HK1110320A - Diketo acids with nucleobase scaffolds: anti-hiv replication inhibitors targeted at hiv integrase - Google Patents

Description

Diketonic acid with nucleobase scaffold: anti-HIV replication inhibitors targeting HIV integrase

RELATED APPLICATIONS

This application claims priority from U.S. patent application 11/047,229 filed on 31/1/2005, which is incorporated herein by reference in its entirety.

The work of making this patent application is supported in part by the National Institutes of health, grant number a 143181. The united states government may reserve certain rights in the invention.

Background

The human immunodeficiency virus, HIV, encodes three key viral enzymes by its reverse transcriptase gene, and these enzymes are critical for replication of the virus [ Fauci, Science 239, 617-622 (1988); katz & Skalka, Annu.Rev.biochem., 63, 133-; frankel, annu, rev, biochem, 67, 1-25 (1998). Thus, these enzymes of the reverse transcriptase gene have been used as targets for attacking potential sites during the development of HIV antiviral chemotherapeutic agents [ De Clercq, J.Med.chem.38, 2491-2517 (1995); clin. microbiol. rev., 10, 674-693 (1997); DeClercq, Nature Reviews: drug Discovery, 11, 13-25 (2002). The discovery of drugs involving two of these enzymes, HIV Reverse Transcriptase (RT) and HIV Protease (PR), and the subsequent clinical use of some of these therapeutics in combination therapy for the treatment of AIDS and AIDS-related complex disease (ARC) in HAART (highly active antiretroviral therapy) has shown that this approach to target key viral enzymes represents a useful antiviral chemotherapeutic approach [ Johnson & Gerber, in "Advances in Internal Medicine," vol.44. mosby: St.Louis, 1-40 (2000); DeClercq, Nature Reviews: drug Discovery, 11, 13-25 (2002); miller & Hazuda, Current Opinion in Microbiology, 4, 535 539 (2001); Asante-Appliah & Skalkaka, adv. Virus Res., 52, 351-; nair, in "Recent Advances in nucleotides: chemistry and Chemistry, "Elsevier Science: netherlands, 149-166 (2002); declercq, Intl.J.biochem.cell biol.36, 1800-. Although HIV RT and HIV PR have been widely used in therapeutic studies, the reverse transcriptase gene, the third enzyme of HIV integrase, has been rarely considered [ Miller & 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) ].

Currently, there is no clinical drug for HIV/AIDS where the mechanism of action is to inhibit HIV integrase. HIV-1integrase is a 32kDa protein encoded at the 3' -end of the reverse transcriptase gene [ Asante-Appliah & Skaika, adv. Virus Res., 52, 351-; esposito & Craigie, adv. Virus Res., 52, 319-333(1999) ]. It involves the integration of HIV DNA into the host cell chromosome. Because integrase has no human counterpart (counterpart) and because it plays an important role in completing the invasion of human cells by HIV, it is an attractive target for the discovery of inhibitors of therapeutic potential.

Binding of HIV DNA to host chromosomal DNA in the nucleus by integrase catalysis, apparently by 3' -processing or clipping of specific defined sequences and chain transfer/integration reactions [ Asante-Appiah & Skalka, adv. Virus Res., 52, 351-369 (1999); esposito & Craigie adv. Virus Res., 52, 319-333(1999) ]. Before the integration process begins, there is the assembly of viral DNA previously generated by reverse transcription on the integrase. HIV integrase recognizes specific sequences in the LTRs of the viral DNA. After assembly of viral DNA on integrase, processing of the viral DNA occurs where there is site-specific endonuclease activity, and both nucleotides cleave from each 3 '-end of the duplex viral DNA, resulting in a tailored viral DNA that is hidden by both nucleotides and has one terminal CAOH-3'. For this initial 3' -processing step, integrase clearly activates the phosphodiester bond towards cleavage. The thus produced recessive viral DNA is in a next step linked to the host cell DNA in the nucleus by a transesterification reaction. In this stage, the integrase is located at the 3' -OH end of the viral DNA and nucleophilic attack is carried out on the phosphodiester bond in the host DNA. In a subsequent stage, there is a 4-6 bp cleavage in the host DNA and the coupling involves ligation of the processed CAOH-3 'viral DNA end with the 5' -phosphate end of the host DNA. Finally, there is repair of the resulting interstitial intermediates mediated by the host cell enzymes, although the action of integrase is also possible here.

Many compounds are inhibitors of HIV integrase, but some of these compounds are non-specific inhibitors of the enzyme, although there is evidence that other compounds may have some specificity. Various types include nucleotides, oligonucleotides, dinucleotides, and promiscuous small molecules including heterocyclic systems, natural products, diketonic acids, sulfones, etc. [ Nair, Rev. Med. Virol., 12, 179. 193 (2002); nair, Current Pharmaceutical Design, 9, 2553-2565 (2003); chi and Nair, bioorg.Med.chem.Lett.14, 4815-; nair and companies, J.am.chem.Soc., 122, 5671-5677(2000) ].

The type of compound that has been studied before as being most directly related to this patent is a diketo acid with aryl or heteroaryl substituents. Some of these compounds are HIV integrase inhibitors, but most often only at the strand transfer step. The integrase inhibition data have been reported in several scientific publications [ Wai, et al, "4-Aryl-2, 4-dioxobutanic acid inhibitors of HIV-1 integrin and viral replication in cells," J.Med.chem.43, 4923-; pais, G.C.G., et al, "structural activity of 3-aryl-1, 3-diketo-containing compounds as HIV-1 integrin inhibitors," J.Med.chem.45, 3184-; marchand, c, et, Structural determinants for HIV-1 interaction by β -diketo acids, "j.biol.chem.277, 12596-; sechi, M., et al, "Design and synthesis of novel index beta-diketo acid derivatives as HIV-1 integrin inhibitors," J.Med. chem.47, 5298-; zhang, et al, "Azido-conjugating aryl β -ketoacid HIV-1 integrin inhibitors," bioorg. med. chem. lett.13, 1215-. Other publications in this field are indirectly related to this patent application.

The mechanism of inhibition of HIV integrase by diketonic acids may be due to the interaction of functional groups on these compounds with metal ions in the integrase active site, resulting in functional chelation of these key metal cofactors [ Grobler, j.a., et al, proc.natl.acad.sci.u.s.a.99, 6661-one 6666(2002) ].

The most directly related patents to this application are: selnick, H.G.et al, (Merck & Co.Ltd.), "Preparation of nitro-stabilizing 4-heterocyclic-2, 4-dioxygenic acids usefukul as HIV integrase inhibitors," WO 9962513; young, s.d., et al, (Merck & co.ltd.), "Preparation of aromatic and heteroaromatic 4-aryl-2, 4-dioxygenic acid derivatives as HIV integrase inhibitors," WO 9962897; fujishita, t., et al, Yoshinaga, t., et al, (Shionogi & co. ltd.), "Preparation of aromatic heterocyclic compounds having HIV integumenting inhibiting activities," WO 0039086; akihiko, s., (Shionogi & co.ltd.), "Medicinal compositions relating properties," WO 0196329; payne, L.S., et al, (Merck & Co.Ltd.; Tularik, Inc.), "Preparation of 1, 3-diaryl-1, 3-polyurethanes as HIV integrase inhibitors," WO 0100578; egbertson, m., et al, (Merck & co.ltd.), "HIV integrase inhibitors," WO 9962520.

Some of the patents cited above are closely related. However, the patents or publications do not describe the type of compounds of the present invention. In particular, the compounds of the present invention have a nucleobase (nucleobase) scaffold, which is required for effective activity and has not been previously recognized.

The structures of the three most active compounds described in previous patents and publications are shown below. They are the best representatives of previously known inhibitors. They inhibit the strand transfer step in the HIV integrase assay, but do not show significant inhibition of the 3' -processing step of integrase action.

In vitro anti-HIV Activity data

Compound number: S-1360L-731988L-708906

IC₅₀(μM)： 0.14^* 1.0 5.5^**

CC₅₀(μM)： 110^*Does not give 88.3^**

Therapeutic index: 786^*Not given 16^**

The patent: WO 0196329 WO 9962513 WO 9962520

The publication: hazuda, D.J., et al,

Science 287，646-650 Science 287，646-650

(2000) (2000)

^*anti-HIV-1 data from Yoshinaga et al was obtained from Proc.9th Conference on retrovirosisand optronistic innovations, 2002(no 8, p 55), by Decercq, int.J. biochem.&Cell biol., 36, 1800-.

^**These in vitro anti-HIV-1 data are generated by the Declercq laboratory [ Pannecouque, C., et al., Current Biology, 12, 1169-]Reported for compound L-708906.

However, the type of compound described by us in the present invention is not only important because of the strong inhibition of the 3' -processing and strand transfer steps of HIV integrase, but also because of its enhanced potency and therapeutic index, as demonstrated by the in vitro anti-HIV activity. The key to the design of our compounds is the nucleic acid base (nucleobase) scaffold, which is required for effective activity and has not been previously recognized.

As an example, the compounds of the invention shown below with uracil scaffolds (see also general formula I) have a therapeutic index > 10,000 and higher activity than AZT (therapeutic index ═ 5,511) in vitro anti-HIV activity compared with AZT (PBMC cell-based assay). This compound also has much higher activity than the anti-HIV integrase inhibitors previously described in the above patents and publications. The therapeutic index for the previously reported well-known HIV integrase inhibitor (see compound number S-1360 in the above table) was only 786 in an in vitro anti-HIV assay.

In vitro anti-HIV Activity data for Compounds of the invention

IC₅₀ 0.02μM

CC₅₀ ＞200μM

Therapeutic index > 10,000

Summary of The Invention

A novel class of diketo acids constructed on a nucleobase scaffold (nucleobase scaffold) and designed as inhibitors of HIV replication by inhibiting HIV integrase is described. These compounds can be represented by general formula I (and include tautomers, regioisomers, geometric isomers and optical isomers thereof, as well as pharmaceutically acceptable salts thereof, if appropriate), wherein the moiety depicted by the square (square) is a molecular scaffold consisting of a nucleobase (nucleobase) derivative. These compounds are useful for the prevention or treatment of infection by HIV and for the treatment of AIDS and ARC, either as compounds, or as their pharmaceutically acceptable salts, together with pharmaceutically acceptable carriers, either alone or in combination with antivirals, immunomodulators, antibiotics, vaccines and other therapeutic agents. Methods of treating AIDS and ARC and methods of treating or preventing HIV infection are also described.

Detailed description of the invention

The following terms will be used throughout the specification to describe the present invention. Unless otherwise indicated, the terms used to describe the present invention are to be given their ordinary meaning as understood by those skilled in the art.

Unless otherwise indicated, the term "compound" as used herein refers to any specific compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and, if appropriate, optical isomers and pharmaceutically acceptable salts thereof. The term compound, when used in this context, generally refers to a single compound, but may also include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of the disclosed compounds.

The term "patient" or "subject" as used in the context of this specification is used to describe an animal, generally a mammal and preferably a human, which is treated, including prophylactic treatment, with the compositions of the invention provided herein. For the treatment of those infections, disorders or disease states, which are specific to a particular animal, e.g., a human patient, the term patient refers to the particular animal.

The term "effective", as used herein, unless otherwise specified, is used to describe the quantity of a compound or composition that is used to produce or cause an intended result in the context of treating a viral, microbial, or other disease state, disorder, or condition associated with HIV, ARC, or AIDS, or in the production of another compound, agent, or composition. The term encompasses all other effective amount or effective concentration terms described in this application.

The term "nucleobase scaffold" as used throughout the specification refers to a nucleobase selected from uracil, xanthine, hypoxanthine and purine which contains at least four substituents at four substitutable positions on the nucleobase, one of which is a keto acid as defined herein, wherein the other three R's are keto acids, wherein the other three R's are¹、R²And R³As defined herein.

