3Alkyl,

4) C _1-3Alkoxyl,

5)CF ₃，

G) benzyl,

H) be selected from the substituted benzyl that following substituent group replaces by 1-3:

1) halogen,

2) hydroxyl,

3) C _1-3Alkyl,

4) C _1-3Alkoxyl,

5)CF ₃，。

R ⁵Be selected from:

A) CO ₂R ^c, R wherein ^cBe selected from:

1) C _1-6Alkyl,

2)H，

3) sodium salt or the acceptable salt of other pharmacy,

B) P (O) (OR ^d) (OR ^e), R wherein ^dAnd R ^eCan be identical or different, and be selected from:

1) C _1-6Alkyl,

2)H，

3) sodium salt or the acceptable salt of other pharmacy.

Some embodiment preferred comprise following chemical compound: it is based on 2-pyridone (pyridin-2-ones) skeleton, and wherein said diketone acid moieties is in the 3-position of pyridone ring:

R wherein ¹And R ²Be benzyl independently or on phenyl ring, be selected from fluorine, chlorine, C by 1～3 _1-4Alkyl, C _2-4The benzyl that the substituent group of thiazolinyl, methoxyl group independently replaces;

R wherein ³Be H, C _1-3Alkyl, C _2-3Thiazolinyl, fluorine, chlorine, methoxyl group;

R wherein ⁴Be H, F, Cl, OH

R wherein ⁵Be CO ₂H or P (O) are (OH) ₂Or the acceptable salt of its pharmacy.

The present invention also comprises the pharmaceutical composition that is preferred for suppressing hiv integrase, and it comprises chemical compound of the present invention and pharmaceutically acceptable carrier, additive or the excipient of effective dose.Being used for the treatment of the pharmaceutical composition that infects HIV for example or treatment AIDS or ARC is also included among the present invention.The present invention also comprises and is used to suppress viral enzyme, the method for hiv integrase, and suppress the HIV growth or duplicate or treat the method that HIV infects or treat AIDS or ARC.In addition, the present invention relates to pharmaceutical composition, with combining form, comprise chemical compound of the present invention for the treatment of effective dose and the combination that is selected from the following medicine that is used for the treatment of AIDS for the treatment of effective dose: (i) AIDS or HIV antiviral agent, (ii) anti-infective, (iii) immunomodulator, (iv) other useful therapeutic agent comprises antibiotic and other antiviral agent.

For described pyridone skeleton and R ¹, R ², R ³And R ⁴, chemical compound of the present invention can have regional isomer, and these regional isomerism forms comprise in the present invention.Chemical compound can have geometric isomer, and these forms comprise in the present invention.

Also can there be tautomer in chemical compound of the present invention.Therefore, term " and tautomer " tautomer for example Ia and the Ib (as follows) that are used to describe formula I chemical compound.Chemical compound and tautomer thereof by the representative of name general formula I are appreciated that also to comprise tautomer Ia and Ib with regard to purpose of the present invention.Similarly,, be appreciated that with regard to purpose of the present invention, also comprise tautomer (I) and (Ib) for chemical compound (Ia).This is equally applicable to tautomer (Ib).

When relating to R ¹, R ², R ³, R ⁴And R ⁵Variable when in any formula I, occurring more than one time, the definition the when definition when at every turn occurring is independent of each other situation.Determine that except those structures the present invention also comprises the pyridone of regional isomerism.As long as in context, pyridone and variable be combined to form stable chemical compound, this makes up permission.

Chemical compound of the present invention is used to suppress hiv integrase, and prevention or treatment HIV infection and treatment are called the disease of AIDS.Treatment AIDS or inhibition or treatment HIV infect to be defined as and comprise that treating widely HIV infects disease: AIDS, ARC with actual or contact HIV potentially (for example by blood transfusion, body fluid exchange, pin puncture, the blood samples of patients of contact infection during medicine (medical) or dental operation, and alternate manner).

The present invention also comprises other application.For example, chemical compound of the present invention is used to prepare and finish the screening experiment of antiviral compound, comprises isolated viral enzyme mutant body and further understands this enzyme, hiv integrase.

The present invention also provides the chemical compound of structural formula (I) to be used for suppressing hiv integrase and to be used for the treatment of AIDS or the purposes of ARC pharmaceutical composition in preparation.

Can be with " known pharmacy is acceptable " salt form administration chemical compound of the present invention.Described " known pharmacy is acceptable " salt form is meant and comprises for example acetate of the acceptable salt of all pharmacy; lactobionate; benzene sulfonate; laruate; benzoate; malate; bicarbonate; maleate; disulfate; mandelate; biatrate; mesylate; borate; MB; bromide; methyl nitrate (methylnitrate); Ca-EDTA; camsilate; mucate; carbonate; naphthalene sulfonate; chloride; nitrate; Clavulanate; N-methyl glucoside amine; citrate; ammonium salt; dihydrochloride; oleate; edetate; oxalates; ethanedisulphonate; pamoate; propionic ester dodecyl sulphate (estolate); palmitate; esilate; fumarate; phosphate; hydrophosphate; gluceptate; Polygalacturonate; gluconate; Salicylate; glutamate, Glu; stearate; glycolyl arsanilic acid salt (glycollylarsanilate); sulfate; hexylresorcin salt (hexylresorcinate); basic acetate; breathe out amine salt (hydrabamine); succinate; hydrobromate; tannate; hydrochloride; tartrate; Hydroxynaphthoate; teoclate (teoclate); iodide; toluene fulfonate; different thiosulfate; triethiodide; lactate; panoate; valerate and other can change that dissolubility or hydrolysising characteristic maybe can be used for continuing discharging or the salt of prodrug formulation as dosage form.The acceptable salt of pharmacy of the present invention comprises having for example those of sodium, potassium, calcium, lithium, magnesium, zinc of counter ion counterionsl gegenions, and from alkali for example ammonium, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N, N '-dibenzyl-ethylenediamin, chloroprocaine (chloroprocaine), diethanolamine, procaine, N-benzyl-1-phenylethylamine, diethylamine, piperazine, three (hydroxymethyl) aminomethane, and those of Tetramethylammonium hydroxide.

Similarly, exist carboxylic acid (COOH) or under the situation of alcohol groups, can use the acceptable ester of pharmacy, acetate for example, maleate, pivaloyl oxygen methyl ester (pivaloyloxymethyl) and other, more preferably C ₁-C ₂₀Become known for improving dissolubility or hydrolysis properties in ester and this area as those esters that continue release or prodrug formulation.The acceptable ester of pharmacy also can comprise and wherein has phosphonate group [PO (OH) ₂] situation.Two one phosphonic acids that are connected on the pyridone skeleton are also included among the present invention.

The chemical compound of the present invention of treatment effective dose can be oral to the patient, parenteral, suction spraying or rectum be with the dosage unit preparations form administration, and described dosage unit preparations contains pharmaceutically acceptable carrier, adjuvant and solvent (comprising the nano-particle drug release mode).Term " pharmacy is acceptable " is meant that carrier, diluent or other additive must be compatible with other composition in the preparation, and harmless for patient or receiver.Pharmaceutical composition can be oral administration suspensoid or tablet, nasal spray and injectable formulation (injection aqueous or oil-based suspension or suppository).This Therapeutic Method comprises in the present invention.Used administering mode (, quick-release tablet oral with solution or suspension, nose aerosol or inhalant, injection or suspension or with the suppository rectally) relates in the known technology of field of pharmaceutical preparations.

Chemical compound of the present invention can with preferred dosage form (for example tablet) and preferably with the divided dose of about 0.1～200mg/kg body weight to the human oral administration.Concrete dosage level and administration frequency for any concrete patient can change, and this depends on following various factors, comprise: the duration of compound activity, chemical compound metabolism and effect, patient age, body weight, health status, sex, diet, administering mode and time, excretion rate, drug regimen, concrete disease serious degree, and patient's situation of receiving treatment.

The present invention also comprise hiv integrase inhibitor formula I chemical compound and one or more other therapeutic agents for example AIDS antiviral agent, other antiviral agent, immunomodulator, anti-infective, antibiotic, vaccine or as the treatment of other therapeutic agent combination of describing in addition herein effectively make up.Some examples are as follows:

Antiviral agent, anti-infective, immunomodulator, opportunistic infection medicine, be used for its of AIDS Its related drugs

Medicine name Manufacturer Therapeutic use

097 Hoechst/Bayer HIV infects, AIDS,

(NNRT suppresses ARC

Agent)

Amprenivir Glaxo Wellcome HIV infects, AIDS,

141W94, (protease suppresses GW141 ARC

Agent)

Abacavir Glaxo Wellcome HIV infects, AIDS,

(1592U89) ARC (RT inhibitor)

GW?1592

Acemannan Carrington Labs ARC

(Irving，TX)

Aciclovir Burroughs Wellcome HIV infects, AIDS,

ARC makes up with AZT

AD-439 Tanox Biosystems HIV infects, AIDS,

ARC

AD-519 Tanox Biosystems HIV infects, AIDS,

ARC

Two volts of adefovirdipivoxil Gilead Sciences HIV infects

Ester Ethigen (Los ARC, PGL HIV sun

AL-721 Angeles, CA) property, AIDS

Interferon-alpha Glaxo Wellcome Kaposi sarcoma, HIV,

Make up with the w/ azidothymidine AZT

Ansamycin Adria Laboratories ARC

LM?427 (Dublin，OH)

Erbamont(Stamford，

CT)

In and the unsettled Advanced Biotherapy of pH AIDS, ARC

The anti-Concepts of the unusual interferon of α (Rockville,

Body MD)

AR 177 Aronex Pharm HIV infect, AIDS,

ARC

β-fluoro-ddA National Cancer AIDS-relevant disease

Institute

BMS-232623 Bristol-Myers HIV infects, AIDS,

(CGP-73547) (protease suppresses Squibb/Novartis ARC

Agent)

BMS-234475 Bristol-Myers HIV infects, AIDS,

(CGP-61755) (protease suppresses Squibb/Novartis ARC

Agent)

CI-1012 Warner-Lambert HIV-1 infects

Cidofovir Gilead Science CMV retinitis, bleb

Rash, human papillomavirus

Sulfogel Polysaccharide A JI Pharma USA HIV infects

(Curdlan?sulfate)

Cytomegalovirus M edImmune CMV retinitis

Immunoglobulin

Cymevene Syntex vision threatens (Sight

Ganciclovir threatening) CMV

Periphery CMV

Retinitis

DdI Bristol-Myers Squibb HIV infects, AIDS,

Didanosine ARC; With AZT/d4T

Combination

DMP-450 AVID (Camden, NJ) HIV infects, AIDS,

(protease suppresses ARC

Agent)

Efavirenz DuPont Merck HIV infects, AIDS,

(DMP-266) (non-nucleoside RT presses down ARC

Preparation

EL10 Elan Corp, PLC HIV infects

(Gainesville，GA)

Famciclovir Smith Kline herpes zoster, herpes simplex

FTC Emory University HIV infects, AIDS,

(reverse transcriptase suppresses ARC

Agent)

GS 840 Gilead HIV infect, AIDS,

(reverse transcriptase suppresses ARC

Agent)

HBY097 Hoechst Marion HIV infects, AIDS,

(non-nucleoside reverses Roussel ARC

Transcriptase inhibitors)

Hypericin VIMRxPharm. HIV infects, AIDS,

ARC

Recombined human interferon-Triton Biosciences AIDS, KaposiShi meat

(Almeda, CA) tumor, ARC

Alferon N Interferon Scienes ARC, AIDS

Indinavir Merck HIV infects, AIDS,

ARC, asymptomatic HIV

Positive; With

The AZT/ddI/ddC combination

ISIS-2922 ISIS Pharmaceuticals CMV retinitis

KNI-272 Natl.Cancer Institute HIV-relevant disease

Lamivudine, 3TC Glaxo Wellcome HIV infects, AIDS,

(reverse transcriptase suppresses ARC

Agent); Also has AZT

Lobucavir Bristol-Myers Squibb cmv infection

Nelfinavir Agouron HIV infects, AIDS,

(protease suppresses Pharmaceuticals ARC

Agent)

Nevirapine Boeheringer HIV infects, AIDS,

Ingleheim ARC (RT inhibitor)

Novapren Novaferon Labs, the Inc. hiv inhibitor

(Akron，OH)

Peptide T Peninsula Labs AIDS

The octapeptide sequence (Belmont, CA)

Phosphonoformic acid trisodium Astra Pharm. CVV retinitis, HIV

Products, Inc. infects, other CMV

PNU-140690 Pharmacia Upjohn HIV infects, AIDS,

(protease suppresses ARC

Agent)

Probucol Vyrex HIV infects, AIDS

RBC-CD4 Sheffield Med.Tech HIV infects, AIDS,

(Houston，TX) ARC

Ritonavir Abbott HIV infects, AIDS,

(protease suppresses ARC

Agent)

Saquinavir Hoffmann-LaRoche HIV infects, AIDS,

(protease suppresses ARC

Agent)

Stavudine; D4T Bristol-Myers Squibb HIV infects, AIDS,

Two dehydrogenation deoxyribosylthymine ARC

Valaciclovir Glaxo Wellcome Genital HSV and

Cmv infection

Ribavirin Viratek/ICN (the asymptomatic HIV sun of Costa

Mesa, CA) property, LAS, ARC

VX-478 Vertex HIV infects, AIDS,

ARC

Zalcitabine Hoffmann-LaRoche uses the HIV sense of AZT

Dye AIDS, ARC

Zidovudine; AZT Glaxo Wellcome HIV infects, AIDS,

ARC, the Kaposi sarcoma,

With other therapeutic combination

Tenofovir diisoproxil Gilead HIV infects, AIDS,

Fumarate (RT inhibitor)

Combivir

GSK HIV infects, AIDS,

(RT inhibitor)

Abacavir succinate (or GSK HIV infection, AIDS,

Match is advanced

(reverse transcriptase inhibitors)

(or T-20) Roche/Trimeris HIV infects, AIDS,

Viral fusion inhibitor

AS-101 Wyeth-Ayerst AIDS

Bropirimine Pharmacia Upjohn AIDS in late period

Acemannan Carrington Labs, Inc. AIDS, ARC

(Irving，TX)

CL246,738 American Cyanamid AIDS, KaposiShi meat

Lederle Labs tumor

EL10 Elan Corp, PLC HIV infects

(Gainesville，GA)

FP-21399 Fuki Immuno CD4+ cell fusion

The Blocks HIV of PHARM

IFN-Genentech ARC organizes with w/TNF

Close

Granulocyte Genetics Institute AIDS

Macrophage colony stimulates because of Sandoz

Son

Granulocyte Hoeschst-Roussel AIDS

Macrophage colony stimulates because of Immunex

Son

Granulocyte Schering-Plough AIDS organizes with w/AZT

Macrophage colony stimulates because of closing

Son

HIV core granule immunity Rorer seropositivity HIV

Promoter

IL-2 Cetus AIDS organizes with w/AZT

Interleukin-2 closes

IL-2 Hoffman-LaRoche AIDS，ARC，HIV，

Interleukin-2 Immunex and w/AZT combination

IL-2 Chiron AIDS, the cd4 cell meter

The interleukin-2 number increases

(aldeslukin)

The intravenous Cutter Biological of immunoglobulin infant acquired immunity

(Immune Globulin (Berkeley, CA) deficit syndrome (Pediatric

Intravenous) AIDS), organize with w/AZT

(people) closes

IMREG-1 Imreg (New Orleans, AIDS, KaposiShi meat

LA) tumor, ARC, PGL

IMREG-2 Imreg (New Orleans, AIDS, KaposiShi meat

The LA tumor, ARC, PGL

Imuthiol diethyl dimercapto Merieux Institute AIDS, ARC

Carbaminate (Imuthiol

Diethyl Dithio

Carbamate)

α-2 interferon Schering Plough Kaposi sarcoma

w/AZT，AIDS

Met-enkephalin TNI Pharmaceutical AIDS, ARC

(Chicago，IL)

MTP-PE Ciba-Geigy Corp. Kaposi sarcoma

Muramyl-tripeptide

Granulocyte Amgen AIDS organizes with w/AZT

Colony stimulating factor closes

Remune Immune Response immunization therapy

Corp.

rCD4 Genentech AIDS，ARC

Solvable people recombinates

CD4-IgG

rCD4-IgG?Hybrids AIDS，ARC

The solvable people CD4 Biogen AIDS that recombinates, ARC

Interferon-ALPHA 2a Hoffman-LaRoche Kaposi sarcoma,

AIDS, AR, with

The w/AZT combination

SK﹠amp; F1-6528 Smith Kline HIV infects

Solvable T4

Thymopentin Immunobiology HIV infects

Research Institute

(Annandale，NJ)

Tumor necrosis factor (TNF) Genentech ARC is with the w/ IFN-

Combination

AK602 Kumamoto University HIV infects and (to enter and merge

The Japan inhibitor)

Alovudine Medivir, UK Ltd. HIV infects (nucleoside

The RT inhibitor)

Amdoxovir RFS Pharma, LLC HIV and HBV infect

Treatment (nucleoside RT inhibitor)

AMD070 AnorMED, Inc. HIV infect and (to enter and melt

Close (entry and fusion)

Inhibitor)

(protease presses down in Atazanavir (Reyataz) Bristol-Myers Squibb HIV infection

Preparation)

AVX754 (apricitabine) Avexa Ltd. HIV infects (nucleoside

The RT inhibitor

Bevirimat Panacos HIV infects (the ripe inhibition

The Pharmaceuticals agent)

BI-201 BioInvent HIV infection (gene therapy,

Blocking-up HIV tat gene).

