WO2011041512A2

WO2011041512A2 - Compositions and methods for treating mlv-infection, and preventing and treating mlv-initiated diseases

Info

Publication number: WO2011041512A2
Application number: PCT/US2010/050864
Authority: WO
Inventors: Raymond F. Schinazi; Ila Singh
Original assignee: Emory University; University Of Utah
Priority date: 2009-10-02
Filing date: 2010-09-30
Publication date: 2011-04-07
Also published as: WO2011041512A3

Abstract

Compositions and methods for inhibiting infection by XMRV or other MLV are disclosed. Also disclosed are methods for treating cancers resulting from infection by XMRV or other MLV, and for preventing such cancers. The anti- XMRV/anti-MLV compounds are predominantly integrase inhibitors, such as globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir, and also reverse transcriptase inhibitors AZT, tenofovir, and tenofovir DF. The compounds are also useful for treating chronic fatigue syndrome or other diseases with neuroimmune symptoms resulting from an infection by XMRV or other MLV. The compositions can also include other therapeutic agents known for treating prostate cancer, breast cancer, lymphomas, and leukemias, such as anti-androgenic agents, radioisotopes, and conventional anti-cancer compounds.

Description

COMPOSITIONS AND METHODS FOR TREATING MLV-INFECTION, AND PREVENTING AND TREATING MLV-INITIATED DISEASES

Field of the Invention

This invention is generally in the area of the treatment of infection with a murine leukemia virus (MLV), such as Xeno tropic murine leukemia-related retrovirus (XMRV), a recently discovered virus with a strong link to prostate cancer and other illnesses in humans, and poly tropic endogenous murine retroviruses (PMRV) and modified poly tropic murine retroviruses (MPMV), which are closely related to XMRV.

Background of the Invention

XMRV is the first gammaretrovirus known to infect human cells and humans. Other viruses of the gammaretrovirus genus cause leukemias and sarcomas in multiple rodent, feline, and primate species but have not yet been shown to cause cancers or other illnesses in humans. About three years ago, XMRV was isolated from prostate cancer samples, but its connection to prostate cancer was not understood [Reference 73]. A more recent study examined 233 prostate cancer samples and 101 samples without prostate cancer, and found that this virus was present in over one fourth (27%) of prostate cancers. XMRV was found specifically in malignant cells, and was more likely to be found in the more aggressive prostate cancers [Schlaberg R., Choe D. J., Brown K. R., Thaker H. M., and I. R. Singh (2009) XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proc. Natl. Acad. Sci. USA, 106: 16351-16356]. All of these findings are consistent with XMRV being a possible cause for carcinogenesis in a subset of prostate cancers.

It is now estimated that 20-25% of human cancers worldwide have a known viral etiology (Pagano et al., "Infectious agents and cancer: criteria for a causal relation," Semin Cancer Biol. 2004 Dec;14(6):453-71)

Prostate cancer is the second most common form of cancer, and the second leading cause of cancer death, among men in the US. There is accumulating evidence that inflammation of the prostate may contribute to prostate cancer (29, reviewed in 36, 50). Epidemiological studies implicate prostatitis and sexually transmitted diseases with an increased risk of prostate cancer (19, 33), and germline variation in genes associated with immune responses modulate prostate cancer risk (52). Epidemiological data also correlate intake of antioxidants and antiinflammatory drugs with a decreased risk (13, 49). Some histopathologists have proposed a lesion called proliferative inflammatory atrophy to be a precursor of prostate cancer (18, 46, 53). Proliferative inflammatory atrophy consists of focal atrophic lesions associated with chronic inflammation, often adjacent to foci of prostatic intraepithelial neoplasia (PIN) or prostate cancer. These lesions are possibly due to regenerative proliferation of prostatic epithelial cells in response to injury caused by inflammatory oxidants. All of this data is consistent with the possibility of a novel infectious agent causing a chronic inflammation that leads ultimately to cancer.

Familial studies have led to the identification of several loci with linkage to a high propensity toward prostate cancer, termed HPCs (11). One of these genes, HPC1, was mapped to chromosome lq24-25 (67) and later was identified with the RNASEL gene (10). This gene encodes the antiviral enzyme RNase L, strongly activated by the interferon response to viral infection. Hypomorphic alleles of RNASEL, especially homozygous deficiencies, were linked to prostate cancer in numerous studies in Finland and the US (see 65 for review).

Stimulated by these findings, Drs. Ganem, DeRisi and colleagues surveyed prostate tumor tissues from individuals harboring the R462Q variant of RNase L using their DNA microarray of conserved sequences from all known viruses (the Virochip). The study resulted in the identification of RNAs of a novel retrovirus, termed XMRV, in about half of the homozygous mutant patients (73). More recent data [Schlaberg et al., Proc. Natl. Acad. Sci. USA, 106: 16351-16356] involving a study of 334 patients with prostate cancer and without did not find any correlation between the R462Q variant of RNase L and either prostate cancer or XMRV infection. This latter finding is important because it moves the population at risk for XMRV infection from a small, genetically predisposed fraction homozygous for the R462Q RNase L variant (approximately 10% of the US population), to all men.

Gammaretroviruses cause cancer in animals by well-characterized mechanisms. Upon entering the cell, the viral RNA is copied into DNA and this DNA inserts into the host cell chromosome at random locations. If such an insertion occurs near a gene that promotes cell growth, viral sequences can lead to inappropriate activation of this gene. Multiple rounds of viral infection are typically needed for the activating insertion to occur. Cells containing the activation insertion are selected over others, leading over time to a distinctly clonal

population. An antiviral agent would prevent such rounds of infection, thus preventing the development of a cancer. Accordingly, it would be useful to have agents capable of inhibiting this recently discovered virus in order to treat or prevent those types of prostate cancer caused by XMRV, alone or as part of a treatment regimen. The pharmacological inhibition of viral replication, as currently achieved with HIV-1, could markedly limit the pathological consequences of chronic XMRV infection.

In addition to XMRV, another recent study showed that other MLV-related viruses (i.e., murine leukemia viruses) may also be causative agents for CFS (Lo et al., "Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors," Proc Natl Acad Sci USA. 2010 Sep 7; 107(36): 15874-9 (Epub 2010 Aug 23, also published as a comment in Proc Natl Acad Sci U S A. 2010 Sep 7;107(36): 15661 and Proc Natl Acad Sci U S A. 2010 Sep 7; 107(36): 15666-7). Lo et al. stated that the gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs, and were even less closely related to those of ecotropic MLVs. Other variations between these viruses were discussed by Liu et al. (J Virol. 2010 Sep 15. [Epub ahead of print]), Evolution of functional and sequence variants of the mammalian XPR1 receptor for mouse xenotropic gammaretro viruses and the human-derived XMRV). Liu discusses the similarities and differences between XMRV and X-MLV.

These viruses, viz. polytropic endogenous murine retroviruses (PMRV) and modified polytropic murine retroviruses (MPMV) are very closely related to XMRV, and all fall under Murine leukemia viruses or MLVs. Sequence comparisons of these viruses reveal over 90% identity at the nucleotide level, which is akin to the identity of random HIV-1 isolates within the United States, which typically have between 85 and 95% identity. Thus, it is very likely that compounds that inhibit replication of one of these viruses will inhibit that of all other closely related viruses.

Accordingly, it would be useful to have anti-retroviral agents, and methods for treating and preventing chronic fatigue syndrome, for preventing and treating XMRV- related prostate cancer, and for preventing and treating other cancers and illnesses where XMRV or other MLVs serve as one of the initiating factors. The present invention provides such agents and methods.

Summary of the Invention

Compositions and methods for treating and preventing XMRV infection, as well as infection by other MLVs, such as polytropic endogenous murine retroviruses (PMRV), modified polytropic murine retroviruses (MPMV), all of which fall under the general category of murine leukemia viruses (MLVs), are disclosed. Compositions and methods for treating cancers and other disorders, such as chronic fatigue syndrome, resulting from an infection from XMRV or another related MLV, are also disclosed.

Further disclosed are "theranostic" methods, wherein patients are first screened for the presence or absence of an XMRV infection, or infection by another MLV, and those patients with an XMRV or other MLV infection are then screened for the presence or absence of a disorder associated with such infection.

The diagnosis of the XMRV or other MLV infection can be performed, for example, using one or more of a quantitative PCR assay and immunohistochemistry (1HC) with an anti-XMRV (or anti-MLV) specific antiserum. The diagnosis of the disorder associated with the XMRV or other MLV infection can involve routine assays associated with the disorder, which typically involve looking for indicia that is either predictive of a risk for developing a disease associated with XMRV or other MLV infection, or for actually having a disease associated with XMRV or other MLV infection. In the case of cancer, the indicia can include elevated PSA levels (or other markers or genetic tests) or abnormal cells or tissue identified in a punch biopsy, in the case of prostate cancer, a mammogram or a needle biopsy in the case of breast cancer, or abhorrent surface marker staining in the case of leukemia.

Those patients identified as being at risk for developing a disease associated with XMRV or other MLV infection, such as by elevated PSA levels, or abnormal but precancerous tissue, can be prophylactically treated with one or more anti- XMRV agents (which agents are also believed to be active against other MLV). Those persons identified as both having an active XMRV or other MLV infection, and also having a disease associated with XMRV or other MLV infection, are treated for the XMRV or other MLV infection with antiviral drug or combinations including two or more antiviral agents for XMRV or other MLV, and optionally also for the disease, such as by administering anti-cancer drugs, hormone therapy, or radioisotopes to a patient with prostate cancer.

Compositions useful for treating an XMRV or other MLV infection include one or more compounds that inhibit XMRV or other MLV infection and a pharmaceutically acceptable carrier. The compounds useful for inhibiting XMRV or other MLV infection include, but are not limited to, reverse transcriptase inhibitors, tenofovir and tenofovir disoproxil fumarate (tenofovir DF), a prodrug form of tenofovir, and Integrase inhibitors, including but not limited to globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir with or without a pharmacokinetic (PK) booster such as ritonavir or Gilead's pharmacoenhancing agent (also referred to as a PK booster), GS 9350. In one embodiment, in order to minimize the occurrence of XMRV mutants, combination antiviral therapy is administered.

The XMRV retrovirus is associated with human prostate cancer, breast cancer, and various forms of lymphoma and leukemia, and is an initiating factor in prostate tumorigenesis, tumorigenesis in other tissues or organs, and Chronic Fatigue Syndrome (CFS). While XMRV is a retrovirus, not all retroviral compounds are active in inhibiting XMRV. Indeed, since there is not a strong homology between HIV and XMRV, as shown, for example, in Fig. 7 for the similarity between XMRV and HIV integrase proteins. It thus stands to reason that not all anti-HIV compounds are anti-XMRV compounds. That said, Applicants have surprisingly discovered that reverse transcriptase inhibitors, tenofovir and tenofovir DF as well as integrase inhibitors globoidnan A, L-000870812, Raltegravir and Elvitegravir (GS 9137 or JTK-303), drugs that are useful in treating HIV infection, are also useful in treating XMRV or other MLV infection, and, accordingly, are useful in treating or preventing XMRV-initiated cancers.

The anti-XMRV compound(s) can be administered alone or in combination with other therapeutic agents, including other antiviral agents, anti-cancer drugs, radioisotopes, anti- androgenic compounds, and the like.

Brief Description of the Drawings

Figure 1 is an autoradiograph depicting viral release from XMRV-infected cells treated with various compounds. Cells infected with XMRV were treated with compounds A-O. Supernatants were collected every 24 h, and measured for RT activity by measuring the incorporation of radiolabeled nucleosides into DNA by the reverse transcriptase of the XMRV (XMRV RT). The intensity of signal in each spot represents the amount of viral release in the presence of a given compound, and was determined using a phosphorimager. RT activities from days 5 to 8 after the infection are shown for each compound. The concentration of compounds (in μΜ) is on the top of each set of assays. The central column (marked with a "-") is the DMSO control and does not contain any compound. On the right of this central column are the duplicates of the experimental data shown on the left. The right-most column is for approximate quantitation purposes and represents RT activity from different dilutions (10%, 20% and 30%) of a preparation of XMRV whose approximate titers are known.

Figure 2 is an autoradiograph from a repeat of the experiment shown in Figure 1 , but with only Compounds B, C, and H.

Figure 3 is a chart quantifying the viral release shown in Figure 2, with relative RT units shown as a function of μΜ concentration of the compound of interest.

Figures 4-6 are charts showing the results of the analysis shown in Figure 3, but quantifying viral release individually for each compound; for Compound B (Figure 4), Compound C (Figure 5), and Compound H (Figure 6).

Figure 7 is a chart showing the homology between XMRV and other viruses.

Figure 8 is an autoradiograph depicting viral release from XMRV-infected cells treated with various compounds. Cells infected with XMRV were treated with compounds B, C, P, Q, and AZT. Supernatants were collected every 24 h, and measured for RT activity by measuring the incorporation of radiolabeled nucleosides into DNA by the reverse transcriptase of the XMRV (XMRV RT). The intensity of signal in each spot represents the amount of viral release in the presence of a given compound, and was determined using a phosphorimager. RT activities from days 1 to 4 after the infection are shown for each compound. The concentration of compounds (in μΜ and nM) is on the top of each set of assays. The central column (marked with a "-") is the DMSO control and does not contain any compound. On the right of this central column are the duplicates of the experimental data shown on the left. The right-most column is for approximate quantitation purposes and represents RT activity from different dilutions (10%, 20% and 30%) of a preparation of XMRV whose approximate titers are known. Figure 9 is a chart quantifying the viral release shown in Figure 8, with relative RT units shown as a function of μΜ concentration of the compound of interest.

Figure 10 is a table showing the EC5₀, EC9₀ and CC5₀ values of compounds tested in XMRV-infected MCF-7 cells, and in HIV-1 infected peripheral blood mononuclear cells. All compounds were evaluated in duplicate at least three times. Values shown are average of replicate assays. *(45')-8-Chloro-4-methyl-5-(3- methylbut-2-enyl)-3,4,5,6-tetrahydro- 1H-[1,3 ]diazepino[4,5,6-cd]indole-2(2aH)- thione.

Figures 11A-D are plots showing the percent inhibition of XMRV replication in LNCaP cells (%) in the presence of increasing concentrations (μΜ) of antiviral agents. Viral release from XMRV-infected LNCaP cells in the presence of increasing concentrations of (A) ZDV (B) TDF (C) RAL and (D) L-000870812, was determined by measuring RT activity in the supematants. Percent inhibition was calculated based on infected cells exposed to DMSO alone being set to 0% inhibition, and naive cells in the absence of any compounds set at 100% inhibition. Cell viability was checked by microscopy, quantified by the MTT assay, and represented by shaded bars. Data for each compound were derived from an average of at least three independent experiments, each performed in duplicate.

Figure 12 is a table showing the evaluation of drug-drug interactions against XMRV at 50%, 75%, 90%, and 95% inhibition.

Combination Index (CI) values were determined for a mutually exclusive interaction using CalcuSyn program, where CI < 1 indicates synergism, CI = 1 indicates additive effect, and CI > 1 indicates antagonism. Weighted average CI value (CI_wt) was assigned as [CI + 2CI₇₅ + 3CI₉₀ + 4CI₉₅]/10. RAL, raltegravir; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine.

Detailed Description

The antiretroviral compounds described herein show inhibitory activity against XMRV. Therefore, the compounds can be used to treat or prevent XMRV or other MLV infection in a human patient, such as infection by polytropic endogenous murine retroviruses (PMRV) or modified polytropic murine retroviruses (MPMV), which are closely related to XMRV, or reduce the biological activity of the virus. XMRV is responsible for certain types of prostate cancer, including more aggressive forms of prostate cancer, associated with higher Gleason grades, and it is believed that other MLV may also be associated with these disorders. MLV such as XMRV are also responsible for hematologic malignancies and premalignant conditions, including but not limited to lymphomas, leukemias and myelodysplasias. Thus, administration of the compounds described herein to a persons suffering from, or susceptible to, prostate cancer caused by XMRV or other MLV, can be used to treat and/or prevent prostate cancers and cancers involving hematopoietic cells.

In one embodiment, the methods involve administering an effective amount of one or more of the anti-XMRV or anti-MLV compounds described herein, and prodrugs thereof, to a patient in need of treatment thereof.

Pharmaceutical formulations including one or more compounds described herein, in combination with a pharmaceutically acceptable carrier or excipient, are also disclosed. In one embodiment, the formulations include at least one compound described herein and at least one further therapeutic agent.

The present invention will be better understood with reference to the following definitions:

I. Definitions

The term "independently" is used herein to indicate that the variable, which is independently applied, varies independently from application to application. Thus, in a compound such as R"XYR", wherein R" is "independently carbon or nitrogen," both R" can be carbon, both R" can be nitrogen, or one R" can be carbon and the other R" nitrogen.

As used herein, the term "enantiomerically pure" refers to a nucleotide composition that comprises at least approximately 95%, and, preferably, approximately 97%, 98%, 99% or 100% of a single enantiomer of that nucleotide.

As used herein, the term "substantially free of or "substantially in the absence of refers to a nucleotide composition that includes at least 85 to 90% by weight, preferably 95% to 98 % by weight, and, even more preferably, 99% to 100% by weight, of the designated enantiomer of that nucleotide. In a preferred embodiment, the compounds described herein are substantially free of enantiomers.

Similarly, the term "isolated" refers to a nucleotide composition that includes at least 85 to 90% by weight, preferably 95% to 98 % by weight, and, even more preferably, 99% to 100% by weight, of the nucleotide, the remainder comprising other chemical species or enantiomers.

The term "alkyl," as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbons, including both substituted and unsubstituted alkyl groups. The alkyl group can be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et ah , Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. Specifically included are CF₃ and CH₂CF_3.

In the text, whenever the term C(alkyl range) is used, the term independently includes each member of that class as if specifically and separately set out. The term "alkyl" includes C_1-22 alkyl moieties, and the term "lower alkyl" includes C_1-6 alkyl moieties. It is understood to those of ordinary skill in the art that the relevant alkyl radical is named by replacing the suffix "-ane" with the suffix "-yl".

The term "alkenyl" refers to an unsaturated, hydrocarbon radical, linear or branched, in so much as it contains one or more double bonds. The alkenyl group disclosed herein can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to but not limited to those described for substituents on alkyl moieties. Non-limiting examples of alkenyl groups include ethylene, methylethylene, isopropylidene, 1 ,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, and 1,4-butane-diyl.

The term "alkynyl" refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds. The alkynyl group can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to those described above for alkyl moeities. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn- 2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, and hexyn-3-yl, 3,3-dimethylbutyn- 1-yl radicals.

The term "alkylamino" or "arylamino" refers to an amino group that has one or two alkyl or aryl substituents, respectively.

The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis, and are described, for example, in Greene et al., Protective Groups in Organic Synthesis, supra.

The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings can be attached together in a pendent manner or can be fused. Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl, or other aromatic groups that remain after the removal of a hydrogen from an aromatic ring. The term aryl includes both substituted and unsubstituted moieties. The aryl group can be optionally substituted with any moiety that does not adversely affect the process, including but not limited to but not limited to those described above for alkyl moieties. Non-limiting examples of substituted aryl include heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, heteroaralkoxy, arylamino, aralkylamino, arylthio, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, hydroxyaralkyl, hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, carboaralkoxy.

The terms "alkaryl" or "alkylaryl" refer to an alkyl group with an aryl substituent. The terms "aralkyl" or "arylalkyl" refer to an aryl group with an alkyl substituent.

The term "halo," as used herein, includes chloro, bromo, iodo and fluoro. The term "acyl" refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including but not limited to methoxymethyl, aralkyl including but not limited to benzyl, aryloxyalkyl such as phenoxymethyl, aryl including but not limited to phenyl optionally substituted with halogen (F, CI, Br, I), alkyl (including but not limited to C₁ , C₂, C3, and C₄) or alkoxy (including but not limited to C₁ , C₂, C3, and C₄), sulfonate esters such as alkyl or aralkyl sulphonyl including but not limited to methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. , dimethyl-t-butylsilyl) or diphenylmethylsilyl. Aryl groups in the esters optimally comprise a phenyl group. The term "lower acyl" refers to an acyl group in which the non-carbonyl moiety is lower alkyl.

The terms "alkoxy" and "alkoxyalkyl" embrace linear or branched oxy- containing radicals having alkyl moieties, such as methoxy radical. The term "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" radicals can be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.

The term "alkylamino" denotes "monoalkylamino" and "dialkylamino" containing one or two alkyl radicals, respectively, attached to an amino radical. The terms arylamino denotes "monoarylamino" and "diarylamino" containing one or two aryl radicals, respectively, attached to an amino radical. The term "aralkylamino", embraces aralkyl radicals attached to an amino radical. The term aralkylamino denotes "monoaralkylamino" and "diaralkylamino" containing one or two aralkyl radicals, respectively, attached to an amino radical. The term aralkylamino further denotes "monoaralkyl monoalkylamino" containing one aralkyl radical and one alkyl radical attached to an amino radical.

The term "heteroatom," as used herein, refers to oxygen, sulfur, nitrogen and phosphorus. The terms "heteroaryl" or "heteroaromatic," as used herein, refer to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.

The term "heterocyclic," "heterocyclyl," and cycloheteroalkyl refer to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.

Nonlimiting examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1 ,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridines, thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine, phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N⁶-alkylpurines, N⁶-benzylpurine, N⁶-halopurine, N⁶-vinypurine, N⁶- acetylenic purine, N⁶-acyl purine,N⁶-hydroxyalkyl purine, N⁶-thioalkyl purine, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrmidine, uracil, N⁵- alkylpyrimidines, N⁵-benzylpyrimidines, N⁵-halopyrimidines, N⁵-vinylpyrimidine, N⁵-acetylenic pyrimidine, N⁵-acyl pyrimidine, N⁵-hydroxyalkyl purine, and N⁶- thioalkyl purine, and isoxazolyl. The heteroaromatic group can be optionally substituted as described above for aryl. The heterocyclic or heteroaromatic group can be optionally substituted with one or more substituent selected from halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylamino. The heteroaromatic can be partially or totally hydrogenated as desired. As a nonlimiting example, dihydropyridine can be used in place of pyridine. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, i-butyldimethylsilyl, and i-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl. The heterocyclic or heteroaromatic group can be substituted with any moiety that does not adversely affect the reaction, including but not limited to, but not limited to those described above for aryl.

The term "host," as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including but not limited to cell lines and animals, and, preferably, humans. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates (including but not limited to chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly contemplated by the present invention (such as for use in treating monkeys and non-human primates).

The term "MLV" refers to murine leukemia viruses, including XMRV, as well as polytropic endogenous murine retroviruses (PMRV) and modified polytropic murine retroviruses (MPMV), which are closely related to XMRV. The term "MLV other than XMRV" refers to viruses, such as PMRV and MPMV, which, in addition to XMRV, are also implicated in causing chronic fatigue and other disorders in humans.

The term "peptide" refers to various natural or synthetic compound containing two to one hundred amino acids linked by the carboxyl group of one amino acid to the amino group of another.