The term "heteroaryl" refers to a 5 or 6-membered heteroaromatic ring containing 1-2 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the heteroaromatic ring is optionally substituted with 1-3 substituents such as halogen, hydroxy, C_1-3Alkyl radical, C_1-3Alkoxy and CF₃And (4) substitution. The terms heteroaryl and "heteroaromatic ring" are used interchangeably herein.

The term "human immunodeficiency virus" or "HIV" is used to describe human immunodeficiency viruses 1 and 2(HIV-1 and HIV-2).

The terms "ARC" and "AIDS" refer to the immune system syndrome caused by the human immunodeficiency virus, which is characterized by susceptibility to certain diseases and a reduction in T cell counts compared to normal counts. HIV progression progresses from class 1 (asymptomatic HIV disease) to class 2(ARC), to class 3(AIDS), with the severity of the disease progressing.

Class 1 HIV infection is characterized by the patient or subject being HIV positive, asymptomatic (no symptoms) and CD4 cells being greater than 500. If a patient has any of the AIDS-defined conditions listed in Category 2(ARC) or 3(AIDS), then the patient is not in this category. If the patient's T-cell count was once below 500, then the patient is considered in Category 2(ARC) or Category 3 (AIDS).

Class 2(ARC) infections are characterized by the following criteria: the patient has T-cells less than 500 but not less than 200, and the patient does not have any class 3 disease (as described below), but has at least one of the following defined diseases-

Bacillary angiomatosis

Orifice oral pharynx candidiasis (thrush)

Vulvovaginal candidiasis; persistent, frequent or poor response to treatment

Cervical dysplasia (moderate or severe)/carcinoma of the original cervix

Systemic symptoms, e.g. fever (38.5 ℃) or diarrhea lasting more than 1 month

Oral hairy leukoplakia

Herpes zoster (shingles), comprising at least two different outbreaks or more than one dermatome

Idiopathic thrombocytopenic purpura

Leersia hexandra et al

Pelvic inflammatory disease, particularly if associated salpingo-ovarian abscess

Peripheral neuropathy

According to the U.S. government, in category 2 ARC, the immune system represents some sign of injury but it is not life threatening.

Class 3(AIDS) infections are characterized by the following criteria:

your T-cells are below 200 or you have at least one of the following defined diseases-

Candidiasis of the bronchi, trachea or lungs

Esophageal candidiasis

Infiltration uterusNeck cancer^**

O disseminated or pneumococcal sporosis

Cryptococcosis extrapulmonary

Chronic cryptosporidiosis (duration of more than 1 month)

Cytomegalovirus disease (except for liver, spleen or nodules)

Cytomegalovirus retinitis (with loss of vision)

HIV-related encephalopathy

Herpes simplex: chronic ulcers (duration greater than 1 month); or bronchitis, pneumonia or esophagitis

O disseminated or extrapulmonary histoplasmosis

Chronic coccidiosis coli (duration greater than 1 month)

Kaposi's sarcoma

Burkitt's (or equivalent terms) lymphoma

Immunoblastic (or equivalent term) lymphoma

Primary lymphoma of brain

Disseminated or extrapulmonary avium mycobacterial syndrome or m

Any site (lung)^**Or extrapulmonary) of Mycobacterium tuberculosis

Other species or unidentified species of disseminated or M.extrapulmonary Mycobacteria

Pneumocystis carinii pneumonia

Recurrent pneumonia^**

Progressive multifocal leukoencephalopathy

Recurrent Salmonella septicemia

Encephalotoxoplasmosis

Exhaustion syndrome due to HIV

The term "co-administration" means that at least two compounds or compositions are administered to a patient at the same time, such that an effective amount or concentration of each of the two or more compounds can be found in the patient at a given time point. While the compounds of the present invention may be administered to a patient in combination at the same time, the term includes administration of two or more agents simultaneously or at different times, provided that an effective concentration of all of the compounds or compositions administered in combination (co-administers) is found in the patient at a given time.

The present invention relates to compounds of formula I, combinations thereof or pharmaceutically acceptable salts thereof, useful for inhibiting HIV integrase, preventing or treating infection by HIV and treating AIDS and ARC. The compounds of formula I are defined as follows:

including tautomers, regioisomers, geometric isomers and, if appropriate, optical isomers thereof, and pharmaceutically acceptable salts thereof, wherein the nucleobase scaffold and the R group are defined as:

(i) a keto acid having a uracil nucleobase scaffold;

R¹and R²Independently are:

a)H，

b)C_1-6an alkyl group, a carboxyl group,

c)C_1-6a fluoroalkyl group,

d)C_1-6alkyl S (O)_nR, wherein n is selected from 0-2, R is selected from C_1-3Alkyl, phenyl and substituted phenyl, wherein the substituents are selected from the group consisting of:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

e) c having 1 to 3 substituents_5-6Cycloalkyl, wherein the substituents are selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

f)C_1-6an alkenyl group which is a radical of an alkylene group,

g)C_1-6alkyl group CO_nR^aWherein n is selected from 1 and 2, R^aSelected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

h) a phenyl group,

i) substituted phenyl having 1-3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

j) a benzyl group, a phenyl group,

k) substituted benzyl having 1-3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

l) C substituted by phenyl_2-6An alkyl group, a carboxyl group,

m) C substituted by phenyl_2-6Alkyl, said phenyl group may be substituted with 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

n)R^b，

o) by R^bSubstituted C_1-6An alkyl group, a carboxyl group,

wherein each R^bIs a 5 or 6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulphur, said ring being optionally substituted on carbon or nitrogen with 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

R³selected from:

a)H，

b)C_1-6an alkyl group, a carboxyl group,

c) the halogen(s) are selected from the group consisting of,

d) a hydroxyl group(s),

e) a phenylthio group,

f) a substituted phenylthio group having 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

g) a benzyl group, a phenyl group,

h) substituted benzyl having 1-3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

R⁴selected from:

a)CO₂R^cwherein R is^cSelected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

3) sodium or other pharmaceutically acceptable salts thereof,

b)P(O)(OR^d)(OR^e) Wherein R is^dAnd R^eMay be the same or different and is selected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

3) sodium or other pharmaceutically acceptable salts.

(ii) A keto acid having a xanthine nucleobase scaffold;

R¹、R²and R³Independently are:

a)H，

b)C_1-6an alkyl group, a carboxyl group,

c)C_1-6a fluoroalkyl group,

d)C_1-6alkyl S (O)_nR, wherein n is selected from 0-2, R is selected from C_1-3Alkyl, phenyl and substituted phenyl, wherein the substituents are selected from the group consisting of:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

e) c having 1 to 3 substituents_5-6Cycloalkyl, wherein the substituents are selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

f)C_1-6an alkenyl group which is a radical of an alkylene group,

g)C_1-6alkyl group CO_nR^aWherein n is selected from 1 and 2, R^aSelected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

h) a phenyl group,

i) substituted phenyl having 1-3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

j) a benzyl group, a phenyl group,

k) substituted benzyl having 1-3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

l) C substituted by phenyl_2-6An alkyl group, a carboxyl group,

m) C substituted by phenyl_2-6Alkyl, said phenyl group may be substituted with 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

n)R^b，

o) by R^bSubstituted C_1-6An alkyl group, a carboxyl group,

wherein each R^bIs a 5 or 6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulphur, said ring being optionally substituted on carbon or nitrogen with 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

R⁴selected from:

a)CO₂R^cwherein R is^cSelected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

3) sodium or other pharmaceutically acceptable salts thereof,

b)P(O)(OR^d)(OR^e) Wherein R is^dAnd R^eMay be the same or different and is selected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

3) sodium or other pharmaceutically acceptable salts.

(iii) A keto acid having a hypoxanthine nucleobase scaffold;

R¹、R²and R³Independently are:

a)H，

b)C_1-6an alkyl group, a carboxyl group,

c)C_1-6a fluoroalkyl group,

d)C_1-6alkyl S (O)_nR, wherein n is selected from 0-2, R is selected from C_1-3Alkyl, phenyl and substituted phenyl, wherein the substituents are selected from the group consisting of:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

e) c having 1 to 3 substituents_5-6Cycloalkyl, wherein the substituents are selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

f)C_1-6an alkenyl group which is a radical of an alkylene group,

g)C_1-6alkyl group CO_nR^aWherein n is selected from 1 and 2, R^aSelected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

h) a phenyl group,

i) substituted phenyl having 1-3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

j) a benzyl group, a phenyl group,

k) substituted benzyl having 1-3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

l) C substituted by phenyl_2-6An alkyl group, a carboxyl group,

m) C substituted by phenyl_2-6Alkyl, said phenyl group may be substituted with 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

n)R^b，

o) by R^bSubstituted C_1-6An alkyl group, a carboxyl group,

wherein each R^bIs a 5-or 6-membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulfur, said ring being able toSubstituted or unsubstituted on carbon or nitrogen with 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

R⁴selected from:

a)CO₂R^cwherein R is^cSelected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

3) sodium or other pharmaceutically acceptable salts thereof,

b)P(O)(OR^d)(OR^e) Wherein R is^dAnd R^eMay be the same or different and is selected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

3) sodium or other pharmaceutically acceptable salts.

iv) a keto acid with a purine nucleobase scaffold;

R¹、R²and R³Independently are:

a)H，

b)C_1-6an alkyl group, a carboxyl group,

c)C_1-6a fluoroalkyl group,

d)C_1-6alkyl S (O)_nR, wherein n is selected from 0-2, R is selected from C_1-3Alkyl, phenyl and substituted phenyl, wherein the substituents are selected from the group consisting of:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

e) c having 1 to 3 substituents_5-6Cycloalkyl, wherein the substituents are selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

f)C_1-6an alkenyl group which is a radical of an alkylene group,

g)C_1-6alkyl group CO_nR^aWherein n is selected from 1 and 2, R^aSelected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

h) a phenyl group,

i) substituted phenyl having 1-3 substituents selected from the group consisting of:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

j) a benzyl group, a phenyl group,

k) substituted benzyl having 1-3 substituents, wherein the substituents are selected from the group consisting of:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

l) C substituted by phenyl_2-6An alkyl group, a carboxyl group,

m) C substituted by phenyl_2-6Alkyl, said phenyl group may be substituted with 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

n)R^b，

o) by R^bSubstituted C_1-6An alkyl group, a carboxyl group,

wherein each R^bIs a 5 or 6 membered heteroaromatic ring containing 1 to 2 heteroatoms selected from oxygen, nitrogen and sulphur, said ring being optionally substituted on carbon or nitrogen with 1 to 3 substituents selected from:

1) the halogen(s) are selected from the group consisting of,

2) a hydroxyl group(s),

3)C_1-3an alkyl group, a carboxyl group,

4)C_1-3an alkoxy group,

5)CF₃，

R⁴selected from:

a)CO₂R^cwherein R is^cSelected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

3) sodium or other pharmaceutically acceptable salts thereof,

b)P(O)(OR^d)(OR^e) Wherein R is^dAnd R^eMay be the same or different and is selected from:

1)C_1-6an alkyl group, a carboxyl group,

2)H，

3) sodium or other pharmaceutically acceptable salts.

The invention also includes pharmaceutical compositions useful for inhibiting HIV integrase comprising an effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The invention also includes pharmaceutical compositions useful for treating infection by HIV or for treating AIDS or ARC. The invention also includes methods of inhibiting viral enzymes, HIV integrase, and methods of inhibiting HIV growth or replication or treating an HIV infection or treating AIDS or ARC. Furthermore, the present invention relates to a pharmaceutical composition comprising a combination of a therapeutically effective amount of a compound of the present invention and a therapeutically effective amount of an agent for treating AIDS selected from (i) AIDS or an HIV antiviral agent, (ii) an anti-infective agent, (iii) an immunomodulatory agent, (iv) other useful therapeutic agents including antibiotics and other antiviral agents.