BMS-378806 Bristol-Myers Squibb HIV infects (input inhibition

Agent)

BMS-488043 Bristol-Myers Squibb HIV infects and (to enter and melt

Close inhibitor)

(intergrase presses down in BMS-707035 Bristol-Myers Squibb HIV infection

Preparation)

C31G Cellegy HIV infects and other property biography

Pharmaceuticals, Inc broadcast disease (STDs)

Carbopol ReProtect, LLC HIV spreads through sex intercourse

(Carbopol)974P

Calanolide A Sarawak MediChem HIV infects (non-nucleoside RT

Pharmaceuticals, the Inc. inhibitor)

Carrageenin (Carrageenan) FMC Biopolymer HIV microbicide

Sulfate cellulose Polydex prevention HIV infects and it

Pharmaceuticals, its sexually transmitted disease (STD) of Ltd.

The property biography that blue algae antiviral protein-N Cellegy prevention HIV infects

(Cyanovirin-N) Pharmaceuticals, Inc. broadcasts disease

Darunavir Tibotec HIV infects (with Li Tuona

Wei administration altogether)

Delavirdine Pfizer HIV infects (non-nucleoside RT

Inhibitor)

Dextran sulfate Ueno Fine Chemicals prevention HIV infects

Industry，Ltd.

(Videx Bristol-Myers Squibb HIV infects (nucleoside RT to didanosine

(Videx), inhibitor Videx EC))

Efavirenz Bristol-Myers Squibb HIV infects (non-nucleoside RT

Inhibitor)

Elvucitabine Achillion HIV infects (nucleoside RT

The Pharmaceuticals inhibitor)

Emtricitabine Gilead Sciences HIV infects (nucleoside RT

Inhibitor)

(protease presses down in fosamprenavir (Lexiva) GlaxoSmithKline HIV infection

Preparation)

Fozivudine tidoxil Heidelberg Pharma HIV infects and (to enter and melt

Close inhibitor)

(intergrase presses down in GS 9137 Gilead Sciences HIV infection

Preparation)

GSK-873,140 GlaxoSmithKline HIV infect and (to enter and melt

(aplaviroc) close inhibitor)

(intergrase presses down in GSK-364735 GlaxoSmithKline HIV infection

Preparation)

(protease presses down in GW640385 GlaxoSmithKline HIV infection

(brecanavir) preparation)

HG0004 Human Genome HIV infects and (to enter and melt

Sciences closes inhibitor)

HGTV43 Enzo Therapeutics HIV infects (antisense drug)

Hydroxy ethyl cellulose Union Carbide prevention HIV spreads through sex intercourse

INCB9471 Incyte Corporation HIV infects and (to enter and melt

Close inhibitor)

KP-1461 Koronis HIV infects (nucleoside RT

The Pharmaceuticals inhibitor)

(protease presses down in Lopinavir Abbott Laboratories HIV infection

Preparation)

Mifepristone Viral Genomix HIV infection (gene therapy,

(VGX410 intervenes with vpr)

RU486)

(intergrase presses down in MK-0518 Merck HIV infection

Preparation)

The treatment of PA-457 (bevirimat) Panacos HIV

Pharmaceuticals, Inc. (ripe inhibitor)

Poly (I)-Poly (C12U) Hemispherx biological response modifier

(polyinosini) Biopharma, Inc.

(protease presses down in PPL-100 Merck HIV infection

Preparation)

PRO 140 Progenics HIV infect and (to enter and melt

Pharmaceuticals, Inc. closes inhibitor)

PRO 542 Progenics HIV infect and (to enter and melt

Pharmaceuticals, Inc. closes inhibitor)

PRO 2000 Indevus microbicide

Pharmaceuticals，Inc.

Racivir Pharmasset, Inc. HIV infects (nucleoside RT

Inhibitor)

SCH-D (vicriviroc) Schering-Plough Corp HIV infects and (to enter and melt

Close inhibitor)

SP01A Samaritan HIV infects and (to enter and melt

Pharmaceuticals closes inhibitor)

SPL7013 Starpharma microbicide

TAK-652 Takeda HIV infects and (to enter and melt

Close inhibitor)

(protease presses down in tipranavir (Aptivus) Boehringer Ingelheim HIV infection

The Pharmaceuticals preparation)

TNX-355 Tanox, Inc. HIV infect and (to enter and melt

Close inhibitor)

TMC125 (etravirine) Tibotec HIV infects (non-nucleoside RT

Inhibitor)

UC-781 Cellegy microbicide

Pharmaceuticals，Inc

UK-427,857 Pfizer HIV infect and (to enter and melt

(Maraviroc) close inhibitor)

Sending out during valproic acid Abbott treatment HIV infects

Do

VRX496 VIRxSYS gene therapy

Zalcitabine (Hivid) Roche HIV infects (nucleoside RT

Inhibitor)

Valganciclovir (Valcyte) Roche antiviral (among the AIDS

The CMV retinitis)

Clindamycin and primaquine Pharmacia Upjohn PCP

Fluconazol Pfizer cryptococcal meningitis is read

Pearl bacterium disease

Lozenge Squibb Corp. prevents oral candidiasis

Nystatin lozenge

Eflornithine hydrochloride injection Merrell Dow PCP

Agent (Ornidyl)

Eflornithine

(Eflornithine)

Hydroxyethylsulfonic acid. pentamidine LyphoMed PCP treatment

(IM?&?IV) (Rosemont，IL)

The trimethoprim antibacterial

Trimethoprim/sulfanilamide antibacterial

Piritrexim Burroughs Wellcome PCP treatment

Hydroxyethylsulfonic acid. pentamidine Fisons Corporation PCP prevention

Spiramycin Rhone-Poulenc conceals the spore protozoal diarrhea

Intraconazole-R51211 Janssen Pharm histoplasmosis; Latent ball

Bacterium property meningitis

Trimetrexate Warner-Lambert PCP

Daunorubicin NeXstar, Sequus Karposi sarcoma

It is relevant with the w/AZT treatment that recombinant, human red blood cell are given birth to Ortho Pharm.Corp.

The serious anemia of Cheng Su

Recombinant, human growth hormone Serono AIDS-is relevant becomes thin,

Cachexia

Megestrol acetate Bristol-Myers Squibb is relevant with w/AIDS

The treatment of loss of appetite

Testosterone Alza, what Smith Kline AIDS-was relevant becomes thin

Diarrhoea and suction among the nutrition Norwich Eaton AIDS in the intestines and stomach fully

Pharmaceuticals receives bad

Aldesleukin Chiron Corp biological response modifier

(Aldesleukin) (A Dibai

Plain (Proleukin) is situated between)

Amphotericin B (Abelecet, Pfizer, Bristol-Myers antifungal agent

AM Bison (two Squibb

The property mycin B liposome injection

Agent (AmBisome)),

Amphocin, amphotericin B

Injectable powder (Amphotec),

Fungizone)

Azithromycin (Zithromax) Pfizer antibacterial, antibiotic

Calcium hydroxyapatite Bioform Medical, Inc.Dermal filler

(Radiesse

Doxorubicin (liposome) (salt Ortho Biotech, Alza antineoplastic agent

Acid Mycocet Corporation

(Doxil))

Dronabinol (Marinol) Unimed Antiemetics

Pharmaceuticals，Inc.

Entecavir (Baraclude) Bristol-Myers Squibb antiviral

(erythrocyte is given birth to Ortho Biotech anemia to Epoetin Alfa

Become hormone injection (Epogen),

Procrit)

Etoposide (Etopophos (phosphorus Pfizer, Bristol-Myers antineoplastic agent

Hydrochlorate), Toposar, all complete Squibb

The scholar)

Fluconazol (Fluconazole) Pfizer antifungal agent

Interferon (Recombinant Interferon Roche, Schering biological response modifier

(2b), Rodferon-A (2a)-Plough

Isoniazid (Isoniazid) Sandoz, Hoffmann La-is antimycobacterial

(Nydrazid) Roche

Itraconazole (Sporanox) Ortho Biotech, the Janssen antifungal agent

Pharmaceutica

(Megace, Bristol-Myers Squibb is anticachectic for megestrol

Megace?ES)

Paclitaxel (Onxol, taxol) Bristol-Myers Squibb, antineoplastic agent

IVAX?Pharmaceuticals

Peg interferon Roche, the Schering antiviral

(Peginterferon?α-2)?-Plough

(PEG-Intron(2b)，

Pegasys(2a))

Pentamidine (pentamidine aerosol American antiprotozoal drug

Agent (Nebupent)) Pharmaceutical

Partners，Fujisawa

Health?Care，Inc.

Poly--L-lactic acid (Sculptra) Dermik Laboratories Dermal Filler

Rifabutin (Mycobutin) Pharmacia Corporation is antimycobacterial

(Rifadin, Aventis is antimycobacterial for rifampicin

Rimactane) Pharmaceuticals

The synthetic human growth hormone of growth hormone (Somatropin) Pharmacia

Corporation，Serono?Inc

Sulfamethoxazole/methoxy benzyl Alpha care Inc, the Women antibacterial

Pyridine (bactrim First Health Care, King

(Bactrim)，Septra) Pharmaceuticals

(Serostim)

Testosterone (Androderm, Pfizer Inc, Unimed androgens

Androgel, the Depo-testosterone) Pharmaceuticals, Inc.,

Alza Corporation，

Watson?Laboratories

Trimetrexate (Neutrexin) United States antiprotozoal drug

Bioscience Inc，

Medimmune，Inc.

The combination of chemical compound of the present invention and AIDS antiviral agent (comprising the antiviral agent based on the anti-HIV intergrase), other antiviral agent, immunomodulator, anti-infective, antibiotic, vaccine or other therapeutic agent is not limited to listed those of table, but comprise, basically with any combination that is used for the treatment of HIV infection or treatment AIDS or any pharmaceutical composition of ARC.Preferably be combined as chemical compound of the present invention and protease inhibitor (indinavir for example, nelfinavir, ritonavir, Saquinavir and other), reverse transcriptase inhibitors [nucleoside (AZT for example, 3TC, ddC, ddI, d4T, Abacavir and other and/or non-nucleoside (efavirenz for example, nevirapine and other), or the combination of two or more these inhibitor (seeing the above table) is simultaneously or alternating treatment.Quote combination the related application of several typical example be: EPO 0,484,071, U.S.5,413,999, WO 9962513.

In this combination, chemical compound of the present invention and other activating agent can individually dosed or administrations (concurrently administered) simultaneously.In addition, a kind of administration of component can be before other component, simultaneously or administration in succession.

Chemical compound of the present invention and AIDS antiviral agent (as mentioned above, other addresses as described below to some extent), it is listed that the combination of other antiviral agent, immunomodulator, anti-infective, antibiotic, vaccine, other therapeutic agent is not limited to table, but comprise, basically with any combination that is used for the treatment of HIV infection or treatment AIDS or any pharmaceutical composition of ARC.Preferably be combined as chemical compound of the present invention and protease inhibitor (indinavir especially for example, nelfinavir, ritonavir, Saquinavir), reverse transcriptase inhibitors [nucleoside (AZT for example, 3TC, ddC, ddI, d4T, Abacavir and other and/or non-nucleoside (efavirenz for example, nevirapine and other), or the combination of two or more these inhibitor (seeing the above table) is simultaneously or alternating treatment.Quote combination the related application of several typical example be: EPO 0,484,071, U.S.5,413,999, WO 9962513.

In this combination of chemical compound of the present invention and other activating agent, for example as described below, can individually dosed or administration simultaneously with effective dose.In addition, a kind of administration of component can be before other component, simultaneously or administration in succession.

Be effective to HIV or for the indication/disease of treatment HIV or HIV secondary (comprising the disease of AIDS/ARC and secondary or morbid state for example Kaposi sarcoma, hepatitis B virus infection etc.) the favourable medicine or the following example of bioactivator, its can with chemical compound combination of the present invention treatment HIV to be provided to infect or the pharmaceutical composition and the method for other secondary disease or morbid state.In the time of in being included in pharmaceutical composition or Therapeutic Method, these medicines or bioactivator exist to alleviate the disease of this chemical compound of administration or the effective dose of morbid state.

(-) beta-dioxolane (Dioxolane)-G; DXG;

(-) β-arctigenin; Arctigenin (Arctigenin);

(-)-Carbovir; (-)-C-D4G; (-)-Carbovir;

(-)-β-D-2,6-diaminopurine dioxolanes; Amdoxovir; DAPD; APD

(+)-2 '-deoxidation-3 '-oxa--4 '-the sulfo-cytidine; DOTC (+)

(+)-2 '-deoxidation-3 '-oxa--4 '-sulfo--5-fluorine cytidine; DOTFC (+)

(+/-)-Cyclobut-G; A-69992; (+/-)-Lobucavir; C-Oxt-G; Cyclobut-G; C-Oxetanocin-G

·(R)-2QuinCOAsnPhe[CHOHCH2]PipCONHtBu

(R)-3,6-diamino-N-(amino methyl) caproamide; Bellenamine

(R)-PMPA; (R)-9-(2-phosphonium mesitoyl methoxy propyl group) adenine; PMPA-(R); Tenofovir

·(R)-PMPDAP；PMPDAP-(R)

(S)-PMPA; (S)-9-(2-phosphonium mesitoyl methoxy propyl group) adenine; PMPA (S)

(S)-9-(2-phosphonium mesitoyl methoxy propyl group) adenine; (S)-PMPA

α-APA; R89439; Loviride

α-APA derivant; R87232

α-APA derivant; R88703

α-APA enantiomer; R90385

·α-L-AZT；AZT-α-L

α-L-DXC; α-L-dioxolanes-C; DXC-α-L-

·α-L-FTC；FTC-α-L-

α-single methyl fluoride dehydrogenation ornithine methyl ester; MFMOME

1,1 '-Celogen Az; ADA; Azodicarboamide

1-(11-octyl group amino-10-hydroxyl undecyl)-3, the 7-dimethyl xanthine; CT-2576

1-(2 ', 3 '-dideoxy-2 '-fluoro-beta-D-threo form-penta furyl glycosyl) cytosine; Ro 31-6840

1-(2 '-fluoro-2 ', 3 '-dideoxy-B-B-erythro-penta furyl glycosyl) thymus pyrimidine; 2 ' FddT

1-(2OHPr)-4-is substituted (Substit)-piperazine, the thienyl carbamate derivatives

1-(2OHPr)-4-is substituted-piperazine, the thienyl carbamate derivatives

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(3-aminomethyl phenyl) sulfenyl) thymus pyrimidine; HEPT-M

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(thiophenyl)-2-thio-thymine; HEPT-S

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(thiophenyl) thymus pyrimidine; HEPT

1-deoxidation nojirimycin; Deoxidation nojirimycin (Deoxynojirimycin)

141W94; VX-478; Amprenavir;

Approval

The 1592U89 succinate; Abacavir succinate;

Approval

1-amino oxygen base ethamine; AEA

1-methoxyl group oxalyl group-3, the 5-dicaffeoylquinic acid; 1-MO-3,5-DCQA; The dicaffeoylquinic acid derivant

1OH-2 (Cbz-Tle) 3PhPr[14] adjacent formic acid (paracyclophane) derivant of two Parylenes

1OH-2 (Cbz-ValNH) 3PhPr[13] metacyclophane (metacyclophane) derivant

1OH-2 (Cbz-ValNH) 3PhPr[13] the adjacent formic acid derivates of two Parylenes

1OH-2 (Cbz-ValNH) 3PhPr[14] the adjacent formic acid derivates of two Parylenes

1OH-2 (Cbz-ValNH) 3PhPr[17] the adjacent formic acid derivates of two Parylenes

12-deoxidation phorbol-13-(3E, 5E-decadinene acid esters (decadienoate)); The phorbol derivant

16. α-bromine epiandrosterone (Bromoepiandrosterone); Epi-Br; Inactivin; HE 2000; HE2000; PPB2; The DHEA derivant

1-β-D-arabinofuranosyl adenin glycosyl (arabinofuranosyl)-5-(2-bromo vinyl) uracil; BV-ara-U; BVaraU; BV ara-U; Sorivudine; SQ-32756; Bravavir; Brovavir; Usevir; YN-72; Bromo vinyl araU; BVAU