The term "pharmaceutically acceptable salt or prodrug" is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a nucleoside/tide analog which, upon administration to a patient, provides the nucleotide monophosphate compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on functional moieties of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the active compound. The prodrug forms of the compounds of this invention can possess antiviral activity, can be metabolized to form a compound that exhibits such activity, or both

In those embodiments where the integrase inhibitor is a nucleoside, prodrugs also include amino acid esters of the nucleosides (see, e.g. , European Patent Specification No. 99493, the text of which is incorporated by reference, which describes amino acid esters of acyclovir, specifically the glycine and alanine esters which show improved water- solubility compared with acyclovir itself, and US Pat. No. 4,957,924 (Beauchamp), which discloses the valine ester of acyclovir, characterized by side-chain branching adjacent to the a-carbon atom, which showed improved bioavailability after oral administration compared with the alanine and glycine esters). A process for preparing such amino acid esters is disclosed in U.S. Pat. No. 4,957,924 (Beauchamp), the text of which is incorporated by reference. As an alternative to the use of valine itself, a functional equivalent of the amino acid can be used (e.g. , an acid halide such as the acid chloride, or an acid anhydride). In such a case, to avoid undesirable side-reactions, it may be advantageous to use an amino- protected derivative.

II. Active Compound

The anti-XMRV compounds described herein are largely integrase inhibitors, including integrase inhibitors that are active against HIV infection. Representative integrase inhibitors include globoidnan A, L-000870812, S/GSK1349572,

S/GSK1265744, Raltegravir and Elvitegravir with or without a pharmacokinetic (PK) booster such as ritonavir or Gilead's pharmacoenhancing agent (also referred to as a PK booster), GS 9350.

Suitable integrase inhibitors include those described in: U.S. Patent Application No. 11/595,429, entitled "HIV INTEGRASE INHIBITORS" filed in the name of B. Narasimhulu Naidu, et al. on November 10, 2006 and published on May 17, 2007 as U.S. Publication No. 20070111985 and assigned to Bristol-Meyers Squibb Company.

U.S. Patent Application No. 11/561,039, entitled "HIV INTEGRASE INHIBITORS" filed in the name of B. Narasimhulu Naidu, et al. on November 17, 2006 and published on June 7, 2007 as U.S. Publication No. 20070129379 and assigned to Bristol-Meyers Squibb Company.

U.S. Patent Application No. 11/599,580, entitled "HIV INTEGRASE INHIBITORS" filed in the name of B. Narasimhulu Naidu, et al. on November 14, 2006 and published on May 17, 2007 as U.S. Publication No. 20070112190 and assigned to Bristol-Meyers Squibb Company.

U.S. Patent Application No. 11/754,462, entitled "HIV INTEGRASE INHIBITORS" filed in the name of B. Narasimhulu Naidu, et al. on May 29, 2007 and published on December 6, 2007 as U.S. Publication No. 20070281917 and assigned to Bristol-Meyers Squibb Company.

U.S. Patent Application No. 11/768,458, entitled "HIV INTEGRASE INHIBITORS" filed in the name of Michael A. Walker, et al. on June 26, 2007 and published January 3, 2008 as U.S. Publication No. 20080004265 and assigned to Bristol-Meyers Squibb Company.

U.S. Patent Application No. 12/132,145, entitled "HIV INTEGRASE INHIBITORS" filed in the name of B. Narasimhulu Naidu, et al. on June 3, 2008; published on December 11, 2008 as U.S. Publication No. 20080306051 and assigned to Bristol-Meyers Squibb Company.

U.S. Patent Application No. 11/505,149, entitled "BICYCLIC HETEROCYCLES AS HIV INTEGRASE INHIBITORS" filed in the name of B. Narasimhulu Naidu, et al. on August 16, 2006 and published on December 7, 2006 as U.S. Publication No. 20060276466.

U.S. Patent Application No. 11/590,637, entitled "HIV INTEGRASE INHIBITORS" filed in the name of B. Narasimhulu Naidu, et al. on October 31, 2006 and published on May 17, 2007 as U.S. Publication No. 20070111984 and assigned to Bristol-Meyers Squibb Company.

U.S. Patent Application No. 12/162,975, entitled "USE OF 6-(3-CHLORO-2- FLUOROBENZYL)-1-[(2S)-1-HYDROXY-3-METHYLBUTAN-2-YL]-7- METHOXY-4-OXO-1,4-D1HYDROQUINOLINE-3-CARBOXYLIC ACID OR SALT THEREOF FOR TREATING RETROVIRUS INFECTION" filed in the name of Yuji Matsuzaki, et al. on February 1, 2007 and published on January 15, 2009 as U.S. Publication No. 20090018162.

U.S. Patent Application No. 11/767,021, entitled "6-(HETEROCYCLYL- SUBSTITUTED BENZYL)-4-OXOQUINOLINE COMPOUND AND USE THEREOF AS HIV INTEGRASE INHIBITOR" filed in the name of Motohid, Satoh, et al. on June 22, 2007 and published on August 28, 2008 as U.S. Publication No. 20080207618.

U.S. Patent Application No. 12/042,628, entitled "USE OF QUINOLINE DERIVATIVES WITH ANTI-INTEGRASE EFFECT AND APPLICATIONS THEREOF" filed in the name of Aurelia Mousnier, et al. on March 5, 2008 and published on July 3, 2008 as U.S. Publication No. 20080161350 and assigned to Bioalliance Pharma SA.

U.S. Patent Application No. 12/169,367, entitled "NOVEL PYRIMIDINEC ARB OX AMIDE DERIVATIVES" filed in the name of Scott L. Harbeson on July 8, 2008 and published on February 5, 2009 as U.S. Publication No. 20090035324.

U.S. Patent Application No. 10/587,857, entitled "NAPHTHYRIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY AGAINST HIV INTEGRASE" filed in the name of Teruhiko Taishi, et al. on February 2, 2005 and published on September 10, 2009 as U.S. Publication No. 20090227621.

U.S. Patent Application No. 11/500,387, entitled "NITROGEN- CONTAINING HETEROARYL COMPOUNDS HAVING INHIBITORY ACTIVITY AGAINST HIV INTEGRASE" filed in the name of Masahiro Fuji, et al. on August 8, 2006 and published on December 28, 2006 as U.S. Publication No. 20060293334.

U.S. Patent Application No. 12/097,859, entitled "METHODS FOR IMPROVING THE PHARMACOKINETICS OF HIV INTEGRASE INHIBITORS" filed in the name of Brian P. Kearney, et al. on December 29, 2006 and published on September 17, 2009 as U.S. Publication No. 20090233964 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 11/807,303, entitled "PRE- ORGANIZED TRICYCLIC INTEGRASE INHIBITOR COMPOUNDS" filed in the name of James M. Chen, et al. on May 25, 2007 and published on January 29, 2009 as U.S. Publication No. 20090029939 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 10/587,601, entitled "HIV INTEGRASE INHIBITORS" filed in the name of Philip Jones, et al. on March 1, 2005 and published on July 12, 2007 as U.S. Publication No. 20070161639 and assigned to Merck and Co., Inc.

U.S. Patent Application No. 10/592,222, entitled "HIV INTEGRASE INHIBITORS" filed in the name of Peter D. Jones, et al. on March 4, 2005 and published on January 10, 2008 as U.S. Publication No. 20080009490 and assigned to

Merck and Co., Inc.

U.S. Patent Application No. 11/992,531, entitled "HIV INTEGRASE INHIBITORS" filed in the name of Vincenzo Summa, et al. on September 26, 2006 and published on September 3, 2009 as U.S. Publication No. 20090221571 and assigned to Merck and Co., Inc.

U.S. Patent Application No. 10/587,682, entitled "HIV INTEGRASE INHIBITORS" filed in the name of Wei Han, et al. on March 9, 2005 and published on August 2, 2007 as U.S. Publication No. 20070179196 and assigned to Merck and Co., Inc.

U.S. Patent Application No. 11/641,508, entitled "N-SUBSTITUTED HYDROXYPYRIMIDINONE C ARB OX AMIDE INHIBITORS OF HIV INTEGRASE" filed in the name of Benedetta Crescenzi, et al. on December 19, 2006 and published on May 31, 2007 as U.S. Publication No. 20070123524 and assigned to Merck and Co., Inc.

U.S. Patent Application No. 11/435,671, entitled "INTEGRASE INHIBITOR COMPOUNDS" filed in the name of Zhenhong R. Cai, et al. on May 16, 2006 and published on March 29, 2007 as U.S. Publication No. 20070072831 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 11/804,041, entitled "INTEGRASE INHIBITORS" filed in the name of Zhenhong R. Cai, et al. on May 16, 2007 and published on March 6, 2008 as U.S. Publication No. 20080058315 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 11/880,854, entitled "NOVEL HIV REVERSE TRANSCRIPTASE INHIBITORS" filed in the name of Hongyan Guo, et al. on July 24, 2007 and published on March 20, 2008 as U.S. Publication No. 20080070920 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 10/585,504, entitled "PYRIMIDYL PHOSPHONATE ANTIVIRAL COMPOUNDS AND METHODS OF USE" filed in the name of Haolun Jin, et al. on November 1, 2005 and published on June 26, 2008 as U.S. Publication No. 20080153783 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 11/579,772, entitled "HIV INTEGRASE INHIBITORS" filed in the name of John S. Wai, et al. on May 3, 2005 and published on November 20, 2008 as U.S. Publication No. 20080287394 and assigned to Merck and Co., Inc.

U.S. Patent Application No. 10/591,914, entitled "HIV INTEGRASE INHIBITORS" filed in the name of Matthew M. Morrissette, et al. on March 4, 2005 and published on June 12, 2008 as U.S. Publication No. 20080139579 and assigned to Merck and Co., Inc.

U.S. Patent Application No. 11/629,153, entitled "HIV INTEGRASE INHIBITORS" filed in the name of John S. Wai, et al. on June 3, 2005 and published on June 18, 2008 as U.S. Publication No. 20080015187 and assigned to Merck and Co., Inc.

U.S. Patent Application No. 12/043,636, entitled "HIV INTEGRASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND METHOD FOR THEIR USE" filed in the name of Qiyue Hu, et al. on March 6, 2008 and published on September 11, 2008 as U.S. Publication No. 20080221154 and assigned to Pfizer, Inc.

PCT WO 2007/019098, entitled "HIV INTEGRASE INHIBITORS," listing SmithKline Beecham Corporation, Shionogi & Co. Ltd., and Takashi Kawasuji as applicants, and Brian Johns as an inventor, published on February 15, 2007.

U.S. Patent Application No. 12/306,198, entitled "MODULATORS OF PHARMACOKINETIC PROPERTIES OF THERAPEUTICS" filed in the name of Desai, Manoj C, et al. and was published on November 26, 2009 as U.S. Publication No. 20090291952 and is assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 12/274,107, entitled, "INTEGRASE INHIBITORS" filed November 19, 2008 in the name of Jabri, Salman Y., et al. and was published on November 26, 2009 as U.S. Publication No. 20090291921 and is assigned to Gilead Sciences, Inc. U.S. Patent Application No. 12/215,605 "ANTIVIRAL COMPOUNDS" filed on June 26, 2008 in the name of Cho, Aesop, et al., and was published on October 15, 2009 as U.S. Publication No. 20090257978 and is assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 12/097,859 METHODS FOR IMPROVING THE PHARMACOKINETICS OF HIV INTEGRASE INHIBITORS filed on December 29, 2006 in the name of Kearney; Brian P., et al. and published on September 17, 2009 as U.S. Publication No. 20090233964 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 11/658,419, entitled "PHOSPHONATE ANALOGS OF HIV INHIBITOR COMPOUNDS" filed July 26, 2005 in the name of Boojamra; Constantine G., et al. and was published on August 13, 2009 as U.S. Publication No. 20090202470 and is assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 12/215,601, entitled, "ANTIVIRAL COMPOUNDS" filed on June 26, 2008 in the name of Cottell, Jeromy J., et al. and published on July 23, 2009 as U.S. Publication No. 20090186869 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 12/217,496 entitled "MODULATORS OF PHARMACOKINETIC PROPERTIES OF THERAPEUTICS" in the name of Desai, Manoj C, et al. and published on July 16, 2009 as U.S. Publication No. 20090181902 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 12/340,419 entitled "INHIBITORS OF CYTOCHROME P450" filed on December 19, 2008 in the name of Desai, Manoj C. et al. and published on July 9, 2009 as U.S. Publication No. 20090175820 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 12/195,161 entitled "COMPOSITIONS AND METHODS FOR COMBINATION ANTIVIRAL THERAPY" filed on August 20,

2008 in the name of Dahl, Terrence C. et al. and published on June 4, 2009 as U.S. Publication No. 20090143314 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 12/208,952 entitled "PROCESS AND INTERMEDIATES FOR PREPARING INTEGRASE INHIBITORS" filed on September 11, 2008 in the name of Dowdy, Eric, et al. and published on April 16,

2009 as U.S. Publication No. 20090099366 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 12/147,220 entitled "THERAPEUTIC COMPOSITIONS AND METHODS" filed on June 26, 2008 in the name of Kearney, Brian P. et al and published on April 9, 2009 as U.S. Publication No. 20090093482 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.12/147,041 entitled "THERAPEUTIC COMPOSITIONS AND METHODS" filed on June 26, 2008 in the name of Kearney, Brian P. et al., published on April 9, 2009 as U.S. Publication No. 20090093467 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.12/215,266 entitled "ANTIVIRAL COMPOUNDS" filed on June 26, 2008 in the name of Cai, Zhenhong R. et al., published February 19, 2009 as U.S. Publication No. 20090047252 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.12/204,174 entitled "COMPOSITIONS AND METHODS FOR COMBINATION ANTIVIRAL THERAPY" filed on September 4, 2008 in the name of Dahl, Terrence C, et al., published on February 5, 2009 as U.S. Publication No. 20090036408 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.10/585,504 entitled "PYRIMIDYL PHOSPHONATE ANTIVIRAL COMPOUNDS AND METHODS OF USE" filed on November 1, 2005 in the name of Jin, Haolun et al., published on June 26, 2008 as U.S. Publication No. 20080153783 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.11/853,606 entitled "PROCESS AND INTERMEDIATES FOR PREPARING INTEGRASE INHIBITORS" filed on September 11, 2007 in the name of Dowdy, Eric, et al, published May 29, 2008 as U.S. Publication No. 20080125594 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.11/644,811 entitled "PROCESSES AND INTERMEDIATES USEFUL FOR PREPARING INTEGRASE INHIBITOR COMPOUNDS" filed on December 21, 2006 in the name of Evans, Jared W. et al., published on February 14, 2008 as U.S. Publication No. 20080039487 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.10/586,627 entitled "USE OF ADEFOVIR OR TENOFOVIR FOR INHIBITING MMTV-LIKE VIRUSES INVOLVED IN BREAST CANCER AND PRIMARY BILIARY CIRRHOSIS" filed on July 20, 2007 in the name of Cihlar, Tomas, et al., published on December 6, 2007 as U.S. Publication No. 20070281911 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.11/435,671 entitled "INTEGRASE INHIBITOR COMPOUNDS" filed on May 16, 2006 in the name of Cai, Zhenhong R. et al., published on March 29, 2007 as U.S. Publication No. 20070072831 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.11/190,225 entitled "PHOSPHONATE ANALOGS OF HIV INHIBITOR COMPOUNDS" filed on July 26, 2005 in the name of Boojamra, Constantine G. et al., published on March 1, 2007 as U.S. Publication No. 20070049754 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.10/511,182 entitled "NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS" filed on February 28, 2005 in the name of Chen, James M. et al., published on June 15, 2006 as U.S. Publication No. 20060128692 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.11/033,422 entitled "PYRIMIDYL PHOSPHONATE ANTIVIRAL COMPOUNDS AND METHODS OF USE" filed on January 11, 2005 in the name of Jin, Haolun et al., published on December 22, 2005 as U.S. Publication No. 20050282839 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.11/040,929 entitled "METHODS OF INHIBITION OF MMTV-LIKE VIRUSES" filed on January 21, 2005 in the name of Cihlar, Tomas et al., published on October 27, 2005 as U.S. Publication No. 20050239753 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.10/423,496 entitled "CELLULAR ACCUMULATION OF PHOSPHONATE ANALOGS OF HIV PROTEASE INHIBITOR COMPOUNDS" filed on April 25, 2003 in the name of Arimilli, Murty N. et al., published on September 22, 2005 as U.S. Publication No. 20050209197 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.10/424, 130 entitled "NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS" filed on April 25, 2003 in the name of Chen, James M. et al., published on September 8, 2005 as U.S. Publication No. 20050197320 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No.10/944,118 entitled "AZA-QUINOLINOL PHOSPHONATE INTEGRASE INHIBITOR COMPOUNDS" filed on September 17, 2004 in the name of Jin, Haolun et al., published on June 23, 2005 as U.S. Publication No. 20050137199 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 10/903,288 entitled "NUCLEOBASE PHOSPHONATE ANALOGS FOR ANTIVIRAL TREATMENT" filed on July 30, 2004 in the name of Krawczyk, Steven H., published on March 17, 2005 as U.S. Publication No. 20050059637 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 10/757,141 entitled "COMPOSITIONS AND METHODS FOR COMBINATION ANTIVIRAL THERAPY" filed January 13, 2004 Dahl, Terrance C. et al., published on November 11, 2004 as U.S. Publication No. 20040224917 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 10/757,122 entitled "COMPOSITIONS AND METHODS FOR COMBINATION ANTIVIRAL THERAPY" filed on January 13, 2004 Dahl, Terrance C. et al., published on November 11, 2004 as U.S. Publication No. 20040224916 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 10/687,373 entitled "PRE- ORGANIZED TRICYCLIC INTEGRASE INHIBITOR COMPOUNDS" filed on October 16, 2003 in the name of Chen, James M. et al., published on August 26, 2004 as U.S. Publication No. 20040167124 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 10/687,374 entitled "PRE- ORGANIZED TRICYCLIC INTEGRASE INHIBITOR COMPOUNDS" filed on October 15, 2003 in the name of Chen, James M. et al., published on August 12, 2004 as U.S. Publication No. 20040157804 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 10/424,186 entitled "METHOD AND COMPOSITIONS FOR IDENTIFYING ANTI-HIV THERAPEUTIC COMPOUNDS" filed on April 25, 2003 in the name of Birkus, Gabriel et al., published on June 24, 2004 as U.S. Publication No. 20040121316 and assigned to Gilead Sciences, Inc.

U.S. Patent Application No. 11/820,444 entitled "DIKETO ACIDS WITH NUCLEOBASE SCAFFOLDS: ANTI-HIV REPLICATION INHIBITORS TARGETED AT HIV INTEGRASE" filed on June 19, 2007 in the name of Nair, Vasu et al., published on November 8, 2007 as U.S. Publication No. 20070259823 and assigned to the University of Georgia Research Foundation, Inc.

U.S. Patent Application No. 11/047,229 entitled "DIKETO ACIDS WITH NUCLEOBASE SCAFFOLDS: ANTI-HIV REPLICATION INHIBITORS TARGETED AT HIV INTEGRASE" filed on January 31, 2005 in the name of Nair, Vasu et al., published on August 3, 2006 as U.S. Publication No. 20060172973.

U.S. Patent Application No. 11/827,959 entitled "PYRIDINONE DIKETO ACIDS: INHIBITORS OF HIV REPLICATION" filed on July 13, 2007 in the name of Nair, Vasu et al., published on January 24, 2008 as U.S. Publication No. 20080020010 and assigned to the University of Georgia Research Foundation, Inc.

Additional integrase inhibitors include L-870,810 (Merck), INH-001 (Inhibitex), L870810 (Merck), PL-2500, composed of pryidoxal 1-5-phosphate derivatives (Procyon) monophores (Sunesis), V-165 (Rega Institute, Belgium), Mycelium integrasone (a fungal polyketide, Merck), GS 9224 (Gilead Sciences), AVX-I (Avexa), ITI-367, an oxadiazol pre-integrase inhibitor (George Washington University), GSK364735 (GSK/Shionogi), GS-9160 (GSK), S-1360 (Shionogi- GlaxoSmithKline Pharmaceuticals LLC), RSC 1838 (GSK Shionogi), GS-9137 (taken alone or with Norvir) (Gilead), MK-2048 (Merck), S/GSK 1349572 and S/GSK 1265744 (no need for a PK booster) (GSK/Shionogi), 6-(3-chloro-2- fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-y- l]-7-methoxy-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (U.S. Patent Application Publication No. 20090018162), S-1360, L-870810, MK-0518 (Merck), C-2507 (Merck), BMS 538158 (Bristol Myers Squibb), and L-900564 (Merck).

The str is shown below:

Nair et al., J Med Chem. 2006 January 26; 49(2): 445-447, discloses the following integrase inhibitors:

nd

Additional integrase inhibitors are disclosed in Pais et al., J Med Chem. 2002 Jul 18;45(15):3184-94.

Several integrase inhibitors are peptides, including those disclosed in Divita et al., Antiviral Research, Volume 71, Issues 2-3, September 2006, Pages 260-267.

Another integrase inhibitor that can be used in the methods of treatment described herein include 118-D-24, which is disclosed, for example, in Vatakis, Journal of Virology, April 2009, p. 3374-3378, Vol. 83, No. 7.

Additional integrase inhibitors include those described in McKeel et al., "Dynamic Modulation of HIV- 1 Integrase Structure and Function by Cellular LEDGF Protein, JBC Papers in Press. Published on September 18, 2008 as Manuscript M805843200.

Other representative integrase inhibitors include dicaffeoylquinic acids (DCQAs), such as those disclosed in Zhu et al., "Irreversible Inhibition of Human Immunodeficiency Virus Type 1 Integrase by Dicaffeoylquinic Acids," Journal of Virology, April 1999, p. 3309-3316, Vol. 73, No. 4.

There are also various nucleoside compounds active as integrase inhibitors, including those disclosed in Mazumder, A., N. Neamati, J. P. Sommadossi, G. Gosselin, R. F. Schinazi, J. L. Imbach, and Y. Pommier. 1996. Effects of nucleotide analogues on human immunodeficiency virus type 1 integrase. Mol. Pharmacol. 49:621-628.