For R¹、R²And R³The compounds of the present invention may have regioisomers, and these regioisomeric forms are included within the scope of the present invention. The compounds of the present invention may have asymmetric centers and may exist in the form of optical isomers, all of which are included in the scope of the present invention. The compounds may have geometric isomers, and these forms are included in the present inventionWithin the scope of the present invention.

The compounds of the invention may also exist in tautomeric forms. Thus, the term "and tautomers thereof" is used to describe tautomeric forms of the compounds of formula I, such as Ia and Ib (shown below).

The compounds represented by formula I and tautomers thereof are understood to include tautomers Ia and Ib as well for purposes of the present invention. Similarly, when referring to compound (Ia), it is understood that for the purposes of the present invention, the tautomers (I) and (Ib) are meant as well. This also applies to tautomer (Ib).

When R is involved¹、R²、R³、R⁴When a variant of (b) is present more than once in any formula I, their definitions in each case are irrelevant. Combinations of nucleobases and variants are permissible only if these combinations result in stable compounds.

The compounds of the present invention are useful for inhibiting HIV integrase, preventing or treating infection by HIV and treating the disease known as AIDS. Treatment of AIDS or prevention or treatment of HIV infection is defined to include treatment of a wide variety of HIV infection states: AIDS, ARC, and actual or potential exposure to HIV (e.g., by blood transfusion, exchange of body fluids, bites, needle sticks, exposure to the patient's blood in a medical or dental procedure, and other means).

Other applications are also part of the invention. For example, the compounds of the invention are useful in the preparation of antiviral compounds and in screening assays for the same, including the isolation of viral enzyme variants and further understanding of the enzyme, HIV integrase.

The invention also provides the use of a compound of formula (I) for the preparation of a pharmaceutical composition useful for inhibiting HIV integrase and for treating AIDS or ARC.

The compounds of the invention may be administered in the form of "well-known pharmaceutically acceptable" salts. The latter is meant to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, methanesulfonate, borate, methyl bromide, methyl nitrate, calcium edetate, camphorsulfonate, mucate, carbonate, naphthalenesulfonate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate, propionate laurylsulfate, palmitate, ethanesulfonate, fumarate, phosphate, biphosphate, glucoheptonate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolylargonate, glycolylsalicylate, glycolylgallate, and the like, Sulfate, hexylresorcinol formate, basic acetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, 8-chlorophylline, iodide, tosylate, isothionate, triiodonium, lactate, pancoate, valerate, and others that may be used as agents to modify solubility or hydrolytic properties or may be used in sustained release or prodrug formulation dosage forms. Pharmaceutically acceptable salts of the invention include those having counterions, for example, sodium, potassium, calcium, lithium, magnesium, zinc and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane and tetramethylammonium hydroxide.

Further, in the case where a carboxylic acid (-COOH) or alcohol group is present, a pharmaceutically acceptable ester such as an acetate, maleate, pivaloyloxymethyl, etc., may be used, more preferably C₁-C₂₀Esters and use as sustained release or prodrug formulations for improved solubility or hydrolysis characteristics known in the artThose esters of the agents. Pharmaceutically acceptable esters may also be used in the presence of phosphonic acid groups [ -PO (OH) ]₂]In the case of (1). Diketophosphonic acids attached to nucleobase scaffolds are also part of the invention.

A therapeutically effective amount of a compound of the invention may be administered to a patient orally, parenterally, by inhalation spray, or rectally, in dosage unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles, including nanoparticulate methods of administration. The term "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the patient or subject. The pharmaceutical compositions may be administered in the form of oral suspensions or tablets, nasal sprays, and injectable preparations (injectable aqueous or oily suspensions or suppositories). Such treatment forms part of the present invention. The administration routes used (oral, e.g. solution or suspension, immediate release tablet, nasal aerosol or inhalation, injection solution or suspension, or rectal administration in the form of suppositories) involve techniques well known in the art of pharmaceutical formulation.

The compounds of the present invention may be administered orally to humans in preferred forms (e.g., tablets) and in divided doses within the preferred dosage range of about 0.1-200mg/kg body weight. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolism and duration of action of that compound, the age, body weight, general health, sex, diet, mode and frequency of administration, rate of excretion, drug combination and the severity of the particular condition and the treatment being effected by the patient.

The present invention also encompasses therapeutically effective combinations of the HIV integrase inhibitor compounds of formula I with one or more other therapeutic agents, such as AIDS antivirals, other antivirals, immunomodulators, anti-infective agents, antibiotics, vaccines or other therapeutic agents. Some examples are shown below.

Antiviral agents

Name of drug Manufacturer(s) Therapeutic uses

097 Hoechst/Bayer HIV infection, AIDS, ARC (NNRT)

Inhibitors)

Amprenavir (Amprenivir) Glaxo Wellcome HIV infection, AIDS, ARC (protein)

141W94, GW141 enzyme inhibitors)

Abacavir (1592U89) Glaxo Wellcome HIV infection, AIDS, ARC (RT)

GW 1592 inhibitor

Carrington Labs (Irving, TX) ARC acetate

Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC, and

AZT combinations

AD-439 Tanox Biosystems HIV infection, AIDS, ARC

AD-519 Tanox Biosystems HIV infection, AIDS, ARC

HIV infection with Gilead Sciences

AL-721 Ethigen (Los Angeles, CA) ARC, PGL HIV positive,

AIDS

interferon-alpha Glaxo Wellcome Kaposi's sarcoma and HIV in combination w-

In zidovudine

Ansamycin Adria Laboratories (Dublin, OH) ARC

LM 427 Erbamont(Stamford，CT)

Antibodies, Advanced Biotherapy AIDS, ARC, which neutralize pH instability

Interferon-alpha Concepts (Rockville, Md.)

AR 177 Aronex Pharm HIV infection, AIDS,

ARC

AIDS-related diseases with beta-fluoro-ddA National Cancer Institute

BMS-232623 Bristol-Myers Squibb/Novartis HIV infection, AIDS,

(CGP-73547) ARC (protease inhibitor)

BMS-234475 Bristol-Myers Squibb/Novartis HIV infection, AIDS,

(CGP-61755) ARC (protease inhibitor)

CI-1012 Warner-Lambert HIV-1 infection

Cidofovir Gilead Science CMV retinitis, herpes,

papilloma virus

Sulfated curdlan (curdlan AJI Pharma USA HIV infection)

sulfate)

Cytomegalovirus immunoglobulin Medlmmune CMV retinitis

Cytomevitamin (Syntex) vision threatening CMV

Ganciclovir (Ganciclovir) peripheral CMV

Retinitis

ddI Bristol-Myers Squibb HIV infection, AIDS,

dideoxyinosine ARC; in combination with AZT/d4T

DMP-450 AVID (Camden, NJ) HIV infection, AIDS, ARC (protein)

Enzyme inhibitors

Epiviren (DMP-266) DuPont Merck HIV infection, AIDS, ARC (non-Nuclear)

Glycoside RT inhibitors

EL10 Elan Corp, PLC (Gainesville, GA) HIV infection

Famciclovir Smith Kline herpes zoster, herpes simplex

FTC Emory University HIV infection, AIDS, ARC (Reversal

Enzyme inhibitors

GS 840 Gilead HIV infection, AIDS, ARC (Reversal of infection)

Enzyme inhibitors

HBY097 Hoechst Marion Roussel HIV infection, AIDS, ARC (non-nuclear)

Glycoside reverse transcriptase inhibitors

Hypericin VIMRx pharm. HIV infection, AIDS, ARC

Recombinant human interferon beta Triton Biosciences (Almeda, CA) AIDS, Kaposi sarcoma, ARC

Interferon sciences ARC, AIDS, Interferon alpha-n 3

Mordenavir Merck HIV infection, AIDS, ARC, none

HIV positive for symptoms; and

AZT/ddI/ddC combinations

ISIS-2922 ISIS Pharmaceuticals CMV retinitis

HIV-related diseases of KNI-272 Natl

Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase)

A transcriptase inhibitor); also together with AZT

Infection with the Lobucavir Bristol-Myers Squibb CMV

Nelfinavir Agouron Pharmaceuticals HIV infection, AIDS, ARC (protein)

Enzyme inhibitors

Nevirapine Boehringer Ingleheim HIV infection, AIDS, ARC (RT)

Inhibitors)

Novapren Novaferon Labs, Inc. (Akron, OH) HIV inhibitors

Peptide T octapeptide sequence Peninsula Labs (Belmont, Calif.) AIDS

Trisodium phosphonoformate Astra pharm products, inc. CVV retinitis, HIV infection,

other CMV

PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protein)

Enzyme inhibitors

Probucol Vyrex HIV infection, AIDS

RBC-CD4 Sheffield Med. Tech (Houston, TX) HIV infection, AIDS, ARC

Ritonavir Abbott HIV infection, AIDS, ARC (protein)

Enzyme inhibitors

Saquinavir Hoffmann-LaRoche HIV infection, AIDS, ARC (protein)

Enzyme inhibitors

Stavudine; d4T didehydro-deoxy Bristol-Myers Squibb HIV infection, AIDS, ARC

Thymidine

Valacyclovir Glaxo Wellcome genital HSV & CMV infection

Ribavirin (ribavirin) Viratek/ICN (Costa Mesa, CA) asymptomatic HIV positive, LAS,

ARC

VX-478 Vertex HIV infection, AIDS, ARC

Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,

ARC, together with AZT

Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS, ARC, card

Bosy sarcoma, in combination with other treatments

Gilead fumarate HIV infection, AIDS, ARC (RT) by tenofovir disoproxil

Salt (Viread)^®) Inhibitors)

Combivir^®GSK HIV infection, AIDS, ARC (RT)

Inhibitors)

Abacavir succinate (or GSK HIV infection, AIDS, (reverse transcriptase)

Ziagen^®) Inhibitors)

Fuzeon^®(or T-20) Roche/Trimeris HIV infection, AIDS, viral fusion

Inhibitors

Immunomodulator

Name of drug Manufacturer(s) Therapeutic uses

AS-101 Wyeth-Ayerst AIDS

Bromopirine Pharmacia Upjohn advanced AIDS

Acamelanam Carrington Labs, Inc. (Irving, TX) AIDS, ARC

CL246, 738 American Cyanamid AIDS, Kaposi sarcoma

Lederle Labs

EL10 Elan Corp, PLC (Gainesville, GA) HIV infection

FP-21399 Fuki Immuno PHARM blocks HIV fusion with CD4+ cells

Interferon gamma Genentech ARC in combination w/TNF

Granulocyte macrophage Genetics Institute AIDS

Colony stimulating factor Sandoz

Granulocyte macrophage Hoeschst-Roussel AIDS

Colony stimulating factor Immunex

Granulocyte macrophage Schering-Plough AIDS, combination w/AZT

Colony stimulating factor

Rorer seropositive HIV as HIV core particle immunostimulant

IL-2 Cetus AIDS, combination w/AZT

Interleukin-2

IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in combination

In interleukin-2 Immunex w/AZT

IL-2 Chiron AIDS, CD4 cell count increase

Interleukin-2

(aldesleukin)

Intravenous immunoglobulin (human) Cutter Biological (Berkeley, Calif.) childhood AIDS in combination w/AZT

In

IMREG-1 hnreg (New Orleans, LA) AIDS, Kaposi's sarcoma, ARC,

PGL

IMREG-2 Imreg (New Orleans, LA AIDS, Kaposi's sarcoma, ARC,

PGL

sodium diethyldimercaptocarbamate Merieux Institute AIDS, ARC

Alpha-2 interferon Schering Plough Kaposi sarcoma w/AZT, AIDS

Methionine-enkephalin TNI Pharmaceutical (Chicago, IL) AIDS, ARC

MTP-PE Ciba-Geigy Corp. Kaposi sarcoma

Muramyl-tripeptides

Granulocyte colony stimulating factor Amgen AIDS in combination w/AZT

Remune immunee Response Corp

rCD4 Genentech AIDS，ARC

Recombinant soluble human CD4-IgG

rCD4-IgG hybrid (Hybrids) AIDS, ARC

Recombinant soluble human CD4 Biogen AIDS, ARC

Interferon alpha 2a Hoffman-LaRoche Kaposi's sarcoma, AIDS, AR,

combination w/AZT

SK & F1-6528 Smith Kline HIV infection

Solubility T4

Thymopentin Immunobiology Research HIV infection

Institute(Annandale，NJ)