2 ', 3 '-two dehydrogenations-3 '-deoxycytidine; D4C

2 ', 3 '-dideoxy two dehydrogenation guanosines; D4G

2 ', 3 '-two dehydrogenations-3 '-deoxyribosylthymine; D4T; Stavudine; Approval

2 ', 3 '-dideoxy-3 '-fluoro-4-sulfo-breast glycosides; 3 '-F-4-Thio-ddT

2 ', 3 '-dideoxy-3 '-fluoro-5-broxuridine; FddBrU

2 ', 3 '-dideoxy-3 '-fluoro-5-5-chloro-5-deoxyarabinosylcytosine; 3 '-F-5-Cl-ddC

2 ', 3 '-dideoxy-3 '-fluoro-5-chloriduria glycosides; 935U83; 5-chloro-2 ', 3 '-dideoxy-3 '-floxuridine; FddClU; Raluridine,

2 ', 3 '-dideoxy-5-ethyl cytidine; 5-Et-ddC

2 ', 3 '-DIDEOXYADENOSINE; D2A; DdAdo; DdA

2 ', 3 '-dideoxy two dehydrogenation adenosines; D4A

2 ', 3 '-the dideoxy guanosine; D2G; DdG

2 ', 3 '-dideoxy-3 '-hydroxymethyl cytidine; 3 '-hydroxymethyl-ddC; BEA-005

2,5 '-dehydration-3 '-azido-2 ', 3 '-di-deoxyuridine; AZU-2,5 '-dehydration

2,5 '-dehydration-3 '-azido-3 '-deoxyribosylthymine; AZT-2,5 '-dehydration

·2′，5′diSilySpiroT；TSAO-T

·2′，5′diSilySpiroT；TSAO-me^3T

2,6-diaminourea-2 ', 3 '-dideoxy purine-9-ribofuranoside (ribofuranoside); DdDAPR; DAPDDR; 2,6-diaminourea-ddP

2,6-diaminopurine-2 ', 3 '-dideoxy two dehydrogenation nucleoside; DdeDAPR

2,6-diaminopurine-3 '-fluoro-2 ', 3 '-di-deoxynucleoside; 3 '-F-ddDAPR

2-aminobenzyl statine (statine) valyl Cbz derivant; The statine derivant

2-glycine amide-5-chlorphenyl 2-pyrrolyl ketone; GCPK

·[2-PyridCH2NCH3CO-Val-NHCH(Bz)]CHOHCHOH；A-77003

2 '-azido-2 ', 3 '-DIDEOXYADENOSINE; 9-(2 '-azido-2 ', 3 '-dideoxy-β-D-erythro penta furyl glycosyl (pentofuranosyl)) adenine; 2 '-N3ddA

2 '-FddA (B-D-threo form); F-ddA; '-F-dd-ara-A; 9-(2 '-fluoro-2 ', 3 '-dideoxy-B-D-threo form penta furyl glycosyl) adenine; Lodensine

2 '-N3ddA (B-D-threo form); 9-(2 '-azido-2 ', 3 '-dideoxy-β-threo form penta furyl glycosyl) adenine

·2-NaphCOAsnPhe[CHOHCH2]Pro-OtBu

2-nitrobenzophenone phenylsulfone; NPPS

3-(3-oxo-1-acrylic)-3 '-azido-3 '-deoxyribosylthymine; 3-(3-oxo-1-acrylic) AZT

3-(phenyl sulfonyl)-indole derivatives; L-737,126

3,5-DCQA; 3, the 5-dicaffeoylquinic acid; Dicaffeoylquinic acid

3 '-azido-2 ', 3 '-dideoxy-5-[(cyano methyl) the oxygen base] uridnine; 3 '-N3-5-cyano methyl oxygen base-ddU

3 '-azido-2 ', 3 '-dideoxy-5-aminouridine; 3 '-N3-5-NH2-ddU

3 '-azido-2 ', 3 '-assorted (deaza) uridnine of dideoxy-5-azepine-6-denitrification, 3 '-the C-analog of N3-ddU

3 '-azido-2 ', 3 '-dideoxy-5-broxuridine; 3 '-N3-5-Br-ddU; AZddBrU

3 '-azido-2 ', 3 '-dideoxy-5-5-chloro-5-deoxyarabinosylcytosine; 3 '-Az-5-Cl-ddC

3 '-azido-2 ', 3 '-dideoxy-5-dimethylamino uridnine; 3 '-N3-5-NMe2-ddU

3 '-azido-2 ', 3 '-dideoxy-5-ethyl uridnine; 3 '-N3-5-EtddU; CS-85; AZddEtU

3 '-azido-2 ', 3 '-dideoxy-5-fluorine cytidine; 3 '-N3-5-F-ddC

3 '-azido-2 ', 3 '-dideoxy-5-floxuridine; AZddFU

3 '-azido-2 ', 3 '-dideoxy-5-hydroxyuridine; 3 '-N3-5-OH-ddU

3 '-azido-2 ', 3 '-dideoxy-5-iodo uridnine; 3 '-N3-5-I-ddU; AZddIU

3 '-azido-2 ', 3 '-dideoxy-5-methylamino uridnine; 3 '-N3-5-NHMe-ddU

3 '-azido-2 ', 3 '-dideoxy-5-methylcytidine; CS-92; 3 '-N3-5-Me-ddC

3 '-azido-2 ', 3 '-dideoxy-5-thiocyano uridnine; 3 '-N3-5-SCN-ddU

3 '-azido-2 ', 3 '-dideoxy-5-trifluoromethyl uridnine; 3 '-N3-5-CF3-ddU

3 '-azido-2 ', 3 '-zalcitabine; CS-91; 3 '-N3-ddC

3 '-azido-2 ', 3 '-the dideoxy guanosine; AZG; 3 '-N3ddG

3 '-azido-2 ', 3 '-dideoxy-N4--5-dimethyl cytidine; 3 '-N3-N4-5-diMe-ddC

3 '-azido-2 ', 3 '-dideoxy-N4-OH-5-methylcytidine; 3 '-N3-N4-OH-5-Me-ddC

3 '-azido-2 ', 3 '-di-deoxyuridine; CS-87; 3 '-N3ddU; AZdU; Uravidine

3 '-azido-3 '-deoxidation-6-azathymidine; 3 ' AZ-6AzaT

3-azido-3 '-deoxyribosylthymine base (thymidilyl)-(5 ', 5 ')-2 ', 3 '-dideoxy-5 '-adenylic acid;

AZT-P-ddA

3 '-azido-3 '-the deoxyribosylthymine base-(5 ', 5 ')-2 ', 3 '-dideoxy-5 '-adenylic acid, 2-cyano ethyl ester;

AZT-P(CyE)-ddA

3 '-azido-3 '-the deoxyribosylthymine base-(5 ', 5 ')-2 ', 3 '-dideoxy-5 '-inosinic acid; AZT-P-ddI

3 '-azido-3 '-deoxyribosylthymine-5 '-(butyl methoxyl group valine (valinyl)) phosphate ester;

5′MeOValPO3(Bu)AZT

3 '-azido-5-chloro-2 ', 3 '-di-deoxyuridine; AzddClUrd; AzddClU

3 '-deoxyribosylthymine; DdT

3 '-FddA (B-D-erythro); 9-(3 '-fluoro-2 ', 3 '-dideoxy-B-D-erythro penta furyl glycosyl) adenine

3 '-FddC; 3 '-fluoro-2 ', 3 '-zalcitabine

3 '-FddG; 3 '-fluoro-2 ', 3 '-the dideoxy guanosine

3 '-FddT; Alovudine; FddT; FddThD; 3 '-FLT; FLT

3 '-FddU; 3 '-fluoro-2 ', 3 '-di-deoxyuridine,

3 '-fluoro-2 ', 3 '-dideoxy-5-iodo uridnine; FddIU

3 '-N3-ddA; 9-(3 '-azido-2 ', 3 '-dideoxy-B-B-erythro penta furyl glycosyl) adenine

3TC; Lamivudine;

Approval;

Lamivudine and zidovudine; 3TC ﹠amp; AZT; Approval

4 '-acetylamino phenyl 4-guanidine benzoate (guadinobenzoate); AGB

4 '-Az-3 '-dT; 4 '-azido-3 '-deoxyribosylthymine

4 '-Az-5CldU; 4 '-azido-5-chloro-2 '-BrdU,

4 '-AzdA; 4 '-azido-2 '-deoxyadenosine

4 '-AzdC; 4 '-azido-2 '-deoxycytidine

4 '-AzdG; 4 '-azido-2 '-deoxyguanosine

4 '-AzdI; 4 '-azido-2 '-deoxyinosine

4 '-AzdU; 4 '-azido-2 '-BrdU,

4 '-azido-2 '-deoxidation-β-D-erythro-penta furyl glycosyl-5-methyl-2,4-dioxo pyrimidine; 4 '-the azido thymidine

4 '-cyano group breast glycosides; 4 '-CN-T

4-methyl-5-(pyrazinyl)-3H-1,2-dithiole (dithiole)-3-thioketone; Oltipraz

5 '-[(1,4-dihydro-1-methyl-3-pyridine radicals carbonyl) oxygen base]-3 '-azido-2 ', 3 '-deoxyribosylthymine; DP-AZT; HP-AZT; The AZT prodrug; AZT-DHP

5 '-[[(Z)-and 4-amino-crotyl] methylamino]-5 '-deoxyadenosine; MDL 73811

5 '-alkyl polyglucoside carbonic ester of 3 '-azido-3 '-deoxyribosylthymine; AcNHGlc-hexyl-CO3 AZT

5Cl3PhS-2 indole CONH2

5-fluoro-2 ', 3 '-zalcitabine; 5-F-ddC

5-methyl-3 '-azido-2 ', 3 '-the different cytidine of dideoxy; MeAZddIsoC

6-O-bytyry Castanospermine; BuCast; MDL 28,574; Celgosivir

6-chloro-9-(2,3-dideoxy-β-D-glycerol penta furyl glycosyl)-9H-purine; D2ClP; 6-chloro-ddP; CPDDR; 6Cl-ddP

6-dimethylaminopurine-2 ', 3 '-di-deoxynucleoside; N-6-dimethyl ddA; DMAPDDR

7-chloro-N-methyl-5-(1H-pyrroles-2-yl)-3H-1, the 4-benzodiazepine

(benzodiazepin)-2-amine; Ro 24-7429

7-chloro-5-(2-pyrrole radicals)-3H-1, the 4-benzodiazepine

-2 (H)-ketone; Ro 5-3335

8-chloro-TIBO; Tivirapine; R86183

9-(2,3-dideoxy-β-D-ribofuranosyl (ribofuranosyl))-6-(methyl mercapto) purine; D2SMeP

Two (OHMe) cBu of 9-[] A; A-69463; Cyclobutyl-A; Cyclobut-A; C-Europe tower mycin (oxetanocin) A

·A-76890

·A-77212

A-80987; The ritonavir derivant

A-81525; The ritonavir derivant

A-83962; The ritonavir derivant

A-98881; Azacyclo-urea (Azacyclic urea) derivant

AA; The L-ascorbic acid; Calcium ascorbate

·AAP-BHAP；U-104489；PNU-104489

A Bakawei ﹠amp; Lamivudine and zidovudine; Three associations only

ABC ﹠amp; (-)-3TC ﹠amp; AZT

ABT-378; Lopinavir; The composition of Kaletra;

ABT-378 ﹠amp; ABT-538;

Lopinavir and ritonavir;

With

ABT-538;

Ritonavir; The composition of Kaletra; Approval

Acemannan

Adefovirdipivoxil; PMEA; GS-0393

Adefovir dipivoxil; BisPom PMEA; GS-840;

AG-1343;

Nelfinavir; Approval

AG1350; LY316957; The similar thing of nelfinavir-octahydro-thienopyridine

The AHPBA analog; R-87366

Alpha-lipoic acid; Alpha-lipoic acid; Thioctic acid (Thioctic acid)

·ALX40-4C

·AMD3100；JM3100

The phosphoric acid amprenavir; VX-175; GW433908; GW433908A ( ^*Sodium salt ^*); GW433908G ( ^*Calcium salt ^*); Fosamprenavir

·Ancer?20；Z-100

Antisense 25-aggressiveness phosphorothioate (phosphorothioate); GEM91

·Atazanavir；CGP-73547；BMS-232632；BMS?232632；Zrivada；Latazanavir；

Ah 's dimension is fixed; U-87201E; The BHAP derivant

Aurintricarboxylic acid (Aurintricarboxylic acid); Dupont ATA; Dupont DA639; SD-095345; ATA

AY 9944; Anti-form-1, two (2-dichloro benzyl amino-ethyl) the cyclohexane extraction dihydrochlorides of 4-

AZT; Zidovudine; Azido breast glycosides;

AZT-PO3 (CH3)-AZT; O, O '-two (3 '-azido-3 '-methyl phosphonate of deoxyribosylthymine-5 '-yl)

Baicalin; TJN-151

Belulinic acid Betulinic acid (Betulinic acid); Mairin

Belulinic acid Betulinic acid, 3-O-(3 ', 3 '-the dimethyl succinate ester)

The BHAP derivant

The BHAP derivant;

Delavirdine; U-90152

The BHAP derivant; U-88204E

BI-RG-587; Nevirapine;

Approval

·BILA?1906?BS

BILA 2011 BS; Palinavir

·BILA?2185?BS

Two (2-nitrobenzophenone) sulfone; Two (2NO2Ph) SO2; NSC633001

Two-ValHOEt-N2aza-peptide isostere; CGP 53820

Two-ValHOEt-N2aza-peptide isostere; CGP 53820 analog

·BMS-186318

·BocPhe[CHOH(CH2)3CH＝CHPhCO]IleAMBI；L-687,908

·BzOCValPhe[diCHOH(RR)]PheValBzOC

·BzOCValPhe[diCHOH(SS)]PheValBzOC

C2-Sym phosphine (Phosphinic) amide derivatives (HOECHST AG)

·Calanolide?A；NSC675451

·Calanolide?B

Capravirine; S-1153

Castanospermine

·CbzAF(CHOHCH2)AVVOMe

·Cbz-Asn-Apns-Pro-NH-tBu；KNI-102

CGP 61755; LASINAVIR BMS-234475 Lasinavir [INN

·CGP?64222

·CNI-H0294

Coactinon; I-EBU; The HEPT derivant; MKC-442; Emivirine

·Conocurvone；NSC650891

Coviracil; (-) FTC; (-)-2 ', 3 '-dideoxy-5-fluoro-3 '-thia cytidine (thiacytidine); Emtricitabine; Emtriva

C-Europe tower mycin-G; A-69992; (+-) Lobucavir; C-Oxt-G; Cyclobut-G; (+-) Cyclobut-G

Indinavir; MK639; L-735,524; Approval

The sulfogel polysaccharide

·CV-N；Cyanovirin-N

Ring urea amide; SD146

Cyclosporin A;

[Me-Ile-4] cyclosporin A; SDZ NIM 811

D4A (L); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-DIDEOXYADENOSINE

D4FC; D-D4FC; 2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy-5-fluorine cytidine; DPC 817

D4FC (L); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy-5-fluorine cytidine

D4G (L); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-the dideoxy guanosine

D4I (L); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-didanosine

·DABO

DdC; Zalcitabine; Zalcitabine;

DdI; Didanosine; Didanosine;

Dehydroepiandrosterone; DHEA; Astenile (Prasterone); Dehydroepiandrosterone

(Dehydroisoandrosterone)；EL-10

Dextran sulfate

Two caffeic acid esters; L-chicoric acid (Chicoric acid)

DMP-266;

Efavirenz; Approval

·DMP-323；XM-323

·DMP-450

Docosanol; Just-docosanol

DOTC (-); (-)-2 '-deoxidation-3 '-oxa--4 '-sulfo-cytidine (thiocytidine)

DOTFC (-); (-)-2 '-deoxidation-3 '-oxa--4 '-sulfo--5-flurocytosine

DP-178; Pentafuside; T-20; GP41 127-162 AA; Enfuvirtide;

E-BPTU; The HEPT derivant; NSC 648400

E-EBU; The HEPT derivant; The MKC-442 derivant

E-EBU-dM; The HEPT derivant; The MKC-442 derivant

E-EPSeU; The HEPT derivant; The MKC-442 derivant

E-EPU; The HEPT derivant; The MKC-442 derivant

Ebselen

Etoposide

The epoxy steroid derivatives; (4 α, 5 α, 17 β)-17-hydroxyl-3-oxo-4,5-epoxy androstane-2-Methanamide

Eulicin

Fenalamide A1 (fenalamide A1); Phenalamide A1; Stipiamide

·Fleephilone

Fluoro quinolone derivative; K-12

Fortovase

Saquinavir; Ro31-8959; Approval

Foscarnet; Phosphine formic acid; Foscarnet sodium (Foscavir);

·FPMDAP；

·FPMPA

·FPMPG

GPGRAF eight aggressiveness; SPC3

Hammerhead shape (Hammerhead) is anti--and gag RNA constitutes enzyme, B

·Harziphilone

HBY 097; Quinoxaline derivant

The HEPT derivant; The MKC-442 derivant

The HOCH2CH2 isostere; Thienopyridine (Thienopyrid) CON thienyl urea alkane (urethane) derivant

The HOCH2CH2 isostere; Thienopyridine CON thienyl urethane derivant

The HOCH2CH2 isostere; Thienopyridine CON thienyl urethane derivant; LY326188

·HPMPA

·HPMPDAP

HU; Hydroxyurea; Hydrea

Hydroxocobalamine

Hypericin

Ingenol 3,5, the 20-triacetate; ITA; RD3-2118

The ingenol derivant; RD4-2138

Calophylloide (Inophyllum) B

Calophylloide P

·iQoa-Mta-Apns-Thz-NH-tBu；KNI-272

IsoquinCON furyl urea alkane analog

IsoquinCON thienyl urea alkane analog

·KNI-154；Noa-Asn-Apns-Thz-NH-tBu

·KNI-174；Noa-Asn-Apns-Dmt-NH-tBu

·KNI-227；Qoa-Mta-Apns-Thz-NH-tBu

·L-685,434

L-685, the 434-6-hydroxy derivatives

L-685, the 434-OEtMorph derivant; L-689,502

·L-685,434-OEtNMe2

L-685, the 434-OPrMorph derivant

L-697,593; The 2-Pyridione derivatives

L-697,639; The 2-Pyridione derivatives

L-697,661; The 2-Pyridione derivatives

·L-FddC；β-L-5F-ddC

Lamivudine and zidovudine;

3TC ﹠amp; AZT; Approval

·LY289612

The LY289612 analog

LY-300046-HCl; The PETT derivant; Trovirdine

LY314163; Saquinavir/nelfinavir derivant.