The anti-XMRV compounds (for example, integrase inhibitors) described herein include those described in U.S. Publication 20080221154. Such compounds are represented by Formula I: Formula I

wherein:

Ri, R₂ and R₃ are each independently: hydrogen; — C(O)OR_c; or an alkyl, alkenyl, heteroalkyl, or haloalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; — O- - ; - - OR_c; NR_CR_C; C(O)NR_cR_cNR_cC(O)NR_cR_c; NR_cC(O)R_c; NR_CC(NR_C)NR_CR_C; SR_C; S(O)R_c; S(O)₂R_c; S(O)₂NR_cR_c; and alkyl, aryl, cycloalkyl, heteroaryl, and alkoxy-heteroaryl groups, unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogens; — C(R_C)₃; - -OH; and alkyl, alkenyl, aryl and heteroaryl groups, unsubstituted or substituted with one or more independently selected R_c groups,

where R_c is one or more substituents independently selected from the group consisting of: halogens; hydrogen; OH; unsubstituted alkyl; unsubstituted alkenyl; unsubstituted alkynyl; unsubstituted aryl; unsubstituted cycloalkyl; unsubstituted heterocycloalkyl; unsubstituted heteroaryl; aryl and heteroaryl groups substituted with one or more substituents independently selected from the group consisting of halogen and alkyl; or two or more R_c groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group;

R₄ is hydrogen or an alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl group, unsubstituted or substituted with — OR_d where R_d is an unsubstituted alkyl group;

R₅ is hydrogen or an alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl group;

R₆ is hydrogen or an alkyl, alkenyl, alkynyl, heteroalkyl, or haloalkyl group, unsubstituted or substituted with an aryl group;

R₄ and R₆ together with the N to which R₅ is attached cyclize to form the following compound represented by the Formula Id: Formula Id

wherein R_i2 and R_i3 are each independently:

hydrogen; - - C(O)OR_c; or an alkyl, alkenyl, heteroalkyl, or haloalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; - -0- -; - -OR_c; NR_CR_C; C(O)NR_cR_c; NR_cC(O)NR_cR_c; NR_cC(O)R_c; NR_CC(NR_C)NR_CR_C; SR_C; S(O)R_c; S(O)₂R_c; S(O)₂NR_cR_c; and alkyl, aryl, cycloalkyl, heteroaryl, and alkoxy-heteroaryl groups, unsubstituted or substituted by one or more substituents independently selected from the group consisting of:

halogens; - - C(R_C)₃; - -OH; and alkyl, alkenyl, aryl and heteroaryl groups, unsubstituted or substituted with one or more independently selected R_c, groups,

where R_c is one or more substituents independently selected from the group consisting of: halogens; hydrogen; unsubstituted alkyl; unsubstituted alkenyl; unsubstituted alkynyl; unsubstituted aryl; unsubstituted cycloalkyl; unsubstituted heterocycloalkyl; unsubstituted heteroaryl; aryl and heteroaryl groups substituted with one or more substituents independently selected from the group consisting of halogen and alkyl; or two or more R_c, groups together cyclize to form part of a heteroaryl or heterocycloalkyl group unsubstituted or substituted with an unsubstituted alkyl group; and

n is 1, 2 or 3;

R₇ is hydrogen or an alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

halogens; and aryl, cycloalkyl, heterocycloalkyl, and heteroaryl groups, unsubstituted or substituted with one or more halogen groups;

X is C or N;

Y is C or N;

Z is C or N; and

there is a double bond between X and the 6-membered ring and Z and the 6- membered ring; or between X and Y; or between Y and Z; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof.

In another aspect, the invention is directed to compounds represented by Formula I:

wherein:

Ri is hydrogen or — C(O)OR_c, where R_c is an unsubstituted alkyl, unsubstituted alkenyl, or unsubstituted alkynyl group;

R₂ is hydrogen or an alkyl, alkenyl, or heteroalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

- -O- -; - - NR_dR_d; - - OR_d; halogens; and an aryl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

halogens; — C(R_d)₃; unsubstituted alkyl, alkyl-R_d, alkenyl-R_d, and aryl groups,where R_d is one or more substituents independently selected from the group consisting of hydrogen; unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted aryl groups; R₃ is hydrogen or an alkyl, alkenyl, or heteroalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of:

- -O- -; - - OR_e; and, alkyl, aryl, cycloalkyl, and heteroaryl groups, unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens; — H; and aryl or heteroaryl groups, substituted with one or more R_e substituents,where R_e is one or more substituents independently selected from the group consisting of halogens; hydrogen; OH; unsubstituted alkyl; and aryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen and alkyl;

R₄ is hydrogen or an alkyl group, unsubstituted or substituted with— OR_f, where R_f is an unsubstituted alkyl group;

R₅ is hydrogen or an alkyl group; R₆ is hydrogen or an alkyl group unsubstituted or substituted with an aryl group; R₄ and R₆ together with the N to which R₆ is attached cyclize to form the following compound represented by the Formula Id:

wherein R_i2 and R_i3 are each independently hydrogen; and

n is 1 ;

R₇ is hydrogen or an alkyl, alkenyl, or aryl group, unsubstituted or substituted with an aryl group,

unsubstituted or substituted with one or more halogens;

X is C or N;

Y is C;

Z is C or N;

and there is a double bond between X and the 6-membered ring and Z and the 6-membered ring; or between X and Y; or between Y and Z;

or a pharmaceutically acceptable salt pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof.

In yet another aspect, the invention is directed to compounds of the Formula I where

Ri is hydrogen or - - C(O)0-ethyl;

R₂ is hydrogen, methyl, ethyl, propyl, vinyl, allyl, or benzyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens, - - , OH, amino, and phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, ethyl, phenyl, benzyl, 2- phenylethyl, 3-phenylallyl, and 2 -phenyl vinyl;

R₃ is methyl, ethyl, butyl, or benzyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens, OH, methyl, cyclohexyl, - - , thiadiazole, thiophenyl, and phenoxy, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens, phenyl, and ethoxy;

R₄ is hydrogen, methyl or methoxymethyl;

R₅ is hydrogen or methyl;

R₆ is hydrogen, methyl, or benzyl;

R₇ is hydrogen, methyl, benzyl, phenyl, allyl, or tert-butyl, unsubstituted or substituted with one

or more halogens; and

R₄ and R₆ together with the N to which R₆ attaches cyclize to form a pyrrole -2 -one.

The invention is also directed to compounds having the Formula I:

where

Ri is hydrogen or - - C(O)0-ethyl;

R₂ is selected from hydrogen; hydroxymethyl; methoxymethyl; ethoxymethyl; 2- phenylvinyl; 3-phenylprop-1-enyl; [(2-phenylvinyl)oxy]methyl; dimethylaminomethyl; benzyloxymethyl; 4-fluorobenzyl; 2-phenylvinyl; 2-phenylethyl; 3-phenylpropyl; 2- phenylethoxymethyl; [(phenylprop-2-enyl)oxy] methyl; [(3-phenylallyl)oxy]methyl; methyl; ethyl; and allyl;

R₃ is selected from hydrogen; 2,4-difluorobenzyl; 2,3-difluorobenzyl; 4-fluorobenzyl; 3-chloro-2,6-difluorobenzyl; 3-chloro-5-fluoro-2-hydroxybenzyl; 5-chloro-thiophen-2- ylmethyl; 3-chloro-2-fluorobenzyl; 2,3-dichlorobenzyl; 5-ethoxy-[1,2,3]thiadiazol^-ylmethyl; 3-methyl-butyl; 2-cyclohexyl-ethyl; 2,4-difluoro-phenoxymethyl; 3,5-difluoro-2- hydroxybenzyl; 2-chloro.₄-fluoro-phenoxymethyl; 3-chloro-5-fluoro-2-hydroxybenzyl; 4- fluoro-phenoxymethyl; 5-fluoro-2-hydroxy-benzyl; 2,3,4-trifluoro-phenoxymethyl; 3,4,5- trifluoro-2-hydroxybenzyl; 2-chloro-phenoxymethyl; and 5-chloro-2-hydroxy-benzyl;

R₄ is hydrogen, methyl or methoxymethyl;

R₅ is hydrogen or methyl;

R₆ is hydrogen, methyl, or benzyl;

R₇ is hydrogen, methyl, benzyl, phenyl, pentafluorobenzyl, allyl, tert-butyl; and

R₄ and R₆ together with the N to which R₆ attaches cyclize to form a pyrrol-2-one.

Inventive compounds represented by the Formula I include, but are not limited to, the following compounds represented by Formula la, lb, Ic and Ie

Preferred Integrase agents of the invention include compounds represented by Formula I wherein:

R₂ is hydrogen or an alkyl, alkenyl, or heteroalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of - - O- - ; - - NR_dR_d; - - OR_d; halogens; and an aryl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; — C(R_d)₃; unsubstituted alkyl, alkyl-R_d, alkenyl-R_d, and aryl groups, where R_d is one or more substituents independently selected from the group consisting of hydrogen; unsubstituted alkyl, unsubstituted alkenyl, and unsubstituted aryl groups;

R₃ is hydrogen or an alkyl, alkenyl, or heteroalkyl group, unsubstituted or substituted with one or more substituents independently selected from the group consisting of - - O- - ;— OR_e; and, alkyl, aryl, cycloalkyl, and heteroaryl groups, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens; — H; and aryl or heteroaryl groups, substituted with one or more R_e substituents,where R_e is one or more substituents independently selected from the group consisting of halogens; hydrogen; OH; unsubstituted alkyl; and aryl unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen and alkyl;

R₅ is hydrogen or an alkyl group;

R₆ is hydrogen or an alkyl group unsubstituted or substituted with an aryl group; R₄ and R₆ together with the N to which R₆ is attached cyclize to form the following compound represented by the Formula Id,

Formula Id

wherein Ri2 and Ri3 are each independently hydrogen; and

n is 1 ;

R₇ is hydrogen or an alkyl, alkenyl, or aryl group, unsubstituted or substituted with an aryl group, unsubstituted or substituted with one or more halogens X is C or N

Y is C

Z is C or N; and there is a double bond between X and the 6-membered ring and Z and the 6- membered ring; or between X and Y; or between Y and Z; or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof.

More preferred are HIV Integrase agents of the Formula I, where Ri is hydrogen or - -

C(O)0-ethyl;

R₂ is hydrogen, methyl, ethyl, propyl, vinyl, allyl, or benzyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogens, - - O- - , OH, amino, and phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of methyl, ethyl, phenyl, benzyl, 2- phenylethyl, 3-phenylallyl, and 2-phenylvinyl;

R₃ is methyl, ethyl, butyl, or benzyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens, OH, methyl, cyclohexyl, - - O- - , thiadiazole, thiophenyl, and phenoxy, unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogens, phenyl, and ethoxy;

R₄ is hydrogen, methyl or methoxymethyl;

R₅ is hydrogen or methyl;

R₆ is hydrogen, methyl, or benzyl;

R₇ is hydrogen, methyl, benzyl, phenyl, allyl, or tert-butyl, unsubstituted or substituted with one or more halogens; and

R₄ and R₆ together with the N to which R₆ attaches cyclize to form a pyrrole-2-one.

Even more preferred are HIV Integrase agents of the Formula I, where Ri is hydrogen or - -C(O)0-ethyl;

R₂ is selected from hydrogen; hydroxymethyl; methoxymethyl; ethoxymethyl; 2- phenylvinyl; 3-phenylprop-1-enyl; [(2-phenylvinyl)oxy]methyl; dimethylaminomethyl; benzyloxymethyl;

4-fluorobenzyl; 2-phenylvinyl; 2-phenylethyl; 3-phenylpropyl; 2-phenylethoxymethyl; [(phenylprop-2-enyl)oxy]methyl;(3-phenylallyl)oxy]methyl;methyl;ethyl; and allyl;

R₃ is selected from hydrogen; 2,4-difluorobenzyl; 2,3-difluorobenzyl; 4- fluorobenzyl; 3-chloro-2,6-difluorobenzyl; 3-chloro-5-fluoro-2-hydroxybenzyl; 5-chloro- thiophen-2-ylmethyl; 3-chloro-2-fluorobenzyl;2,3-dichlorobenzyl; 5-ethoxy-[1,2,3]thiadiazol. 4-ylmethyl; 3-methyl-butyl; 2-cyclohexyl-ethyl;2,4-difluoro-phenoxymethyl; 3,5-difluoro-2- hydroxybenzyl; 2-chloro.₄-fluoro-phenoxymethyl; 3-chloro-5-fluoro-2-hydroxybenzyl; 4- fluoro-phenoxymethyl; 5-fluoro-2-hydroxy-benzyl; 2,3,4-trifluoro-phenoxymethyl; 3,4,5- trifluoro-2-hydroxybenzyl; 2-chloro-phenoxymethyl; and 5-chloro-2-hydroxy-benzyl;

R₄ is hydrogen, methyl or methoxymethyl;

R₅ is hydrogen or methyl;

R₆ is hydrogen, methyl, or benzyl;

R₇ is hydrogen, methyl, benzyl, phenyl, pentafluorobenzyl, allyl, tert-butyl;

Most preferred are the compounds set forth in the examples below, including the following compounds:

l-(2,4-Difluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carbox- amide: l-(2,4-Difluorobenzyl)-N-hydroxy-N-methyl-1H-pyrrolo[2,3-c]py- ridine-5- carboxamide: l-(4-Huorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxamid- e; l-(4-Fluorobenzyl)-N-hydroxy-N-methyl-1H-pyrrolo[2,3-c]pyridine-5- carboxamide;

N-Benzyl-1-(4-fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-c- arboxamide; l-(3-chloro-2,6-difluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine- -5- carboxamide;

l-(5-Chloro-thiophen-2-ylmethyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridin- e-5- carboxamide; l-(3-Chloro-2-fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-c- arboxamide;

l-(2,3-Dichlorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carbox- amide; l-(5-Ethoxy-[1,2,3]thiadiazol^-ylmethyl)-N-hydroxy-1H-pyrrol- o[2,3-c]pyridine-5- carboxamide;

l-(2,4-Difluorobenzyl)-N-hydroxy^-methyl-1H-pyrrolo[2,3-c]pyridine- -5- carboxamide;

l-(2,4-Difluorobenzyl)_3-ethoxymethyl-N-hydroxy-1H-pyrrolo[2,3-c]py- ridine-5- carboxamide; l-(2,4-Difluorobenzyl)-N-hydroxy_3-hydroxymethyl-1H-pyrrolo[2,3-c]p- yridine-5-carboxamide; l-(2,4-Difluorobenzyl).₃-dimethylaminomethyl-N-hydroxy-1H- pyrrolo[2- ,3-c]pyridine-5-carboxamide;

3-Benzyloxymethyl-1-(2,4-difluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c- ]pyridine- 5-carboxamide;

3-(2,4-Difluorobenzyl)-N-hydroxy.₃H-imidazo[4,5-c]pyridine-6-carbox- amide; l-(2,4-Difluorobenzyl)-N-hydroxy-1H-imidazo[4,5-c]pyridine-6- - carboxamide;

1 -(2,4-Difluorobenzyl)_3-ethoxymethyl-N-hydroxy-N-methyl- 1 H-pyrrolo- [2,3- c]pyridine-5-carboxamide;

l-(2,4-Difluorobenzyl)-N-hydroxy_3-hydroxymethyl-N-methyl-1H-pyrrol- o[2,3- c]pyridine-5-carboxamide;

l-(2,4-Difluorobenzyl)_3-dimethylaminomethyl-N-hydroxy-N-methyl-1H- - pyrrolo[2,3-c]pyridine-5-carboxamide;

l-(2,4-Difluorobenzyl)-N-methoxy-1H-pyrrolo[2,3-c]pyridine-5-carbox- amide; l-(2,4-Difluorobenzyl)_3-ethoxymethyl-N-methoxy-1H-pyrrolo[2,- 3-c]pyridine-5- carboxamide;

l-(2,4-Difluorobenzyl)_3-hydroxymethyl-N-methoxy-1H-pyrrolo[2,3-c]p- yridine-5- carboxamide;

l-(2,4-Difluorobenzyl)_3-dimethylaminomethyl-N-methoxy-1H-pyrrolo[2- ,3- c]pyridine-5-carboxamide;

N-Benzyloxy-1-(2,4-difluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carb- oxamide; N-Benzyloxy_3-(4-fluorobenzyl)_3H-imidazo[4,5-c]pyridine-6- - carboxamide;

3-(4-Fluorobenzyl)-N-memoxy.₃H-imidazo[4,5-c]pyridine-6-carboxamid- e;

3-(4-Fluorobenzyl)-N-phenoxy.₃H-imidazo[4,5-c]pyridine-6-carboxam- ide;

3-(4-Fluorobenzyl)-N-[(pentafluorobenzyl)oxy].₃H-imidazo[4,5-c]- pyridine - carboxamide;

N-(Allyloxy)_3-(4-fluorobenzyl)_3H-imidazo[4,5-c]pyridine-6-carboxa- mide;

6-(2,4-Difluorobenzyl)-2-hydroxy-1,6-dihydrodipyrrolo[3,2-d:3'- ,4'-b]pyridin_₃(2H)- one;

3-(23-Difluorobenzyl)-N-phenoxy.₃H-imidazo[4,5-c]pyridine-6-carbox- amide; 3-(2,3-Difluorobenzyl)-N-methoxy_3H-imidazo[4,5-c]pyridine-6- - carboxamide; N-Allyloxy.3-(23-difluorobenzyl)_3H-imidazo[4,5-c]pyridine-6-carbo- xamide; 1 -(4-Fluorobenzyl)-N-phenoxy- 1 H-imidazo [4,5-c]pyridine-6-car- boxamide;

N-tert-Butoxy.3-(2,3-difluorobenzyl)_3H-imidazo[4,5-c]pyri- dine-6-carboxamide; N-Methoxy_3-(3-methyl-butyl).₃H midazo[4,5-c]pyridine-6-carboxamid- e;

3-(3-Methyl-butyl)-N-phenoxy_3H-imidazo[4,5-c]pyridine-6-carboxam- ide;

3-(2-Cyclohexyl-ethyl)-N-phenoxy.₃H-imidazo[4,5-c]pyridine-6-ca- rboxamide: 3-(2-Cyclohexyl-ethyl)-N-methoxy.₃H-imidazo[4,6-c]pyridin- e-6-carboxamide; N-Allyloxy.3-(2-cyclohexyl-ethyl).₃H-imidazo[4,5-c]pyridine-6-carbo- xamide; l-(2,4-Difluorobenzyl)-N-hydroxy^-methoxymethyl-1H-pyrrolo[- 2,3-c]pyridine-5- carboxamide;

l-(2,4-Difluorobenzyl)-N-hydroxy_3-(2-phenylvinyl)-1H-pyrrolo[2,3-c- ]pyridine-5- carboxamide;

l-(2,4-Difluorobenzyl)-N-hydroxy.₃-(3-phenylprop-1-enyl)-1H-pyrrolo- [2,3- c]pyridine-5-carboxamide;

l-(2,4-Difluorobenzyl)-N-hydroxy_3-(2-phenylethyl)-1H-pyrrolo[2,3-c- ]pyridine-5- carboxamide;

l-(2,4-Difluorobenzyl)-N-hydroxy.₃-(3-phenylpropyl)-1H-pyrrolo[2,3- - c]pyridine-5- carboxamide;

1 -(2,4-Difluorobenzyl)-N-hydroxy_3- { [(2-phenylethyl)oxy] methyl } - 1 H- - pyrrolo [2,3- c]pyridine-5-carboxamide;

1 -(2,4-Difluorobenzyl)-N-hydroxy_3- { [(3-phenylallyl)oxy]methyl } - 1H- - pyrrolo[2,3- c]pyridine-5-carboxamide;

l-(2,4-Difluorobenzyl)-N-hydroxy_3-methyl-1H-pyrrolo[2,3-c]pyridine- -5- carboxamide;

l-(2,4-Difluorobenzyl)_3-ethyl-N-hydroxy-1H-pyrrolo[2,3-c]pyridine- - 5- carboxamide; 3-Allyl-1-(2,4-difluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine- - 5- carboxamide;

l-(2,4-Difluorobenzyl)-N-hydroxy-7-methyl-1H-pyrrolo[2,3-c]pyridine- -5- carboxamide;

Ethyl l-(2,4-Difluorobenzyl)-5-hydroxycarbamoyl-1H-pyrrolo[2,3-c]pyridine-2-car- boxylate;

3-(2,4-Difluoro-phenoxymethyl)-1-ethyl-N-hydroxy-1H-pyrrol- o[3,2-c]pyridine- carboxamide;

3-(3,5-Difluoro-2-hydroxybenzyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c- ]pyridine-6- carboxamide;

3-(2-Chloro^-fluoro-phenoxymethyl)- 1 -ethyl-N-hydroxy- 1H-pyrrolo [3,- 2- c]pyridine-6-carboxamide;

3-(3-Chloro-5-fluoro-2-hydroxybenzyl)-l -ethyl-N-hydroxy- 1H-pyrrolo[- 3,2- c]pyridine-6-carboxamide;

l-Ethyl_3-(4-fluoro-phenoxymethyl)-N-hydroxy-1H-pyrrolo[3,2-c]pyrid- ine-6- carboxamide;

l-Ethyl_3-(5-fluoro-2-hydroxybenzyl)-N-hydroxy-1H-pyrrolo[3,2-c]pyr- idine-6- carboxamide;

l-Ethyl-N-hydroxy_3-(2,3,4-trifluoro-2-phenoxymethyl)-1H-pyrrolo[3,- 2-c]pyridine- 6-carboxamide;

l-Ethyl-N-hydroxy_3-(3,4,5-trifluoro-2-hydroxybenzyl)-1H-pyrrolo[3,- 2-c]pyridine- 6-carboxamide;

3-(2-Chloro-phenoxymethyl)-l ethyl-N-hydroxy- 1H-pyrrolo[3,2-c]pyridine- carboxamide;

3-(5-Chloro-2-hydroxy-benzyl)-l -ethyl-N-hydroxy- 1H-pyrrolo[3,2-c]py- ridine-6- carboxamide and pharmaceutically acceptable salts thereof.

Synthesis of HIV Integrase Agents

The compounds can be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available. The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other HIV Integrase agents of the invention. For example, the synthesis of non-exemplified compounds according to the invention may be performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having adaptability for preparing other compounds of the invention.

Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art. For example, the preparation of free amines from common salt forms and stock reagent solutions can be useful for small-scale reactions. See also Abdel- Magid et al., "Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride," J. Org. Chem. 61 : 3849 (1996).

The following scheme shows the synthesis of the final compounds, and detailed syntheses of the various intermediates are disclosed in U.S. Publication 20080221154.