Tumor Necrosis Factor (TNF) Genentech ARC in combination with w/gamma interferon

Anti-infective agents

Name of drug Manufacturer(s) Therapeutic uses

Clindamycin and primaquine Pharmacia Upjohn PCP

Fluconazole Pfizer cryptococcal meningitis, candidiasis

Nystatin pastille Squibb Corp. prevention of oral candidiasis

Epinoornithine hydrochloride Merrell Dow PCP

Pentamidine beta-isethionate (IM & IV) lyphoMed (Rosemont, IL) PCP treatment

Trimethoprim antibacterial agent

Trimethoprim/sulfonamides antibacterial agents

Pietraxin Burroughs Wellcome PCP treatment

Pentamidine beta-isethionate Fisons Corporation PCP prevention

Spiromycin Rhone-Poulenc cryptosporidium protozoal diarrhea

Intraconazole-R51211 Janssen Pharm histoplasmosis; cryptococcus meninges

Inflammation of the stomach

Trimethosera Warner-Lambert PCP

Other agents

Name of drug Manufacturer(s) Therapeutic uses

Daunorubicin Nexstar, Sequus Kaposi sarcoma

Recombinant human erythropoietin Ortho pharm

AIDS-related emaciation and cachexia with recombinant human growth hormone Serono

Megestrol acetate Bristol-Myers Squibb for treatment of anorexia-related w/AIDS

Testosterone Alza, Smith Kline associated with AIDS wasting

Complete gastrointestinal nutrition Norwich Eaton Pharmaceuticals has associated diarrhea and absorption with AIDS

Disorder(s)

Combinations of the compounds of the present invention with AIDS antivirals, other antivirals, immunomodulators, anti-infective agents, antibiotics, vaccines, other therapeutic agents are not limited to those listed above, but include, in principle, any combination of any pharmaceutical composition useful in the treatment of HIV infection or in the treatment of AIDS or ARC. Preferred combinations are simultaneous or alternating treatments of the compounds of the invention and protease inhibitors (e.g., monenavir, nelfinavir, ritonavir, saquinavir, etc.), reverse transcriptase inhibitors [ nucleoside (e.g., AZT, 3TC, ddC, ddI, d4T, abacavir, etc., and/or non-nucleoside (e.g., efavirenz, nevirapine, etc.), or some combination of two or more of these inhibitors (see above tables.) some representative examples of related patents that cite combinations are EPO 0,484,071, U.S.5,413,999, WO 9962513.

In these combinations, the compound of the present invention and the other active agent may be administered separately or simultaneously. In addition, one component may be administered before, simultaneously with, or after the other drug.

The following representative examples are provided to illustrate in detail the preparation of the compounds of the present invention. The described embodiments should not be construed as limiting the scope of the invention. Furthermore, the compounds described in the following examples should not be regarded as forming only part of the compounds of the present invention, the constituent parts of which or any combination of their parts may themselves form part of the present invention. This has been mentioned previously in this patent document. Those skilled in the art will readily appreciate that known variations of the reaction conditions and synthetic transformations described in the following preparative procedures may be used to prepare other compounds of the present invention.

Chemical synthesis

The chemistry schemes of representative examples 1-12 are schemes 1 and 2 shown below.

Ra-d：Bn，2-F-Bn，4-F-Bn，4-CF₃-Bn

Scheme 1

a b c d e f

R Bn 2-F-Bn 4-F-Bn 4-CF₃-Bn H 4-F-Bn

R′ Bn 2-F-Bn 4-F-Bn 4-CF₃-Bn Bn Bn

Scheme 2

Representative example 1

4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoic acid methyl ester (3 a).

Step 1: preparation of 5-acetyl-1, 3-dibenzyluracil (2 a).

A suspension of 5-acetyluracil (3.1g, 20mmol) and potassium carbonate (6.9g, 50mmol) in DMF (75mL) was stirred for 20 min. Benzyl bromide (6.0mL, 50mmol) was then added. The resulting mixture was stirred at room temperature for 8 h. DMF was evaporated in vacuo. The residue is purified by column chromatography (dichloromethane: methanol 40: 1). The appropriate fractions (fraction) were concentrated and crystallized from ethanol to give 5.34g of a white solid. The yield thereof was found to be 79.8%. Mp.92-93 ℃.¹HNMR(CDCl₃)：8.23(s，1H)，7.29-7.49(m，10H)，5.17(s，2H)，5.01(s，2H)，2.62(s，3H)。¹³CNMR(CDCl₃)：194.5，160.7，151.0，148.4，136.2，134.4，129.2，129.0，128.9，128.5，128.2，127.8，112.2，53.4，44.9，30.7.FAB-HRMS：[M+H]⁺Calculated value C₂₀H₁₉N₂O₃335.1396, found 335.1412.

Step 2: preparation of methyl 4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoate (3 a).

To a stirred solution of sodium tert-butoxide (577mg, 6mmol) in anhydrous THF (15mL) was added dropwise dimethyl oxalate (472mg, 4mmol) in THF (7mL) followed by 5-acetyl-1, 3-dibenzyluracil (2a) (669mg, 2mmol) in THF (8mL) at room temperature. The resulting mixture was stirred at room temperature for 4h and then acidified to pH 2. The THF was distilled off. In CH₂Cl₂The residue in (100mL) was washed with brine (20mL) and purified by column chromatography (hexane: ethyl acetate, 2: 1). The appropriate fractions were concentrated and crystallized from ethanol to yield 254mg of a yellow solid. The yield thereof was found to be 29.1%. Mp.158-159 ℃.¹HNMR(CDCl₃)：15.04(s，br，1H)，8.36(s，1H)，7.72(s，1H)，7.29-7.49(m，10H)，5.18(s，2H)，5.05(s，2H)，3.92(s，3H)。¹³CNMR(CDCl₃)：185.7，168.8，162.4，159.7，150.5，148.5，136.0，134.0，129.4，129.1，129.0，128.5，128.3，127.9，109.0，101.6，53.7，53.2，45.0.FAB-HRMS：[M+H]⁺Calculated value C₂₃H₂₁N₂O₆421.1400, found 421.1418.

Representative example 2

4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoic acid (4a)

A solution of methyl 4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoate (3a) (757mg, 1.8mmol) in dioxane (100mL) was refluxed with 1N HCl (60mL) for 4 h. The solution was evaporated to dryness. The resulting solid was recrystallized from hexane and ethyl acetate (3: 1) to give 617mg of a pale yellow solid. The yield thereof was found to be 84.2%. Mp.186-188 ℃.¹HNMR(DMSO-d₆)：8.89(s，1H)，7.57(s，1H)，7.24-7.36(m，10H)，5.16(s，2H)，5.02(s，2H)。¹³CNMR(DMSO-d₆)：186.1，169.0，163.2，159.9，151.1，150.2，136.5，135.8，128.7，128.4，128.0，127.8，127.6，127.3，107.7，100.9，52.8，44.2.FAB-HRMS：[M+H]⁺Calculated value C₂₂H₁₉N₂O₆407.1243, found 407.1248.

Representative example 3

4- [1, 3-bis (2-fluorobenzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoic acid methyl ester (3 b).

Step 1: preparation of 1, 3-bis (2-fluorobenzyl) -5-acetyluracil (2b)

The title compound of this step was synthesized using a method similar to that described in step 1 of example 1, except that 2-fluorobenzyl bromide was used instead of benzyl bromide. The yield thereof was found to be 43.9%. Mp.149-150 ℃.¹HNMR(CDCl₃)：8.35(d，1H，J＝1.0Hz)，7.36-7.44(m，2H)，7.04-7.26(m，6H)，5.24(s，2H)，5.07(s，2H)，2.62(s，3H)。¹³CNMR(CDCl₃)：194.3，161.1(d，J＝247.9Hz)，160.7(d，J＝247.9Hz)，160.6，150.8，148.8(d，J＝2.9Hz)，131.3(d，J＝3.4Hz)，130.9(d，J＝8.2Hz)，129.19(d，J＝8.2Hz)，129.17(d，J＝2.9Hz)，124.7(d，J＝3.8Hz)，124.1(d，J＝3.8Hz)，123.1(d，J＝14.5Hz)，121.4(d，J＝14.5Hz)，115.9(d，J＝21.6Hz)，115.5(d，J＝21.6Hz)，112.2，47.8，38.8，30.6。

FAB-HRMS：[M+H]⁺Calculated value C₂₀H₁₇F₂N₂O₃371.1207, found 371.1202.

Step 2: preparation of methyl 4- [1, 3-bis (2-fluorobenzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoate (3 b).

Except using 1, 3-bis (2-fluorobenzyl) -5-acetylThe title compound of this step was synthesized using a method similar to that described in step 2 of example 1 except that 5-acetyl-1, 3-dibenzyluracil was replaced with phenyluracil. The title compound was crystallized from a mixture of hexane and ethyl acetate (3: 1) to obtain a yield of 21.1%. Mp.158-160 ℃.¹HNMR(CDCl₃)：15.06(br，s，1H)，8.52(s，1H)，7.69(s，1H)，7.38-7.46(m，2H)，7.04-7.26(m，6H)，5.25(s，2H)，5.11(s，2H)，3.90(s，3H)。¹³CNMR(CDCl₃)：185.3，169.2，162.4，161.2(d，J＝247.3 Hz)，160.7(d，J＝247.9Hz)，159.6，150.3，148.9(d，J＝3.4Hz)，131.5(d，J＝3.4Hz)，131.2(d，J＝8.7Hz)，129.3(d，J＝8.2Hz)，129.2(d，J＝3.4Hz)，124.8(d，J＝3.8Hz)，124.1(d，J＝3.9Hz)，122.8(d，J＝14.5Hz)，121.2(d，J＝14.3Hz)，116.0(d，J＝21.1Hz)，115.6(d，J＝21.6Hz)，108.9，101.5，53.0，48.2(d，J＝3.4Hz)，38.9(d，J＝4.8Hz)。FAB-HRMS：[M+H]⁺Calculated value C₂₃H₁₉F₂N₂O₆457.1211, found 457.1203.

Representative example 4

4- [1, 3-bis (2-fluorobenzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoic acid (4 b).

Except using 4- [1, 3-bis (2-fluorobenzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl]The title compound was synthesized using a similar method to that described in example 2, except that-2-hydroxy-4-oxobut-2-enoic acid methyl ester (3b) was used instead of 4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoic acid methyl ester. The title compound was crystallized from hexane and ethyl acetate (2: 1) to give an off-white solid. The yield thereof was found to be 56.5%. Mp.178-179 ℃.¹H NMR(DMSO-d6)：15.00(br，s，1H)，14.02(br，s，1H)，8.90(s，1H)，7.55(s，1H)，7.08-7.40(m，8H)，5.23(s，2H)，5.05(s，2H)。¹³CNMR(DMSO-d6)：185.7，169.2，163.0，160.2(d，J＝246.0Hz)，159.8(d，J＝244.6Hz)，159.7，151.2，149.9，130.2，129.0(d，J＝8.2Hz)，128.4(d，J＝3.9Hz)，124.5(d，J＝3.3Hz)，124.3(d，J＝3.3Hz)，123.1(d，J＝13.9Hz)，122.3(d，J＝14.5Hz)，115.4(d，J＝21.1Hz)，115.1(d，J＝21.1Hz)，107.6，100.7，47.8(d，J＝3.4Hz)，38.2(d，J＝4.8Hz)。

FAB-HRMS：[M+H]⁺Calculated value C₂₂H₁₇F₂N₂O₆443.1055, found 443.1045.