LY-73497; N-(2-phenethyl)-N '-(2-thiazolyl) thiourea; PETT

MAP; The allylene putrescine

·Michellamine?A；NSC650898

·Michellamine?B；NSC649324

·Michellamine?F

N-6-Et-ddA; N-ethyl-2 ', 3 '-DIDEOXYADENOSINE

N-6-methyl ddA; N6-methyl-2 ', 3 '-DIDEOXYADENOSINE

Naphthalene 2-sulphonic acid ester polymer (Naphthalene 2-sulphonate polymer); PRO 2000

The similar thing of nelfinavir-octahydro-thienopyridine

Nonoxynolum (Nonoxynol) 9

NSC625487; Thiazole and benzimidazole; TBZ

Oxathiin (Oxathiin) derivant; UC-38

The oxathiin derivant; UC-84

·P9941

Penicillin Et (NH) 2Sym dimer

Benzylpenicillin, ET (NH) 2 derivants

Penicillin, the 2Isoquin-OHPrNH2 analog

The sulphuric acid pentosan; Elmiron; SP54; Sulphuric acid xylan (Xylan Sulfate);

PETT Cl, the F derivant

The PETT derivant

·Phenoxan

The phorbol derivant; Prostratin

·Platanic?acid

·PMEDAP

·PMEG

·PMEHx；PMEI

·PMEMAP

·PMET

PNU-140690; U-140690; Tipranavir

Pyridione derivatives

Quinoxaline 2 40 thione derivatives; S-2720

R14458; The TIBO derivant.

R82150; The TIBO derivant.

R82913; The TIBO derivant

·Resobene

Ribavirin; Virazole

Ro 31-8959-bis-thf derivant

Saquinavir/nelfinavir derivant

SB-205569; Val-Phe-Phe-HOCH2CH2 isostere analog

SC-52151; Compound E

·SDZ?PRI?053

Naganol

·T22

Thalidomide

·Thiangazole；(-)-Thiangazole

Thiazole and iso-indoles (Thiazoloisoindol)-5-ketone

Thiazole and iso-indoles-5-ketone, derivant

Tle-Val-Sta, the 5PhBuCOOH derivant; The statine derivant

·UC-781

Val-Val-Sta, the 5PhBuCOOH derivant; The statine derivant

·VB-11,328

Tenofovir Disoproxil

Be used for the treatment of HIV and infect, or be secondary to the medicine of disease that HIV infects or morbid state and/or bioactivator another be listed as follows described.In these medicines one or more can comprise AIDS/ARC, Kaposi sarcoma, hepatitis B virus infection, other infected by microbes (for example tuberculosis etc.) with treatment HIV or a kind of secondary disease or morbid state with at least a as in addition disclosed two keto acid anti-hiv agents combination (administration altogether) herein.These chemical compounds also use with effective dose.

These chemical compounds comprise: ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine); AZT; Abacavir; Abacavir/lamivudine/zidovudine; Abacavir sulfate; Abacavir sulfate/lamivudine; Abacavir/lamivudine; Abelecet; Aciclovir; Adefovir dipivoxil; Amycin; Agenerase; Aldesleukin; Alovudine; Aluvia; Ambisome; Amdoxovir; Amphocin; Amphotec; Amphotericin B; Polyinosini; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude; Bevirimat; Biaxin; Brecanavir; BufferGel; C31G; CD4-IgG2; CS; CV-N; Calanolide A; Calcium hydroxyapatite; Carbopol 974P; Carrageenan; Carraguard; Sulfate cellulose; Clarithromycin; Combivir; Copegus; Sulfamethoxazole (Cotrimoxazole); Crixivan; Cyanovirin-N; Cymevene; DAPD; DLV; DS; Darunavir; Delavirdine; The Depo-testosterone; Dextran sulfate; Didanosine; Fluconazole; Doxil; Doxorubicin (liposome); Dronabinol; EFV; Efavirenz; Elvucitabine; Emtricitabine; The tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir; Lamivudine; Epoetin Alfa; Epogen; Epzicom; Etopophos (phosphate); Etoposide; Etravirine; FTC; Fluconazol; Fortovase; Fosamprenavir; Foxivudinetidoxil; Fungizone; Fuzeon; GS 9137; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir; Immunoglobulin (Globulin, Immune); Growth hormone (people); Hepsera; Hivid; The human growth hormone; IL-2; INH; Immunoglobulin intravenous (people); Indinavir; Interferon; Interleukin-2, recombinant, people; Recombinant Interferon (2b); Invirase; Isoniazid; Itraconazole; KP-1461; Lamivudine/zidovudine; Lexiva; Lopinavir/ritonavir; MK-0518; Nebupent; Nelfinavir; Neutrexin; Nevirapine; Nuo Wei; Nydrazid; Peptide T; PMPA prodrug (Viread) ' Prezista (Darunavir); PRO 140; PRO2000; PRO 542 (CD4 IGg2); Procrit (Epoetin); Aldesleukin; Racivir; Radiesse; Rrebetol; Delavirdine; Zidovudine; Reyataz; Ribavirin; Rifabutin; Rifadin; Rifampicin; Rimactane; Ritonavir; Rodferon-A (2a); Saquinavir; SCH-D (vicriviroc); Growth hormone; Stavudinie; Sulfamethoxazole/trimethoprim; Testosterone (Sustanon); Sustiva; TNX-355; Taxol; Tenofovir; The tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar; Trimetrexate; Three associations only; Truvada (Emtriva and Viread combination); U-90152S (Delaviridine); UC-781; UK-427,857 (maraviroc); Valcyte; Valganciclovir; Valproic acid; Fan Bishi; Vicriviroc; Videx; Viracept see nelfinaivr (Tennofovir DF); The happy life of dimension; Virazole; Viread; Vitrasert; Zalcitabine; Sai Ruite; Match is advanced; Zidovudine; Zithromax; Zovirax.

Be used for the treatment of HIV and infect, or be secondary to disease that HIV infects or morbid state medicine and/another of bioactivator is listed as follows described.In these medicines one or more can comprise AIDS/ARC, Kaposi sarcoma, hepatitis B virus infection, other infected by microbes (for example tuberculosis etc.) with treatment HIV or a kind of secondary disease or morbid state with at least a as in addition disclosed two keto acid anti-hiv agents combination (administration altogether) herein.These chemical compounds also use with effective dose.

These chemical compounds comprise: ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine); AZT; Abacavir; Abacavir/lamivudine/zidovudine; Abacavir sulfate; Abacavir sulfate/lamivudine; Abacavir/lamivudine; Abelecet; Aciclovir; Adefovir dipivoxil; Amycin; Agenerase; Aldesleukin; Alovudine; Aluvia; Ambisome; Amdoxovir; Amphocin; Amphotec; Amphotericin B; Polyinosini; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude; Bevirimat; Biaxin; Brecanavir; BufferGel; C31G; CD4-IgG2; CS; CV-N; Calanolide A; Calcium hydroxyapatite; Carbopol 974P; Carrageenan; Carraguard; Sulfate cellulose; Clarithromycin; Combivir; Copegus; Sulfamethoxazole; Crixivan; Cyanovirin-N; Cymevene; DAPD; DLV; DS; Darunavir; Delavirdine; The Depo-testosterone; Dextran sulfate; Didanosine; Fluconazole; Doxil; Doxorubicin (liposome); Dronabinol; EFV; Efavirenz; Elvucitabine; Emtricitabine; Emtricitabine; The tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir; Lamivudine; Epoetin Alfa; Epogen; Epzicom; Etopophos (phosphate); Etoposide; Etravirine; FTC; Fluconazol; Fortovase; Fosamprenavir; Foxivudinetidoxil; Fungizone; Fuzeon; GS 9137; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir; Immunoglobulin; Growth hormone (people); Hepsera; Hivid; The human growth hormone; IL-2; INH; Immunoglobulin, intravenous (people); Indinavir; Interferon; Interleukin-2, recombinant, people; Recombinant Interferon (2b); Invirase; Isoniazid; Itraconazole; KP-1461; Lamivudine/zidovudine; Lexiva; Lopinavir/ritonavir; MK-0518; Nebupent; Nelfinavir; Neutrexin; Nevirapine; Nuo Wei; Nydrazid; Peptide T; PMPA prodrug (Viread) ' Prezista (Darunavir); PRO 140; PRO 2000; PRO 542 (CD4IGg2); Procrit (Epoetin); Aldesleukin; Racivir; Radiesse; Rrebetol; Delavirdine; Zidovudine; Reyataz; Ribavirin; Rifabutin; Rifadin; Rifampicin; Rimactane; Ritonavir; Rodferon-A (2a); Saquinavir; SCH-D (vicriviroc); Growth hormone; Stavudinie; Sulfamethoxazole/trimethoprim; Testosterone; Sustiva; TNX-355; Taxol; Tenofovir; The tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar; Trimetrexate; Three associations only; Truvada (Emtriva and Viread combination); U-90152S (Delaviridine); UC-781; UK-427,857 (maraviroc); Valcyte; Valganciclovir; Valproic acid; Fan Bishi; Vicriviroc; Videx; Viracept see nelfinaivr (Tennofovir DF); The happy life of dimension; Virazole; Viread; Vitrasert; Zalcitabine; Sai Ruite; Match is advanced; Zidovudine; Zithromax; Zovirax.

Provide following representative embodiment to describe the preparation of chemical compound of the present invention in detail.Embodiment is not in order to limit scope of the present invention, and should not be interpreted as restriction.And the chemical compound that following embodiment describes only should not regarded as and forms as the sort of chemical compound that the present invention thought, any combination itself of the composition of described chemical compound or their part (moieties) can form other chemical compound.This writes exactly in this patent documentation in advance.Those skilled in the art will understand easily, can prepare these other chemical compounds to change and the synthetic conversion that following preparation method is carried out known reaction condition.

Provide following representative embodiment to describe the preparation of chemical compound of the present invention in detail.Embodiment does not limit scope of the present invention, should not be interpreted as restriction.And the chemical compound that following embodiment describes only should not regarded as and forms as the sort of chemical compound that the present invention thought, any combination itself of the composition of described chemical compound or their part (moieties) can form other chemical compound.This writes exactly in this patent documentation in advance.Those skilled in the art will understand easily, can prepare these other chemical compounds to change and the synthetic conversion that following preparation method is carried out known reaction condition.

Chemosynthesis

Represent embodiment 1

4-(1,5-dibenzyl-1,2-dihydro-2-oxo-pyridin-3-yl)-2-hydroxyl-4-oxo fourth-2 olefin(e) acid (8).

Related procedure (1) is as follows.

Flow process 1

Step 1:5-benzyl pyridine-2-amine (2).

With pyridine-2-amine 1 (14.1g, 149.8mmol) and benzyl chloride (36.0g, mixture heated to 180 284.6mmol) ℃ is until mixture boiling [Kowalski, J.Heterocycl.Chem.28,875-879 (1991)].Temperature progressively rose to 250 ℃ and kept 24 hours in 3 hours then.After the cooling, reactant mixture is washed out from flask with MeOH (60mL), and with 10% NH ₄OH aqueous solution (40mL) is handled.After adding entry (200mL), use CHCl ₃(grease of 2 * 200mL) extraction gained is used anhydrous Na ₂SO ₄Drying, and distill out CHCl ₃Residue separates by distilling under reduced pressure.The fraction of collecting at 130-135 ℃/1mm Hg is further purified on silica gel (EtOAc: hexane, 7: 3) by flash chromatography.Output 9.2g (34%), white solid, mp 79-80 ℃. ¹H NMR (CDCl ₃, 500MHz): δ 3.87 (s, 2H, CH ₂), 4.43 (bs, 2H, NH ₂), 6.48 (d, 1H, CH J=8.5Hz), 7.19-7.33 (m, 6H, Ar-H and CH), 7.99 (d, 1H, CH, J=1.5Hz). ¹³C NMR (CDCl ₃, 125MHz): δ 38.2,108.7, and 126.1,126.4,128.5,128.7,128.9,128.9,138.6,140.9,147.7,156.8.

Step 2:5-benzyl-3-bromopyridine-2-amine (3).

(6.0g is 32.3mmol) at CH to 0 ℃ the 5-benzyl pyridine-2-amine 2 of being cooled to that stirs ₂Cl ₂Dripping bromine in the solution (100mL) (5.1g, 32.3mmol) [Kelly waits the people, J.Am.Chem.Soc.112,8024-8034 (1990)].Bromine decolours immediately, and described mixture was stirred 30 minutes.With the saturated NaHCO of this mixture ₃Solution (100mL) jolting is then with the organic layer anhydrous Na ₂SO ₄Drying, and distillation obtains yellow residue, and it is further purified on silica gel (EtOAc: hexane, 3: 7) with flash chromatography.Output 7.3g (86%), white solid, mp 110-111 ℃. ¹H NMR (CDCl ₃, 500MHz): δ 3.86 (s, 2H, CH ₂), 4.88 (bs, 2H, NH ₂), 7.19-7.35 (m, 5H, Ar-H), 7.50 (d, 1H, CH, J=1.5Hz), 7.94 (d, 1H, CH, J=1.0Hz). ¹³CNMR (CDCl ₃, 125MHz): δ 37.7,104.6, and 126.4,126.4,128.1,128.6,128.6,128.7,140.2,140.8,146.7,154.0; HRMS (M+H) ⁺Value of calculation C ₁₂H ₁₃BrN ₂263.0184, measured value 263.0184.

Step 3:5-benzyl-3-bromopyridine-2 (1H)-ketone (4).

(0.2g adds entry (2) in DMF 0.7mmol) (4mL) solution, (0.378g 3.6mmol) and with reactant mixture at room temperature stirred 30 minutes to add nitrite tert-butyl then to the 5-benzyl-3-bromopyridine-2-amine 3 that stirs.Distill out DMF and excessive reagent, residue is further purified on silica gel (EtOAc: hexane, 1: 1) by flash chromatography.Output 7.3g (86%), white solid, mp 151-152 ℃. ¹H NMR (CDCl ₃, 500MHz): δ 3.77 (s, 2H, CH ₂), 7.17-7.36 (m, 6H, Ar-H and CH), 7.76 (d, 1H, CH, J=1.5Hz) 13.25 (bs, 1H, NH). ¹³CNMR (CDCl ₃, 125MHz): δ 37.3,115.4, and 121.0,126.9,128.8,128.8,128.9,128.9,132.4,138.5,145.3,161.0; HRMS (M+H) ⁺Value of calculation C ₁₂H ₁₁BrNO264.0024, measured value 264.0014.

Step 4:1,5-dibenzyl-3-bromopyridine-2 (1H)-ketone (5).