Additional Integrase inhbitor compounds are disclosed in US Publication No. 20090170846, which compounds are compounds of formula (I),

wherein:

R¹ is hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl, wherein said C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₁-C₈ heteroalkyl groups may be optionally substituted with at least one substituent independently selected from:

halo, - -OR¹2a, - -NCR¹2aR¹2b), - -C^NCR¹2aR¹2b), - -NR¹2aC(O)N(R¹2aR¹2b), - - NR¹2aC^R¹2a, - -NR¹2aC(NR¹2a)N(R¹2aR¹2b), - -SR¹2a, S(O)R¹2a, S(O)₂R¹2a, - - S(O)₂N(R¹2aR¹2b)₂, C_1-C₈ alkyl, C₆-C₁₄ aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl, wherein said C₁-C₈ alkyl, C₆-C14 aryl, C₃-C₈ cycloalkyl, and C₂-C₉ heteroaryl groups are optionally substituted with at least one substituent independently selected from halo, - - C(R¹2aR¹2b R¹2c), - -OH, and C_1-C₈ alkoxy;

R² is hydrogen;

R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, - -NR⁸S(O)₂R⁹, - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - - S(O)₂NR⁸R⁹;

R⁴ is hydrogen, halo, C_1-C₈ alkyl, - -OR¹2a, - -NR¹2aR¹2b, C_1-C₈ heteroalkyl C₂-C₈ alkenyl, or C₂-C₈ alkynyl, wherein said C₁-C₈ alkyl, C₁-C₈ heteroalkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl groups are optionally substituted with at least one R 3;

R⁵ is hydrogen;

R⁶ is hydrogen, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, or C₂-C₈ alkenyl, wherein said C₂-C₈ alkenyl is optionally substituted with at least one - - OR¹2a group;

R⁷ is hydrogen, C₁-C₈ heteroalkyl, C₆-C₁₄ aryl, C₂-C₈ alkenyl, or C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is optionally substituted with at least one C₃-C₈ cycloalkyl or C₆-C14 aryl group;

each R⁸ and R⁹, which may be the same or different, is independently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₈ heterocyclyl, and C₂-C₉ heteroaryl, wherein each of said C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl groups may be optionally substituted by at least one R¹⁰ group; or

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group; each R¹⁰ is independently selected from halo, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, C₂-C₉ heteroaryl, - -(CR^12aR^12b)_tOR⁷, - -C(O)R^12a, --S(O)₂R⁷, (CR^12aR^12b) _zC(O)NR^12aR^12b, - -NR^12aR^12b, and - -CF₃, wherein each of said C_1-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl groups may be optionally substituted with at least one R 4 group; each R^12a, R^12b, and R^12c, which may be the same or different, is independently selected from hydrogen and C₁-C₈ alkyl; each R¹³, which may be the same or different, is independently selected from - - OR¹² , halo, C₆-C14 aryl, C₂-C₉ heteroaryl, C₁-C₈ heteroalkyl, C₃-C₈ cycloalkyl, C₂-C₉ heterocyclyl, and - -C(R^12aR^12bR^12c); each R , which may be the same or different, is independently selected from halogen, alkyl, C₃-C₈ cycloalkyl, - -CF₃, and - -OR^12a; each z, which may be the same or different, is independently selected and is 0, 1, or 2; and

each t, which may be the same or different, is independently selected and is 0, 1, 2, or 3; or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein R¹ is C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C14 aryl wherein said C₆-C14 aryl is optionally substituted with at least one substituent independently selected from halo, - - C R¹2aR¹2bR¹2c), - -OH, and C₁-C₈ alkoxy, or a pharmaceutically acceptable salt or solvate thereof. In yet another embodiment are provided compounds of formula (I), wherein R¹ is C₁- C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C₁₄ aryl, wherein said C₆-C₁₄ aryl is optionally substituted with at least one halo, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein R¹ is - - (CH₂)(C₆-C₁₄ aryl), wherein said C₆-C₁₄ aryl is optionally substituted with at least one halo, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein R¹ is - - (CH₂)(C₆-C₁₄ aryl), wherein said C₆-C 14 aryl is optionally substituted with at least one fluorine, or a pharmaceutically acceptable salt or solvate thereof. In yet another embodiment are provided compounds of formula (I), wherein R¹ is 4-fluorobenzyl, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein R³ is - - NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R³ is - - NR⁸C(O)R⁹, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R³ is - -NR⁸S(O)R⁹, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R³ is - - NR⁸S(O)₂R⁹, or a pharmaceutically acceptable salt or solvate thereof. In yet another embodiment are compounds of formula (I), wherein R³ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹ or - -S(O)₂NR⁸R⁹, or a pharmaceutically acceptable salt or solvate thereof. In yet another embodiment are compounds of formula (I), wherein R³ is - - C(O)NR⁸R⁹, or a pharmaceutically acceptable salt or solvate thereof. In still another embodiment are compounds of formula (I), wherein R³ is - - S(O)NR⁸R⁹ or - -S(O)₂NR⁸R⁹, or a pharmaceutically acceptable salt or solvate thereof. In still another embodiment are compounds of formula (I), wherein R³ is - - S(O)NR⁸R⁹, or a pharmaceutically acceptable salt or solvate thereof. In still another embodiment are compounds of formula (I), wherein R³ is - - S(O)₂NR⁸R⁹, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein R⁴ is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein R⁶ is hydrogen or C₁-C₈ alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R⁶ is hydrogen or - - CH₃, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R⁶ is hydrogen, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R⁶ is C₁-C₈ alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R⁶ is - - CH₃, or a pharmaceutically acceptable salt or solvate thereof.

In still another embodiment are provided compounds of formula (I), wherein R⁷ is hydrogen or C₁-C₈ alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds wherein R⁷ is hydrogen or - - CH₃, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R⁷ is hydrogen, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R⁷ is C₁-C₈ alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R⁷ is - - CH₃, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein each R⁸ and R⁹, which may be the same or different, is independently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl, wherein each of said C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl groups may be optionally substituted by at least one R¹⁰ group, or a pharmaceutically acceptable salt or solvate thereof. In still another embodiment are provided compounds of formula (I), wherein R and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group, or a pharmaceutically acceptable salt or solvate thereof. In yet another embodiment are compounds of formula (I), wherein R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl group, which is optionally substituted with at least one R¹⁰ group, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are compounds of formula (I), wherein R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heteroaryl group, which is optionally substituted with at least one R¹⁰ group, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein:

R¹ is C₁-Cs alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C 14 aryl wherein said C₆-C14 aryl is optionally substituted with at least one substituent independently selected from halo, - -CCR¹2aR¹2bR¹2c), - -OH, and C_1-C₈ alkoxy;

R⁴ is hydrogen;

R⁶ is hydrogen or C₁-C₈ alkyl;

R⁷ is hydrogen or C₁-C₈ alkyl;

R⁸ and R⁹, which may be the same or different, is independently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl, wherein each of said C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl groups may be optionally substituted by at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein:

R¹ is C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C₁₄ aryl, wherein said C₆-C14 aryl is optionally substituted with at least one halo;

R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, - -NR⁸S(O)₂R⁹, - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -

S(O)₂NR⁸R⁹;

R⁴ is

R⁶ is hydrogen or C₁-C

R⁷ is hydrogen or C₁-C

In another embodiment are provided compounds of formula (I), wherein:

R¹ is - - (CH₂)(C₆-C₁₄ aryl), wherein said C₆-C14 aryl is optionally substituted with at least one halo;

R⁴ is hydrogen;

R⁶ is hydrogen or C₁-C₈ alkyl n;

R⁷ is hydrogen or C₁-C₈ alkyl;

In another embodiment are provided compounds of formula (I), wherein:

R¹ is — (CH₂)(C₆-C₁₄ aryl), wherein said C₆-C₁₄ aryl is optionally substituted with at least one fluorine;

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R⁸ and R⁹, which may be the same or different, is independently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₈ heterocyclyl, and C₂-C₉ heteroaryl. wherein each of said C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl groups may be optionally substituted by at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C₁₄ aryl wherein said C₆-C14 aryl is optionally substituted with at least one substituent independently selected from halo, - -CCR¹2aR¹2bR¹2c), - -OH, and C_1-C₈ alkoxy R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl R⁷ is hydrogen or C₁-C₈ alkyl; and

R⁸ and R⁹, which may be the same or different, is independently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl. wherein each of said C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₂ aryl, C₂-C₉ heterocyclyl, and C₂-C₉ heteroaryl groups may be optionally substituted by at least one R¹⁰ group; wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C₁₄ aryl wherein said C₆-C14 aryl is optionally substituted with at least one substituent independently selected from halo, - -CCR¹2aR¹2bR¹2c), - -OH, and C_1-C₈ alkoxy R³ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -S(O)₂NR⁸R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

In another embodiment are provided compounds of formula (I), wherein: R¹ is C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C₁₄ aryl wherein said C₆-C14 aryl is optionally substituted with at least one substituent independently selected from halo, - -CCR¹2aR¹2bR¹2c), - -OH, and C_1-C₈ alkoxy;

R⁴ is hydrogen;

R⁶ is hydrogen or C₁-C₈ alkyl;

R⁷ is hydrogen or C₁-C₈ alkyl;

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein:

R¹ is C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C 14 aryl wherein said C₆-C14 aryl is optionally substituted with at least one substituent independently selected from halo, - -CCR¹2aR¹2bR¹2c), - -OH, and C_1-C₈ alkoxy R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl or a C₂-C₈ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group; and wherein R¹ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is C₁-Cs alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C14 aryl, wherein said C₆-C₁₄ aryl is optionally substituted with at least one halo R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is - - (CH₂)(C₆-C₁₄ aryl), wherein said C₆-C14 aryl is optionally substituted with at least one halo

R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is - - (CH₂)(C₆-C₁₄ aryl), wherein said C₆-C14 aryl is optionally substituted with at least one fluorine

R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl group, which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is 4-fluorobenzyl;

R³ is - -NR⁸C(O)R⁹, - -NR⁸S(O)R⁹, or - -NR⁸S(O)₂R⁹;

R⁴ is hydrogen; R⁶ is hydrogen or C₁-C₈ alkyl;

R⁷ is hydrogen or C₁-C₈ alkyl;

R° and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C. heteroaryl group, which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C 14 aryl wherein said C₆-C₁₄ aryl is optionally substituted with at least one substituent independently selected from halo, - -CCR¹2aR¹2bR¹2c), - -OH, and C_1-C₈ alkoxy R³ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -S(O)₂NR⁸R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is C₁-C₈ alkyl, wherein said C₁-C₈ alkyl is substituted with C₆-C14 aryl, wherein said C₆-C14 aryl is optionally substituted with at least one halo R³ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -S(O)₂NR⁸R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R³ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -S(O)₂NR⁸R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl hydrogen or C₁-C₈ alkyl;

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C. heterocyclyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹ is - - (CH₂)(C₆-C₁₄ aryl), wherein said C₆-C14 aryl is optionally substituted with at least one fluorine

R³ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -S(O)₂NR⁸R⁹

R⁴ is hydrogen or C₁-C₈ alkyl

R⁶ is hydrogen

R⁷ is hydrogen or C₁-C₈ alkyl

In another embodiment are provided compounds of formula (I), wherein R¹ is 4-fluorobenzyl

R³ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -S(O)₂NR⁸R⁹

R⁴ is hydrogen

R⁶ is hydrogen or C₁-C₈ alkyl

R⁷ is hydrogen or C₁-C₈ alkyl

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl or a C₂-C₉ heteroaryl group, each of which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof. In another embodiment are provided compounds of formula (I), wherein: R¹⁰ is 4-fluorobenzyl;

R¹⁰ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -S(O)₂NR⁸R⁹;

R⁴ is hydrogen;

R⁶ is hydrogen or C₁-C₈ alkyl;

R⁷ is hydrogen or C₁-C₈ alkyl;

R⁸ and R⁹ together with the nitrogen atom to which they are attached, form a C₂-C₉ heterocyclyl group, which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds of formula (I), wherein:

R¹ is 4-fluorobenzyl;

R³ is - -C(O)NR⁸R⁹, - -S(O)NR⁸R⁹, or - -S(O)₂NR⁸R⁹;

R⁴ is hydrogen;

R⁶ is hydrogen or C₁-C₈ alkyl;

R⁷ is hydrogen or C₁-C₈ alkyl;

R⁸ and R⁹, together with the nitrogen atom to which they are attached, form a C₂-C₉ heteroaryl group, which is optionally substituted with at least one R¹⁰ group; and wherein R¹⁰ is as defined above; or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment are provided compounds selected from 3-(acetylamino)-1-(4- fluorobenzyl)-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5- - carboxamide; 3-(acetylamino)-1-(4- fluorobenzyl)-N-hydroxy-N-methyl-1H-pyrrolo[2,3-c]py- ridine-5-carboxamide; 1- (4fluorobenzyl)-N-hydroxy_3-[(phenylsulfonyl)amino]-1H-pyrrolo[2,3-c]py- ridine-5- carboxamide; l-(4-fluorobenzyl)-N-hydroxy-N-methyl.₃-[(phenylsulfonyl)amino]-1H-pyrrol- o[2,3-c]pyridine-5-carboxamide; l-(4-fluorobenzyl)-N-hydroxy_₃-[(memylsulfonyl)amino]- 1H-pyrrolo[2,3-c]p- yridine-5-carboxamide; 1 -(4-fluorobenzyl)-N-hydroxy-N-methyl.₃- [(methylsulfonyl)amino]-1H-pyrrol- o[2,3-c]pyridine-5-carboxamide; l-(4-fluorobenzyl)-N- 5- - methoxy-N-3- - (2-morpholin- .4-ylethyl)-1H-pyrrolo[2,3-c]pyridine_3,5-dicarboxamide; N- 3- - [(l-ethylpyrrolidin-2-yl)methyl]-1-(4-fluorobenzyl)-N.ab- out.5- - methoxy- 1H-pyrrolo[2, 3- c]pyridine_3,5-dicarboxamide; l-(4-fluorobenzyl)-N-5- - methoxy-N-3- - [3-(2-oxopyr- rolidin- l-yl)propyl]-1H-pyrrolo[2,3-c]pyridine_3,5-dicarboxamide; l-(4-fluorobenzyl).₃-{ [(2S)-2- (hydroxymethyl)pyrrolidin- 1 -yl]carbonyl } -N- - methoxy- 1H-pyrrolo[2,3-c]pyridine-5- carboxamide; N-3- - [(1,5-dimethyl-1H-pyrazol.₄-yl)methyl]-l -(4-fluorobenzyl- )-N-5- - methoxy- 1H-pyrrolo[2,3-c]pyridine_3,5 -dicarboxamide; 3-{ [3-(dimethylamino)pyrrolidin-1- yl]carbonyl}-1-(4-fluorobenzyl)-N-metho- xy-1H-pyrrolo[2,3-c]pyridine-5-carboxamide; 1- (4-fluorobenzyl)_3- { [3-(hydroxymethyl)piperidin- 1 -yl] carbonyl } -N-methox- y- 1 H- pyrrolo[2,3-c]pyridine-5-carboxamide; l-(4-fluorobenzyl)-N-5- - hydroxy- N-5- - methyl-N.abo- ut.3- - (tetrahydro-1H-pyrrolizin-7a(5H)-ylmethyl)-1H-pyrrolo[2,3-c]py- ridine.₃,5- dicarboxamide; N-3- - [l-cyclopropyl.3-(cyclopropylamino)_3-oxopropyl]-1-(4-fl- uorobenzyl)- N-5- - methoxy- 1H-pyrrolo[2,3-c]pyridine_3,5-dicarbo- xamide; l-(4-fluorobenzyl)-N-5- - hydroxy-N-5- - methy- l-N-3- - [3-(2-oxopyrrolidin-1-yl)propyl]-1H-pyrrolo[2,3-c]pyrid- ine. 3,5 -dicarboxamide; N-3- - [(1,5-dimethyl-1H-pyrazol.₄-yl)methyl]-l -(4-fluorobenzyl- )-N-5- - hydroxy-N-5- - methyl- 1H-pyrrolo[2,3-c]pyridi- ne.₃,5-dicarbo xamide; N-3- - [l-cyclopropyl_₃- (cyclopropylamino)_3-oxopropyl]-1-(4-fl- uorobenzyl)-N-5- - hydroxy-N-5- - methyl- 1H- pyrrolo[2,- 3-c]pyridine.₃,5-dicarboxamide; 3-[(benzylsulfonyl)amino]-1-(4-fluorobenzyl)-N- hydroxy-1H-pyrrolo[2,3-c]p- yridine-5-carboxamide; l-(4-fluorobenzyl)-N-hydroxy_₃- [(1,2,3,4-tetrahydroisoquinolin-7-ylsulfon- yl)amino]-1H-pyrrolo[2,3-c]pyridine-5- carboxamide; 3- { [(5-chloro-2-thienyl)sulfonyl] amino } -1 -(4-fluorobenzyl)-N-hydroxy- 1H-p- yrrolo[2,3-c]pyridine-5-carboxamide; l-(4-fluorobenzyl)-N-hydroxy.₃-{ [(2S)-2-

(hydroxymethyl)pyrrolidin- 1 -yl] ca- rbonyl } -N-methyl- 1 H-pyrrolo [2,3-c]pyridine-5- carboxamide; 1 -(4-fluorobenzyl)-N-hydroxy_₃- { [(2S)-2-(hydroxymethyl)pyrrolidin- 1 -yl]ca- rbonyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxamide; N-3- - [l-cyclopropyl_₃-

(cyclopropylamino).₃-oxopropyl]-1-(4-fl- uorobenzyl)-N-5- - hydroxy- 1H-pyrrolo[2, 3- c]pyridine.₃,5-dicarbo- xamide; l-(4-fluorobenzyl)-N-5- - hydroxy-N-3- - (tetr- ahydro-1H- pyrrolizin-7a(5H)-ylmethyl)-1H-pyrrolo[2,3-c]pyridine.₃,5-dicarb- oxamide; 3-{ [3- (dimethylamino)pyrrolidin-1-yl]carbonyl}-1-(4-fluorobenzyl)- -N-hydroxy-1H-pyrrolo[2,3- c]pyridine-5-carboxamide; l-(4-fluorobenzyl)-N-5- - hydroxy-N-3- - (2-morpholin- ^-ylethyl)- 1 H-pyrrolo [2,3 -c]pyridine.₃,5-dicarboxamide; N-3- - [( 1 ,5-dimethyl- 1 H-pyrazol.₄-yl)methyl] - l-(4-fluorobenzyl- )-N-5- - hydroxy- 1H-pyrrolo[2,3-c]pyridine.₃,5-dicarboxamide; l-(4- fluorobenzyl)-N-5- - hydroxy-N-3- - [3-(2-oxopyr- rolidin-1-yl)propyl]-1H-pyrrolo[2,3- c]pyridine.₃,5-dicarboxamide; 1 -(4-fluorobenzyl)-N-hydroxy_₃- { [3-(hydroxymethyl)piperidin- l-yl]carbonyl- }-1H-pyrrolo[2,3-c]pyridine-5-carboxamide; N-3- - [(l-ethylpyrrolidin-2- yl)methyl]-1-(4-fluorobenzyl)-N.ab- out.5- - hydroxy- 1H-pyrrolo[2,3-c]pyridine.₃,5- dicarboxamide; l-(4-fluorobenzyl)-N-5- - hydroxy-N-5- - methyl-N.abo- ut.3- - (2-morpholin^- ylethyl)-1H-pyrrolo[2,3-c]pyridine.₃,5-dicarbox- amide; l-(4-fluorobenzyl)-N-hydroxy.₃-{ [3- (hydroxymethyl)piperidin-1-yl]ca- rbonyl} -N-methyl- 1H-pyrrolo[2,3-c]pyridine-5- carboxamide ; 3 - [(dimethylamino) sulf onyl] - 1 -(4 -fluorobenzyl) -N-hydroxy- 1 H-pyrrolo [2, 3 -c- ]pyridine-5-carboxamide; 3- [(dimethylamino)sulfonyl] - 1 -(4-fluorobenzyl)-N-hydroxy-N- methyl-1H-pyrr- olo[2,3-c]pyridine-5-carboxamide; 3-{ [(2S)-2-(aminocarbonyl)pyrrolidin-1- yl]sulfonyl}-1-(2,4-difluorobenzyl- )-N-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carbo xamide; 1 -(2,4-difluorobenzyl)-N-hydroxy_₃- { [(2-morpholin^-ylethyl)amino] sulfony- 1 } - 1 H- pyrrolo[2,3-c]pyridine-5-carboxamide; l-(2,4-difluorobenzyl)-N-hydroxy.₃-[(3-oxopiperazin- l-yl)sulfonyl]-1H-pyr- rolo[2,3-c]pyridine-5-carboxamide; l-(2,4-difluorobenzyl)-N- methoxy.₃-[(3-oxopiperazin-1-yl)sulfonyl]-1H-pyr- rolo[2,3-c]pyridine-5-carboxamide; 1- (2,4-difluorobenzyl)-N-methoxy.₃-{ [(2-morpholin^-ylethyl)amino]sulfony- 1}-1H- pyrrolo[2,3-c]pyridine-5-carboxamide; l-(2,4-difluorobenzyl)-N-hydroxy-N-methyl.₃-[(3- oxopiperazin-1-yl) sulfony- l]-1H-pyrrolo[2,3-c]pyridine-5-carboxamide; 3-{ [(2S)-2- (aminocarbonyl)pyrrolidin- 1 -yl] sulfonyl } - 1 -(2,4-difluorobenzyl- )-N-hydroxy-N-methyl- 1 H- pyrrolo[2,3-c]pyridine-5-carboxamide; l-(4-fluorobenzyl)-N5-hydroxy-N5-methyl-N3-[(2S)- tetrahydrofuran-2-ylmeth- yl]-1H-pyrrolo[2,3-c]pyridine.₃,5-dicarboxamide; l-(4- fluorobenzyl)-N5 -hydroxy-N3 -isopropyl-N5 -methyl- 1 H-pyrrolo [2 ,3 -c]pyr- idine_₃ ,5 - dicarboxamide; N3-(2,2-difluoroethyl)-1-(4-fluorobenzyl)-N5-hydroxy-N5-methyl-1H- pyrrolo- [2,3-c]pyridine.₃,5-dicarboxamide; l-(4-fluorobenzyl)_₃-{ [(2R)-2-

(hydroxymethyl)pyrrolidin- 1 -yl]carbonyl } -N- - methoxy- 1H-pyrrolo[2,3-c]pyridine-5- carboxamide; l-(4-fluorobenzyl)-N3-isopropyl-N5-methoxy-1H-pyrrolo[2,3-c]pyridine.₃,5- dicarboxamide; N3-(2,2-difluoroethyl)-1-(4-fluorobenzyl)-N5-methoxy-1H-pyrrolo[2,3- c]pyr- idine.₃,5-dicarboxamide; 3-[(diethylamino)sulfonyl] - 1 -(4-fluorobenzyl)-N-methoxy- 1 H-pyrrolo [2,3 -c]- pyridine-5-carboxamide; l-(4-fluorobenzyl)-N-hydroxy.₃-{ [(3- hydroxypropyl)amino] sulfonyl } -N-methy- 1- 1 H-pyrrolo [2,3 -c]pyridine-5-carboxamide; 1 -(4- fluorobenzyl)_₃ - { [(3 -hydro xypropyl) amino] sulfonyl } -N-methoxy- 1 H-pyrr- olo [2,3 - c]pyridine-5-carboxamide; l-(4-fluorobenzyl)-N-methoxy.₃-{ [(2-methoxypyridin.₃- yl) amino] sulfonyl } - 1 - H-pyrrolo[2,3-c]pyridine-5-carboxamide; 1 -(4-fluorobenzyl)-N- hydroxy_₃- { [(2-methoxypyridin.₃-yl)amino]sulfonyl } -N- -methyl- 1 H-pyrrolo[2,3-c]pyridine- 5-carboxamide; 3- { [(1 ,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl } - 1 -(4-fluorobenzyl)-N- m- ethoxy-1H-pyrrolo[2,3-c]pyridine-5carboxamide; l-(4-fluorobenzyl)-N-methoxy_₃- (morpholin.₄-ylsulfonyl)-1H-pyrrolo[2,3-c]- pyridine -5-carboxamide; 3-{ [(1,4-dioxan-2- ylmethyl) (methyl) amino] sulfonyl } - 1 - (4-fluorobenzyl) -N-h- ydroxy-N-methyl- 1 H- pyrrolo[2,3-c]pyridine-5-carboxamide; and l-(4-fluorobenzyl)-N-hydroxy-N-methyl_₃- (morpholin.₄-ylsulfonyl)-1H-pyrro- lo[2,3-c]pyridine-5-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.

General Procedures (Scheme 1)

The compounds of the present invention can be prepared directly from compound 1-1 (preferably a methyl or ethyl ester) and a substituted or unsubstituted hydroxylamine in the presence of a base, such as, for example, sodium hydroxide or sodium alkoxide in methanol or ethanol (Hauser, C. R., et al., Org. Synth. Coll. Vol. 2, p. 67, John Wiley, New York (1943)). Alternatively, the compound 1-1 can be saponified to the free acid 1-2 using lithium hydroxide or sodium hydroxide in methanol/water mixtures and heating the mixture to 100° C. in a SmithCreator.RTM. microwave for 1 to 5 min. Compound 1-2 can be coupled with a substituted or unsubstituted hydroxylamine using a coupling reagent. Typical coupling reagents and conditions can be used, such as, for example, 0-(azabenzotriazole-1-yl)-l, 1,3,3- tetramethyl uronium hexafluorophosphate (HATU), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide (EDC) in DMF at ambient temperature, or many others that are familiar to those skilled in the art. Other suitable methods are described, for example, in M. B. Smith, J. March, Advanced Organic Chemistry, 5th edition, John Whiley & Sons, p. 508-511 (2001). The use of the preferred conditions described in this scheme would allow for parallel preparation or combinatorial libraries of such hydroxamates 1_₃.