Representative example 5

4- [1, 3-bis (4-fluorobenzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoic acid methyl ester (3 c).

Step 1: 1, 3-bis (4-fluorobenzyl) -5-acetyluracil (2c)

The title compound was synthesized using a method similar to that described in example 1, step 1, except that 4-fluorobenzyl bromide was used instead of benzyl bromide. The yield thereof was found to be 51.8%. Mp.134-135 deg.C.¹HNMR(CDCl₃)：8.22(s，1H)，7.48(dd，2H，J＝9.0，5.5Hz)，7.32(dd，2H，J＝8.5，5.0Hz)，6.99-7.09(m，4H)，5.11(s，2H)，4.97(s，2H)，2.62(s，3H)。¹³CNMR(CDCl₃)：194.3，163.0(d，J＝248.3Hz)，162.4(d，J＝246.4Hz)，160.6，150.9，148.2，132.1(d，J＝3.4Hz)，131.1(d，J＝8.2Hz)，130.23(d，J＝8.5Hz)，130.26(d，J＝2.9Hz)，116.2(d，J＝21.4Hz)，115.3(d，J＝21.5Hz)，112.4，52.9，44.2，30.6.FAB-HRMS：[M+H]⁺Calculated value C₂₀H₁₇F₂N₂O₃371.1207, found 371.1220.

Step 2: preparation of methyl 4- [1, 3-bis (4-fluorobenzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoate (3 c).

The title compound was synthesized using a similar method to that described in step 2 of example 1, except that 1, 3-bis (4-fluorobenzyl) -5-acetyluracil was used instead of 5-acetyl-1, 3-dibenzyluracil. The title compound was recrystallized from ethanol to obtain a yield of 23.5%. Mp.171-173 ℃.¹HNMR(CDCl₃)：15.02(br，s，1H)，8.35(s，1H)，7.71(s，1H)，7.49(m，2H)，7.34(m，2H)，7.09(m，2H)，7.00(m，2H)，5.13(s，2H)，5.02(s，2H)，3.92(s，3H)。¹³CNMR(CDCl₃)：185.3，169.2，163.1(d，J＝248.8Hz)，162.5(d，J＝246.4Hz)，162.4，159.6，150.5，148.2，131.8(d，J＝3.4Hz)，131.2(d，J＝8.2Hz)，130.3(d，J＝8.7Hz)，129.9(d，J＝3.4Hz)，116.4(d，J＝21.6Hz)，115.4(d，J＝21.6Hz)，109.2，101.5，53.14，53.12，44.3.FAB-HRMS：[M+H]⁺Calculated value C₂₃H₁₉F₂N₂O₆457.1211, found 457.1196.

Representative example 6

4- [1, 3-bis (4-fluorobenzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoic acid (4 c).

Except using 4- [1, 3-bis (4-fluorobenzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl]The title compound was synthesized using a similar method to that described in example 2, except that-2-hydroxy-4-oxobut-2-enoic acid methyl ester (3c) was used instead of 4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoic acid methyl ester. The title compound was crystallized from hexane and ethyl acetate (3: 1). The yield thereof was found to be 49.7%. Mp.186-188 ℃.¹HNMR(DMSO-d₆)：15.07(br，s，1H)，14.02(br，s，1H)，8.90(s，1H)，7.56(s，1H)，7.34-7.46(m，4H)，7.10-7.21(m，4H)，5.13(s，2H)，4.98(s，2H)。¹³CNMR(DMSO-d₆)：185.8，169.2，163.1，161.8(d，J＝244.1Hz)，161.3(d，J＝243.2Hz)，159.7，150.8，150.1，132.6(d，J＝2.9Hz)，131.8(d，J＝3.4Hz)，130.2(d，J＝8.2Hz)，129.9(d，J＝8.2Hz)，115.4(d，J＝21.6Hz)，115.0(d，J＝21.0Hz)，107.7，100.7，52.1，43.5.FAB-HRMS：[M+H]⁺Calculated value C₂₂H₁₇F₂N₂O₆443.1055, found 443.1044.

Representative example 7

4- [1, 3-bis (4- (trifluoromethyl) benzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoic acid methyl ester (3 d).

Step 1: preparation of 1, 3-bis (4- (trifluoromethyl) benzyl) -5-acetyluracil (2 d).

The title compound was synthesized using a method similar to that described in example 1, step 1, except that 4- (trifluoromethyl) benzyl bromide was used instead of benzyl bromide. The yield was 65.1% amorphous solid.¹HNMR(CDCl₃)：8.27(s，1H)，7.44-7.66(m，8H)，5.20(s，2H)，5.07(s，2H)，2.63(s，3H)。¹³CNMR(CDCl₃)：194.1，160.5，150.9，148.3，140.0，138.2，131.3(q，J＝32.7Hz)，130.2(q，J＝32.7Hz)，129.3，128.4，126.3(q，J＝3.8Hz)，125.5(q，J＝3.8Hz)，124.0(q，J＝272.0Hz)，123.7(q，J＝272.3Hz)，112.6，53.2，44.5，30.6.FAB-HRMS：[M+H]⁺Calculated value C₂₂H₁₇F₆N₂O₃471.1143, found 471.1148.

Step 2: preparation of methyl 4- [1, 3-bis (4- (trifluoromethyl) benzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoate (3 d).

The title compound was synthesized using a similar method to that described in step 2 of example 1, except that 1, 3-bis (4-trifluoromethyl) benzyl) -5-acetyluracil was used instead of 5-acetyl-1, 3-dibenzyluracil. The title compound was crystallized from a mixture of hexane and ethyl acetate (3: 1) and ethanol to give a yield of 20.3%. Mp.189-191 ℃.¹H NMR(CDCl₃)：14.98(br，s，1H)，8.41(s，1H)，7.70(s，1H)，7.46-7.68(m，8H)，5.21(s，2H)，5.11(s，2H)。¹³C NMR(CDCl₃)：185.0，169.5，162.3，159.5，150.4，148.3，139.7，138.0，131.4(q，J＝32.5Hz)，130.3(q，J＝32.4Hz)，129.4，128.5，126.3(q，J＝3.7Hz)，125.5(q，J＝3.7Hz)，124.0(q，J＝271.9Hz)，123.7(q，J＝272.3Hz)，109.4，101.5，53.4，53.2，44.6.FAB-HRMS：[M+H]⁺Calculated value C₂₅H₁₉F₆N₂O₆557.1147, found 557.1135.

Representative example 8

4- [1, 3-bis (4- (trifluoromethyl) benzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoic acid (4 d).

Except using 4- [1, 3-bis (4- (trifluoromethyl) benzyl) -1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl]The title compound was synthesized using a similar method to that described in example 2, except that-methyl 2-hydroxy-4-oxobut-2-enoate (3d) was used instead of methyl 4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoate. The title compound was recrystallized from hexane and ethyl acetate (3: 1). The yield thereof was found to be 68.2%. Mp.176-178 ℃.¹HNMR(DMSO-d₆)：14.98(br，s，1H)，14.02(br，s，1H)，8.99(s，1H)，7.72(d，2H，J＝8.0Hz)，7.66(d，2H，J＝8.5Hz)，7.59(d，2H，J＝8.5Hz)，7.57(s，1H)，7.51(d，2H，J＝8.0Hz)，5.26(s，2H)，5.09(s，2H)。¹³CNMR(DMSO-d₆)：185.8，169.3，163.1，159.9，151.3，150.2，141.2，140.5，128.4(q，J＝31.5Hz)，128.3，128.2，127.9(q，J＝31.7Hz)，125.4(q，J＝3.8Hz)，125.2(q，J＝3.8Hz)，124.2(q，J＝272.3Hz)，124.1(q，J＝271.8Hz)，108.0，100.7，52.6，43.9.FAB-HRMS：[M+H]⁺Calculated value C₂₄H₁₇F₆N₂O₆543.0991, found 543.1003.

Representative example 9

4- (1-benzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoic acid methyl ester (3 e).

Step 1: preparation of 5-acetyl-1-benzyluracil (2 e).

The title compound was synthesized in 69.9% yield by an analogous method to that described in example 1, step 1, but using 1.1 equivalents of benzyl bromide and 1.0 equivalent of potassium carbonate in DMF. Mp.196-197 ℃.¹HNMR(DMSO-d₆)：11.69(br，s，1H)，8.54(s，1H)，7.30-7.36(m，5H)，5.03(s，2H)，2.44(s，3H)。¹³CNMR(DMSO-d₆)：193.5，161.6，151.5，150.3，136.2，128.7，127.9，127.7，111.8，51.1，30.3.FAB-HRMS：[M+H]⁺Calculated value C₁₃H₁₃N₂O₃245.0926, found 245.0932.

Step 2: preparation of methyl 4- (1-benzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoate (3 e).

The title compound was synthesized using a similar method to that described in example 1, step 2, except that 5-acetyl-1-benzyluracil was used instead of 5-acetyl-1, 3-dibenzyluracil. The title compound was crystallized from ethanol to yield 77.2%. Mp.197-199 ℃.¹HNMR(DMSO-d₆)：11.90(s，1H)，8.82(s，1H)，7.57(s，1H)，7.31-7.37(m，5H)，5.08(s，2H)，3.82(s，3H)。¹³CNMR(DMSO-d₆)：185.9，167.8，162.2，161.0，152.7，149.8，135.9，128.7，127.9，127.7，107.9，100.9，53.0，51.5.FAB-HRMS：[M+H]⁺Calculated value C₁₆H₁₅N₂O₆331.0930, found 331.0928.

Representative example 10

4- (1-benzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoic acid (4 e).

The title compound was synthesized using a similar method to that described in example 2, except that methyl 4- (1-benzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoate (3e) was used in place of methyl 4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoate. The title compound was crystallized from a mixture of tetrahydrofuran and chloroform (2: 3). The yield thereof was found to be 79.7%. Mp.195-197 ℃.¹HNMR(DMSO-d₆)：15.10(br，s，1H)，13.97(br，s，1H)，11.87(s，1H)，8.79(s，1H)，7.54(s，1H)，7.30-7.36(m，5H)，5.08(s，2H)。¹³CNMR(DMSO-d₆)：186.0，169.2，163.2，161.0，152.5，149.9，136.0，128.7，127.9，127.7，108.2，100.8，51.5.FAB-HRMS：[M+H]⁺Calculated value C₁₅H₁₃N₂O₆317.0774, found 317.0769.

Representative example 11

4- [3- (4-Fluorobenzyl) -1-benzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoic acid methyl ester (3f)

Step 1: preparation of 3- (4-fluorobenzyl) -5-acetyl-1-benzyluracil (2 f).

The title compound was synthesized in 93.7% yield by benzylation of 5-acetyl-1-benzyluracil (2e) with 2 equivalents of 4-fluorobenzyl bromide and 2 equivalents of potassium carbonate in DMF. Mp.106-108 ℃.¹HNMR(CDCl₃)：8.23(s，1H)，7.30-7.50(m，7H)，7.00(m，2H)，5.12(s，2H)，5.01(s，2H)，2.61(s，3H)。¹³CNMR(CDCl₃)：194.3，162.4(d，J＝246.4Hz)，160.7，151.0，148.4，134.4，132.1(d，J＝3.4Hz)，131.1(d，J＝8.2Hz)，129.2，128.9，128.2，115.3(d，J＝21.6Hz)，112.3，53.4，44.2，30.6.FAB-HRMS：[M+H]⁺Calculated value C₂₀H₁₈FN₂O₃353.1301, found 353.1310.

Step 2: preparation of methyl 4- [3- (4-fluorobenzyl) -1-benzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoate (3 f).