To 5-benzyl-3-bromopyridine-2 (1H)-ketone 4 (3.5g, 13.5mmol) add NaH (60% mineral oil suspension) (0.5g in the suspension in dry DMF (100mL), 16.2mmol) and stirred 30 minutes, add then benzyl bromide a-bromotoluene (0.1.36g, 7.9mmol) and with mixture room temperature restir 1 hour.DMF is distilled out, and residue is dissolved among the EtOAc (250mL) again, (anhydrous Na is used in 2 * 100mL) washings with saline solution ₂SO ₄Drying also distills out EtOAc, obtains yellow slurry, and it is further purified on silica gel (EtOAc: hexane, 4: 6) by column chromatography and obtains 5.Output 3.8g (83%), yellow solid, mp 89-90 ℃. ¹H NMR (CDCl ₃, 500MHz): δ 3.69 (s, 2H, CH ₂), 5.18 (s, 2H, CH ₂), 7.11 (d, 1H, CH, J=2Hz), 7.12-7.39 (m, 10H, Ar-H), 7.60 (d, 1H, CH, J=2Hz), ¹³C NMR (CDCl ₃, 125MHz): δ 37.4,53.5,117.1,119.1,126.9,128.2,128.2,128.3,128.3,128.6,128.8,128.8,128.9,128.9,134.6,135.8,138.7,143.0,158.3.HRMS (M+H) ⁺Value of calculation C ₁₉H ₁₇BrNO354.0494, measured value 354.0455.

Step 5:3-acetyl group-1,5-dibenzyl-3-pyridine-2 (1H)-ketone (6).

At N ₂In at 70 ℃, with 1, and 5-dibenzyl-3-bromopyridine-2 (1H)-ketone 5 (1.0g, 2.8mmol), two (triphenylphosphine) Palladous chloride. (II) (0.19g, 0.28mmol) and ethoxy vinyl (tributyl) stannum (2.03g, 5.6mmol) mixture heated in dry DMF (50mL) is 1 hour.DMF is distilled out, and residue is dissolved among the EtOAc (50mL) and through Celite pad again filters.HCl (30mL) with 1N stirred 15 minutes with the EtOAc fraction, and (anhydrous Na is used in 2 * 30mL) washings to water ₂SO ₄Drying, distillation obtains yellow residue, and it is further purified on silica gel (EtOAc: hexane, 2: 8) by flash chromatography.Output 0.86g (97%), yellow oil. ¹H NMR (CDCl ₃, 500MHz): δ 2.73 (s, 3H, CH ₃), 3.75 (s, 2H, CH ₂), 5.19 (s, 2H, CH ₂), 7.14-7.40 (m, 11H, Ar-H and CH), 8.04 (d, 1H, CH, J=3Hz). ¹³C NMR (CDCl ₃, 125MHz): δ 31.1,37.5, and 52.5,118.6,126.8,127.8,127.8,127.9,128.2,128.2,128.6,128.6,128.8,128.8,129.0,135.8,138.8,140.7,144.8,160.4,198.0; HRMS (M+H) ⁺Value of calculation C ₂₁H ₂₀NO ₂318.1494, measured value 318.1461.

Step 6:4-(1,5-dibenzyl-1,2-dihydro-2-oxo-pyridin-3-yl)-2-hydroxyl-4-oxo but-2-ene acid methyl ester (7).

To the 3-acetyl group-1 that stirs, (0.1g, (0.30g 3.1mmol), and stirs reactant mixture 15 minutes 5-dibenzyl-3-pyridine-2 (1H)-ketone 6 to add sodium tert-butoxide in THF 0.31mmol) (5mL) solution.Add dimethyl oxalate. (0.37g, THF 3.1mmol) (5mL) solution, and stirring 2 hours under the room temperature.Distill out THF, the HCl (1mL) that adds 1N, with EtOAc (2 * 10mL) extractions, with saturated brine solution (4 * 20mL) washings, use anhydrous sodium sulfate drying, distill out EtOAc and obtain the brown residue, it is at first by ion exchange chromatography (diethylamino cross-linking dextran anion exchange resin (CH ₃CN: H ₂O, 1: 1) purification, and then by flash chromatography at silica gel (CHCl ₃: MeOH, 9.9: 0.1) last purification.Output 0.054g (44%), yellow oil. ¹H NMR (CDCl ₃, 500MHz): δ 3.79 (s, 2H, CH ₂), 3.91 (s, 3H, CH ₃), 5.21 (s, 2H, CH ₂), 7.15-7.42 (m, 11H, Ar-H and CH), 7.98 (s, 1H, alkene CH), 8.24 (d, 1H, CH, J=2.5Hz), ¹³C NMR (CDCl ₃, 100MHz): δ 37.5,52.7, and 53.0,101.8,119.0,123.4,126.9,128.0,128.0,128.3,128.6,128.6,128.9,129.0,129.0,129.1,135.6,138.6,141.4,145.0,159.5,162.6,172.2,185.5; HRMS (M+H) ⁺Value of calculation C ₂₄H ₂₂NO ₅404.1498, measured value 404.1411.

Step 7:4-(1,5-dibenzyl-1,2-dihydro-2-oxo-pyridin-3-yl)-2-hydroxyl-4-oxo fourth-2 olefin(e) acid (8).

At 0 ℃, to 4-(1,5-dibenzyl-1,2-dihydro-2-oxo-the pyridin-3-yl)-2-hydroxyl that stirs-4-oxo but-2-ene acid methyl ester 7 (0.069g, 0.17mmol) MeOH (5mL) solution in add NaOH (0.5mL) solution of 1N, reactant mixture stirred 30 minutes at 0 ℃.Then, will be reflected at ambient temperature stirred 1 hour.With of the HCl neutralization of this reactant mixture, with isolating solid filtering and vacuum drying with 1N.Obtain yellow solid with EtOAc/ hexane recrystallization.Output 0.034g (52%), yellow solid, mp 158-159 ℃. ¹H NMR (CDCl ₃, 500MHz): δ 3.82 (s, 2H, CH ₂), 5.26 (s, 2H, CH ₂), 7.16-7.39 (m, 10H, Ar-H), 7.45 (d, 1H, CH, J=2Hz), 7.98 (s, 1H, alkene CH), 8.26 (d, 1H, CH, J=2Hz), ¹³C NMR (CDCl ₃, 125MHz): δ 37.5,53.3, and 100.8,119.8,123.1,127.0,128.2,128.5,128.5,128.6,128.6,128.9,128.9,129.0,129.1,129.1,135.2,138.4,141.3,145.1,159.5,162.3,173.7; HRMS (M+H) ⁺Value of calculation C ₂₃H ₂₀NO ₅390.1341, measured value 390.1342.

Represent embodiment 2

4-(1,5-dibenzyl-1,4-dihydro-4-oxo pyridine-3-yl)-2-hydroxyl-4-oxo fourth-2 olefin(e) acid (16).

Related procedure (2) is as follows.

Flow process 2

Step 1:3,5-two bromo-pyridine-4-ketone (10)

Through the ice-cold pyridine-4-ketone 9 of 30 fens clockwise (6.98g, 73.4mmol) and KOH (9.52g, dripping bromine in water 146.8mmol) (140mL) solution (7.58mL, 147.5mmol) [Spivey waits the people, J.Org.Chem.65,3154-3159 (2000)].Added back 30 minutes, filtering-depositing, with a large amount of water washings, and vacuum drying.Output 16.17g (87%), yellow solid, 320 ℃ of mp (distillation). ¹H?NMR(DMSO-d ₆，500MHz)：δ12.3(s，1H)，8.26(s，2H). ¹³C?NMR(DMSO-d ₆，125MHz)：δ167.5，138.2，138.2，111.8，111.8。

Step 2:3-bromo-5-(hydroxyl-phenyl-methyl)-pyridine-4-ketone (11)

At-78 ℃, under blanket of nitrogen, to 3, (0.313g 1.24mmol) adds phenyl-magnesium-bromide solution (1.36mL, the THF solution of 1M to 5-two bromo-pyridine-4-ketone 10 in the heterogeneous mixture of anhydrous THF (4mL), 1.36mmol) [people such as Borzilleri, United States Patent (USP) 20050245530].Stir after 15 minutes, add n-BuLi solution (0.68mL, the 2M cyclohexane solution, 1.36mmol), and-78 ℃ under blanket of nitrogen, reactant mixture was stirred 15 minutes.(0.26mL 2.6mmol) and with this mixture stirred 2 hours at-78 ℃ to add benzaldehyde in this mixture.The cancellation of this reactant mixture by adding HOAc (0.38mL) and TFA (0.38mL), vacuum concentration, residue is gone up purification by flash column chromatography at silica gel (dichloromethane: methanol, 95: 5).Output 0.125g (36%), white solid, 123-124 ℃. ¹H?NMR(MeOH-d ₄，500MHz)：δ8.09(s，1H)，7.81(s，1H)，7.38-7.17(m，5H)，5.92(s，1H)，3.83(s，2H). ¹³C?NMR(MeOH-d ₄，125MHz)：δ174.3，144.4，139.7，135.8，133.6，129.4，129.3，128.6，128.0，128.0，114.8，70.8。

Step 3:3-benzyl-5-bromopyridine-4-ketone (12)

3-bromo-5-(hydroxyl-phenyl-methyl) pyridine-4-ketone 11 (0.125g, 91mmol), TFA (16mL) and Et ₃The mixture of SiH in anhydrous methylene chloride (30mL) is in stirring at room 10 hours [Borzilleri waits the people, United States Patent (USP) 20050245530].With the reactant mixture vacuum concentration, residue is gone up purification by flash column chromatography at silica gel (dichloromethane: methanol, 98: 2).Output 0.081g (69%), white solid. ¹H?NMR?(MeOH-d ₄，500MHz)：δ8.12(s，1H)，7.47(s，1H)，7.29-7.17(m，5H)，3.83(s，2H). ¹³C?NMR(MeOH-d ₄，125MHz)：δ175.2，140.7，139.5，136.9，130.8，130.0，130.0，129.5，129.5，127.3，114.1，34.9。

Step 4:1,3-dibenzyl-5-bromo-1H-pyridine-4-ketone (13)

Under blanket of nitrogen, with 3-benzyl-5-bromopyridine-4-ketone 12 (0.57g, 2.16mmol) and NaOEt (0.89mL, 2.37mmol) (0.30mL 2.59mmol) refluxed 1 hour for mixture in dehydrated alcohol (20mL) and benzyl chloride.Solvent distilled away obtain yellow residue, it goes up purification by flash column chromatography at silica gel (dichloromethane: methanol, 98: 2).Output 1.31g (96.7%), yellow solid, mp 120-121 ℃. ¹H NMR (CDCl ₃, 500MHz): δ 7.67 (d, 1H, J=2.4), 7.32-7.07 (m, 10H), 4.83 (s, 1H), 3.78 (s, 2H). ¹³C NMR (CDCl ₃, 125MHz): δ 172.2,139.6,139.1,137.6,134.7,129.9,129.9,129.3,129.3,129.2,129.0,128.6,128.6,127.5,127.6,126.4,114.1,60.3,34.4.HRMS (M+H) ⁺Value of calculation C ₁₉H ₁₆BrNO 354.0494, measured value 354.0499.

Step 5:3-acetyl group-1,5-dibenzyl-1H-pyridine-4-ketone (14)

1,3-dibenzyl-5-bromo-1H-pyridine-4-ketone 13 (1.31g, 2.70mmol), tributyl-(1-ethoxy ethylene base) stannum (1.80mL, 5.18mmol) and two (the triphenylphosphine)-palladiums (II) of dichloro (0.26g, 0.37mmol) mixture in dry DMF (20mL) stirred 8 hours at 95 ℃ under blanket of nitrogen.(3 * 50mL) extractive reaction mixture are with HCl (3 * 50mL) washings, and distilling off solvent of 1N with ethyl acetate.Residue is gone up purification by flash column chromatography at silica gel (dichloromethane: methanol, 98: 2).Output 1.06g (90%), yellow oil. ¹H NMR (CDCl ₃, 500MHz): δ 8.19 (d, 1H, J=2.6), 7.39-7.10 (m, 10H), 6.90 (d, 1H, J=2.5), 4.89 (s, 2H), 3.81 (s, 2H), 2.74 (s, 3H) .HRMS (M+H) ⁺Value of calculation C ₂₁H ₁₉NO ₂318.1494, measured value 318.1493.

Step 6:4-(1,5-dibenzyl-4-oxo-1,4-dihydro-pyridin-3-yl)-2-hydroxyl-4-oxo-but-2-ene acid methyl ester (15).

At the sodium tert-butoxide (0.52g of room temperature to stirring; 5.23mmol) anhydrous THF (13mL) solution in drip dimethyl oxalate. (0.42g; 3.48mmol) THF (6mL) solution; add 3-acetyl group-1 then; 5-dibenzyl-1H-pyridine-4-ketone 14 (0.55g, THF 1.74mmol) (8mL) solution.With the mixture of gained in stirring at room 4 hours, acidify then (pH=6).Crude product is with ethyl acetate (100mL) extraction, water (2 * 100mL) and saline (2 * 100mL) wash, and use anhydrous sodium sulfate drying, and distilling off solvent.Residue is by ion exchange chromatography (diethylamino cross-linking dextran anion exchange resin (CH ₃CN: H ₂O, 1: 1) purification, go up purification by flash chromatography at silica gel (chloroform, 100%) then.Output 0.44g (63%), mp 148-150 ℃. ¹H NMR (CDCl ₃, 500MHz): δ 8.34 (d, J=2.5,1H), 8.12 (s, 1H), 7.40-7.12 (m, 10H), 6.91 (d, J=2.3,1H), 4.94 (s, 2H), 3.88 (s, 3H), 3.82 (s, 2H). ¹³C NMR (CDCl ₃, 125MHz): δ 187.2,175.2, and 170.3,162.7,143.9,138.4,136.9,136.1,133.8,129.4,129.5,129.3,129.1,129.1,128.7,128.6,127.5,127.4,126.5,120.2,102.4,61.2,53.0,33.5.HRMS (M+H) ⁺Value of calculation C ₂₄H ₂₂NO ₅404.1498, measured value 404.1497.

Step 7:4-(1,5-dibenzyl-1,4-dihydro-4-oxo pyridine-3-yl)-2-hydroxyl-4-oxo fourth-2 olefin(e) acid (16).

At 0 ℃, with 4-(1,5-dibenzyl-1,4-dihydro-4-oxo pyridine-3-yl)-2-hydroxyl-4-oxo but-2-ene acid methyl ester 15, (0.080g, 0.19mmol) mixture of NaOH (4mL) in THF (12mL) with 1N stirred 4 hours.THF is distilled away, and (2 * 25mL) extractions, (anhydrous Na is used in 1 * 25mL) washing to residue with saline solution with the HCl acidify of 1N and with EtOAc ₂SO ₄Drying is distilled away EtOAc and is obtained yellow solid.Thick solid grinds with ether, filters and vacuum drying.Last solid grinds with chloroform, filtration and vacuum drying 24 hours. output 0.065g (84%), yellow solid, mp 140-142 ℃. ¹H NMR (CDCl ₃+ MeOH-d ₄, 500MHz): δ 3.80 (s, 2H, CH ₂), 4.97 (s, 2H, CH ₂), 6.95 (t, 1H, CH, J=1Hz), 7.13-7.40 (m, 11H, Ar-H and alkene CH), 8.36 (d, 1H, CH, J=2.5Hz). ¹³C NMR (CDCl ₃, 125MHz): δ 33.4,61.2,120.5,126.5,127.5,127.6,128.6,128.7,128.7,129.1,129.1,129.2,129.2,129.2,129.4,133.8,135.9,137.2,138.2,143.8,163.8,175.4.HRMS (M+H) ⁺Value of calculation C ₂₃H ₂₀NO ₅390.1341, measured value 390.1343.

Claims

1. the chemical compound of general formula I or the acceptable salt of its pharmacy:

2-and 4-pyridone and regional isomer thereof that wherein said skeleton limits for this paper independently;

R ¹And R ²Be H independently of one another; C _1-6Alkyl; C _1-6Fluoro-alkyl; Unsubstituted or substituted C _5-6Cycloalkyl; C _1-6Thiazolinyl; Unsubstituted or substituted phenyl; Unsubstituted or substituted benzyl; C _2-6Alkyl phenyl, described phenyl can be chosen wantonly and be substituted; Unsubstituted or substituted heteroaryl; The C that is replaced by heteroaryl _1-6Alkyl, described heteroaryl is optional to be substituted; C _1-6Alkyl S (O) R or alkyl (SO ₂) R, wherein R is alkyl, phenyl or substituted phenyl; C _1-6Alkyl CO ₂R ^a, R wherein ^aBe C _1-6Alkyl or H; C _1-6Alkyl COR ^a', R wherein ^a' be C _1-6Alkyl;

R ³And R ⁴Be independently selected from H, C _1-6Alkyl, halogen, hydroxyl, the unsubstituted or substituted thiophenyl of unsubstituted or substituted benzyl;

R ⁵Be CO ₂R ^cOr P (O) (OR ^c) (OR ^c), each R wherein ^cBe independently selected from H and C _1-6Alkyl.