The preparation of intermediates and starting materials is described in detail in U.S. Patent Application Publication No. 20090170846

Further integrase inhibitors that can be used in the methods described herein are disclosed in U.S. Publication No. 20080015187. The compounds are (i) 3 -hydroxy^ -oxo_ 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides and 2-carboxylates and tetrahydropyrazolodiazepine analogs thereof and (ii) oxazine and oxazepine analogs of (i), of Formula I and pharmaceutically acceptable salts thereof:

Wherein: Z is O or N(R⁸); R¹ and R² are each independently (1) H, (2) C_1-6 alkyl, (3) C_1-6 haloalkyl, (4) C_1-6 alkyl substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^C)R^D, - -C(O)N(R^c)R^D, - -C(O)R^A, - -C0₂R^A, - -SR^A, - -S(O)R^A, - - S0₂R^A, - -S0₂N(R^c)R^D, - -N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - -N(R^A)S0₂N(R^c)R^D, - -OC(O)N(R^c)R^D, - -N(R^A)C(O)N(R^c)R^D, or - -N(R^A)C(O)C(O)N(R^c)R^D, (5) CycA, (6) AryA, (7) HetA, or (8) C_1-6 alkyl substituted with CycA, AryA, or HetA; R³, R⁴, R⁵ and R⁶ are defined as follows: (A) R³, R⁴, R⁵ and R⁶ are each independently: (1) H, (2)

C₁ _-6 alkyl, (3) C_1-6 haloalkyl, (4) d.₆ alkyl substituted with - -OH, - -0- -C_1-6 alkyl, - -O- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^C)R^D, - -C(O)N(R^c)R^D, - -C(O)R^A, - -C0₂R^A, - -SR^A, - - S(O)R^A, - -S0₂R^A, - -S0₂N(R^c)R^D, - -N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^c)R^D, - -OC(O)N(R^c)R^D, - -N(R^A)C(O)N(R^c)R^D, or - -N(R^A)C(O)C(O)N(R^c)R^D,

(5) C(O)N(R^c)R^D, (6) CycA, (7) AryA, (8) HetA, or (9) C_1-6 alkyl substituted with CycA, AryA, or HetA; or (B) R⁴ and R⁵ are each independently defined as in Part (A) above; and R³ and R⁶ together form a direct bond resulting in a carbon- carbon double bond; or (C) R⁴ and R⁵ together with the carbon atoms to which they are attached form a 5- to 7-membered saturated or unsaturated ring optionally containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the ring is optionally substituted with from 1 to 6 substituents each of which is independently halogen, — C_1-6 alkyl, - -OH, - -O- -C_1-6 alkyl, oxo, - -CN, - -N0₂, or - - N(R^A)R^B; and R³ and R⁶ are either both absent or are each independently defined as in Part (A) above; R⁷ is: (1) OH, (2) 0- -C_1-6 alkyl, (3) O-CycA, (4) 0- -C_1-i₆ alkylene-CycA, (5) 0- -C_1-6 alkylene-AryA, (6) O- -d.6 alkylene-HetA, or (7) N(R^U)R^V; R⁸ is: (1) H, (2) C_1-6 alkyl, (3) C_1-6 haloalkyl, (4) C_1-6 alkyl substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -

CN, - -N0₂, - - N(R^C)R^D, - -C(O)N(R^c)R^D, - -C(O)R^A, - -C0₂R^A, - -SR^A, - -S(O)R^A, - -S0₂R^A, - - S0₂N(R^c)R^D, - -N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - -N(R^A)S0₂N(R^c)R^D, - - OC(O)N(R^c)R^D, - -N(R^A)C(O)N(R^c)R^D, or - -N(R^A)C(O)C(O)N(R^c)R^D, (5) CycA, or (6) C_1-6 alkyl substituted with CycA, AryA, or HetA; n is an integer equal to zero or 1; each R^A is independently - - H or— C_1-6 alkyl; each R^B is independently - - H or— C_1-6 alkyl; R^c and R^D are each independently - - H or— C_1-6 alkyl; or R^c and R^D together with the N atom to which they are both attached form a 3- to 8-membered saturated ring containing (i) the N atom to which they are both attached, (ii) at least two carbon atoms, and (iii) optionally 1 or 2 additional heteroatoms independently selected from N, O and S; wherein the ring is optionally substituted with from 1 to 6 substituents each of which is independently halogen, — C_1-6 alkyl, - -OH, - -O- -C_1-6 alkyl, oxo, - -CN, - -N0₂, or - - N(R^A)R^B; R^u and R^v are each independently:

(i) H, (ii) C_1-6 alkyl, (iii) C_1-6 haloalkyl, (iv) C_1-6 alkyl substituted with - - OH, - -O- -C₁.16 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^C)R^D, - -C(O)N(R^c)R^D, - -C(O)R^A, - -C0₂R^A, - -SR^A, - -S(O)R^A, - -S0₂R^A, - -S0₂N(R^c)R^D, - -N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - - N(R^A)S0₂R^B, - -N(R^A)S0₂N(R^c)R^D, - -OC(O)N(R^c)R^D, - -N(R^A)C(O)N(R^c)R^D, or - - N(R^A)C(O)C(O)N(R^c)R^D, (v) CycA, (vi) HetC, or (vii) C_1-6 alkyl substituted with CycA, AryA, HetA, or HetC, with the proviso that the atom in HetC attached to the alkyl group is not a N atom; or R^u and R^v together with the N atom to which they are both attached form a 3- to 8-membered saturated ring containing (i) the N atom to which they are both attached, (ii) at least two carbon atoms, and (iii) optionally containing 1 or 2 additional heteroatoms independently selected from N, O and S; wherein the saturated ring is optionally fused with a benzene ring and the optionally fused, saturated ring is: (i) optionally substituted with from 1 to 6 substituents each of which is independently halogen, — C_1-6 alkyl, - -OH, - -0- -C_1-6 alkyl, oxo, - -CN, - -N0₂, or - - N(R^A)R^B, and (ii) optionally substituted with 1 or 2 substituents each of which is independently CycA, AryA, HetA, HetC, or C_1-6 alkyl substituted with CycA, AryA, HetA or HetC; each CycA is independently a C₃-8 cycloalkyl which is: (i) optionally substituted with from 1 to 6 substituents each of which is independently halogen, — C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, or— C_1-6 haloalkyl, and (ii) optionally substituted with 1 or 2 substituents each of which is independently: (1) AryB, (2) HetB, (3) CycB, or (4) C_1-6 alkyl substituted with CycB, AryB, or HetB; each AryA is independently an aryl which is: (i) optionally substituted with from

1 to 5 substituents each of which is independently: (1) — C_1-6 alkyl, which is optionally substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - - C(O)N(R^A)R^B, - -C(O)R^A, - -C0₂R^A, - -SR^A, - -S(O)R^A, - -S0₂R^A, - -S0₂N(R^A)R^B, - - N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(O)N(R^A)R^B, - - N(R^A)C(O)N(R^A)R^B, or - -N(R^A)C(O)C(O)N(R^A)R^B, (2) - -0- --C_1-6 alkyl, (3) - -C_1-6 haloalkyl, (4) - -0- -C_1-6 haloalkyl, (5) - -OH, (6) halogen, (7) - -CN, (8) - -N0₂, (9) - -N(R^A)R^B, (10) - -C(O)N(R^A)R^B, (11) - -C(O)R^A, (12) - -C0₂R^A, (13) - -SR^A,

(14) - -S(=O)R^A, (15) - -S0₂R^A, (16) - -S0₂N(R^A)R^B, (17) - -N(R^A)S0₂R^B,

(18) - -N(R^A)S0₂N(R^A)R^B, (19) - -N(R^A)C(O)R^B, (20) - -N(R^A)C(O)- - C(O)N(R^A)R^B, or (21) - -N(R^A)C0₂R^B, and (ii) optionally substituted with 1 or

2 substituents each of which is independently: (1) AryB, (2) HetB, (3) CycB,

(4) - -C_1-6 alkyl substituted with CycB, AryB or HetB, (5) - -C(O)N(R^A)-CycB or (6) - - C(O)0-CycB; each HetA is independently a heteroaryl which is:

(i) optionally substituted with from 1 to 5 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, oxo, or - -OH; and (ii) optionally substituted with 1 or 2 substituents each of which is independently AryB, HetB, CycB, or— C_1-6 alkyl substituted with AryB, HetB or CycB; each AryB is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (21) as defined above in part (i) of the definition of AryA; each HetB is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C_1-6 alkyl, - - C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, or hydroxy; each CycB is independently a C₃-8 cycloalkyl which is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - -C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, or — C_1-6 haloalkyl; HetC is a 4- to 7-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with from 1 to 6 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C₁-16 alkyl, - - O- - C_1-6 haloalkyl, or oxo; each aryl is independently (i) phenyl or (ii) a 9- or 10- membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic; and each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O)₂.

The compounds can be prepared using the following reaction schemes:

5 4 a. dibromoethane, Cs₂C0₃; b. NaN₃; c. Ph₃P, H₂0; d. ^s— X, NaH; e. R⁸NH₂, heat; e.な, Pd C;

f. R^U(R^V)NH, heat; g. NaOH; h. EDC, HOBT, R^U(R^V)NH; i. HBr, HOAc

Still further iniegrase inhibitors include those disclosed in U.S. Publication 00. 20080139579, which compounds are hydroxy polyhydronaphthyridine dione compounds and hydroxy polyhydropyranopyrdine dione compounds of Formula I, and pharmaceutically acceptable salts thereof:

wherein:

Z is O or N- -R⁹; R¹ is— C_1-6 alkyl substituted with R^J, wherein R^J is: (A) aryl or aryl fused to a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the aryl or fused aryl is (i) optionally substituted with from 1 to 5 substituents each of which is independently: (1) — C_1-6 alkyl, which is optionally substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, - -S0₂N(R^A)R^B, - -N(R^A)C(=O)R^B, - - N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(=O)N(R^A)R^B, or - - N(R^A)C(=O)N(R^A)R^B, (2) - -O- -C_1-6 alkyl, (3) - -C_1-6 haloalkyl, (4) - -0- -C_1-6 haloalkyl, (5) - -OH, (6) halo, (7) - -CN, (8) - -N0₂, (9)

N(R^A)R^B, (10) - -C(=O)N(R^A)R^B, (11) - -C(=O)R^A, (12) - -C0₂R^A, (13) - -SR^A,

(18) - -N(R^A)S0₂N(R^A)R^B, (19) - -N(R^A)C(=O)R^B, (20) - -N(R^A)C(=O)- - C(=O)N(R^A)R^B, or (21) - -N(R^A)C0₂R^B, and (ii) optionally substituted with 1 or

2 substituents each of which is independently: (1) aryl, (2) — C_1-6 alkyl substituted with aryl, (3) - -HetA, (4) - -C(=O)- -HetA; or (5) -HetB; wherein each HetA is independently a C₄-7 azacycloalkyl or a C₃-6 diazacycloalkyl, either of which is optionally substituted with from 1 to 3 substituents each of which is independently oxo or C_1-6 alkyl; and wherein each HetB is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halo, — C_1-6 alkyl, - -C_1-6 haloalkyl, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, or hydroxy; or (B) a 5- or 6- membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heteroaromatic ring is: (i) optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, or hydroxy, and (ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or - -C_1-6 alkyl substituted with aryl;R², R³, R⁴ and R⁵ are defined as follows: (A) R², R³, R⁴ and R⁵ are each independently: (1) - - H,

(2) — C_1-6 alkyl, which is optionally substituted with - -OH, - -O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, - -CN, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, - - S0₂N(R^A)R^B, - -N(R^A)C(=O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - - N(R^A)C(=O)N(R^A)R^B, or - -OC(=O)N(R^A)R^B, (3) - -C_1-6 haloalkyl, (4) CycA, (5) AryA, (6) HetC, or (7) - -C_1-6 alkyl substituted with CycA, AryA, or HetC; (B) R² and R⁴ together with the carbon atoms to which each is attached form a carbon-carbon double bond; and R³ and R⁵ are each independently as defined in part A above; (C) R² and R³ together with the carbon atom to which they are both attached form a 3- to 8-membered saturated carbocyclic ring which is optionally substituted with from 1 to 4 substituents each of which is independently - -OH, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, or - - O- - C_1-6 haloalkyl; and R⁴ and R⁵ are each independently as defined in part A above; or (D) R⁴ and R⁵ together with the carbon atom to which they are both attached form a 3- to 8-membered saturated carbocyclic ring which is optionally substituted with from 1 to 4 substituents each of which is independently - -OH, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, or - - O- - C_1-6 haloalkyl; and R² and R³ are each independently as defined in part A above; R⁶ is:

(1)— H, (2) — C_1-6 alkyl, which is optionally substituted with - -OH, - -

O- -C_1-6 alkyl, - -0- -C_1-i₆ haloalkyl, - -CN, - -N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, - -S0₂N(R^A)R^B, - -N(R^A)C(=O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -N(R^A)C(=O)N(R^A)R^B, or - -OC(=O)N(R^A)R^B, (3) - -C_1-6 haloalkyl,

(4) CycA, (5) AryA, (6) HetC, or (7) - -C_1-6 alkyl substituted with CycA, AryA, or HetC;R⁷ and R⁸ are each independently: (1) - -H, (2) - -C_1-6 alkyl, which is optionally substituted with - -OH, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, - - CN, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, - -S0₂N(R^A)R^B, - - N(R^A)C(=O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, N(R^A)C(=O)N(R^A)R^B, or - -OC(=O)N(R^A)R^B, (3) - -C_1-6 haloalkyl, (4) - -C(=O)R^A, (5) - -C0₂R^A, (6) - -C(=O)N(R^A)R^B, (7) - - N(R^A)S0₂N(R^A)R^B, (8) - -R^K, (9) - -C(=O)- -R^K, (10) - -C(=O)N(R^A)- -R^K, (11) - -C(=O)N(R^A)- -C_1-6 alkylene-R^K, or

(12) - -C_1-6 alkyl substituted with R^K, - -C(=O)- -R^K, - -C(=O)N(R^A)- -R^K, or - - C(=O)N(R^A)- - C_1-6 alkylene-R^K;or alternatively R⁷ and R⁸ together with the carbon atom to which they are both attached form a 3- to 8-membered saturated carbocyclic ring which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, - - OH, - -d.6 alkyl, - -C_1-6 haloalkyl, - -0- -C_1-6 alkyl, or - -0- -C_1-6 haloalkyl; R⁹ is:

(1)— H, (2) — C_1-6 alkyl, which is optionally substituted with - -OH, - - O- - C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - - S(O)_nR^A, - -S0₂N(R^A)R^B, - -N(R^A)C(=O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -N(R^A)C(=O)N(R^A)R^B, or - -OC(=O)N(R^A)R^B, (3) - -C_1-6 haloalkyl,

(4) CycA, (5) AryA, (6) HetC, or (7) - -C_1-6 alkyl substituted with CycA, AryA, or HetC; each n is independently an integer equal to zero, 1, or 2; each R^A is independently H or C_1-6 alkyl; each R^B is independently H or C_1-6 alkyl; each R^K is independently CycA, AryA, or HetC; each CycA is independently a C₃-8 cycloalkyl, which is optionally substituted with from 1 to 4 substituents each of which is halogen, - -OH, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, or - - O- - C_1-6 haloalkyl; each AryA is independently an aryl, which is (a) optionally substituted with from 1 to 5 substituents each of which is independently — C_1-6 alkyl, — C_1-6 alkylene-OH, — C_1-6 alkylene-O- - C_1-6 alkyl, — C_1-6 alkylene- 0- -C_1-6 haloalkyl, - -C_1-6 alkylene-N(R^A)R^B, - -C_1-6 alkylene-C(=O)N(R^A)R^B, - -C_1-6 alkylene- C(=O)R^A, - -C_1-6 alkylene-C0₂R^A, - -C_1-6 alkylene-S(O)_nR^A, - -0- -C_1-6 alkyl, - -C_1-6 haloalkyl, - - O- -C_1-6 haloalkyl, - -OH, halo, - -N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, or - -S0₂N(R^A)R^B, and (b) optionally substituted with C₃-8 cycloalkyl, aryl, HetD, or - -C_1-6 alkyl substituted with C3-8 cycloalkyl, aryl, or HetD; each HetC is independently a 4- to 7- membered saturated or unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is (a) optionally substituted with from 1 to 4 substituents each of which is halogen, - - C_1-6 alkyl, - -C_1-6 haloalkyl, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, OH, or oxo, and (b) optionally substituted with C3-8 cycloalkyl, aryl, HetD, or — C_1-6 alkyl substituted with C3-8 cycloalkyl, aryl, or HetD; each HetD is independently a 4- to 7 -membered saturated or unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S; and each aryl is independently (i) phenyl or (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic.

The compounds can be prepared, for example, using the following general procedures.

The synthesis of precursors, and the detail regarding the reaction schemes shown above, is provided in U.S. Publication No. 2008/0139579.

Still further integrase inhibitors include those disclosed in U.S. Publication No. 20080287394. The compounds are of Formula I below, and pharmaceutically acceptable salts thereof:

wherein: R¹ is: (1) - -C_1-6 alkyl, (2) - -C_1-6 alkyl substituted with - -0H, - -0- -C_1-6 alkyl, - -O- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(O)N(R^A)R^B, - -C(O)R^A, - -C0₂R^A, - -SR^A, - - S(O)R^A, - -S0₂R^A, - -S0₂N(R^A)R^B, - -N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(O)N(R^A)R^B, - -N(R^A)C(O)N(R^A)R^B, or - -N(R^A)C(O)C(O)N(R^A)R^B, (3) - - C₃-8 cycloalkyl, which is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - - CN, — C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, — C _1-6 haloalkyl, or - - O- - C_1-6 haloalkyl, (4) — C_1-6 alkyl substituted with C₃-8 cycloalkyl, wherein the C₃-8 cycloalkyl is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - - CN, — C _1-6 alkyl, - -OH, - - O- - C _1-6 alkyl, — C_1-6 haloalkyl, or - -O- - C _1-6 haloalkyl, (5) heteroaryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of substituents (1) to (26) as defined below in part (i) of Part B of the definition of R^J, (6) — C _1-6 alkyl substituted with R^J, wherein R^J is: (A) aryl which is: (i) optionally substituted with from 1 to 5 substituents each of which is independently: (1) — C_1-6 alkyl, which is optionally substituted with - -OH, - - O- -C₁.6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(O)N(R^A)R^B, - -C(O)R^A, - - C0₂R^A, - -SR^A, - -S(O)R^A, - -S0₂R^A, - -S0₂N(R^A)R^B, - -N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - - N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(O)N(R^A)R^B, - -N(R^A)C(O)N(R^A)R^B, or - - N(R^A)C(O)C(O)N(R^A)R^B, (2) -O -C_1-6 alkyl, (3) - --C_1-6 haloalkyl, (4) - -0- -d_

6 haloalkyl, (5) - -OH, (6) halogen, (7) - -CN, (8) - -N0₂, (9) N(R^A)R^B, (10) - -C(O)N(R^A)R^B, (11) - -C(O)R^A, (12) - -C0₂R^A, (13) - -SR^A, (14) - -S(O)R^A, (15) - -S0₂R^A, (16) - -S0₂N(R^A)R^B, (17) - -N(R^A)S0₂R^B, (18) N(R^A)S0₂N(R^A)R^B, (19) - -N(R^A)C(O)R^B, (20) - -N(R^A)C(O)- -C(O)N(R^A)R^B, or (21) - - N(R^A)C0₂R^B, and (ii) optionally substituted with 1 or 2 substituents each of which is independently: (1) - - C₃-8 cycloalkyl, (2) aryl, (3) — C _1-6 alkyl substituted with aryl, -C3-8 cycloalkyl, HetA, or HetB, (4) -HetA, (5) - -C(O)-HetA; or (6) -HetB; wherein: each cycloalkyl is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - - CN, — C_1-6 alkyl, - -OH, - - O- - C _1-6 alkyl, — C _1-6 haloalkyl, or - - O- - C _1-6 haloalkyl, each aryl is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (21) as defined above in part (i) of Part A of the definition of R^J, each HetA is independently (i) a - - C₄-7 azacycloalkyl or oxacycloalkyl or thiacycloalkyl or (ii) a - - C₃-6 diazacycloalkyl or oxazacyclo alkyl or thiazacycloalkyl, wherein the S in the thiacycloalkyl or thiazacycloalkyl is optionally oxidized to S(O) or S0₂, and wherein any of the rings defined in (i) or (ii) is optionally substituted with from 1 to 4 substituents each of which is independently oxo, - -C₁.6 alkyl, - -C(O)R^A, - -C0₂R^A, - -SR^A, - -S(O)R^A, or - -S(O)₂R^A; and each HetB is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently any one of the substituents (1) to (26) as defined below in part (i) of Part B of the definition of R^J, or (B) heteroaryl which is: (i) optionally substituted with from 1 to 6 substituents each of which is independently: (1) — C_1-6 alkyl, (2) — C_1-6 alkyl substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - - C(O)N(R^A)R^B, - -C(O)R^A, - -C0₂R^A, - - SR^A, - -S(O)R^A, - -S(O)₂R^A, - -S(O)₂N(R^A)R^B, - - N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S(O)₂R^B, - -N(R^A)S(O)₂N(R^A)R^B, - -OC(O)N(R^A)R^B, - - N(R^A)C(O)N(R^A)R^B, or - -N(R^A)C(O)C(O)N(R^A)R^B, (3) - -0- -C_1-6 alkyl, (4) - -C_1-6 haloalkyl, (5) - -0- -C_1-6 haloalkyl, (6) - -OH, (7) -oxo, (8) halogen, (9) - -CN, (10) - -NO₂, (11) - -N(R^A)R^B, (12) - -C(O)N(R^A)R^B, (13) - -C(O)R^A,

(14) - -C(O)- -C_1-6 haloalkyl, (15) - -C(O)OR^A, (16) - -OC(O)N(R^A)R^B, (17) - -SR^A,