The title compound was synthesized using a similar method to that described in example 1, step 2, except that 3- (4-fluorobenzyl) -5-acetyl-1-benzyluracil was used instead of 5-acetyl-1, 3-dibenzyluracil. The title compound was crystallized from ethanol to obtain a yield of 30.5%. Mp.165-167 ℃.¹HNMR(CDCl₃)：15.04(br，s，1H)，8.36(s，1H)，7.72(s，1H)，7.28-7.52(m，7H)，7.01(t，2H，J＝8.5Hz)，5.15(s，2H)，5.06(s，2H)，3.93(s，3H)。¹³CNMR(CDCl₃)：185.4，169.2，162.5(d，J＝246.8Hz)，162.4，159.7，150.5，148.4，134.1，131.9(d，J＝3.4Hz)，131.2(d，J＝8.2Hz)，129.4，129.1，128.3，115.4(d，J＝21.6Hz)，109.1，101.5，53.7，53.1，44.3.FAB-HRMS：[M+H]⁺Calculated value C₂₃H₂₀FN₂O₆439.1305, found 439.1294.

Representative example 12

4- [3- (4-Fluorobenzyl) -1-benzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl ] -2-hydroxy-4-oxobut-2-enoic acid (4 f).

With 4- [3- (4-fluorobenzyl) -1-benzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl]-methyl 2-hydroxy-4-oxobut-2-enoate (3f) instead of methyl 4- (1, 3-dibenzyl-1, 2, 3, 4-tetrahydro-2, 4-dioxopyrimidin-5-yl) -2-hydroxy-4-oxobut-2-enoate, the title compound was synthesized using a similar method to that described in example 2. The title compound was crystallized from a mixture of hexane and ethyl acetate (2: 1). The yield thereof was found to be 64.0%. Mp.188-190 ℃.¹HNMR(DMSO-d₆)：15.05(br，s，1H)，14.01(br，s，1H)，8.87(s，1H)，7.56(s，1H)，7.30-7.37(m，7H)，7.12(m，2H)，5.15(s，2H)，4.99(s，2H)。¹³CNMR(DMSO-d₆)：185.7，169.2，163.1，161.4(d，J＝243.0Hz)，159.7，150.8，150.1，135.6，132.6(d，J＝3.4Hz)，129.9(d，J＝8.2Hz)，128.6，127.9，127.7，115.5(d，J＝21.6Hz)，107.7，100.7，52.7，43.5.FAB-HRMS：[M+H]⁺Calculated value C₂₂H₁₈FN₂O₆425.1149, found 425.1156.

Representative example 13

4- (9-benzyl-9H-purin-6-yl) -2-hydroxy-4-oxo-but-3-enoic acid (11).

The relevant scheme is scheme 3 shown below.

Scheme 3

Step 1: 9-Benzylaldenine (6)

To a suspension of adenine (5) (5.00g, 37.0mmol) in dry DMF (120mL) at room temperature was added NaH (1.77g, 44.4 mmol). The reaction mixture was stirred for 30min and the resulting white suspension was warmed at 60 ℃ for a further 30 min. Benzyl bromide (7.59g, 44.4mmol) was added and the mixture was stirred at 60 ℃ for 24 h. TLC of the reaction mixture indicated the formation of two products. The DMF was evaporated under reduced pressure and the residue was treated with water (20 mL). The white solid was isolated, filtered and dried in vacuo. Separating and purifying by flash column chromatography using CHCl₃MeOH (9: 1). 9-benzyladenine: yield 5.5 g. (66%); mp 231-;¹H NMR(DMSO-d₆)：δ5.38(s，2H，CH₂) 7.29-7.33(m, 7H, Ar-H and NH)₂) 8.17(s, 1H, purine C)₈-H), 8.28(s, 1H, purine C)₂-H). 7-benzyladenine: yield 1.8 g. (21%). Mp 252-.¹H NMR(DMSO-d₆)：δ5.53(s，2H，CH₂) 7.29-7.48(m, 5H, Ar-H), 7.81(s, 1H, purine C)₈-H)，8.0-8.1(br，2H，NH₂) 8.6(s, 1H, purine C)₂-H)。

Step 2: 9-benzyl-6-iodopurine (7)

To a stirred suspension of 9-benzyladenine (6) (1.00g, 4.4mmol) in dry acetonitrile (50mL) at 0-5 deg.C (ice bath) was added diiodomethane (5.82g, 21.7mmol) followed by tert-butyl nitrite (2.24g, 21.7 mmol). While maintaining cooling, the solution was bubbled with nitrogen for 30 min. The ice bath was removed and the reaction mixture was heated at 60-65 ℃ for 5h under nitrogen atmosphere. Acetonitrile and excess reagent were distilled off, and the obtained residue was redissolved in chloroform (100mL) and washed with a saturated aqueous sodium sulfite solution (2X 50mL), followed by a brine solution (2X 50 mL). The chloroform layer was dried over anhydrous sodium sulfate and concentrated to give a reddish oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexanes (3: 7). Yield: 0.519 g. (34%). Mp 152-.¹H NMR(DMSO-d₆)：δ5.51(s，2H，CH₂) 7.31-7.36(m, 5H, Ar-H), 8.65(s, 1H, purine C)₈-H), 8.83(s, 1H, purine C)₂-H)。¹³C NMR(DMSO-d₆)：δ47.4，123.2，128.1，128.1，128.4，129.2，129.2，136.5，138.4，146.9，148.3，152.4。

And step 3: 9-benzyl-6- (. alpha. -ethoxyvinyl) purine (8).

A mixture of 9-benzyl-6-iodopurine (7) (1.00g, 2.8mmol), bis (triphenylphosphine) palladium (II) chloride (0.208g, 0.02mmol) and ethoxyvinyl (tributyl) tin (2.07g, 3.8mmol) in dry DMF (4mL) was taken in N₂Heating at 100 deg.C for 6 h. TLC indicated the reaction was complete. The DMF was evaporated under reduced pressure and the resulting residue redissolved in EtOAc (50mL) and then filtered through a plug of celite (pad). The solvent (EtOAc) was distilled off and the residue obtained was purified by flash chromatography. Product produced by birthAmount 0.393g (47%). Mp 114-.¹H NMR(CDCl₃)：δ1.55(t，3H，CH₃，J＝7.5Hz)，4.13(q，2H，CH₂J ═ 13.7Hz), 4.99(d, 1H, CH, J ═ 3Hz), 5.48(s, 2H, CH for benzyl)₂) 6.16(d, 1H, CH, J ═ 3Hz), 7.30-7.38(m, 5H, Ar-H), 8.09(s, 1H, purine C)₈-H), 9.07(s, 1H, purine C)₂-H)。¹³C NMR(CDCl₃)：δ14.3，47.3，63.7，94.7，127.8，127.8，128.6，129.1，129.2，130.3，135.0，144.4，152.1，152.3，152.4，155.4。

And 4, step 4: 4- (9-benzyl-9H-purin-6-yl) -4-ethoxy-2-oxo-but-3-enoic acid methyl ester (9)

To a stirred solution of 9-benzyl-6- (. alpha. -ethoxyvinyl) purine (8) (0.20g, 0.70mmol) and pyridine (0.688mL, 0.72g, 28.5mmol) in dry chloroform (10mL) at 0 deg.C was added methyl chlorooxoacetate (1.048g, 0.784mL, 28.5mmol) in dry chloroform (5 mL). The reaction mixture was allowed to reach ambient temperature, stirred for 3 days, then washed with water (2X 10mL) and dried over anhydrous sodium sulfate. The solvent was evaporated off and the dark reddish slurry was purified by column chromatography. Yield 110mg (42%).¹H NMR(CDCl₃)：1.53(t，3H，CH₃，J＝6.5Hz)，3.80(s，3H，CH₃)，4.36(q，2H，CH₂J ═ 6.5Hz), 5.49(s, 2H, CH of benzyl group)₂) 6.72(s, 1H, CH for alkene), 7.36(m, 5H, Ar-H), 8.07(s, 1H, purine C)₈-H), 9.10(s, 1H, purine C)₂-H)。 ¹³C NMR(CDCl₃): δ 14.1, 31.0, 47.5, 52.9, 67.0, 99.6, 128.0, 128.0, 128.8, 129.3, 129.3, 131.3, 134.7, 145.5, 152.0, 152.6, 162.4, 167.4, and 179.7.

And 5: 4- (9-benzyl-9H-purin-6-yl) -2-hydroxy-4-oxo-but-2-enoic acid methyl ester (10).

4- (9-benzyl-9H-purin-6-yl) -4-ethoxy-2-oxo-but-3-enoic acid methyl ester (9) (100mg, 0.20mmole) obtained in the above step in CH₂Cl₂(20mL) at room temperature with stirring and FeCl₃.6H₂O (0.125g, 0.40 mmole). The reaction mixture was stirred at 40 ℃ for 5 h. The chloroform was distilled off and the resulting residue treated with 1N HCl (50mL) for 1h, then extracted with EtOAc (4X 20 mL). The extract was dried over anhydrous sodium sulfate and EtOAc was distilled off to give a brownish residue which was purified by ion exchange chromatography (diethylamino sephadex anion exchange resin, CH)₃CN∶H₂O (1: 1) eluent). Yield 5.2 mg. Mp 166-.¹H NMR(CDCl₃)δ3.99(s，3H，CH₃) 5.54(s, 2H, CH of benzyl)₂) 7.35-7.41(m, 5H, aromatic), 7.9(s, 1H, CH for olefins), 8.3(s, 1H, purine C)₈-H), 9.19(s, 1H, purine C)₂-H)。¹³CNMR(CDCl₃) δ 47.7, 53.4, 101.4, 128.0, 128.0, 128.9, 129.3, 131.8, 134.5, 147.4, 152.3, 154.3, 162.1, 172.8, and 185.7. FAB-HRMS: [ M + H ]]⁺Calculated value C₁₇H₁₅N₄O₄339.1093, found 339.1083.

Step 6: synthesis of 4- (9-benzyl-9H-purin-6-yl) -2-hydroxy-4-oxo-but-3-enoic acid (11)

To a stirred solution of methyl 4- (9-benzyl-9H-purin-6-yl) -2-hydroxy-4-oxo-but-3-enoate (10) (17mg, 0.05mmol) in THF (5mL) at 0 deg.CTo the solution was added a solution of 1N NaOH (0.5mL), and the reaction mixture was stirred at 0 ℃ for 2 h. The reaction mixture was extracted with ether (2X 10mL), and the aqueous layer was acidified with dilute HCl and extracted with ethyl acetate (2X 25 mL). The organic extracts were washed with brine solution, dried over anhydrous sodium sulfate and concentrated. The crude solid was purified by trituration with ether to give 4mg of product. The yield thereof was found to be 25%. Mp 152-.¹H NMR(CDCl₃): Δ 5.27(s, 2H, CH of benzyl)₂) 6.39(s, 1H, CH of alkene),. 7.23-7.29(m, 5H, Ar-H), 8.78(s, 1H, purine C)₈-H), 8.84(s, 1H, purine C)₂-H)。EIMS(m/z)：[M+1]Calculated value C₁₆H₁₃N₄O₄325, found value 325.

Representative example 14

4- (9-benzyl-9H-purin-8-yl) -2-hydroxy-4-oxobut-2-enoic acid (17).

The relevant scheme is scheme 4 shown below.

Scheme 4

4- (9-benzyl-9H-purin-8-yl) -2-hydroxy-4-oxobut-2-enoic acid (17).

Step 1. as described in step 1 of example 13.