2. the chemical compound of claim 1 or the acceptable salt of its pharmacy, described chemical compound has following structure:

R wherein ¹And R ²Be benzyl or the benzyl that replaced by 1～3 substituent group on aromatic ring independently of one another, described substituent group is selected from halogen, hydroxyl, methoxyl group, methyl, ethyl, propyl group, CF ₃, or-CH ₂R ^bBase, wherein R ^bBe 5-or 6-unit heteroaryl;

R ³And R ⁴Be H, C independently _1-6Alkyl, halogen, benzyl, substituted benzyl, thiophenyl or the thiophenyl that is replaced by 1～3 substituent group on phenyl ring, described substituent group is selected from halogen, hydroxyl, methoxyl group, methyl, ethyl, propyl group, CF ₃

R wherein ⁵Be CO ₂R, wherein R is selected from H and C _1-6Alkyl.

3. the chemical compound of claim 1 or the acceptable salt of its pharmacy, described chemical compound has following structure:

R wherein ¹And R ²Be benzyl or the benzyl that replaced by 1～3 substituent group on aromatic ring independently of one another, described substituent group is selected from halogen, hydroxyl, methoxyl group, methyl, ethyl, propyl group, CF ₃, or R wherein ¹And R ²Be independently-CH ₂R ^b, R wherein ^bIt is 5-or 6-unit hetero-aromatic ring;

R wherein ³And R ⁴Be H, C independently _1-6Alkyl, halogen, benzyl, substituted benzyl, thiophenyl or the thiophenyl that is replaced by 1～3 substituent group on phenyl ring, described substituent group is selected from halogen, methoxyl group, methyl, ethyl, propyl group, CF ₃

R wherein ⁵Be P (O) (OR) (OR) that wherein said R base is identical or different, and is selected from H or C _1-6Alkyl.

4. the chemical compound of claim 1 or the acceptable salt of its pharmacy, described chemical compound has following structure:

R wherein ¹And R ²Be the benzyl that is replaced by 1～3 substituent group on benzyl or the aromatic ring independently of one another, described substituent group is selected from halogen, hydroxyl, methoxyl group, methyl, ethyl, propyl group, CF ₃, or-CH ₂R ^bBase, wherein R ^bBe 5-or 6-unit heteroaryl;

R ³And R ⁴Be H, C independently _1-6Alkyl, halogen, benzyl, substituted benzyl, thiophenyl or have 1～3 substituent substituted thiophenyl on phenyl ring, described substituent group is selected from halogen, hydroxyl, methoxyl group, methyl, ethyl, propyl group, CF ₃

R wherein ⁵Be CO ₂R, wherein R is selected from H and C _1-6Alkyl.

5. the chemical compound of claim 1 or the acceptable salt of its pharmacy, described chemical compound has following structure:

R wherein ¹And R ²Be the benzyl that is replaced by 1～3 substituent group on benzyl or the aromatic ring independently of one another, described substituent group is selected from halogen, hydroxyl, methoxyl group, methyl, ethyl, propyl group, CF ₃, or R wherein ¹And R ²Be independently-CH ₂R ^b, R wherein ^bBe 5-or 6-unit hetero-aromatic ring;

R wherein ⁵Be P (O) (OR) (OR) that wherein R is identical or different, and is selected from H or C _1-6Alkyl.

6. the chemical compound of claim 1, it is selected from

4-(1,5-dibenzyl-1,2-dihydro-2-oxo-pyridin-3-yl)-2-hydroxyl-4-oxo but-2-ene acid;

4-(1,5-dibenzyl-1,4-dihydro-4-oxo pyridine-3-yl)-2-hydroxyl-4-oxo but-2-ene acid;

3-acetyl group-1,5-dibenzyl-3-pyridine-2 (1H)-ketone;

3-acetyl group-1,5-dibenzyl-1H-pyridine-4-ketone;

4-(1,5-dibenzyl-1,2-dihydro-2-oxo-pyridin-3-yl)-2-hydroxyl-4-oxo but-2-ene acid methyl ester; With

4-(1,5-dibenzyl-4-oxo-1,4-dihydro-pyridin-3-yl)-2-hydroxyl-4-oxo-but-2-ene acid methyl ester, or the acceptable salt of their pharmacy.

7. the chemical compound of claim 1, it is selected from

4-(1,5-dibenzyl-1,2-dihydro-2-oxo-pyridin-3-yl)-2-hydroxyl-4-oxo but-2-ene acid; With

4-(1,5-dibenzyl-1,4-dihydro-4-oxo pyridine-3-yl)-2-hydroxyl-4-oxo but-2-ene acid, or

The acceptable salt of their pharmacy.

8. the chemical compound of claim 1 or the acceptable salt of its pharmacy, described chemical compound has following structure:

R wherein ¹And R ²Be benzyl or the benzyl that replaced by 1～3 substituent group on phenyl ring independently, described substituent group is selected from fluorine, chlorine, C _1-4Alkyl, C _2-4Thiazolinyl and methoxyl group;

R ³Be H, C _1-3Alkyl, C _2-3Thiazolinyl, fluorine, chlorine or methoxyl group;

R ⁴Be H, F, Cl or OH; With

R ⁵Be CO ₂H or P (O) are (OH) ₂

9. the chemical compound of claim 1, wherein R ¹And R ²In at least one is a benzyl.

10. the chemical compound of claim 1, wherein R ¹And R ²Be benzyl.

11. the chemical compound of claim 8, wherein R ¹And R ²Be benzyl.

12. each chemical compound, wherein R among claim 1-5 and the 8-11 ³And R ⁴Be H, methyl, fluorine or chlorine independently.

13. each chemical compound, wherein R among claim 1-5 and the 8-12 ³And R ⁴Be H, fluorine or chlorine independently.

14. each chemical compound, wherein R among claim 1-5 and the 8-13 ³And R ⁴H respectively does for oneself.

15. each chemical compound, wherein R among claim 1-5 and the 8-14 ⁵Be CO ₂H, or the acceptable salt of its pharmacy.

16. pharmaceutical composition comprises among the claim 1-15 that treats effective dose each chemical compound and pharmaceutically acceptable carrier, additive or excipient.

17. the property rights profit requires 16 pharmaceutical composition, wherein said compositions suppresses the hiv integrase among the human host, and described hiv integrase is wild type and mutant.

18. pharmaceutical composition, first chemical compound that comprises among the claim 1-15 that treats effective dose each, at least a other combination of compounds with the treatment effective dose, and pharmaceutically acceptable carrier, additive or excipient, described other chemical compound is selected from i) other anti-hiv agent, the ii) anti-infective except anti-hiv agent, iii) immunomodulator, iv) other is selected from the composition of medicine in the table shown in the description 17-28 page or leaf.

19. the compositions of claim 18, wherein said anti-infective are antiviral agent, it is selected from protease inhibitor, reverse transcriptase inhibitors, other integrase inhibitor or its combination.

20. the compositions of claim 19, wherein said reverse transcriptase inhibitors are nucleoside compound.

21. the compositions of claim 19, wherein said reverse transcriptase inhibitors are the non-nucleoside chemical compound.

22. the compositions of claim 19, wherein said other integrase inhibitor are the chemical compound of non-pyrimidinone compound.

23. each compositions among the claim 16-22, it is oral or parenteral dosage form.

24. each compositions among the claim 16-22, it is mixed with the suction spraying or rectal suppository is used for administration.

25. the method for a pharmaceutical compositions, described method comprise with among the claim 1-15 each chemical compound and pharmaceutically acceptable carrier, additive or excipient composition with the preparation mixture, and prepare oral or parenteral dosage form from described mixture.

26. treat the method that patient HIV infects for one kind, described method comprises in the claim 16-24 of described patient's effective dosage each compositions.

27. a minimizing has the patient's of HIV infection risk the method for HIV infection potential, described method comprises in the claim 16-24 of described patient's effective dosage each compositions.

28. a treatment has the patient's of AIDS or ARC method, comprises in the claim 16-24 of described patient's drug treatment effective dose each compositions.

29. a method that suppresses experimenter's hiv integrase, described method comprise in the claim 16-24 of described experimenter's drug treatment effective dose each compositions.

30. each method among the claim 26-29, wherein said experimenter is the people.

31. each method among the claim 26-30, wherein said anti-HIV or other drug are listed chemical compound in the description 17-28 page or leaf invading the exterior.

32. treat the method that human host HIV infects, comprise compositions for one kind to described host's administration claim 27.

33. the method for claim 32, wherein said compositions comprises the chemical compound of effective dose

34. pharmaceutical composition, comprise among the claim 1-15 of effective dose each first chemical compound and at least a anti-HIV-1 compounds of effective dose or description 17-28 page or leaf invading the exterior in other listed combination of compounds, and with the combination of pharmaceutically acceptable carrier, additive or excipient.

35. claim 16,18 or 34 pharmaceutical composition, wherein said chemical compound is

36. the pharmaceutical composition of claim 16 also comprises at least a other chemical compound, described chemical compound is selected from (-) beta-dioxolane-G (DXG); (-) β-arctigenin (arctigenin); (-)-Carbovir (-)-C-D4G; (-)-2 ', 3 '-dideoxy-5-fluoro-3 '-thia cytidine (FTC); (-)-β-D-2,6-diaminopurine dioxolanes (DAPD); (+)-2 '-deoxidation-3 '-oxa--4 '-sulfo-cytidine (dOTC+); (+)-2 '-deoxidation-3 '-oxa--4 '-sulfo--5-fluorine cytidine (dOTFC+); (+/-)-Lobucavir;

(R)-and 2QuinCOAsnPhe[CHOHCH2] PipCONHtBu; (R)-3,6-diamino-N-(amino methyl) caproamide (Bellenamine); (R)-9-(2-phosphonium mesitoyl methoxy propyl group) adenine (tenofovir); (R)-PMPDAP; (S)-9-(2-phosphonium mesitoyl methoxy propyl group) adenine ((S)-PMPA); PMPA (S); α-APA (loviride); R87232; R88703; α-APA enantiomer (R90385);

α-L-AZT; α-L-dioxolanes-C (α-L-DXC); α-L-FTC;

α-single methyl fluoride dehydrogenation ornithine methyl ester (MFMOME); 1,1 '-Celogen Az (ADA); 1-(11-octyl group amino-10-hydroxyl undecyl)-3,7-dimethyl xanthine (CT-2576);

1-(2 ', 3 '-dideoxy-2 '-fluoro-beta-D-threo form-penta furyl glycosyl) cytosine (Ro 31-6840);

1-(2 '-fluoro-2 ', 3 '-dideoxy-β-D-erythro-penta furyl glycosyl) thymus pyrimidine (2 ' FddT);

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(3-aminomethyl phenyl) sulfenyl) thymus pyrimidine (HEPT-M);

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(thiophenyl)-2-thio-thymine (HEPT-S);

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(thiophenyl) thymus pyrimidine (HEPT);

Deoxidation nojirimycin (1-deoxidation nojirimycin); Amprenavir; Abacavir succinate (match is advanced); 1-amino oxygen base ethamine (AEA); 1-methoxyl group oxalyl group-3, and the 5-dicaffeoylquinic acid (1-MO-3,5-DCQA); 1OH-2 (Cbz-Tle) 3PhPr[14] the adjacent formic acid derivates of two Parylenes; 1OH-2 (Cbz-ValNH) 3PhPr[13] the adjacent formic acid derivates of dimerization meta-xylene; 1OH-2 (Cbz-ValNH) 3PhPr[13] the adjacent formic acid derivates of two Parylenes;

1OH-2 (Cbz-ValNH) 3PhPr[14] the adjacent formic acid derivates of two Parylenes; 1OH-2 (Cbz-ValNH) 3PhPr[17] the adjacent formic acid derivates of two Parylenes; 12-deoxidation phorbol-13-(3E, 5E-decadinene acid esters); 16. α-bromine epiandrosterone (Epi-Br) or (Inactivin); 1-β-D-arabinofuranosyl adenin glycosyl-5-(2-bromo vinyl) uracil (Sorivudine); 2 ', 3 '-two dehydrogenations-3 '-deoxycytidine (D4C);

2 ', 3 '-dideoxy two dehydrogenation guanosines (D4G); 2 ', 3 '-two dehydrogenations-3 '-deoxyribosylthymine (D4T) (stavudine); 2 ', 3 '-dideoxy-3 '-fluoro-4-sulfo-thymidine (3 '-F-4-Thio-ddT);

2 ', 3 '-dideoxy-3 '-fluoro-5-broxuridine (FddBrU); 2 ', 3 '-dideoxy-3 '-fluoro-5-5-chloro-5-deoxyarabinosylcytosine (3 '-F-5-Cl-ddC); 2 ', 3 '-dideoxy-3 '-fluoro-5-chloriduria glycosides (935U83) (raluridine); 2 ', 3 '-dideoxy-5-ethyl cytidine (5-Et-ddC); 2 ', 3 '-DIDEOXYADENOSINE (ddA);

2 ', 3 '-dideoxy two dehydrogenation adenosines (d4A); 2 ', 3 '-dideoxy guanosine (ddG);

2 ', 3 '-dideoxy-3 '-hydroxymethyl cytidine (3 '-hydroxymethyl-ddC); 2,5 '-dehydration-3 '-azido-2 ', 3 '-di-deoxyuridine (AZU-2,5 '-dehydration); 2,5 '-dehydration-3 '-azido-3 '-deoxyribosylthymine (AZT-2,5 '-dehydration); 2 ', 5 ' diSilySpiroT (TSAO-T); 2 ', 5 ' diSilySpiroT (TSAO-me^3T); 2,6-diaminourea-2 ', 3 '-dideoxy purine-9-ribofuranoside (ddDAPR) (2, the 6-diaminourea-ddP); 2,6-diaminopurine-2 ', 3 '-dideoxy two dehydrogenation nucleoside (ddeDAPR); 2,6-diaminopurine-3 '-fluoro-2 ', 3 '-di-deoxynucleoside (3 '-F-ddDAPR); 2-aminobenzyl statine valyl Cbz derivant; 2-glycine amide-5-chlorphenyl 2-pyrrolyl ketone (GCPK); [2-PyridCH2NCH3CO-Val-NHCH (Bz)] CHOHCHOH (A-77003); 2 '-azido-2 ', 3 '-DIDEOXYADENOSINE (2 '-N3ddA); 2 '-F-dd-ara-A (Lodensine); 2 '-FddT; 2 '-N3ddA; 2 '-N3ddA (β-D-threo form); 2-NaphCOAsnPhe[CHOHCH2] Pro-OtBu; 2-nitrobenzophenone phenylsulfone (NPPS); 3-(3-oxo-1-acrylic)-3 '-azido-3 '-deoxyribosylthymine (3-(3-oxo-1-acrylic) AZT); 3-(3-oxo-1-acrylic) AZT; L-737,126; 3, and the 5-dicaffeoylquinic acid (3,5-DCQA); 3 '-azido-3 '-deoxidation-6-azathymidine; 3 '-azido-2 ', 3 '-dideoxy-5-[(cyano methyl) the oxygen base] uridnine; 3 '-azido-2 ', 3 '-dideoxy-5-aminouridine; 3 '-azido-2 ', 3 '-the assorted uridnine of dideoxy-5-azepine-6-denitrification; 3 '-azido-2 ', 3 '-dideoxy-5-broxuridine; 3 '-azido-2 ', 3 '-dideoxy-5-5-chloro-5-deoxyarabinosylcytosine (3 '-Az-5-Cl-ddC); 3 '-azido-2 ', 3 '-dideoxy-5-dimethylamino uridnine; 3 '-azido-2 ', 3 '-dideoxy-5-ethyl uridnine; 3 '-azido-2 ', 3 '-dideoxy-5-fluorine cytidine; 3 '-azido-2 ', 3 '-dideoxy-5-floxuridine; 3 '-azido-2 ', 3 '-dideoxy-5-hydroxyuridine; 3 '-azido-2 ', 3 '-dideoxy-5-iodo uridnine; 3 '-azido-2 ', 3 '-dideoxy-5-methylamino uridnine; 3 '-azido-2 ', 3 '-dideoxy-5-methylcytidine; 3 '-azido-2 ', 3 '-dideoxy-5-thiocyano uridnine; 3 '-azido-2 ', 3 '-dideoxy-5-trifluoromethyl uridnine; 3 '-azido-2 ', 3 '-zalcitabine; 3 '-azido-2 ', 3 '-the dideoxy guanosine; 3 '-azido-2 ', 3 '-dideoxy-N4--5-dimethyl cytidine; 3 '-azido-2 ', 3 '-dideoxy-N4-OH-5-methylcytidine; 3 '-azido-2 ', 3 '-di-deoxyuridine (Uravidine); 3 '-azido-3 '-deoxidation-6-azathymidine; 3-azido-3 '-the deoxyribosylthymine base-(5 ', 5 ')-2 ', 3 '-dideoxy-5 '-adenylic acid; 3 '-azido-3 '-the deoxyribosylthymine base-(5 ', 5 ')-2 ', 3 '-dideoxy-5 '-adenylic acid, 2-cyano ethyl ester; 3 '-azido-3 '-the deoxyribosylthymine base-(5 ', 5 ')-2 ', 3 '-dideoxy-5 '-inosinic acid (AZT-P-ddI); 3 '-azido-3 '-deoxyribosylthymine-5 '-(butyl methoxyl group valine) phosphate ester; 3 '-azido-5-chloro-2 ', 3 '-di-deoxyuridine; 3 '-deoxyribosylthymine (ddT); 9-(3 '-fluoro-2 ', 3 '-dideoxy-β-D-erythro penta furyl glycosyl) adenine;