(18) - -S(O)R^A, (19) - -S(O)₂R^A, (20) - -S(O)₂N(R^A)R^B, (21) - -N(R^A)S(O)₂R^B, (22) - -N(R^A)S(O)₂N(R^A)R^B, (23) - -N(R^A)C(O)R^B, (24) - -N(R^A)C(O)N(R^A)R^B, (25) - -N(R^A)C(O)- -C(O)N(R^A)R^B, or (26) - -N(R^A)C0₂R^B, and (ii) optionally substituted with 1 or 2 substituents each of which is independently: (1) - - C₃-8 cycloalkyl, (2) aryl, (3) — C_1-6 alkyl substituted with aryl, - - C₃-8 cycloalkyl, HetA, or HetB, (4) -HetA, (5) - -C(O)-HetA; or (6) -HetB; wherein: each cycloalkyl is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - - CN, — C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, — C_1-6 haloalkyl, or - - O- - C_1-6 haloalkyl, each aryl is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (21) as defined above in part (i) of Part A of the definition of R^J, each HetA is independently as defined in Part (A)(ii) of the definition of R^J, and each HetB is independently as defined in Part (A)(ii) of the definition of R^J; (7) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (21) as defined above in part (i) of Part A of the definition of R^J; R² is: (1) - -H, (2) - -C_1-6 alkyl, (3) - -C_1-6 haloalkyl, (4) - -C_1-6 alkyl substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(O)N(R^A)R^B, - -C(O)R^A, - -C0₂R^A, - - SR^A, - -S(O)R^A, - -S0₂R^A, - -S0₂N(R^A)R^B, - - N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(O)N(R^A)R^B, - - N(R^A)C(O)N(R^A)R^B, or - -N(R^A)C(O)C(O)N(R^A)R^B, or (5) - -C_1-6 alkyl substituted with HetC, - -C(O)-HetC, - -S0₂-HetC, - -N(R^A)C(O)-HetC, or - -N(R^A)C(O)C(O)-HetC;

wherein HetC is a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms, zero to 1 O atom, and zero to 1 S atom, where the S is optionally oxidized to S(O) or S(O)₂, with the proviso that the ring is attached to the rest of the molecule via a ring N atom, and wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, - - CN, — C_1-6 alkyl, - -OH, oxo, - - C(O)R^A, - -C0₂R^A, - -S(O)R^A, - -SR^A, - -S(O)₂R^A, - -CH₂- -CH=CH₂, - -0- -C_1-6 alkyl, - -C_1-6 haloalkyl, - -C_1- 6 alkylene-CN,— C_1-6 alkylene-OH, or— C_1-6 alkylene-O- - C_1-6 alkyl; or alternatively R¹ and R² together with the ring nitrogen to which R¹ is attached and the ring carbon to which R² is attached form a 5- to 7-membered, saturated heterocyclic ring in which the portion of the ring formed from R¹ and R² is a 3- to 5-membered methylene chain in which one of the methylene moieties is optionally replaced with N(H), wherein the chain is optionally substituted with from 1 to 3 substituents each of which is independently— C_1-6 alkyl, - -OH, or oxo; R³ is: (1) - -H, (2) - -C_1-6 alkyl, (3) - -C_1-6 haloalkyl, (4) - -C_1-6 alkyl substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, — N(R^A)R^B, - - C(O)N(R^A)R^B, - -C(O)R^A, - -C0₂R^A, - - SR^A, - -S(O)R^A, - -S0₂R^A, - -S0₂N(R^A)R^B, - - N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(O)N(R^A)R^B, - - N(R^A)C(O)N(R^A)R^B, or - -N(R^A)C(O)C(O)N(R^A)R^B, (5) - -C_1-6 alkyl substituted with HetD, - -C(O)-HetD, - -S0₂-HetD, - -N(R^A)C(O)-HetD, or - -N(R^A)C(O)C(O)-HetD, (6) CycM, AryM, or HetM, or (7) - -C_1-6 alkyl substituted with CycM, AryM, or HetM; wherein: HetD independently has the same definition as HetC; CycM is - - C₃-8 cycloalkyl which is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - - CN, — C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, — C_1-6 haloalkyl, or - - O- - C_1-6 haloalkyl; AryM is aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (21) as defined above in part (i) of Part A of the definition of R^J; and HetM is heteroaryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (26) as defined above in part (i) of Part B of the definition of R^J; or alternatively R² and R³ together with the carbon atoms to which they are attached form: (i) a 3- to 8-membered saturated carbocyclic ring which is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - - CN, — C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, — C_1-6 haloalkyl, or - -O- - C_1-6 haloalkyl, (ii) a benzene ring, which is optionally substituted with from 1 to 4 substituents each of which is independently any one of the substituents (1) to (21) as defined above in part (i) of Part A of the definition of R^J, (iii) a 4- to 7-membered, saturated or mono- unsaturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)₂, and wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, - -CN, - -C_1-6 alkyl, - -OH, oxo, - -C(O)R^A, - -C0₂R^A, - - S(O)R^A, - -SR^A, - -S(O)₂R^A, - -CH₂- -CH=CH₂, - -O- -d.e alkyl, - -C_1-6 haloalkyl, - --C_1-6 alkylene- CN, - -C_1-6 alkylene-OH, or— C_1-6 alkylene-O- - C_1-6 alkyl, or (iv) a 5- or 6-membered heteroaromatic ring, which is optionally substituted with from 1 to 3 substituents each of which is independently any one of the substituents (1) to (26) as defined above in part (i) of Part B of the definition of R^J; wherein R⁶ and R⁷ are absent, when R² and R³ together with the carbon atoms to which they are attached form a benzene ring or a heteroaromatic ring; R⁴ is: (1) - -H, (2) - -C_1-6 alkyl, (3) - -C_1-6 haloalkyl, (4) - -C_1-6 alkyl substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - - C(O)N(R^A)R^B, - -C(O)R^A, - -C0₂R^A, - -SR^A, - -S(O)R^A, - -S0₂R^A, - -S0₂N(R^A)R^B, - - N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(O)N(R^A)R^B, - - N(R^A)C(O)N(R^A)R^B, or - -N(R^A)C(O)C(O)N(R^A)R^B, (5) - -OH, (6) -O-C^ alkyl,

(7) - -O- -C_1-6 haloalkyl, (8) - -CN, (9) - -N0₂, (10) - -N(R^C)R^D,

(11) - -C(O)N(R^c)R^D, (12) - -C(O)R^A, (13) - -C0₂R^A, (14) - -SR^A, (15) - -S(O)R^A, (16) - -S0₂R^A, (17) - -S0₂N(R^A)R^B, (18) - -N(R^A)C(O)R^B, (19) - -N(R^A)C0₂R^B, (20) - -N(R^A)S0₂R^B, (21) - - N(R^A)S0₂N(R^A)R^B, (22) - -OC(O)N(R^A)R^B, (23) N(R^A)C(O)N(R^A)R^B, (24) - -N(R^A)C(O)C(O)N(R^A)R^B, (25) halogen, (26) - -S- -

C(O)N(R^c)R^D, (27) - -N=C(R^A)- -N(R^C)R^D, (28) - -C(O)N(R^A)- -C_1-6 alkylene-N(R^c)R^D,

(29) - -C(O)- -C_1-6 alkylene-N(R^c)R^D, (30) - -C(O)N(R^A)- -C_1-6 alkylene-C_1-6 haloalkyl, (31) - -C(O)- -C_1-6 alkylene-C_1-6 haloalkyl, (32) - -N(S0₂R^A)- -V,

(33) - -N[C(O)R^A]- -V, (34) - -C_1-6 alkyl substituted HetE, - -C(O)-HetE, - -S0₂-HetE, - - N(R^A)C(O)-HetE, or - -N(R^A)C(O)C(O)-HetE, (35) - -C_1-6 alkyl substituted with CycL, AryL, HetL, or HetS, or (36) -T-R^L, wherein: T is a single bond, O, C(O),

C(O)N(R^A), N(R^A)C(O), S, S(O), S(O)₂, N(R^A)S(O)₂, S(O)₂N(R^A), 0- -C_1-6 alkylene, C(O)- - d.₆ alkylene, C(O)N(R^A)- -C₁.₆ alkylene, N^XXOV-d.e alkylene, S- -C_1-6 alkylene, S(O)- - C_1-6 alkylene, S(O)₂- -C_1-6 alkylene, C_1-6 alkylene-S, C_1-6 alkylene-S(O), C_1-6 alkylene-S(O)₂, C_1-6 alkylene-O, C_1-6 alkylene-C(O), C_1-6 alkylene-C(O)N(R^A), C_1-6 alkylene-N(R^A)C(O), C_1-6 alkylene-N(R^A)S(O)₂, or C_1-6 alkylene-S(O)₂N(R^A); V is (i) - -CH₂- -C₂-6 alkenyl or (ii) - - C_1-6 alkyl substituted with C(O)N(R^c)R^D, CycL, AryL, HetL, or HetS; and R^L is CycL,

AryL, HetL, or HetS;

CycL is - - C₃-8 cycloalkyl which is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - - CN, — C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, — C_1-6 haloalkyl, or - -O- - C_1-6 haloalkyl; AryL is aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (21) as defined above in part (i) of Part A of the definition of R^J; HetE independently has the same definition as HetC; HetL is heteroaryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (26) as defined above in part (i) of Part B of the definition of R^J; HetS is a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)₂, with the proviso that HetS is attached to the rest of the molecule via a ring carbon atom; and wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, - - CN, — C_1-6 alkyl, - -OH, oxo, - -C(O)R^A, - -C0₂R^A, - -S(O)R^A, - -SR^A, - -S(O)₂R^A, - -CH₂- -CH=CH₂, - -0- -d_ 6 alkyl, - -C_1-6 haloalkyl, - -C_1-6 alkylene-C(O)N(R^A)R^B, - -C_1-6 alkylene-CN, - -C_1-6 alkylene-OH, or— C_1-6 alkylene-O- - C_1-6 alkyl; R⁵ is: (1)— C_1-6 alkyl, (2) — C_1-6 alkyl substituted with - - OH, - -O- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(O)N(R^A)R^B, - -C(O)R^A, - -C0₂R^A, - -SR^A, - -S(O)R^A, - -S0₂R^A, - -S0₂N(R^A)R^B, - -N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - - N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(O)N(R^A)R^B, - -N(R^A)C(O)N(R^A)R^B, or - - N(R^A)C(O)C(O)N(R^A)R^B, (3) - -C₃-8 cycloalkyl, which is optionally substituted with from 1 to 6 substituents each of which is independently halogen, — CN, - - C_1-6 alkyl, - -OH, - - O- -C_1-6 alkyl, - -C_1-6 haloalkyl, or - -0- -C_1-6 haloalkyl, (4) - -C_1-6 alkyl substituted with - - C₃-8 cycloalkyl, wherein the - - C3-8 cycloalkyl is optionally substituted with from 1 to 6 substituents each of which is independently halogen, - -CN, - - C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, - - C_1-6 haloalkyl, or— O- - C_1-6 haloalkyl, (5) heteroaryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (26) as defined above in part (i) of Part B of the definition of R^J, (6) — C_1-6 alkyl substituted with R^K, wherein R^K independently has the same definition as R^J as set forth above in the definition of R¹, or (7) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of the substituents (1) to (21) as defined above in part (i) of Part A of the definition of R^J; and with the proviso that R⁵ is — C_1-6 alkyl substituted with R^K, when R¹ is other than - -C_1-6 alkyl substituted with R^J; R⁶ and R⁷ are each independently— H or— C_1-6 alkyl; or alternatively R³ and R⁷ together with the carbon atom to which they are attached form (i) a 3- to 8-membered saturated carbocyclic ring which is optionally substituted with from 1 to 6 substituents each of which is independently halogen, — CN, - - C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, — C_1-6 haloalkyl, or— O- - C_1-6 haloalkyl or (ii) a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)₂, and wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, - -CN, - -C_1-6 alkyl, - -OH, oxo, - -C(O)R^A, - -C0₂R^A, - -S(O)R^A, - -SR^A, - -S(O)₂R^A, - -CH₂- -CH=CH₂,- -0- -C₁_6 alkyl, - --C_1-6 haloalkyl, - -C_1-6 alkylene-CN, - -C_1-6 alkylene-OH, or— C_1-6 alkylene-O- - C_1-6 alkyl, each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocyclic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O)₂; each R^A is independently - - H or— C_1-6 alkyl;

each R^B is independently - - H or— C_1-6 alkyl; each R^c is independently - - H or— C_1-6 alkyl; and each R^D is independently— H or— C_1-6 alkyl; or alternatively R^c and R^D together with the N to which they are both attached form a 4- to 7-membered, saturated or mono- unsaturated heterocyclic ring containing the N to which they are both attached and optionally containing 1 or 2 additional heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)₂, and wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, - -CN, - -C_1-6 alkyl, - -OH, oxo, - -C(O)R^A, - -C0₂R^A, - -S(O)R^A, - -SR^A, - -S(O)₂R^A, - -CH₂- -C₂-6 alkenyl, - -0- -C_1-6 alkyl, - -C_1-6 haloalkyl, - -C_1-6 alkylene-CN, - -C_1-6 alkylene-OH, or — C_1-6 alkylene-O- - C_1-6 alkyl.

The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

Compounds of Formula I of the present invention can be prepared as shown in Schemes 1 to 5. Scheme 1 presents a general method for the preparation of compounds of the present invention embraced by Formula (I), wherein piperazin-2-one 1-1 is treated with dialkylalkoxymethylenemalonate 1-2 and then with a deprotonating agent (e.g., Li or Na bis(trimethylsilyl)amide or Na hydride) at a temperature in a range of from about 0 to 80° C. in an anhydrous non-protic solvent (e.g., DMF or THF) to give alkyl 8-hydroxy-1-oxo- 1,2,3,4-tetrahydropyrrolopyrazine-7-carboxylate \ . The phenolic hydroxyl group on intermediate \ is capped with appropriate protecting group (e.g., benzyl, methyl, or toluenesulfonyl), and is halogenated with a brominating agent (e.g., bromine or N- bromosuccinimide) in an appropriate solvent (e.g., a halogenated hydrocarbon such as dichloro me thane or chloroform) to give the bromide 1-6. Conversion of bromide 1-6 to the corresponding carbonyl derivative 1-7 or 1-9 is achieved via a palladium catalyzed coupling reaction with vinyl alkylethers (Littke et al J. Am. Chem. Soc. 2001, 6989; Cabri et al Tetrahedron Lett. 1991, 1753) or appropriately substituted trialkyl(vinyl)tin 1-8 followed by an oxidation of the vinyl group (Littke et al J. Am. Chem. Soc. 2002, 6343; Ley et al Org. Lett. 2003, 185). Further elaboration of 1-7 or 1-9 to a compound of Formula I can be achieved through the formation of the third pyridazine ring by reaction with an appropriately substituted hydrazine. Alternatively, 1-10 can also be obtained by reaction of 1-7 or 1-9 with hydrazine, followed by alkylation with a suitable alkylating reagent. The protecting group on the phenolic hydroxy group can be removed before or after the formation of the tricyclic system. A description of protecting groups suitable for use herein and of methods for their attachment to and cleavage from the hydroxy group are described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 and in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999, and 2nd edition, 1991.

Certain of the dialkylalkoxymethylenemalonates suitable for use as 1-2 (e.g., diethylethoxymethylenemalonate or dimethylmethoxy-methylenemalonate) are available from commercial sources. Others can be obtained by preparative methods known in the art. For example, heterocyclylalkyloxy-methylene malonates can be prepared by the method described in Boger et al., J. Org. Chem 1988, 3408, or routine variations thereof.

1-1

The piperazin-2-one 1-1 can be obtained by alkylation of amine-protected piperazin-2-one 2-1 followed by deprotection, as depicted in Part A of Scheme 2 and described in Choi et al., J. Med. Chem. 1999, 3647; Najman-Bronzewska et al., Pharmazie 1997, 198; Fryer et al., J. Org. Chem. 1991, 3715, Dinsmore et al, Organic Prep. & Procedures International. 2002, 369, or routine variations thereof. Alternatively, piperazin-2- one 1-1 can be derived from cyclization of the dialkylacetal precursor 2.₃, followed by catalytic hydrogenation of the cyclization product 1 as depicted in Part B of Scheme 2 and described in DiMaio et al, JCS Perkin 1, 1989, 1687 and Kitamura et al., J. Med. Chem., 2001, 2438. Sequential hydrogenation of the olefin (e.g., a Pd or Pt catalyst such as Pt on charcoal) followed by cleavage of the CBZ protecting group (e.g., Pd on charcoal or Pd hydroxide on charcoal) in a suitable protic solvent such as an alcohol (e.g., methanol or ethanol) under an atmosphere of hydrogen gas provided the required piperazin-2-one 1-1. Similarly, reaction of glycinamde 2-5 with pyruvic aldehyde provided the key pyrazinone 2-6, which was hydro genated to provide piperazin-2-one 1-1 as depicted in Part C of Scheme 2, and as described in Wilfred et al., JCS Chem Comm., 1980, 334. Hydrogenation in the presence of appropriate catalyst, chiral ligands, and additives provided optically enriched piperazin-2-one 1-1 in a manner similar those described in Zhang et al, Chem. Rev, 2003, 3029 and Angew. Chem. Int. Ed. 2001, 3425. Alternatively, stepwise reductive alkylation of aldehyde 2-7 with a suitably substituted amine and treatment of the resultant material with haloacetyl halide (such as chloroacetyl chloride or bromo acetylbromide) provided the intermediate 2-8. Based induced cyclization, followed by deprotection of the amino group provided piperazin-2-one 1- 1 as depicted in Part D of Scheme 2 and described in Williams, et al., J. Med. Chem., 1999, 3779, and Lewis, et al., J. Med. Chem., 1995, 923. Alternatively, stepwise reduction of N-Boc aminoacid carboxamide 2-9 with an appropriate reducing reagent such as lithium aluminum hydride and coupling of the resultant amine with haloacetic acid can afford the intermediate amide 2-10. Based induced cyclization, followed by deprotection of the amino group provided piperazin-2-one 1-1 as depicted in Part E of Scheme 2 and described in Schanen et al., Tetrahedron Lett, 1994, 2533 & Synthesis, 1996, 833; Pohlmann et al., J. Org. Chem., 1997, 1016. Piperazin-2-one 1-1 can alternatively be also prepared using methods described in Bernotas et al., Tetrahedron Lett. 1996, 7339; Saari et al., J. Med. Chem. 1990, 2590; Sugihara et al., J. Med. Chem. 1998, 489, Dinsmore et al, Organic Prep. & Procedures International. 2002, 369, or routine variations thereof.

nued

An alternative method for the preparation of compounds of the present invention embraced by Formula I is shown in Scheme 3, wherein dibromopyridazinone 3-1 is treated with base and alkylating reagent in an anhydrous, non-protic solvent such as DMF to give alkyl dibromopyridazinone 3-2. Reaction of the dibromide with piperazinone 1-1 in a solvent (e.g., an alkyl alcohol such as ethanol) provides the addition product 3-3 (Betti et al J. Med. Chem. 2003, 3555). Conversion of bromide 3-3 to the corresponding tricyclic product can be achieved via a palladium catalyzed carbonylation followed by a base catalyzed cyclization (Zhuang et al J. Med. Chem. 2003, 453).

A general method for the preparation of compounds of Formula I in which the R⁴ substituent bears an amino group linked directly to the tricyclic system is shown in Scheme 4, wherein the bicyclic bromo ester 1 -6 is treated with zinc cyanide in the presence of palladium catalyst as described in Maddaford S. P. et al SynLett, 2236, 2003 to provide the corresponding nitrile 4-1. Reaction of the nitrile 4-1 with substituted hydrazines provides the tricyclic intermediate 4-2. Removal of the protecting group affords compound 4-3. The appropriate sequence of alkylation/acylation or alkylation/allylation or bisalkylation of 4-2 can provide 4-4, followed by deprotection to give 4-5.

Scheme 4

When R⁵ is benzyl or substituted benzyl, nitrile 4-1 is alternatively and preferably treated with hydrazine to provide the corresponding tricyclic intermediate 4-6, which can be regio-selectively benzylated to provide intermediate 4-2 (see Scheme 4A).

A general method for the preparation of compounds of Formula I in which the R⁴ substituent bears an oxygen linker connected to the tricyclic system as is shown in Scheme 5, wherein the bicyclic ester 1-5 is hydrolyzed to the corresponding acid and converted to the corresponding acid chloride 5-1. Treatment of the acid chloride with appropriate substituted hydrazine provides the required hydrazine amide 5-2 (Fassler A. et al, J. Med Chem. 1996, 3203-2316). Bromination of 5-2 and selective removal of the protecting group on the hydrazine amide provides intermediate 5-3. Palladium (0) catalyzed carbonylation and cyclization provides the tricyclic intermediate 5-4. Removal of the protecting group leads to analog 5-5. The tricyclic intermediate 5-4 can be further elaborated by treatment with alkylating reagents/base or diazoalkanes to provide a mixture of O- and N-alkylated products. The O-alkylation product can be separated and the protecting group removed to provide analog 5-7.

Additional integrase inhibitors include those disclosed in US Publication No. 20070161639.

These integrase inhibitors are pyridopyrazine- and pyrimidopyrazine-dione compounds of Formula I, and pharmaceutically acceptable salts thereof:

wherein:

G is C- -R¹, CH- -R¹, N, or N- -R²;

Q is C- -R³, C- -R⁴, CH- -R³ or CH- -R⁴, with the proviso that (i) when G is C- -R¹, then Q is C- -R³, (ii) when G is CH- -R¹, then Q is CH- -R³, (iii) when G is N, then Q is C- -R⁴, and (iv) when G is N- -R², then Q is CH- -R⁴; bond " a" is a single bond or a double bond between G and Q, with the proviso that (i) when G is N or C- - R¹, bond "a" is a double bond, and (ii) when G is CH- -R¹ or N- -R², bond "a" is a single bond; R¹ is: (1) H, (2) halogen, (3) C_1-6 alkyl, (4) C_1-6 alkyl substituted with: (a) - - N(R^A)R^B, (b) - -N(R^A)- -C(=O)- -R^B,

(c) - -N(R^A)- -S0₂R^B, (d) - -N(R^A)- -C_1-6 alkylene-O- -C_1-6 alkyl, (e) N(R^A)- -C(=O)- -C(=O)- -N(R^A)R^B, (f) - -OH, (g) -HetD, or (h) - -N(R^A)- -C_1-6 alkylene-HetA, (5) HetA, (6) C(=O)- -R^A, (7) C(=O)-aryl, or (8) C(=O)-

HetA; R² is H or C_1-6 alkyl; R³ is: (1) H, (2) C_1-6 alkyl, (3) C_1-6 alkyl substituted with: (a) - -N(R^A)R^B, (b) - -N(R^A)- -C(=O)- -R^B, (c) - -N(R^A)- -S0₂R^B, (d)

N(R^A)- -C_1-6 alkylene-O- -C_1-6 alkyl, (e) - -N(R^A)- -C(=O)- -C(=O)- -N(R^A)R^B, (f) -HetD,

(g) - -N(R^A)- -C i_6 alkylene-HetA, or (4) C(=O)- -C_1-6 alkyl, (5) C0₂H, (6) C(=O)- -0- -C_1-6 alkyl, (7) C(=O)N(R^A)R^B, or (8) C(=O)-HetF; R⁴ is: (1) H, (2)

C_1-6 alkyl, or (3) C_1-6 alkyl substituted with: (a) - - N(R^A)R^B, (b) - -N(R^A)- -C(=O)- -R^B,

(c) - -N(R^A)- -S0₂R^B, (d) - -N(R^A)- -C_1-6 alkylene-O- -C_1-6 alkyl, (e) N(R^A)- -C(=O)- -C(=O)- -N(R^A)R^B, (f) -HetD, or (g) - -N(R^A)- -C_1-6 alkylene-HetA;

R⁵ is: (1) H, (2) C_1-6 alkyl, or (3) C_1-6 alkyl substituted with: (a) - -C0₂H,

(b) - -C(=O)- -0- -C_1-6 alkyl, (c) - -C(=O)- -C_1-6 alkyl, (d) - - N(R^A)R^B, (e) - -C(=O)N(R^A)R^B, (f) - -N(R^A)- -C(=O)- -R^B, (g) - -N(R^A)- -S0₂R^B, (h)

N(R^A)- -C(=O)- -C(=O)- -N(R^A)R^B, (i) -HetF, (j) - -C(=O)-HetF, or (k)

N(R^A)- -C(=O)- -C(=O)-HetF; or alternatively R⁴ and R⁵ together with the carbon atoms to which each is attached and the fused ring N atom therebetween form a ring such that the compound of Formula I is a compound of Formula la or lb: wherein k is an integer equal to 1 or 2; R⁶ is H or C_1-6 alkyl; R⁷ is C_1-6 alkyl substituted with T, wherein T is:

(A) aryl or aryl fused to a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the aryl or fused aryl is optionally substituted with from 1 to 5 substituents each of which is independently: (1) - -C_1-6 alkyl optionally substituted with - -OH, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^Awhere n is an integer equal to zero or 1 or 2, - -S0₂N(R^A)R^B, - -N(R^A)C(=O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(=O)N(R^A)R^B, or - -N(R^A)C(=O)N(R^A)R^B, (2) - -0- -C_1-6 alkyl,

(3) - -d.6 haloalkyl, (4) -O-C^ haloalkyl, (5) - -OH, (6) halo, (7) - -CN, (8) - -N0₂, (9) - -N(R^A)R^B, (10) - -C(=O)N(R^A)R^B, (11) - -C(=O)R^A,

(12) - -C0₂R^A, (13) - -SR^A, (14) - -S(=O)R^A, (15) - -S0₂R^A, (16) - -S0₂N(R^A)R^B,

(17) - -N(R^A)S0₂R^B, (18) - -N(R^A)S0₂N(R^A)R^B, (19) - -N(R^A)C(=O)R^B, (20) - -N(R^A)C(=O)- -C(=O)N(R^A)R^B, (21) - -N(R^A)C0₂R^B, (22) phenyl, (23) benzyl, (24) -HetB, (25) - -C(=O)-HetB, or (26) -HetC, or (B) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heteroaromatic ring is (i) optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - -0- -C_1-6 haloalkyl, or hydroxy; and (ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or— C_1-6 alkyl substituted with aryl; R⁸ is: (1) H, (2) d_₆ alkyl, (3) N(R^A)R^B, (4) N(R^A)- -C0₂R^B, (5) N(R^A)- -S0₂R^B,

(6) N(R^A)- -C(=O)- -R^B, (7) N(R^A)- -C(=O)- -N(R^A)R^B, (8) N(R^A)- -C(=O)- -C(=O)- -N(R^A)R^B, (9) HetF, (10) N(R^A)- -C(=O)-HetF, or (11) N(R^A)- -C(=O)- -

C(=O)-HetF; R⁹ is H, C_1-6 alkyl, or C_1-6 alkyl substituted with U, wherein U independently has the same definition as T; each R 0 is independently H or C_1-6 alkyl; each HetA is independently: (A) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heteroaromatic ring is attached to the rest of the compound via a carbon atom in the ring, and wherein the heteroaromatic ring is: (i) optionally substituted with 1 or 2 substituents each of which is independently a— C_1-4 alkyl; and (ii) optionally substituted with aryl or — C_1-4 alkylene-aryl; or (B) a 9- or 10-membered aromatic heterobicyclic fused ring system containing from

1 to 4 heteroatoms independently selected from N, O and S; wherein the fused ring system consists of a 6-membered ring fused with either a 5-membered ring or another 6-membered ring, either ring of which is attached to the rest of the compound via a carbon atom; wherein the ring of the fused ring system attached to the rest of the compound via the carbon atom contains at least one of the heteroatoms; and wherein the fused ring system is: (i) optionally substituted with 1 or 2 substituents each of which is independently a — C_1-4 alkyl; and (ii) optionally substituted with aryl or - -C_1-4 alkylene-aryl; each HetB is independently a C -7 azacycloalkyl or a C3-6 diazacycloalkyl, either of which is optionally substituted with from 1 to 4 substituents each of which is oxo or C_1-6 alkyl; each HetC is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halo, — C_1-6 alkyl, - - C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, or hydroxy; or each HetD is independently a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and a total of from 1 to 4 heteroatoms independently selected from 1 to 4 N atoms, from 0 to 2 O atoms, and from 0 to 2 S atoms, wherein any ring S atom is optionally oxidized to SO or S0₂, and wherein the heterocyclic ring is optionally fused with a benzene ring, and wherein the heterocyclic ring is attached to the rest of the compound via a N atom in the ring, and wherein the heterocyclic ring is: (i) optionally substituted with 1 or 2 substituents each of which is independently a - -C_1-4 alkyl, - -C_1-4 alkylene-N(R^A)R^B, or - -C(=O)OR^A; and (ii) optionally substituted with aryl, — C_1-4 alkylene-aryl, HetE, or — C_1-4 alkylene-HetE; wherein HetE is (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S or (ii) a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S; each HetF is independently a 4- to 7-membered saturated heterocyclic ring containing 1 or 2 N atoms, zero or 1 O atom, and zero or 1 S atom, wherein any ring S atom is optionally oxidized to SO or S0₂, and wherein the heterocyclic ring is attached to the rest of the compound via a N atom in the ring, and wherein the heterocyclic ring is optionally substituted with 1 or 2 substituents each of which is independently a— C_1-6 alkyl; each aryl is independently phenyl or naphthyl; each R^A is independently H or C_1-6 alkyl; and each R^B is independently H or C_1-6 alkyl.

A general synthetic strategy for preparing the compounds is set forth in Scheme 1.

Further details on the synthesis of the compounds, and their intermediates, is provided in detail in U.S. Publication No. 200706139.

Additional integrase inhibitors include those disclosed in US Publication No. 20080009490. The compounds are bicyclic uracil compounds and compounds related thereto. More particularly, the present invention includes compounds of Formula I, and pharmaceutically acceptable salts thereof:

wherein: bond "a" is a single bond or a double bond; bond "b" is a double bond when bond "a" is a single bond; and bond "b" is a single bond when bond "a" is a double bond; Y is O, S, or NR⁵, when bond "a" is a single bond; Y is N(R⁶)R⁷, when bond "a" is a double bond; R¹ is C_1-6 alkyl substituted with T, wherein T is: (A) aryl which is:

(i) optionally substituted with from 1 to 5 substituents each of which is independently: (1) — C_1-6 alkyl optionally substituted with - -OH, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(O)N(R^A)R^B, - -C(O)R^A, - -C0₂R^A, - - SR^A, - -S(O)R^A, - - S0₂R^A, - -S0₂N(R^A)R^B, - -N(R^A)C(O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - -OC(O)N(R^A)R^B, or - -N(R^A)C(O)N(R^A)R^B, (2) - -0- -C_1-6 alkyl, (3) - -C_1-6 haloalkyl,

(4) - -O- -C_1-6 haloalkyl, (5) - -OH, (6) halo, (7) - -CN, (8) - -N0₂,

(9) - -N(R^A)R^B, (10) - -C(O)N(R^A)R^B, (11) - -C(O)R^A, (12) - -C0₂R^A, (13) - -SR^A, (14) - -S(O)R^A, (15) - -S0₂R^A, (16) - -S0₂N(R^A)R^B, (17) - -N(R^A)S0₂R^B,

(18) - -N(R^A)S0₂N(R^A)R^B, (19) - -N(R^A)C(O)R^B, (20) - -N(R^A)C(O)- -C(O)N(R^A)R^B, or (21) - -N(R^A)C0₂R^B, and

(ii) optionally substituted with from 1 to 3 substituents each of which is independently: (1) -HetA, (2) -HetB, (3) phenyl, (4) benzyl, or (5) - -C(O)- -HetA, or (B) heteroaryl which is: (i) optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - -0- -C_1-6 haloalkyl, or - -OH; and

(ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or— C_1-6 alkyl substituted with aryl; R² is: (1) H, (2) C_1-6 alkyl, or (3) C_1-6 alkyl substituted with - -C0₂R^A or - -C(O)N(R^c)R^D; or alternatively R¹ and R² together with the atom to which each is attached form a saturated 5- or 6-membered ring containing the nitrogen to which R¹ is attached, optionally a second nitrogen atom and a balance of carbon atoms; wherein the saturated 5- or 6-membered ring is substituted with T as defined above;

R³ is: (1) H, (2) C_1-6 alkyl, or (3) C_1-6 alkyl substituted with: (a) - -OH,

(b) - -O- -C_1-6 alkyl, (c) - -N(R^E)₂, (d) - - N(R^E)R^F, (e) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently halo, — C_1-6 alkyl, - - O- - C _1-6 alkyl,— C_1-6 haloalkyl, or - -OH, (f) - - O- - C _1-6 alkylene-aryl, in which the aryl is optionally substituted with from 1 to 5 substituents each of which is independently halo, — C _1-6 alkyl, - - O- - C _1-6 alkyl, — C _1-6 haloalkyl, or - -OH, (g) heteroaryl, which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C_1-6 alkyl, - - C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, or - -OH, or (h) heteromonocycle, which is optionally substituted with from 1 to 6 substituents each of which is independently halogen, — C _1-6 alkyl, — C _1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, or oxo; R⁴ is absent when bond "a" is a double bond;

R⁴ is as follows when bond "a" is a single bond: (1) H, (2) C_1-6 alkyl, (3) C _1-6 alkyl substituted with 1 or 2 substituents each of which is independently: (a) - -OH, (b) - -O- -C i_6 alkyl, (c) - -C_1-6 haloalkyl, (d) - -C0₂R^A, (e) - -C(O)N(R^c)R^D, (f) C(O)C(O)N(R^A)R^B, (g) - -S- -d.6 alkyl, (h) - -S-aryl, (i) - -S^- -C^ alkyl, (j) - -S(O)-aryl, (k) - -S0₂- -C_1-6 alkyl, (1) - -S0₂-aryl, (m) - -N(R^E)₂, (n) - - N(R^E)R^F, (o)- - C₃-8 cycloalkyl, which is

(i) optionally substituted with from 1 to 6 substituents each of which is independently - -C₁.6 alkyl, - -OH, - -0- -C _1-6 alkyl, or - -C _1-6 haloalkyl, and

(ii) optionally substituted with (a) aryl, (b) — C _1-6 alkylene-aryl, (c) heteroaryl optionally substituted with from 1 to 3 substituents each of which is independently a — C _1-6 alkyl, or (d) heteromonocycle optionally substituted with from 1 to 4 substituents each of which is independently— C_1-6 alkyl, — C _1-6 alkylene-aryl, or oxo, (p) aryl, which is:

(i) optionally substituted with from 1 to 5 substituents each of which is independently halo, — C_1-6 alkyl, - - O- - C _1-6 alkyl, — C _1-6 haloalkyl, or - -OH, and

(ii) optionally substituted with (a) heteroaryl optionally substituted with from 1 to 3 substituents each of which is independently a — C _1-6 alkyl, or (b) heteromonocycle optionally substituted with from 1 to 4 substituents each of which is independently — C_1-6 alkyl, — C _1-6 alkylene-aryl, or oxo, (q) bicyclic or tricyclic carbocycle, which is optionally substituted with from 1 to 7 substituents each of which is independently halogen, — C_1-6 alkyl, — C _1-6 haloalkyl, OH, - - O- - C _1-6 alkyl, or - - O- - C_1-6 haloalkyl, (r) heteroaryl, which is:

(i) optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C _1-6 alkyl,— C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, or - -OH, and

(ii) optionally substituted with (a) aryl, (b) — C_1-6 alkylene-aryl or (c) heteromonocycle optionally substituted with from 1 to 4 substituents each of which is independently— C_1-6 alkyl,— C_1-6 alkylene-aryl, or oxo, (s) heteromonocycle, which is:

(i) optionally substituted with from 1 to 6 substituents each of which is independently halogen, - -C_1-6 alkyl, - -C_1-6 haloalkyl, - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - -C(O)- -C_1-6 alkyl, - -C(O)C(O)N(R^A)R^B, or oxo, and

(ii) optionally substituted with: (a) — C_1-6 alkylene-C₃-8 cycloalkyl, (b) aryl, (c) — C_1-6 alkylene-aryl, (d) heteroaryl optionally substituted with from 1 to 3 substituents each of which is independently a— C_1-6 alkyl, (e) heteromonocycle optionally substituted with from 1 to 4 substituents each of which is independently— C_1-6 alkyl, - - C_1-6 alkylene-aryl, or oxo, or (f) — C(O)- - C_1-6 alkylene-heteromonocycle wherein the heteromonocycle is optionally substituted with from 1 to 4 substituents each of which is independently— C_1-6 alkyl,— C_1-6 alkylene-aryl, or oxo, or (s) bicyclic or tricyclic heterocycle, which is optionally substituted with from 1 to 7 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, — O- - C_1-6 alkyl, — O- - C_1-6 haloalkyl, - - C(O)- -C_1-6 alkyl, or oxo; (4) C₂-6 alkenyl, (5) C₃-8 cycloalkyl which is: (a) optionally substituted with from 1 to 6 substituents each of which is independently— C_1-6 alkyl, - -OH, - - O- - C_1-6 alkyl, or— C_1-6 haloalkyl, and (b) optionally substituted with:

(i) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently halo, — C_1-6 alkyl, — O- - C_1-6 alkyl, — C_1-6 haloalkyl, or - -OH,

(ii) heteroaryl, which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, — O- - C_1-6 alkyl, — O- - C_1-6 haloalkyl, or - -OH, (iii) heteromonocycle, which is

(i) optionally substituted with from 1 to 6 substituents each of which is independently halogen, - -C _1-6 alkyl, - --C_1-6 haloalkyl, - -0- --C_1-6 alkyl, -O-C^ haloalkyl, - -C(O)- -C₁.₆ alkyl, or oxo, and

(ii) optionally substituted with— C_1-6 alkylene-aryl, or (iv) N(R^A)R^B, (6) aryl, which is: (a) optionally substituted with from 1 to 5 substituents each of which is independently halo, — C_1-6 alkyl, — O- - C_1-6 alkyl, — C_1-6 haloalkyl, or - -OH, and (b) optionally substituted with

(i) heteroaryl optionally substituted with from 1 to 3 substituents each of which is independently a — C_1-6 alkyl, or (ii) heteromonocycle optionally substituted with from 1 to 4 substituents each of which is independently— C_1-6 alkyl,— C_1-6 alkylene-aryl, or oxo, (7) bicyclic or tricyclic carbocycle, which is optionally substituted with from 1 to 7 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, OH, - - O- - C_1-6 alkyl, or - -O- - C_1-6 haloalkyl, (8) heteroaryl, which is (a) optionally substituted with from

1 to 4 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, — O- - C_1-6 alkyl,— O- - C_1-6 haloalkyl, or - -OH, and (b) optionally substituted with (i) aryl or (ii) heteromonocycle optionally substituted with from 1 to 4 substituents each of which is independently— C_1-6 alkyl, — C_1-6 alkylene-aryl, or oxo, (9) heteromonocycle, which is (a) optionally substituted with from 1 to 6 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, - - C(O)- -C_1-6 alkyl, - -C(O)C(O)N(R^A)R^B, or oxo, and (b) optionally substituted with: (i) - - C_1-6 alkylene-C₃-8 cycloalkyl, (ii) aryl, (iii) — C_1-6 alkylene-aryl, (iv) heteroaryl optionally substituted with from 1 to 3 substituents each of which is independently a— C_1-6 alkyl, (v) heteromonocycle optionally substituted with from 1 to 4 substituents each of which is independently— C_1-6 alkyl, — C_1-6 alkylene-aryl, or oxo, or (vi) C(O)- - C_1-6 alkylene -heteromonocycle wherein the heteromonocycle is optionally substituted with from 1 to 4 substituents each of which is independently— C_1-6 alkyl, — C_1-6 alkylene-aryl, or oxo, or (10) bicyclic or tricyclic heterocycle, which is optionally substituted with from 1 to 7 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - -O- -d.6 alkyl, -O -C_1-6 haloalkyl, - -C(O)- - -C_1-6 alkyl, or oxo; R⁵ is: (1) H, (2) C _1-6 alkyl, (3) C_1-6 alkyl substituted with: (a) C₃-8 cycloalkyl, which is optionally substituted with from 1 to 5 substituents each of which is independently C_1-6 alkyl, halo, or - - O- - C_1-6 alkyl, (b) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently any one of substituents (1) to (21) as defined above in Part A of the definition of T, (c) HetB, (d) - - N(R^A)R^B, (e) - -N(R^A)- -C(O)- -R^B, (f) - -N(R^A)- -S0₂R^B, or (g) - -N(R^A)- -C(O)- -C(O)- -N(R^A)R^B, (4) C(O)R^u, or (5) S0₂R^v; R⁶ is C _1-6 alkyl;

R⁷ is C_1-6 alkyl, C(O)R^u, or S0₂R^v; or alternatively R⁶ and R⁷ together with the nitrogen atom to which they are attached form a ring selected from the group consisting of: wherein the asterisk * denotes the point of attachment of the ring to the rest of the compound; and Z is O, S, S(O), S(O)₂, or N- -R^w; each HetA is independently a C₄-7 azacycloalkyl or a C₃-6 diazacycloalkyl, either of which is optionally substituted with from 1 to 4 substituents each of which is independently C_1-6 alkyl or oxo; each HetB is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halo, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, or - -OH; each aryl is independently phenyl, indenyl, indanyl, naphthyl, or tetrahydronaphthyl; each bicyclic carbocycle is independently a bridged or fused two-ring system containing from 7 to 11 carbons, in which each ring is either saturated or unsaturated, but neither ring is aromatic; each tricyclic carbocycle is independently a bridged or fused or bridged and fused three-ring system containing from 8 to 12 carbons, in which each ring is either saturated or unsaturated, but no ring is aromatic; each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S or (ii) a 8- or 12-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein one or both of the rings in the ring system contain at least one heteroatom, at least one ring is aromatic, and any

5 atom in a ring which is not aromatic is optionally present in the form of a monoxide or dioxide; each heteromonocycle is independently a 4- to 7-membered saturated or mono- unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S; each bicyclic heterocycle is independently a 7- to 11-membered bridged or fused two-ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, in which each ring is either saturated or unsaturated, but neither ring is aromatic, and one or both rings in the ring system contain at least one heteroatom;

each tricyclic heterocycle is independently an 8- to 12-membered bridged or fused or bridged and fused three-ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, in which each ring is either saturated or unsaturated, but no ring is an aromatic, and one or two or all three of the rings contain at least one heteroatom; each R^A is independently H or C_1-6 alkyl; each R^B is independently H or C_1-6 alkyl; each R^c is independently H, C_1-6 alkyl, or C_1-6 alkyl substituted with aryl or OH; each R^D is independently H, C_1-6 alkyl, or C_1-6 alkyl substituted with aryl or OH; each R^E is independently H, C_1-6 alkyl, or C_1-6 alkyl substituted with aryl; each R^F is independently O- - C_1-6 alkyl, S0₂- -C_1-6 alkyl, S0₂-aryl, S0₂- -N(R^c)R^D, C(O)- -C_1-6 alkyl, C(O)-aryl, C(O)- - N(R^C)R^D, C(S)- -C_1-6 alkyl, C(S)-aryl, or C(S)- -N(R^C)R^D; R^u is C _1-6 alkyl, 0- -C_1-6 alkyl, C₃-8 cycloalkyl, C_1-6 alkyl substituted with C₃-8 cycloalkyl, N(R^A)R^B, or C(O)- -N(R^A)R^B; R^v is C_1-

6 alkyl, C₃-8 cycloalkyl, C_1-6 alkyl substituted with C₃-8 cycloalkyl, or N(R^A)R^B; and R^w is H, C_1-6 alkyl, C₃-8 cycloalkyl, C_1-6 alkyl substituted with C₃-8 cycloalkyl, C(O)R^u, or S0₂R^v.

A first class of the present invention includes compounds of Formula II, and pharmaceutically acceptable salts thereof, wherein:

Y is O, S or NR⁵;

R¹ is CH₂T, wherein T is:

(1) phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, chloro, methyl, trifluoromethyl, methoxy, CN, - - S0₂CH₃, - - C(=O)NH(CH₃), or - -C(=O)N(CH₃)₂,

(2) naphthyl,

(3) pyridyl, (4) isoquinolinyl, or

(5) quinolinyl; R² is H, C_1-3 alkyl, (CH₂)_1-2- -C0₂CH₃, (CH₂)_1-2- -C(O)NH- -CH₃, or (CH₂)₁_₂- - C(O)N(CH₃)₂; or alternatively R¹ and R² together with the nitrogen ring atom and carbon ring atom to which each is respectively attached form a ring of formula: wherein T is as defined above and the asterisks * denote the points of attachment of the ring to the rest of the compound; R³ is

(1) H,

(2) C_1-3 alkyl,

(3) (CH₂)_1-2- -OH,

(4) (CH₂)_1-2- -OCH₃,

(5) ((¾)_1-2- -ΝΗ₂,

(6) (CH₂)_1-2- -NHCCH,),

(7) (CH₂)_1-2- -NCCH,),,

(8) (CH₂)_1-2- -N(OCH₃)CH₃,

(9) (CH₂)₁_₂--NH--CH₂-phenyl,

(10) (CH₂)_1-2- -N(CH₃)- -CH₂-phenyl,

(11) (CH₂)₁_₂--NH--C(O)CH₃,

(12) (CH₂)_1-2--N(CH₃)--C(O)CH₃,

(13) (CH₂)_1-2- -NH- -C(O)C(CH₃)₃,

(14) (CH₂)_1-2--N(CH₃)--C(O)C(CH₃)₃,

(15) (CH₂)_1-2- -NH- -C(O)-phenyl,

(16) (CH₂)_1-2- -N(CH₃)- -C(O)-phenyl,

(17) (CH₂)_1-2- -NH- -C(O)N(CH₃)₂,

(18) (CH₂)_1-2- -N(CH₃)- -C(O)N(CH₃)₂,

(19) (CH₂)_1-2- -NH- -C(S)N(CH₃)₂,

(20) (CH₂)_1-2- -N(CH₃)- -C(S)N(CH₃)₂,

(21) (CH₂)_1-2- -NH- -S0₂CH₃,

(22) (CH₂)_1-2- -N(CH₃)S0₂CH₃,

(23) (CH₂)_1-2-phenyl,

(24) (CH₂)_1-2- -OCH₂-phenyl,

(25) (CH₂)₁_₂-HetC, wherein HetC is a heteroaromatic ring selected from the group consisting of pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, thiazolyl, and isothiazolyl,

(26) (CH₂)₁_₂-HetD, wherein HetD is a saturated heterocyclic ring selected from the group consisting of piperidinyl, piperazinyl, morpholinyl, thiomorphohnyl, thiazohdinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl, wherein the saturated heterocyclic ring is optionally substituted with 1 or 2 oxo groups and is optionally substituted with 1 or 2 methyl groups, or

(27) (CH₂)₁_₂-HetD, wherein HetD is benzopiperidinyl; R⁴ is

(1) H,

(2) d.₄ alkyl,

(3) C_1-5 alkyl substituted with:

(a) - -OCH₃,

(b) - -CF₃,

(c) - -C0₂- -C_1-4 alkyl,

(d) - -NH(C_1-4 alkyl),

(e) - -N(C_1-4 alkyl)₂,

(f) - -SCH₃,

(g) - -SCH₂CH₃,

(h) --C3-₆ cycloalkyl, which is optionally substituted with — C_1-4 alkyl, - - OCH₃, — CF₃, - -OH, phenyl, morpholinyl optionally substituted with CH₃, piperidinyl optionally substituted with CH₃, or piperazinyl optionally substituted with CH₃,

(i) aryl selected from the group consisting of phenyl and naphthyl, wherein the aryl is optionally substituted with 1 or 2 substituents each of which is independently halo, - - CH₃, - - OCH₃, - -CF₃, or - -OH,

(j) a heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and imidazo[1,2-a]pyridinyl,

(k) a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and dioxanyl, where the saturated heterocyclic ring is optionally substituted with methyl, - -C(O)CH₃, - -C(O)C(O)N(CH₃)₂, or oxo and optionally substituted with - - CH₂-cyclopropyl, benzyl or a heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, and pyrazinyl, or

(1) l-azabicyclo[4.4.0]decyl,

(4) C_1-3 alkyl substituted with - -C0₂- -C_1-4 alkyl and with - -SCH₃ or - -SCH₂CH₃,

(5) C₁-₃ alkyl substituted with a saturated heterocyclic ring and either a C₃-6 cycloalkyl or a heteroaryl,

wherein the saturated heterocyclic ring is selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl, wherein the saturated ring is optionally substituted with 1 or 2 methyl groups, and

wherein the heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, and furanyl, (6) C₁-3 alkyl substituted with two C₃-6 cycloalkyl groups that are the same or different,

(7) (CH₂)_1-2CH=CH₂,

(8) C₃-7 cycloalkyl optionally substituted with -C₁ alkyl, --OH, --OCH₃, - -CF₃, phenyl, or a saturated heterocyclic ring selected from the group consisting of piperidinyl, piperazinyl, and morpholinyl, where the saturated heterocyclic ring is optionally substituted with 1 or 2 methyl groups, (9) aryl selected from the group consisting of phenyl, naphthyl and indanyl, where the phenyl is optionally substituted with — C_1-4 alkyl, — OCH₃, - - CF₃, or a saturated heterocyclic ring selected from the group consisting of piperidinyl, piperazinyl, and morpholinyl, where the saturated heterocyclic ring is optionally substituted with 1 or 2 methyl groups,

(10) adamantyl which is optionally substituted with methyl or OH,

(11) heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, and thiochromanyl in which the S atom is optionally in the form of a monoxide or dioxide, where the heteroaryl is optionally substituted with 1 or 2 substituents each of which is independently a - - CH₃, - -OCH₃, or a saturated heterocyclic ring selected from the group consisting of piperidinyl, piperazinyl, and morpholinyl, where the saturated heterocyclic ring is optionally substituted with 1 or 2 methyl groups,

(12) a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl, wherein the saturated heterocyclic ring is optionally substituted (i) with from 1 to 6 methyls, (ii) with 1 or 2 substituents each of which is independently - -CF₃, - -C(O)CH₃, - -C(O)C(O)N(CH₃)₂, or oxo and (iii) with - - CH₂-cyclopropyl, benzyl, - - C(O)CH₂-morpholinyl, or - - C(O)CH₂- piperidinyl, or

(13) l-azabicyclo[2.2.2]octyl or l-azabicyclo[4.4.0]decyl; and R⁵ is H, CH₃, or CH₂- phenyl.