Step 2: synthesis of 9-benzylpurine (12)

To a stirred suspension of 9-benzyladenine (6) (22.0g, 97.6mmol) in anhydrous THF (500mL) was added tert-butyl nitrite (9.34g, 478.5mmol), and the reaction was mixedThe compound was heated at 60-65 ℃ for 4h under nitrogen atmosphere. THF and excess reagent were distilled off, and the obtained residue was redissolved in chloroform (100mL) and washed with a brine solution (2X 50 mL). The chloroform layer was dried over anhydrous sodium sulfate and evaporated to give a reddish oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexanes (8: 2). Yield 10.68g (42.3%). Mp 99-100 ℃.¹H NMR(CDCl₃)：δ5.49(s，2H，CH₂) 7.34-7.40(m, 5H, Ar-H), 8.10(s, 1H, purine C)₆-H), 9.06(s, 1H, purine C)₈H) 9.20(s, 1H, purine C)₂H)。

And step 3: 9-benzyl-8-bromo-9H-purine (13)

To a stirred solution of 12(10.68g, 50.7mmol) in chloroform (500mL) was added N-bromosuccinamide (45.20g, 253.9mmol), and the reaction mixture was stirred under nitrogen and at reflux temperature for 5 h. The reaction mixture was transferred to a separatory funnel and washed with saturated sodium sulfite solution (2X 250mL), followed by brine solution (2X 250 mL). The chloroform fraction was dried over anhydrous sodium sulfate and concentrated, and the resulting reddish oil was purified by flash chromatography on silica gel eluting with EtOAc/hexane (4: 6). Yield 6.05 g. (41.2%). Mp 119-121 ℃;¹H NMR(CDCl₃)：δ5.53(s，2H，CH₂) 7.35-7.39(m, 5H, Ar-H), 9.03(s, 1H, purine C)₈-H), 9.09(s, 1H, purine C)₂-H)。

And 4, step 4: 9-benzyl-8- (. alpha. -ethoxyvinyl) purine (14)

9-benzyl-8-bromopurine 13(1.0g, 3.4 mmol)) A mixture of bis (triphenylphosphine) palladium (II) chloride (0.242g, 0.30mmol) and ethoxyvinyl (tributyl) tin (1.49g, 4.14mmol) in dry DMF (50mL) in N₂Heating at 65 deg.C for 48 h. The DMF was evaporated under reduced pressure and the resulting residue redissolved in EtOAc (50mL) and then filtered through a plug of celite. The EtOAc was distilled off and the residue obtained was purified by flash chromatography. Yield 0.579g (59.7%).¹HNMR(CDCl₃)：δ1.33(t，3H，CH₃，J＝7.5Hz)，3.99(q，2H，CH₂J ═ 13.7Hz), 4.66(d, 1H, CH, J ═ 3Hz), 5.34(d, 1H, CH, J ═ 3Hz), 5.48(s, 2H, CH for benzyl), 4.66 (c, 1H, c, J ═ 3Hz), 5.34 (c, c₂) 7.30-7.38(m, 5H, Ar-H), 9.09(s, 1H, purine C)₈-H), 9.2(s, 1H, purine C)₂-H)。¹³CNMR(CDCl₃)：δ14.2，47.3，64.2，91.8，126.8，126.8，127.7，128.6，128.6，133.1，136.4，148.2，151.2，151.9，152.8，153.0。

And 5: synthesis of 4- (9-benzyl-9H-purin-8-yl) -4-ethoxy-2-oxo-but-3-enoic acid methyl ester (15).

To a stirred solution of 9-benzyl-8- (. alpha. -ethoxyvinyl) purine (14) (0.579g, 2.0mmol) and pyridine (2.08g, 24.7mmol) in dry chloroform (15mL) at 0 deg.C was added methyl chlorooxoacetate (3.03g, 24.7mmol) in dry chloroform (10 mL). The reaction mixture was placed in a refrigerator for 15 h. Then, the mixture was washed with water (2X 20mL), and the organic layer was dried over anhydrous sodium sulfate. The chloroform was removed to give a dark reddish slurry which was purified by column chromatography. Yield 0.538g (77%).¹H NMR(CDCl₃)：1.17(t，3H，CH₃，J＝6.5Hz)，3.68(s，3H，CH₃)，3.93(q，2H，CH₂J ═ 6.5Hz), 5.35(s, 2H, CH for benzyl)₂) 6.45(s, 1H, CH for olefin), 7.12-7.22(m, 5H, Ar-H), 8.99(s, 1H, purine C)₆-H)，9.08(s, 1H, purine C)₂-H)。¹³C NMR(CDCl₃)：δ13.7，46.8，53.2，67.2，102.2，127.8，128.3，128.7，130.9，133.0，135.2，149.1，149.4，152.1，153.5，162.1，180.3。

Step 6: 4- (9-benzyl-9H-purin-8-yl) -2-hydroxy-4-oxo-but-3-enoic acid methyl ester (16).

4- (9-benzyl-9H-purin-6-yl) -4-ethoxy-2-oxo-but-3-enoic acid methyl ester (15) (210mg, 0.50mmole) obtained in the above step in CH₂Cl₂(60mL) at room temperature with stirring and FeCl₃.6H₂O (0.262g, 0.9 mmole). The reaction mixture was stirred at 40 ℃ for 6h, concentrated and the residue obtained was treated with 1N HCl (50mL) for 5min, followed by extraction with EtOAc (4X 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a pale yellow residue, which was purified by ion exchange chromatography. The yield was 90 mg. (46%). Mp 137-138 ℃;¹H NMR(CDCl₃)δ3.98(s，3H，CH₃) 6.03(s, 2H, CH of benzyl)₂) 7.29-7.41(m, 5H, aromatic), 7.68(s, 1H, alkene CH), 9.21(s, 1H, purine C)₆-H), 9.39(s, 1H, purine C)₂-H)。¹³CNMR(CDCl₃) δ 47.6, 53.5, 102.2, 128.0, 128.0, 128.1, 128.3, 128.8, 132.8, 135.9, 146.8, 151.6, 152.5, 155.3, 161.9, and 186.2. FAB-HRMS: [ M + H ]]⁺Calculated value C₁₇H₁₅N₄O₄339.1093, found 339.1099.

And 7: synthesis of 4- (9-benzyl-9H-purin-8-yl) -2-hydroxy-4-oxo-but-3-enoic acid (17).

To a stirred solution of methyl 4- (9-benzyl-9H-purin-8-yl) -4-ethoxy-2-oxo-but-3-enoate (16) (0.020g, 0.059mmol) in MeOH (3mL) at 0 ℃ was added a solution of 1n naoh (1mL), followed by stirring of the reaction mixture at 0 ℃ for 30min, then at ambient temperature for 30 min. The reaction mixture was neutralized with 1N HCl and the precipitated solid was filtered, dried and triturated with chloroform to give a yellow solid. Yield: 14mg (73%). Mp 162-.¹HNMR(DMSO-d₆): 5.90(s, 2H, CH of benzyl)₂) 7.26-7.37(m, 6H, Ar-H and H for alkenes), 9.16(s, 1H, purine C)₆-H), 9.49(s, 1H, purine C)₂-H)。NMR(CDCl₃)：δ47.6，101.5，124.7，126.6，127.5，127.5，127.5，128.8，128.9，128.9，137.1，137.5，153.0，155.2，163.9，192.9.FAB-HRMS：[M+H]⁺Calculated value C₁₆H₁₃N₄O₄325.0936, found 325.0924.

Representative example 15

4- (1, 9-benzyl-6, 9-dihydro-6-oxo-1H-purin-8-yl) -4-hydroxy-2-oxo-but-3-enoic acid (24).

The relevant scheme is scheme 5 shown below.

Scheme 5

Step 1. as described in step 1 of example 13.

Step 2: synthesis of 9-benzyl-8-bromoadenine (18).

To a stirred solution of 9-benzylpurine (6) (15.0g, 66.5mmol) in chloroform (750mL) was added N-bromosuccinimide (59.26g, 332.9mmol), and the reaction mixture was stirred at reflux temperature under nitrogen for 3 h. The reaction mixture was then transferred to a separatory funnel and washed with saturated aqueous sodium sulfite (2X 250mL), followed by brine solution (2X 250 mL). The chloroform fraction was dried over anhydrous sodium sulfate and concentrated to give a reddish oil which was purified by flash chromatography on silica gel eluting with EtOAc/hexanes (4: 6). Yield 9.72 g. (48%). Mp 199-¹HNMR(CDCl₃) Δ 5.39(s, 2H, CH of benzyl)₂) 7.29-7.33(m, 5H, Ar-H), 8.29(s, 1H, purine C)₂-H)。

And step 3: 9-benzyl-6, 9-dihydro-6-oxo-8-bromopurine (19)

To a stirred suspension of 9-benzyl-8-bromoadenine (18) (2.60g, 8.5mmol) in DMF (100mL) was added tert-butyl nitrite (4.31g, 41.8mmol), and the reaction mixture was heated at 60-65 ℃ for 3h under nitrogen. The DMF and excess reagent were distilled off under reduced pressure and the residue obtained was triturated with EtOAc (20 mL). The isolated yellow solid was filtered off and then dried in vacuo. Yield 1.41g (54%) Mp 182 ℃.1H NMR (CDCl)₃) Δ 5.39(s, 2H, CH of benzyl)₂) 7.21-7.42(m, 5H, Ar-H), 8.19(s, 1H, purine C2-H), 12.59(s, 1H, NH).

And 4, step 4: 1, 9-dibenzyl-6, 9-dihydro-6-oxo-8-bromopurine (20).

To a suspension of 9-benzyl-6, 9-dihydro-6-oxo-8-bromopurine (19) (1.20g, 3.8mmol) in dry DMF (25mL) was added NaH (0.113g, 4.6mmol) followed by benzyl bromide (0.807g, 4.6 mmol). The mixture was stirred at room temperature for 15 h. DMF was removed under reduced pressure and the residue obtained was dissolved in EtOAc (50mL) and washed with brine solution (2X 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give a yellow syrup which was purified by column chromatography on silica gel (EtOAc: hexane, 4: 6). Yield 1.20g (80%). Mp 161-162 ℃.¹H NMR(CDCl₃) Δ 5.27(s, 2H, CH of benzyl)₂) 5.34(s, 2H, CH for benzyl), 7.28-7.37(m, 10H, Ar-H), 8.02(s, 1H, purine C)₂-H)。¹³C NMR(CDCl₃)δ47.8，49.3，124.8，126.0，127.7，127.7，128.3，128.3，128.4，128.9，128.9，129.1，134.7，135.8，147.4，149.0，155.5，184.1.FAB-HRMS：[M+2H]Calculated value C₁₉H₁₇BrN₄O397.0487, found 397.0497.

And 5: synthesis of 1, 9-dibenzyl-6, 9-dihydro-6-oxo-8- (. alpha. -ethoxyvinyl) purine (21)

A mixture of 1, 9-dibenzyl-6, 9-dihydro-6-oxo-8-bromopurine (20) (1.20g, 3.04mmol), bis (triphenylphosphine) palladium (II) chloride (0.213g, 0.3mmol) and ethoxyvinyl- (tributyl) tin (2.19g, 6.07mmol) in dry DMF (50mL) was taken in N₂Heating at 70 deg.C for 22 h. The DMF was distilled off and the resulting residue was dissolved in EtOAc (100mL) and then filtered through a plug of celite. The solvent was distilled off, and the residue was purified by flash chromatography (EtOAc: hexane, 6: 4). Yield 0.989g (88%). Mp 167-.¹H NMR(CDCl₃)δ1.26(t，3H，CH₃，J＝7.5Hz)，3.86(q，2H，CH₂J7 Hz), 4.46(d, 1H, CH, J2.5 Hz), 5.26(s, 2H, CH of benzyl)₂)，5.32(d，1H，CH₂J ═ 3Hz), 5.60(s, 2H, CH of benzyl group)₂) 7.10-7.37(m, 10H, Ar-H), 7.99(s, 1H, purine C)₂-H)。¹³C NMR(CDCl₃) δ 14.1, 47.8, 49.1, 63.8, 90.2, 123.5, 126.6, 126.6, 127.5, 127.5, 128.2, 128.7, 128.7, 128.9, 129.1, 129.1, 136.2, 136.7, 146.2, 146.9, 148.9, 151.9, and 156.6. FAB-HRMS: [ M + H ]]⁺Calculated value C₂₃H₂₃N₄O₂387.1821, found 387.1815.