3 '-fluoro-2 ', 3 '-dideoxy-5-iodo uridnine (FddIU); 3 '-fluoro-2 ', 3 '-zalcitabine (3 '-FddC); 3 '-fluoro-2 ', 3 '-the dideoxy guanosine (3 '-FddG); 3 '-fluoro-2 ', 3 '-di-deoxyuridine (3 '-FddU); 9-(3 '-azido-2 ', 3 '-dideoxy-β-D-erythro penta furyl glycosyl) adenine; 3TC (lamivudine); 3TC﹠amp; AZT (Combivir); 4 '-acetylamino phenyl 4-guanidine benzoate; 4 '-azido-3 '-deoxyribosylthymine; 4 '-azido-5-chloro-2 '-BrdU; 4 '-azido-2 '-deoxyadenosine; 4 '-azido-2 '-deoxycytidine; 4 '-azido-2 '-deoxyguanosine; 4 '-azido-2 '-deoxyinosine; 4 '-azido-2 '-BrdU; 4 '-azido breast glycosides; 4 '-cyano group breast glycosides; 4-methyl-5-(pyrazinyl)-3H-1,2-dithia cyclopentenes-3-thioketone (oltipraz); 5 '-[(1,4-dihydro-1-methyl-3-pyridine radicals carbonyl) oxygen base]-3 '-azido-2 ', 3 '-deoxyribosylthymine (DP-AZT); 5 '-[[(Z)-and 4-amino-crotyl] methylamino]-5 '-deoxyadenosine (MDL 73811); 5 '-alkyl polyglucoside carbonic ester of 3 '-azido-3 '-deoxyribosylthymine; 5Cl3PhS-2 indole CONH2; 5-fluoro-2 ', 3 '-zalcitabine; 5-methyl-3 '-azido-2 ', 3 '-the different cytidine of dideoxy; Celgosivir; 6-chloro-9-(2,3-dideoxy-β-D-glycerol penta furyl glycosyl)-9H-purine; 6-dimethylaminopurine-2 ', 3 '-di-deoxynucleoside; Ro 24-7429; Ro 5-3335; Tivirapine; 9-(2,3-dideoxy-β-D-ribofuranosyl)-6-(methyl mercapto) purine; 9-(2 '-azido-2 ', 3 '-dideoxy-B-D-threo form penta furyl glycosyl) adenine; C-Europe tower mycin A; (+-) Lobucavir; A-76890; A-77003; A-77212; A-80987; A-81525; A-83962; A-98881; PNU-104489; Three associations only; Lopinavir; Kaletra; Lopinavir and ritonavir;

With the promise Wei; Azodicarboamide; Adefovirdipivoxil; Adefovir dipivoxil

Nelfinavir; AG1350 (LY316957); R-87366; Alpha-lipoic acid; Alovudine (3 '-FddT); ALX40-4C; AMD3100 (JM3100); Amdoxovir (APD); Phosphoric acid amprenavir (fosamprenavir); Ancer 20 (Z-100); Atazanavir (Latazanavir); Ah 's dimension is fixed; The aurintricarboxylic acid; AY 9944; 3 '-azido-5-chloro-2 ', 3 '-di-deoxyuridine; AZT; α-L-AZT; O, O '-two (3 '-azido-3 '-methyl phosphonate of deoxyribosylthymine-5 '-yl); Baicalin (TJN-151); Belulinic acid Betulinic acid (Mairin); Belulinic acid Betulinic acid, 3-O-(3 ', 3 '-the dimethyl succinate ester); Delavirdine (U-90152); U-g8204E; Nevirapine; BILA 1906 BS; BILA2011 BS (palinavir); BILA 2185 BS; NSC633001; CGP 53820; Two-ValHOEt-N2aza-peptide isostere (CGP 53820 analog); BMS-186318; L-687,908; Brovavir; BzOCValPhe[diCHOH (RR)] PheValBzOC; BzOCValPhe[diCHOH (SS)] PheValBzOC; C2-Sym phosphonic amide derivant (HOECHSTAG); NSC675451; Calanolide B; Capravirine (S-1153); Carbovir; Castanospermine; CGP 61755 (LASINAVIR BMS-234475 Lasinavir [INN); CGP 64222; CNI-H0294; Emivirine; Conocurvone (NSC650891); Emtricitabine; C-Oxetanocin-G; Indinavir; The sulfogel polysaccharide; Blue algae antiviral protein-N; SD146; Cyclosporin A; SDZ NIM 811; L-2 ', 3 '-two dehydrogenations-2 ', 3 '-DIDEOXYADENOSINE (L-D4A); 2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy-5-fluorine cytidine (DD4C); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy-5-fluorine cytidine (LD4C); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy guanosine (LD4G); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-didanosine (LD4I); DABO; DdI; DdC; DMP-323; DMP-450; (-)-2 '-deoxidation-3 '-oxa--4 '-the sulfo-cytidine; (-)-2 '-deoxidation-3 '-oxa--4 '-sulfo--5-flurocytosine; Pentafuside (Enfuvirtide); Etoposide; Efavirenz; Emtriva; K-12 (fluorine quinoline); Saquinavir; Foscarnet; Phosphine formic acid; Foscarnet sodium; FPMDAP; FPMPA; FPMPG; Gene Expression Modulator 91 (GEM91); Hammerhead shape resists-gagRNA formation enzyme B; Harziphilone; HBY 097 (quinoxaline derivant); E-EBU; E-EPSeU; E-EPU; NSC 648400; E-EBU-dM; Zalcitabine; LY326188; Ingenol 3,5,20-triacetate (ITA); Calophylloide B; KNI-272; RD3-2118; KNI-102; KNI-154; KNI-174; KNI-227; L-685,434; L-689,502; L-697,593; L-697,639; L-697,661; LY289612; Trovirdine; LY-73497; L-735,524; N-ethyl-2 ', 3 '-DIDEOXYADENOSINE; N6-methyl-2 ', 3 '-DIDEOXYADENOSINE; Noa-Asn-Apns-Thz-NH-tBu; Nonoxinol 9; Ritonavir; NSC625487; NSC649324; NSC650898; UC-38; UC-84; P9941; Palinavir; The sulphuric acid pentosan; Elmiron; SP54; PNU-140690 (tipranavir); S-2720; R14458; R82150; R82913; R86183; RD4-2138; Resobene; Reyataz; Ribavirin; 7-chloro-N-methyl-5-(1H-pyrroles-2-yl)-3H-1, the 4-benzodiazepine

-2-amine; 7-chloro-5-(2-pyrrole radicals)-3H-1, the 4-benzodiazepine

-2 (H)-ketone; LY314163; SB-205569; Compound E; SD-095345SD146; SDZ PRI 053; SPC3; Naganol; T22; Thalidomide; Thiangazole; Thiazole and iso-indoles-5-ketone; U-104489; U-140690; U-87201E; U-88204E; UC-781; VB-11,328; VX-478; 141W94; XM-323 and composition thereof.

37. the pharmaceutical composition of claim 16 also comprises other chemical compound, described other chemical compound is selected from ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine); AZT; Abacavir; Abacavir/lamivudine/zidovudine; Abacavir sulfate; Abacavir sulfate/lamivudine; Abacavir/lamivudine; Abelecet; Aciclovir; Adefovir dipivoxil; Amycin; Agenerase; Aldesleukin; Alovudine; Aluvia; Ambisome; Amdoxovir; Amphocin; Amphotec; Amphotericin B; Polyinosini; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude; Bevirimat; Biaxin; Brecanavir; BufferGel; C31G; CD4-IgG2; CS; CV-N; Calanolide A; Calcium hydroxyapatite; Carbopol 974P; Carrageenan; Carraguard; Sulfate cellulose; Clarithromycin; Combivir; Copegus; Sulfamethoxazole; Crixivan; Blue algae antiviral protein-N; Cymevene; DAPD; DLV; DS; Darunavir; Delavirdine; The Depo-testosterone; Dextran sulfate; Didanosine; Fluconazole; Doxil; Doxorubicin (liposome); Dronabinol; EFV; Efavirenz; Elvucitabine; Emtricitabine; The tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir; Lamivudine; Epoetin Alfa; Epogen; Epzicom; Etopophos (phosphate); Etoposide; Etravirine; FTC; Fluconazol; Fortovase; Fosamprenavir; Foxivudine tidoxil; Fungizone; Fuzeon; GS 9137; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir; Immunoglobulin; Growth hormone (people); Hepsera; Hivid; The human growth hormone; IL-2; INH; Immunoglobulin, intravenous (people); Indinavir; Interferon; Interleukin-2, recombinant, people; Recombinant Interferon (2b); Invirase; Isoniazid; Itraconazole; KP-1461; Lamivudine/zidovudine; Lexiva; Lopinavir/ritonavir; MK-0518; Nebupent; Nelfinavir; Neutrexin; Nevirapine; Nuo Wei; Nydrazid; Peptide T; PMPA prodrug (Viread) ' Prezista (Darunavir); PRO 140; PRO 2000; PRO 542 (CD4IGg2); Procrit (Epoetin); Aldesleukin; Racivir; Radiesse; Rrebetol; Delavirdine; Zidovudine; Reyataz; Ribavirin; Rifabutin; Rifadin; Rifampicin; Rimactane; Ritonavir; Rodferon-A (2a); Saquinavir; SCH-D (vicriviroc); Growth hormone; Stavudinie; Sulfamethoxazole/trimethoprim; Testosterone; Sustiva; TNX-355; Taxol; Tenofovir; The tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar; Trimetrexate; Three associations only; Truvada (Emtriva and Viread combination); U-90152S (Delaviridine); UC-781; UK-427,857 (maraviroc); Valcyte; Valganciclovir; Valproic acid; Fan Bishi; Vicriviroc; Videx; Viracept see nelfinaivr (Tennofovir DF); The happy life of dimension; Virazole; Viread; Vitrasert; Zalcitabine; Sai Ruite; Match is advanced; Zidovudine; Zithromax; Shu Wei treats and composition thereof.

38. each compositions among the claim 34-37, wherein said compositions is treated human host's described HIV and is infected by suppressing hiv integrase at least, and described intergrase is wild type and mutant.

39. each compositions among the claim 34-38, it is oral or parenteral dosage form.

40. each compositions among the claim 34-38, it is mixed with the suction spraying or rectal suppository is used for administration.

41. treat the method that patient HIV infects for one kind, described method comprises in the claim 34-40 of described patient's effective dosage each compositions.

42. a minimizing has the patient's of HIV infection risk the method for HIV infection potential, described method comprises in the claim 34-40 of described patient's effective dosage each compositions.

43. a treatment has the patient's of AIDS or ARC method, comprises in the claim 34-40 of described patient's drug treatment effective dose each compositions.

44. a method that suppresses experimenter's hiv integrase, described method comprise in the claim 34-40 of described experimenter's drug treatment effective dose each compositions.

45. each method among the claim 41-44, wherein said experimenter is the people

46. each compositions is used for the treatment of purposes in patient's the medicine of HIV in preparation among claim 16-24 and the 34-40.

47. each compositions is used for reducing the purposes that the patient contacts the medicine of HIV possibility of infection in preparation among claim 16-24 and the 34-40.

48. each compositions is used for the treatment of purposes in the medicine of the patient with AIDS or ARC in preparation among claim 16-24 and the 34-30.

49. each compositions is used for suppressing the purposes of medicine of experimenter's hiv integrase among claim 16-24 and the 34-40 in preparation.

50. the purposes of claim 46-49, wherein said experimenter is people patient.

51. the method that treatment human host's HIV infects, comprise first chemical compound and the acceptable salt of pharmacy thereof to the following structure of described host's combination medicine-feeding effective dose, with the combination of at least a other chemical compound and composition thereof, also make up pharmaceutically acceptable carrier, additive or excipient:

2-and 4-pyridone and regional isomer thereof that skeleton described in the formula I limits for this paper independently;

R ¹And R ²Be H independently of one another; C _1-6Alkyl; C _1-6Fluoro-alkyl; Unsubstituted or substituted C _5-6Cycloalkyl; C _1-6Thiazolinyl, unsubstituted or substituted phenyl; Unsubstituted or substituted benzyl; C _2-6Alkyl phenyl, described phenyl can be chosen wantonly and be substituted; Unsubstituted or substituted heteroaryl; The C that is replaced by heteroaryl _1-6Alkyl, described heteroaryl is optional to be substituted; C _1-6Alkyl S (O) R or alkyl (SO ₂) R, wherein R is alkyl, phenyl or substituted phenyl; C _1-6Alkyl CO ₂R ^a, R wherein ^aBe C _1-6Alkyl or H, C _1-6Alkyl COR ^a', R wherein ^a' be C _1-6Alkyl;

R ⁵Be CO ₂R ^cOr P (O) (OR ^c) (OR ^c), each R wherein ^cBe independently selected from H and C _1-6Alkyl,

Described other chemical compound is selected from: (-) beta-dioxolane-G (DXG); (-) β-arctigenin (arctigenin); (-)-Carbovir (-)-C-D4G; (-)-2 ', 3 '-dideoxy-5-fluoro-3 '-thia cytidine (FTC); (-)-β-D-2,6-diaminopurine dioxolanes (DAPD); (+)-2 '-deoxidation-3 '-oxa--4 '-sulfo-cytidine (dOTC+); (+)-2 '-deoxidation-3 '-oxa--4 '-sulfo--5-fluorine cytidine (dOTFC+); (+/-)-Lobucavir; (R)-and 2QuinCOAsnPhe[CHOHCH2] PipCONHtBu; (R)-3,6-diamino-N-(amino methyl) caproamide (Bellenamine); (R)-9-(2-phosphonium mesitoyl methoxy propyl group) adenine (tenofovir); (R)-PMPDAP; (S)-9-(2-phosphonium mesitoyl methoxy propyl group) adenine ((S)-PMPA); PMPA (S); α-APA (loviride); R87232; R88703; α-APA enantiomer (R90385);

α-L-AZT; α-L-dioxolanes-C (α-L-DXC); α-L-FTC;

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(thiophenyl)-2-thio-thymine (HEPT-S);

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(thiophenyl) thymus pyrimidine (HEPT);

With the promise Wei; Azodicarboamide; Adefovirdipivoxil; Adefovir dipivoxil Nelfinavir; AG1350 (LY316957); R-87366; Alpha-lipoic acid; Alovudine (3 '-FddT); ALX40-4C; AMD3100 (JM3100); Amdoxovir (APD); Phosphoric acid amprenavir (fosamprenavir); Ancer 20 (Z-100); Atazanavir (Latazanavir); Ah 's dimension is fixed; The aurintricarboxylic acid; AY 9944; 3 '-azido-5-chloro-2 ', 3 '-di-deoxyuridine; AZT; α-L-AZT; O, O '-two (3 '-azido-3 '-methyl phosphonate of deoxyribosylthymine-5 '-yl); Baicalin (TJN-151); Belulinic acid Betulinic acid (Mairin); Belulinic acid Betulinic acid, 3-O-(3 ', 3 '-the dimethyl succinate ester); Delavirdine (U-90152); U-88204E; Nevirapine; BILA 1906 BS; BILA 2011BS (palinavir); BILA 2185BS; NSC633001; CGP 53820; Two-ValHOEt-N2aza-peptide isostere (CGP 53820 analog); BMS-186318; L-687,908; Brovavir; BzOCValPhe[diCHOH (RR)] PheValBzOC; BzOCValPhe[diCHOH (SS)] PheValBzOC; C2-Sym phosphonic amide derivant (HOECHSTAG); NSC675451; Calanolide B; Capravirine (S-1153); Carbovir; Castanospermine; CGP 61755 (LASINAVIR BMS-234475 Lasinavir [INN); CGP 64222; CNI-H0294; Emivirine; Conocurvone (NSC650891); Emtricitabine; C-Oxetanocin-G; Indinavir; The sulfogel polysaccharide; Blue algae antiviral protein-N; SD146; Cyclosporin A; SDZ NIM 811; L-2 ', 3 '-two dehydrogenations-2 ', 3 '-DIDEOXYADENOSINE (L-D4A); 2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy-5-fluorine cytidine (DD4C); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy-5-fluorine cytidine (LD4C); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy guanosine (LD4G); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-didanosine (LD4I); DABO; DdI; DdC; DMP-323; DMP-450; (-)-2 '-deoxidation-3 '-oxa--4 '-the sulfo-cytidine; (-)-2 '-deoxidation-3 '-oxa--4 '-sulfo--5-flurocytosine; Pentafuside (Enfuvirtide); Etoposide; Efavirenz; Emtriva; K-12 (fluorine quinoline); Saquinavir; Foscarnet; Phosphine formic acid; Foscarnet sodium; FPMDAP; FPMPA; FPMPG; Gene Expression Modulator 91 (GEM91); Hammerhead shape is anti--and gagRNA constitutes enzyme, B; Harziphilone; HBY 097 (quinoxaline derivant); E-EBU; E-EPSeU; E-EPU; NSC 648400; E-EBU-dM; Zalcitabine; LY326188; Ingenol 3,5,20-triacetate (ITA); Calophylloide B; KNI-272; RD3-2118; KNI-102; KNI-154; KNI-174; KNI-227; L-685,434; L-689,502; L-697,593; L-697,639; L-697,661; LY289612; Trovirdine; LY-73497; L-735,524; N-ethyl-2 ', 3 '-DIDEOXYADENOSINE; N6-methyl-2 ', 3 '-DIDEOXYADENOSINE; Noa-Asn-Apns-Thz-NH-tBu; Nonoxinol 9; Ritonavir; NSC625487; NSC649324; NSC650898; UC-38; UC-84; P9941; Palinavir; The sulphuric acid pentosan; Elmiron; SP54; PNU-140690 (tipranavir); S-2720; R14458; R82150; R82913; R86183; RD4-2138; Resobene; Reyataz; Ribavirin; 7-chloro-N-methyl-5-(1H-pyrroles-2-yl)-3H-1, the 4-benzodiazepine

-2-amine; 7-chloro-5-(2-pyrrole radicals)-3H-1, the 4-benzodiazepine

52. the method for claim 51, wherein said first chemical compound is

53. treat the method that human host HIV infects for one kind, comprise first chemical compound and the acceptable salt of pharmacy thereof to the following formula of described host's combination medicine-feeding effective dose, with the combination of at least a other chemical compound and composition thereof, also combination has pharmaceutically acceptable carrier, additive or excipient:

R ³And R ⁴Be independently selected from H, C _1-6Alkyl, halogen, hydroxyl, unsubstituted or substituted benzyl, unsubstituted or substituted thiophenyl;

Described at least a other chemical compound is selected from: ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine); AZT; Abacavir; Abacavir/lamivudine/zidovudine; Abacavir sulfate; Abacavir sulfate/lamivudine; Abacavir/lamivudine; Abelecet; Aciclovir; Adefovir dipivoxil; Amycin; Agenerase; Aldesleukin; Alovudine; Aluvia; AM Bison; Amdoxovir; Amphocin; Amphotec; Amphotericin B; Polyinosini; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude; Bevirimat; Biaxin; Brecanavir; BufferGel; C31G; CD4-IgG2; CS; CV-N; Calanolide A; Calcium hydroxyapatite; Carbopol 974P; Carrageenan; Carraguard; Sulfate cellulose; Clarithromycin; Combivir; Copegus; Sulfamethoxazole; Crixivan; Blue algae antiviral protein-N; Cymevene; DAPD; DLV; DS; Darunavir; Delavirdine; The Depo-testosterone; Dextran sulfate; Didanosine; Fluconazole; Doxil; Doxorubicin (liposome); Dronabinol; EFV; Efavirenz; Elvucitabine; Emtricitabine; The tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir; Lamivudine; Epoetin Alfa; Epogen; Epzicom; Etopophos (phosphate); Etoposide; Etravirine; FTC; Fluconazol; Fortovase; Fosamprenavir; Foxivudine tidoxil; Fungizone; Fuzeon; GS 9137; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir; Immunoglobulin; Growth hormone (people); Hepsera; Hivid; The human growth hormone; IL-2; INH; Immunoglobulin, intravenous (people); Indinavir; Interferon; Interleukin-2, recombinant, people; Recombinant Interferon (2b); Invirase; Isoniazid; Itraconazole; KP-1461; Lamivudine/zidovudine; Lexiva; Lopinavir/ritonavir; MK-0518; Nebupent; Nelfinavir; Neutrexin; Nevirapine; Nuo Wei; Nydrazid; Peptide T; PMPA prodrug (Viread) ' Prezista (Darunavir); PRO 140; PRO 2000; PRO 542 (CD4 IGg2); Procrit (Epoetin); Aldesleukin; Racivir; Radiesse; Rrebetol; Delavirdine; Zidovudine; Reyataz; Ribavirin; Rifabutin; Rifadin; Rifampicin; Rimactane; Ritonavir; Rodferon-A (2a); Saquinavir; SCH-D (vicriviroc); Growth hormone; Stavudinie; Sulfamethoxazole/trimethoprim; Testosterone; Sustiva; TNX-355; Taxol; Tenofovir; The tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar; Trimetrexate; Three associations only; Truvada (Emtriva and Viread combination); U-90152S (Delaviridine); UC-781; UK-427,857 (maraviroc); Valcyte; Valganciclovir; Valproic acid; Fan Bishi; Vicriviroc; Videx; Viracept see nelfinaivr (Tennofovir DF); The happy life of dimension; Virazole; Viread; Vitrasert; Zalcitabine; Sai Ruite; Match is advanced; Zidovudine; Zithromax; Zovirax and composition thereof.

54. the method for claim 53, wherein said first chemical compound is

55. pharmaceutical composition comprises the chemical compound of the following structure of effective dose:

With the combination of at least a other chemical compound of effective dose and composition thereof, also combination has pharmaceutically acceptable carrier, additive or excipient, and described other chemical compound is selected from

(-) beta-dioxolane-G (DXG); (-) β-arctigenin (arctigenin); (-)-Carbovir (-)-C-D4G; (-)-2 ', 3 '-dideoxy-5-fluoro-3 '-thia cytidine (FTC); (-)-β-D-2,6-diaminopurine dioxolanes (DAPD); (+)-2 '-deoxidation-3 '-oxa--4 '-sulfo-cytidine (dOTC+); (+)-2 '-deoxidation-3 '-oxa--4 '-sulfo--5-fluorine cytidine (dOTFC+); (+/-)-Lobucavir;

α-L-AZT; α-L-dioxolanes-C (α-L-DXC); α-L-FTC;

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(thiophenyl)-2-thio-thymine (HEPT-S);

The 1-[(2-hydroxyl-oxethyl) methyl]-6-(thiophenyl) thymus pyrimidine (HEPT);

3 '-fluoro-2 ', 3 '-dideoxy-5-iodo uridnine (FddIU); 3 '-fluoro-2 ', 3 '-zalcitabine (3 '-FddC); 3 '-fluoro-2 ', 3 '-the dideoxy guanosine (3 '-FddG); 3 '-fluoro-2 ', 3 '-di-deoxyuridine (3 '-FddU); 9-(3 '-azido-2 ', 3 '-dideoxy-β-D-erythro penta furyl glycosyl) adenine; 3TC (lamivudine); 3TC ﹠amp; AZT (Combivir); 4 '-acetylamino phenyl 4-guanidine benzoate; 4 '-azido-3 '-deoxyribosylthymine; 4 '-azido-5-chloro-2 '-BrdU; 4 '-azido-2 '-deoxyadenosine; 4 '-azido-2 '-deoxycytidine; 4 '-azido-2 '-deoxyguanosine; 4 '-azido-2 '-deoxyinosine; 4 '-azido-2 '-BrdU; 4 '-azido breast glycosides; 4 '-cyano group breast glycosides; 4-methyl-5-(pyrazinyl)-3H-1,2-dithia cyclopentenes-3-thioketone (oltipraz); 5 '-[(1,4-dihydro-1-methyl-3-pyridine radicals carbonyl) oxygen base]-3 '-azido-2 ', 3 '-deoxyribosylthymine (DP-AZT); 5 '-[[(Z)-and 4-amino-crotyl] methylamino]-5 '-deoxyadenosine (MDL 73811); 5 '-alkyl polyglucoside carbonic ester of 3 '-azido-3 '-deoxyribosylthymine; 5Cl3PhS-2 indole CONH2; 5-fluoro-2 ', 3 '-zalcitabine; 5-methyl-3 '-azido-2 ', 3 '-the different cytidine of dideoxy; Celgosivir; 6-chloro-9-(2,3-dideoxy-β-D-glycerol penta furyl glycosyl)-9H-purine; 6-dimethylaminopurine-2 ', 3 '-di-deoxynucleoside; Ro 24-7429; Ro 5-3335; Tivirapine; 9-(2,3-dideoxy-β-D-ribofuranosyl)-6-(methyl mercapto) purine; 9-(2 '-azido-2 ', 3 '-dideoxy-B-D-threo form penta furyl glycosyl) adenine; C-Europe tower mycin A; (+-) Lobucavir; A-76890; A-77003; A-77212; A-80987; A-81525; A-83962; A-98881; PNU-104489; Three associations only; Lopinavir; Kaletra; Lopinavir and ritonavir; With the promise Wei; Azodicarboamide; Adefovirdipivoxil; Adefovir dipivoxil

Nelfinavir; AG1350 (LY316957); R-87366; Alpha-lipoic acid; Alovudine (3 '-FddT); ALX40-4C; AMD3100 (JM3100); Amdoxovir (APD); Phosphoric acid amprenavir (fosamprenavir); Ancer 20 (Z-100); Atazanavir (Latazanavir); Ah 's dimension is fixed; The aurintricarboxylic acid; AY 9944; 3 '-azido-5-chloro-2 ', 3 '-di-deoxyuridine; AZT; α-L-AZT; O, O '-two (3 '-azido-3 '-methyl phosphonate of deoxyribosylthymine-5 '-yl); Baicalin (TJN-151); Belulinic acid Betulinic acid (Mairin); Belulinic acid Betulinic acid, 3-O-(3 ', 3 '-the dimethyl succinate ester); Delavirdine (U-90152); U-88204E; Nevirapine; BILA 1906 BS; BILA2011BS (palinavir); BILA 2185 BS; NSC633001; CGP 53820; Two-ValHOEt-N2aza-peptide isostere (CGP 53820 analog); BMS-186318; L-687,908; Brovavir; BzOCValPhe[diCHOH (RR)] PheValBzOC; BzOCValPhe[diCHOH (SS)] PheValBzOC; C2-Sym phosphonic amide derivant (HOECHSTAG); NSC675451; Calanolide B; Capravirine (S-1153); Carbovir; Castanospermine; CGP 61755 (LASINAVIR BMS-234475 Lasinavir [INN); CGP 64222; CNI-H0294; Emivirine; Conocurvone (NSC650891); Emtricitabine; C-Oxetanocin-G; Indinavir; The sulfogel polysaccharide; Blue algae antiviral protein-N; SD146; Cyclosporin A; SDZ NIM 811; L-2 ', 3 '-two dehydrogenations-2 ', 3 '-DIDEOXYADENOSINE (L-D4A); 2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy-5-fluorine cytidine (DD4C); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy-5-fluorine cytidine (LD4C); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-dideoxy guanosine (LD4G); L-2 ', 3 '-two dehydrogenations-2 ', 3 '-didanosine (LD4I); DABO; DdI; DdC; DMP-323; DMP-450; (-)-2 '-deoxidation-3 '-oxa--4 '-the sulfo-cytidine; (-)-2 '-deoxidation-3 '-oxa--4 '-sulfo--5-flurocytosine; Pentafuside (Enfuvirtide); Etoposide; Efavirenz; Emtriva; K-12 (fluorine quinoline); Saquinavir; Foscarnet; Phosphine formic acid; Foscarnet sodium; FPMDAP; FPMPA; FPMPG; Gene Expression Modulator 91 (GEM91); Hammerhead shape resists-gagRNA formation enzyme B; Harziphilone; HBY 097 (quinoxaline derivant); E-EBU; E-EPSeU; E-EPU; NSC 648400; E-EBU-dM; Zalcitabine; LY326188; Ingenol 3,5,20-triacetate (ITA); Calophylloide B; KNI-272; RD3-2118; KNI-102; KNI-154; KNI-174; KNI-227; L-685,434; L-689,502; L-697,593; L-697,639; L-697,661; LY289612; Trovirdine; LY-73497; L-735,524; N-ethyl-2 ', 3 '-DIDEOXYADENOSINE; N6-methyl-2 ', 3 '-DIDEOXYADENOSINE; Noa-Asn-Apns-Thz-NH-tBu; Nonoxinol 9; Ritonavir; NSC625487; NSC649324; NSC650898; UC-38; UC-84; P9941; Palinavir; The sulphuric acid pentosan; Elmiron; SP54; PNU-140690 (tipranavir); S-2720; R14458; R82150; R82913; R86183; RD4-2138; Resobene; Reyataz; Ribavirin; 7-chloro-N-methyl-5-(1H-pyrroles-2-yl)-3H-1, the 4-benzodiazepine

-2-amine; 7-chloro-5-(2-pyrrole radicals)-3H-1, the 4-benzodiazepine

56. pharmaceutical composition comprises the chemical compound of the following structure of effective dose:

Also made up pharmaceutically acceptable carrier, additive or excipient with the combination of at least a other chemical compound of effective dose and composition thereof,

Described other chemical compound is selected from ACV; AK602; AMD070; APV; ATV; ATZ; AVX754 (apricitabine); AZT; Abacavir; Abacavir/lamivudine/zidovudine; Abacavir sulfate; Abacavir sulfate/lamivudine; Abacavir/lamivudine; Abelecet; Aciclovir; Adefovir dipivoxil; Amycin; Agenerase; Aldesleukin; Alovudine; Aluvia; AM Bison; Amdoxovir; Amphocin; Amphotec; Amphotericin B; Polyinosini; Amprenavir; Androderm; Androgel; Apricitabine; Aptivus; Atazanavir; Atripla; Azithromycin; BMS-378806; BMS-488043; Bactrim; Baraclude; Bevirimat; Biaxin; Brecanavir; BufferGel; C31G; CD4-IgG2; CS; CV-N; Calanolide A; Calcium hydroxyapatite; Carbopol 974P; Carrageenan; Carraguard; Sulfate cellulose; Clarithromycin; Combivir; Copegus; Sulfamethoxazole; Crixivan; Blue algae antiviral protein-N; Cymevene; DAPD; DLV; DS; Darunavir; Delavirdine; The Depo-testosterone; Dextran sulfate; Didanosine; Fluconazole; Doxil; Doxorubicin (liposome); Dronabinol; EFV; Efavirenz; Elvucitabine; Emtricitabine; The tenofovir disoproxil fumarate; Emtriva; Enfufirtide; Entecavir; Lamivudine; Epoetin Alfa; Epogen; Epzicom; Etopophos (phosphate); Etoposide; Etravirine; FTC; Fluconazol; Fortovase; Fosamprenavir; Foxivudine tidoxil; Fungizone; Fuzeon; GS 9137; GSK-873,140 (aplaviroc); GW433908; GW640385 (brecanavir); Ganciclovir; Immunoglobulin; Growth hormone (people); Hepsera; Hivid; The human growth hormone; IL-2; INH; Immunoglobulin, intravenous (people); Indinavir; Interferon; Interleukin-2, recombinant, people; Recombinant Interferon (2b); Invirase; Isoniazid; Itraconazole; KP-1461; Lamivudine/zidovudine; Lexiva; Lopinavir/ritonavir; MK-0518; Nebupent; Nelfinavir; Neutrexin; Nevirapine; Nuo Wei; Nydrazid; Peptide T; PMPA prodrug (Viread) ' Prezista (Darunavir); PRO 140; PRO 2000; PRO 542 (CD4 IGg2); Procrit (Epoetin); Aldesleukin; Racivir; Radiesse; Rrebetol; Delavirdine; Zidovudine; Reyataz; Ribavirin; Rifabutin; Rifadin; Rifampicin; Rimactane; Ritonavir; Rodferon-A (2a); Saquinavir; SCH-D (vicriviroc); Growth hormone; Stavudinie; Sulfamethoxazole/trimethoprim; Testosterone; Sustiva; TNX-355; Taxol; Tenofovir; The tenofovir disoproxil fumarate; Testosterone; Tipranavir; Toposar; Trimetrexate; Three associations only; Truvada (Emtriva and Viread combination); U-90152S (Delaviridine); UC-781; UK-427,857 (maraviroc); Valcyte; Valganciclovir; Valproic acid; Fan Bishi; Vicriviroc; Videx; Viracept see nelfinaivr (Tennofovir DF); The happy life of dimension; Virazole; Viread; Vitrasert; Zalcitabine; Sai Ruite; Match is advanced; Zidovudine; Zithromax; Zovirax and composition thereof.