Step 6: 4- (1, 9-benzyl-6, 9-dihydro-6-oxo-1H-purin-8-yl) -4-ethoxy-2-oxo-but-3-enoic acid methyl ester (22).

To a stirred solution of 1, 9-dibenzyl-6, 9-dihydro-6-oxo-8- (ethoxyvinyl) purine (21) (0.620g, 1.6mmol) and pyridine (1.61g, 19.2mmol) in dry chloroform (30mL) was added methyl chlorooxoacetate (1.77mL, 19.2mmol) in dry chloroform (10mL) at 0 deg.C, and the reaction mixture was left in the refrigerator for 48 h. The reaction mixture was washed with water (2X 100mL), followed by drying over anhydrous sodium sulfate. The chloroform was distilled off to give a yellow syrup which was isolated by column chromatography (EtOAc: hexane, 4: 6). Yield 0.584g (77%).¹H NMR(CDCl₃)δ1.14(t，3H，CH₃，J＝6.5Hz)，3.66(s，3H，CH₃)，3.87(q，2H，CH₂J ═ 7Hz), 5.19(s, 2H, CH of benzyl group)₂) 5.23(s, 2H, CH of benzyl)₂) 6.25(s, 1H, CH for olefin), 7.09-7.62(m, 10H, Ar-H), 7.98(s, 1H, purine, C)₂-H)。¹³C NMR(CDCl₃)δ13.7，47.3，49.2，52.8，66.6，102.6，123.7，127.4，127.4，128.0，128.0，128.2，128.3，132.1，132.2，135.4，136.0，143.8，147.9，148.6，156.3，162.0，162.7，181.3.FAB-HRMS：[M+H]⁺Calculated value C₂₆H₂₅N₄O₅473.1824, found 473.1810.

And 7: 4- (1, 9-benzyl-6, 9-dihydro-6-oxo-1H-purin-8-yl) -2-hydroxy-4-oxo-but-3-enoic acid methyl ester (23).

Will be in CH₂Cl₂(150mL) of methyl 4- (1, 9-benzyl-6, 9-dihydro-6-oxo-1H-purin-8-yl) -4-ethoxy-2-oxo-but-3-enoate (22) (0.584g, 1.2mmole) in FeCl₃.6H₂O (0.567g, 2.1mmole) and the reaction mixture was stirred at 40 ℃ for 3 h. The solvent was removed and the resulting residue treated with 1N HCl (50mL) for 5min, then extracted with EtOAc (4X 20mL) and dried over anhydrous sodium sulfate. The solvent was removed to give a pale yellow residue which was purified by ion exchange Chromatography (CH)₃CN∶H₂O, 1: 1) purification. Yield 0.502 g. (91%). Mp 178-.¹HNMR(CDCl₃)：3.84(s，3H，CH₃) 5.21(s, 2H, CH of benzyl)₂) 5.77(s, 2H, CH of benzyl)₂) 7.19-7.30(m, 10H, Ar-H), 7.65(s, 1H, CH for olefins), 8.07(s, 1H, purine C2-H).¹³C NMR(CDCl₃)：δ48.1，49.5，53.2，102.5，119.3，124.8，127.9，127.9，128.2，128.2，128.4，128.7，128.7，128.8，129.2，129.2，135.5，135.9，143.1，149.4，150.0，156.7，162.2，162.2，184.1，185.9.FAB-HRMS：[M+H]+ calculated value C₂₄H₂₁N₄O₅445.1511, found 445.1520.

And 8: synthesis of 4- (1, 9-benzyl-6, 9-dihydro-6-oxo-1H-purin-8-yl) -4-hydroxy-2-oxo-but-3-enoic acid (24).

To a stirred solution of methyl 4- (1, 9-benzyl-6, 9-dihydro-6-oxo-1H-purin-8-yl) -2-ethoxy-4-oxo-but-3-enoate (23) (0.110g, 0.24mmol) in MeOH (10mL) at 0 deg.C was added a solution of 1N NaOH (2 mL). The reaction mixture was stirred at 0 ℃ for 30min and then at room temperature for 1 h. Neutralization was then carried out with 1N HCl and the isolated solid was filtered off, dried and triturated with ether to give a yellow solid. Yield 91mg (86%). Mp 167 deg.C (decomposition).¹HNMR(DMSO-d₆) Δ 5.27(s, 2H, CH of benzyl)₂) 5.80(s, 2H, CH of benzyl)₂) 7.25(s, 1H, CH for olefin), 7.27-7.37(m, 10H, Ar-H), 8.77(s, 1H, purine C)₂-H)。¹³CNMR(CDCl₃)δ47.9，49.4，101.4，123.9，127.6，127.6，128.2，128.2，128.7，128.9，129.1，137.2，137.2，150.4，151.6，156.5，163.9，176.0，179.5.FAB-HRMS：[M+H]⁺Calculated value C₂₃H₁₉N₄O₅431.1355, found 431.1373.

Claims (49)

1. A compound of structural formula I (including any tautomer, regioisomer, geometric isomer or optical isomer) and pharmaceutically acceptable salts thereof:

wherein said nucleobase scaffold is independently uracil, xanthine, hypoxanthine, or purine;

R¹and R²Each independently H, C_1-6Alkyl radical, C_1-6Fluoroalkyl, unsubstituted or substituted C_5-6Cycloalkyl radical, C_1-6Alkenyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, C_2-6Alkylphenyl wherein the phenyl moiety may be optionally substituted, unsubstituted or substituted heteroaryl, C substituted by heteroaryl_1-6Alkyl wherein heteroaryl is optionally substituted, C_1-6Alkyl S (O) R or alkyl (SO)₂) R wherein R is alkyl, phenyl or substituted phenyl, C_1-6Alkyl group CO₂R^aWherein R is^aIs C_1-6Alkyl radicals or H, C_1-6Alkyl group COR^a' wherein R^aIs' a C_1-6An alkyl group;

R³selected from H, C_1-6Alkyl, halogen, hydroxy, unsubstituted or substituted benzyl or unsubstituted or substituted phenylthio;

R⁴is CO₂R^cOR P (O) (OR)^c)(OR^c) Wherein each R is^cIndependently of each other H and C_1-6An alkyl group.

2. The compound of claim 1, having the structure:

wherein R is¹And R²Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring, wherein the substituents are selected from the group consisting of halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃or-CH₂R^bGroup, wherein R^bIs 5-or 6-membered heteroaryl;

R³is H, C_1-6Alkyl, halogen, benzyl, substituted benzyl, phenylthio or substituted phenylthio having 1 to 3 substituents on the phenyl ring, the substituents being selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃；

Wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

3. The compound of claim 1, having the structure:

wherein R is¹And R²Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring,

wherein said substituents are selected from the group consisting of halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹And R²Independently is-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is³Is H, C_1-6Alkyl, halogen, benzyl, substituted benzyl, phenylthio or substituted phenylthio having 1 to 3 substituents on the phenyl ring, the substituents being selected from the group consisting of halogen, methoxy, methyl, ethyl, propyl, CF₃；

Wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H or C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

4. The compound of claim 1, having the structure:

wherein R is¹And R²Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring,

wherein said substituents are selected from the group consisting of halogen, hydroxy, methyl, methoxy, ethyl, propyl, CF₃Or wherein R is¹And R²Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

R³selected from H, C_1-6Alkyl, halogen, benzyl, substituted benzyl, phenylthio or substituted phenylthio having 1 to 3 substituents on the phenyl ring, the substituents being selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃(ii) a And

R⁴is CO₂R, wherein R is H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

5. The compound of claim 1, having the structure:

wherein R is¹And R²Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring, wherein the substituents are selected from the group consisting of halogen, hydroxy, methyl, methoxy, ethyl, propyl, CF₃Or wherein R is¹And R²Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is³Selected from H, C_1-6Alkyl, halogen, benzyl, substituted benzyl, phenylthio or substituted phenylthio having 1 to 3 substituents on the phenyl ring, the substituents being selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃；

Wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

6. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

7. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Independently is-CH₂R, wherein R is a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

8. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R, wherein R is a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

9. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

10. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Selected from benzyl or having aromatic ringsSubstituted benzyl of 1 to 3 substituents selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Independently is-CH₂R, wherein R is a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R，

Wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

11. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

12. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring, said substituents being selected from the group consisting of halogen, hydroxy, methoxy, methyl, ethylPropyl group, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R is selected from C_1-6Alkyl, H, sodium, or other pharmaceutically acceptable salts.

13. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from C_1-6Alkyl, H, sodium, or other pharmaceutically acceptable salts.

14. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

15. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

16. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected fromH and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

17. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from C_1-6Alkyl, H, sodium, or other pharmaceutically acceptable salts.

18. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

19. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

20. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

21. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

22. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

23. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

24. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

25. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

26. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

27. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each one of which isIndependently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring, said substituents being selected from the group consisting of halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

28. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen, hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is CO₂R wherein R is selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

29. The compound of claim 1, having the structure:

wherein R is¹、R²And R³Each independently is benzyl or substituted benzyl having 1-3 substituents on the aromatic ring selected from halogen,Hydroxy, methoxy, methyl, ethyl, propyl, CF₃Or wherein R is¹、R²And R³Each is independently-CH₂R^bWherein R is^bIs a 5-or 6-membered heteroaromatic ring;

wherein R is⁴Is P (O) (OR) wherein the R groups may be the same or different and are selected from H and C_1-6An alkyl group, a carboxyl group,

and pharmaceutically acceptable salts thereof.

30. A pharmaceutical composition for the treatment of HIV infection comprising a therapeutically effective amount of a compound of any one of claims 1-29 and a pharmaceutically acceptable carrier, additive or excipient.

31. The pharmaceutical composition of claim 30, wherein said composition treats said HIV infection by inhibiting HIV integrase in a human host.

32. The pharmaceutical composition of claim 30, further combined with a therapeutically effective amount of at least one compound selected from the group consisting of i) an additional anti-HIV agent, ii) an anti-infective agent other than an anti-HIV agent, and iii) an immunomodulatory agent.

33. The composition of claim 32, wherein the anti-infective agent is an antiviral agent selected from the group consisting of a protease inhibitor, a reverse transcriptase inhibitor, and combinations thereof.

34. The composition of claim 33, wherein the reverse transcriptase inhibitor is a nucleoside compound.

35. The composition of claim 33, wherein the reverse transcriptase inhibitor is a non-nucleoside compound.

36. The composition of any one of claims 30-35, which is an oral dosage form or a parenteral dosage form.

37. A composition according to any one of claims 30 to 35, which is formulated for administration as an inhalation spray or as a rectal suppository.

38. A pharmaceutical composition prepared by admixing a compound of any one of claims 1-29 and a pharmaceutically acceptable carrier, additive, or excipient.

39. A method of treating HIV infection in a patient, said method comprising administering to said patient an effective amount of the composition of claim 30.

40. A method of treating HIV infection in a patient, said method comprising administering to said patient an effective amount of the composition of any one of claims 30-38.

41. A method of reducing the likelihood of HIV infection in a patient at risk of such infection, said method comprising administering to said patient an effective amount of a composition according to any one of claims 30 to 38.

42. A method of treating an AIDS or ARC patient comprising administering to said patient a therapeutically effective amount of the composition of any one of claims 30-38.

43. A method of inhibiting HIV integrase in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-29.

44. The method of claim 43, wherein said patient is a human.

45. Use of a compound according to any one of claims 1 to 29 in the manufacture of a medicament for the treatment of HIV in a patient.

46. Use of a compound according to any one of claims 1 to 29 in the manufacture of a medicament for reducing the likelihood of an HIV infection in a patient who will be exposed to an HIV infection.

47. Use of a compound according to any one of claims 1 to 29 in the manufacture of a medicament for the treatment of an AIDS or ARC patient.

48. Use of a compound of any one of claims 1-29 in the manufacture of a medicament for inhibiting HIV integrase in a patient.

49. The use of claim 48, wherein said patient is a human patient.