A sub-class of the first class includes compounds of Formula II, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined above in the first class, and wherein any ring nitrogen in any saturated heterocyclic ring contained in R³ and R⁴ is a tertiary amine per se or is a tertiary amine formed by attachment of the ring nitrogen to the rest of the molecule via a carbon atom or by attachment of a substituent group on the ring nitrogen via a carbon atom in the substituent. Formula II is shown below:

An example of a saturated heterocyclic ring containing tertiary amine per se is 1- azabicyclo[2.2.2]octyl. As another example, in this sub-class, when R⁴ is C₁.5 alkyl substituted with a piperazine which in turn is mono-substituted with acetyl, R⁴ is:

s alkyl N N— C(0)Cな

wherein the asterisk * is the point of attachment of R4 to the rest of the molecule:

A second class of the present invention includes compounds of Formula IV, and pharmaceutically acceptable salts thereof:

wherein: Y is O or N- - CH₂-phenyl; T is: (1 ) phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, chloro, methyl, trifluoromethyl, methoxy, CN, - -S0₂CH₃, - - C(=O)NH(CH₃), or - -C(=O)N(CH₃)₂,

(2) naphthyl,

(3) pyridyl,

(4) isoquinolinyl, or

(5) quinolinyl; R² is:

(1 ) H,

(2) CH₂- -C(O)NH(C_1-4 alkyl), or

(3) CH₂- -C(O)N(C_1-4 alkyl)₂; R³ is:

(1 ) H,

(2) C_1-5 alkyl,

(3) (CH₂)_1-2-OH,

(4) (CH₂)_1-2-0- -C_1-4 alkyl,

(5) (CH₂)_1-2- -NH₂,

(6) (CH₂)_1-2-NH(C_1-4 alkyl),

(7) (CH₂)_1-2-N(C_1-4 alkyl)₂,

(8) (CH₂)_1-2-N(0- -C_1-4 alkyl)-C_1-4 alkyl,

(9) (CH₂)_1-2 - -NH- -CH₂-phenyl,

(10) (CH₂)_1-2- -N(CH₃)-CH₂-phenyl,

(1 1 ) (CH₂)_1-2-NH - -C(O)- -C_1-4 alkyl,

(12) (CH₂)_1-2- - N(CH₃)- - C(O)- -C_1-4 alkyl,

(13) (CH₂)_1-2- -NH- -C(O)-phenyl,

(14) (CH₂)_1-2-N(CH₃)-C(O)-phenyl,

(15) (CH₂)_1-2-NH- -C(O)N(C_1-4 alkyl)₂,

(16) (CH₂)_1-2- - N(CH₃)- - C(O)NH(C_1-4 alkyl),

(17) (CH₂)_1-2- - N(CH₃)- - C(O)NH(C_1-4 alkyl)₂,

(18) (CH₂)_1-2-NH- -C(S)N(C_1-4 alkyl)₂,

(19) (CH₂)_1-2-N(CH₃)-C(S)NH(C_1-4 alkyl),

(20) (CH₂)_1-2-N(CH₃)-C(S)N(C_1-4 alkyl)₂,

(21 ) (CH₂)_1-2-N-H- -S02- -C_1-4 alkyl,

(22) (CH₂)_1-2-N(CH₃)-S0₂-C_1-4 alkyl,

(23) (CH₂)_1-2-phenyl,

(24) (CH₂)_1-2- -OCH₂-phenyl,

(25) (CH₂)_1-2-HetC, where HetC is a heteroaromatic ring selected from the group consisting of pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl, wherein the hetero aromatic ring is optionally substituted with 1 or 2 substituents each of which is independently halo or a C_1-4 alkyl, or

(26) (CH₂)₁_₂-HetD, where HetD is a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl; wherein the saturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently oxo or a C_w alkyl; R⁴ is

(1) H,

(2) C_1-4 alkyl,

(3) (CH₂)_1-3L¹ or ΟΗ(ΟΗ₃)-ΐ , wherein L¹ is:

(a) - -O- -d.₄ alkyl,

(b) - -CF₃,

(c) - -CO₂- -C_1-4 alkyl,

(d) - -NH(C_1-4 alkyl),

(e) - -N(C_1-4 alkyl)₂,

(f) - -S- -C_1-4 alkyl,

(g) — C₃-6 cycloalkyl, which is optionally substituted with— C_1-4 alkyl, - - OCH₃, — CF₃, - -OH, phenyl, morpholinyl optionally substituted with CH₃, piperidinyl optionally substituted with CH₃, or piperazinyl optionally substituted with CH₃,

(i) aryl selected from the group consisting of phenyl and naphthyl, where the phenyl is optionally substituted with 1 or 2 substituents each of which is independently halo, - - CH₃, - -OCH₃, - -CF₃, or - -OH,

(1) l-azabicyclo[4.4.0]decyl,

(4) C₁-₃ alkyl, either of which is substituted with:

(a) - -C0₂- -C_1-4 alkyl and with - -SCH₃ or - -SCH₂CH₃, (b) a saturated heterocyclic ring and with either a C₃-6 cycloalkyl or a heteroaryl, wherein

(i) the saturated heterocyclic ring is selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl, wherein the saturated ring is optionally substituted with 1 or 2 methyl groups, and

(ii) the heteroaryl is selected from the group consisting of pyridyl, pyrimidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, and furanyl,

(c) two C3-6 cycloalkyl groups that are the same or different,

(5) (CH₂)₀.iC(CH₃)₂(CH₂)_0-1-L² wherein L² is -C0₂-C_1-4 alkyl or a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl, wherein the saturated ring is optionally substituted with 1 or 2 methyl groups,

(6) CH(CH₃)CH₂- -0- -C₁.4 alkyl,

(7) (CH₂)_1-2CH=CH,,

(8) C₃-7 cycloalkyl optionally substituted with -C₁ alkyl, - -OH, - -OCH₃, - -CF₃, phenyl, or a saturated heterocyclic ring selected from the group consisting of piperidinyl, piperazinyl, and morpholinyl, where the saturated heterocyclic ring is optionally substituted with 1 or 2 methyl groups, (9) aryl selected from the group consisting of phenyl, naphthyl and indanyl, where the phenyl is optionally substituted with — C_1-4 alkyl, — OCH₃, - - CF₃, or a saturated heterocyclic ring selected from the group consisting of piperidinyl, piperazinyl, and morpholinyl, where the saturated heterocyclic ring is optionally substituted with 1 or 2 methyl groups,

(10) adamantyl which is optionally substituted with methyl or OH,

(11) heteroaryl selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, and thiochromanyl in which the S atom is optionally in the form of a monoxide or dioxide, where the heteroaryl is optionally substituted with 1 or 2 substituents each of which is independently a — CH₃, - -OCH₃, or a saturated heterocyclic ring selected from the group consisting of piperidinyl, piperazinyl, and morpholinyl, where the saturated heterocyclic ring is optionally substituted with 1 or 2 methyl groups, (12) a saturated heterocyclic ring selected from the group consisting of piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, thiadiazepanyl, dithiazepanyl, azepanyl, diazepanyl, thiadiazinanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl, wherein the saturated heterocyclic ring is optionally substituted (i) with from 1 to 6 methyls, (ii) with 1 or 2 substituents each of which is independently - -CF₃, - -C(O)CH₃, - -C(O)C(O)N(CH₃)₂, or oxo and (iii) with - -CH₂- cyclopropyl, benzyl, - - C(O)CH₂-morpholinyl, or - - C(O)CH₂-piperidinyl, or

(13) l-azabicyclo[2.2.2]octyl or l-azabicyclo[4.4.0]decyl.

A first sub-class of the second class includes compounds of Formula IV, and pharmaceutically acceptable salts thereof, wherein Y is O; T is 4-fluorophenyl; R² is H; R³ is H; and all other variables are as defined in the first class.

A second sub-class of the second class includes compounds of Formula IV, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined in the second class, and wherein any ring nitrogen in any saturated heterocyclic ring contained in R³ and R⁴ is a tertiary amine per se or is a tertiary amine formed by attachment of the ring nitrogen to the rest of the molecule via a carbon atom or by attachment of a substituent group on the ring nitrogen via a carbon atom in the substituent.

A third sub-class of the second class includes compounds of Formula IV, and pharmaceutically acceptable salts thereof, wherein each of the variables is as defined in the first sub-class, and wherein any ring nitrogen in any saturated heterocyclic ring contained in R³ and R⁴ is a tertiary amine per se or is a tertiary amine formed by attachment of the ring nitrogen to the rest of the molecule via a carbon atom or by attachment of a substituent group on the ring nitrogen via a carbon atom in the substituent.

Another embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds set forth in Examples 1 to 87 below.

Still another embodiment of the present invention is a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds set forth in Examples 1, 3, 4 to 6, 10, 13, 15, 17, 19, 20, 23, 36, 38 to 47, 49, 51, 57 to 61, 76 to 78, 80, 81, 84, 86 and 87 of the application.

The compounds can be synthesized by using the following reaction schemes.

33

Additional information on the synthesis of the compounds is detailed in U.S. Publication No. 20080009490.

Further integrase inhibitors include those disclosed in US Publication No. 20090221571. The compounds are 3-hydroxy_-4-oxo_-4H-pyrido[1,2-a]pyrimidine-2- carboxamide compounds of Formula I, and pharmaceutically acceptable salts thereof:

whereinR¹, R², R³, and R⁴ are each independently: (1) R^A, (2) R^E, (3) C(O)R^A,

(4) C(O)R^E, (5) C(O)OR^A, (6) C(O)OR^E, (7) C(O)N(R^A)R^B, (8)

C(O)N(R^A)R^E, (9) OC(O)R^A, (10) OC(O)R^E, (II) OC(O)N(R^A)R^B, (12)

OC(O)N(R^A)R^E, (13) N(R^A)R^B, (14) N(R^A)R^E (15) N(R^A)C(O)R^B, (16)

N(R^A)C(O)R^E, (17) N(R^A)C(O)OR^B, (18) N(R^A)C(O)OR^E, (19) N(R^A)C(O)N(R^A)R^B,

(20) N(R^A)C(O)N(R^A)R^E (21) N(R^A)C(O)C(O)N(R^A)R^B, (22)

N(R^A)C(O)C(O)N(R^A)R^E (23) N(R^A)S(O)₂R^B, (24) N(R^A)S(O)₂R^E, (25)

N(R^A)S(O)₂N(R^A)R^B, (26) N(R^A)S(O)₂N(R^A)R^E, (27) OR^A, (28) OR^E, (29) SR^A, S(O)R^A, or S(O)₂R^A, (30) SR^E, S(O)R^E, or S(O)₂R^E, (31) S(O)₂N(R^A)R^B, (32) S(O)₂N(R^A)R^E, (33) CycA, AryA, HetA, or HetR, (34) C_1-6 alkyl substituted with CycA, AryA, HetA, or HetR, (35) J-CycA, J- AryA, J-HetA, or J- HetR,

(36) C_1-6 alkylene-J-CycA, C_1-6 alkylene-J-AryA, C_1-6 alkylene-J-HetA, or C_1-6 alkylene-J- HetR, (37) J-C_1-6 alkylene-CycA, J-C_1-6 alkylene-AryA, J-C_1-6 alkylene-HetA, or J-C_1-6 alkylene-HetR, (38) C_1-6 alkylene-J-C_1-6 alkylene-CycA, C_1-6 alkylene-J-C_1-6 alkylene-AryA, C_1-6 alkylene-J-C_1-6 alkylene-HetA, or C_1-6 alkylene-J-C_1-6 alkylene-HetR, or (39) halogen;with the proviso that no more than one of R¹, R², R³, and R⁴ is other than R^A, R^E, or C_1-6 alkyl substituted with CycA, AryA, HetA, or HetR;

R⁵ is R^A, R^E, or R^F;

R⁶ is C_1-6 alkyl substituted with CycB, AryB, HetB, or HetS;

J is: (1) 0, (2) S, (3) S(O), (4) S(O)₂, (5) C(O), (6) C(O)0,

(7) C(O)N(R^A), (8) C(O)N(R^F), (9) N(R^A), (10) N(R^F), ( 11) N(R^A)C(O),

(12) N(R^F)C(O), (13) N(R^A)C(O)C(O), (14) N(R^F)C(O)C(O), (15)

N(R^A)C(O)0, (16) N(R^F)C(O)0 (17) N(R^A)S(O)₂, or (18) N(R^F)S(O)₂; each R^A is independently H or C_1-6 alkyl; each R^B is independently H or C_1-6 alkyl; each R^F is independently C_1-6 haloalkyl or C_1-6 alkyl substituted with OH, O- - C_1-6 alkyl, O- - C_1-6 haloalkyl, CN, N0₂, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C0₂R^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, N(R^A)- -0- -C_1-6 alkyl, N(R^A)C(O)R^B, N(R^A)C0₂R^B, N(R^A)S(O)₂R^B, N(R^A)S(O)₂N(R^A)R^B, OC(O)R^A, OC(O)N(R^A)R^B, or N(R^A)C(O)N(R^A)R^B; each R^F is independently C_1-6 alkyl substituted with CycA, AryA, HetA, or HetR; each CycA is independently C₃-8 cycloalkyl which is optionally substituted with a total of from 1 to 6 substituents, wherein: (i) from zero to 6 substituents are each independently: (1) halogen,

(2) CN (3) C_1-6 alkyl, (4) OH, (5) 0- -C_1-6 alkyl, (6) C_1-6 haloalkyl, or (7) O- - C_1-6 haloalkyl, and (ii) from zero to 2 substituents are each independently: (1) CycE, (2) AryE, (3) O-AryE, (4) HetE, (5) HetF, or

(6) C_1-6 alkyl substituted with CycE, AryE, O-AryE, HetE, O-HetE, or HetF; each AryA is independently aryl which is optionally substituted with a total of from 1 to 6 substituents, wherein: (i) from zero to 6 substituents are each independently: (1) C_1-6 alkyl, (2) C_1-6 alkyl substituted with OH, 0- -C_1-6 alkyl, 0- -C_1-6 haloalkyl, CN, N0₂, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C0₂R^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, N(R^A)C(O)R^B, N(R^A)C0₂R^B, N(R^A)S(O)₂R^B, N(R^A)S(O)₂N(R^A)R^B, OC(O)R^A, OC(O)N(R^A)R^B, N(R^A)C(O)N(R^A)R^B, or N(R^A)C(O)C(O)N(R^A)R^B, (3) 0- --C_1-6 alkyl,

(4) C_1-6 haloalkyl, (5) 0- -C_1-6 haloalkyl, (6) OH, (7) halogen, (8)

CN, (9) N0₂, (10) N(R^A)R^B, (11) C(O)N(R^A)R^B, (12) C(O)R^A, (13) C(O)- - d.6 haloalkyl, (14) C(O)OR^A, (15) OC(O)R^A, (16) OC(O)N(R^A)R^B, (17) SR^A,

(18) S(O)R^A, (19) S(O)₂R^A, (20) S(O)₂N(R^A)R^B, (21) N(R^A)S(O)₂R^B, (22) N(R^A)S(O)₂N(R^A)R^B, (23) N(R^A)C(O)R^B, (24) N(R^A)C(O)N(R^A)R^B, (25) N(R^A)C(O)- -C(O)N(R^A)R^B, or (26) N(R^A)C0₂R^B, and (ii) from zero to 2 substituents are each independently: (1) CycE, (2) O-CycE (3) AryE, (4) O-AryE, (5) HetE, (6) O-HetE, (7) HetF, (8) 0-HetF or (9) C_1-6 alkyl substituted with CycE, O-CycE, AryE, O-AryE, HetE, O-HetE, O-HetF, or HetF; each HetA is independently heteroaryl which is optionally substituted with a total of from 1 to 6 substituents, wherein:

(i) from zero to 6 substituents are each independently: (1) C_1-6 alkyl, (2) C_1-6 alkyl substituted with OH, 0- -C_1-6 alkyl, 0- -C_1-6 haloalkyl, CN, N0₂, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C0₂R^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, N(R^A)C(O)R^B, N(R^A)C0₂R^B, N(R^A)S(O)₂R^B, N(R^A)S(O)₂N(R^A)R^B, OC(O)R^A, OC(O)N(R^A)R^B, N(R^A)C(O)N(R^A)R^B, or N(R^A)C(O)C(O)N(R^A)R^B, (3) 0- -C_1-6 alkyl, (4) C_1-6 haloalkyl, (5) 0- --C_1-6 haloalkyl, (6) OH, (7) oxo, (8) halogen, (9) CN, (10) N0₂,

(11 ) N(R^A)R^B, (12) C(O)N(R^A)R^B, (13) C(O)R^A, (14) C(O)- -C_1-6 haloalkyl, (15) C(O)OR^A, (16) OC(O)R^A, (17) OC(O)N(R^A)R^B, (18) SR^A, (19) S(O)R^A, (20) S(O)₂R^A, (21) S(O)₂N(R^A)R^B, (22) N(R^A)S(O)₂R^B, (23)

N(R^A)S(O)₂N(R^A)R^B, (24) N(R^A)C(O)R^B, (25) N(R^A)C(O)N(R^A)R^B, (26) N(R^A)C(O)- -C(O)N(R^A)R^B, or (27) N(R^A)C0₂R^B, and (ii) from zero to 2 substituents are each independently: (1) CycE, (2) O-CycE (3) AryE, (4) O-AryE, (5) HetE, (6) O-HetE, (7) HetF, (8) O-HetF or (9) C_1-6 alkyl substituted with CycE,

O-CycE, AryE, O-AryE, HetE, O-HetE, O-HetF, or HetF; each HetR is independently (i) a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)₂ or (ii) a 6- to 10-membered saturated or mono- unsaturated, bridged or fused beterobicyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)₂; and wherein the saturated or mono-unsaturated heterocyclic or heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents, wherein:

(i) from zero to 4 substituents are each independently halogen, CN, C_1-6 alkyl, OH, oxo, C(O)R^A, C0₂R^A, S(O)R^A, SR^A, S(O)₂R^A, 0- -C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkylene-CN, C_1-6 alkylene-OH, or C_1-6 alkylene-O- - C_1-6 alkyl; and

(ii) from zero to 2 substituents are each independently CycE, O-CycE, AryE, O-AryE, HetE, O-HetE, HetF, O-HetF, or C_1-6 alkyl substituted with CycE, O-CycE, AryE, O-AryE, HetE, O-HetE, HetF, 0-HetF;CycB independently has the same definition as CycA;AryB independently has the same definition as AryA;HetB independently has the same definition as HetA;HetS independently has the same definition as HetR; each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic, or (iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; each heteroaryl is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic is optionally S(O) or S(O)₂; each CycE is independently C3-8 cycloalkyl which is optionally substituted with a total of from 1 to 4 substituents, wherein: (i) from zero to 4 substituents are each independently halogen, C_1-6 alkyl, OH, O- - C _1-6 alkyl, C _1-6 haloalkyl, or O- - C _1-6 haloalkyl, and (ii) from zero to 2 substituents are each independently CycG, AryG, HetG, HetH, or C_1-6 alkyl substituted with CycG, AryG, O-AryG, HetG, or HetH; each AryE is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with a total of from 1 to 5 substituents, wherein: (i) from zero to 5 substituents are each independently halogen, CN, N0₂, C_1-6 alkyl, C _1-6 haloalkyl, OH, 0- -C _1-6 alkyl, 0- -C _1-6 haloalkyl, C(O)N(R^A)R^B, C(O)R^A, C0₂R^A, SR^A, S(O)R^A, S0₂R^A, S0₂N(R^A)R^B, or S0₂N(R^A)C(O)R^B, and (ii) from zero to 2 substituents are each independently CycG, AryG, HetG, HetH, or C_1-6 alkyl substituted with CycG, AryG, O-AryG, HetG, or HetH; each HetE is independently (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, or (ii) a 9- or 10-membered fused heterobicyclic ring selected from 2,3- dihydrobenzo-1,4-dioxinyl and benzo-1,3-dioxolyl; and wherein the heteroaromatic ring or the heterobicyclic ring is optionally substituted with a total of from 1 to 4 substituents wherein: (i) from zero to 4 substituents are each independently halogen, C_1-6 alkyl, C_1-

6 haloalkyl, 0- -C _1-6 alkyl, 0- -C _1-6 haloalkyl, OH, C(O)R^A, C0₂R^A, S0₂R^A, N(R^A)R^B, N(R^A)C(O)N(R^A)R^B, or N(R^A)C0₂R^B, and (ii) from zero to 2 substituents are each independently CycG, AryG, HetG, HetH, or C _1-6 alkyl substituted with CycG, AryG, O-AryG, HetG, or HetH; each HetF is independently a 4- to 7-membered, saturated or mono- unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)₂, and wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with a total of from 1 to 4 substituents, wherein:

(i) from zero to 4 substituents are each independently halogen, CN, C_1-6 alkyl, OH, oxo, O- -C₁.6 alkyl, C _1-6 haloalkyl, 0- -C _1-6 haloalkyl, C(O)R^A, C0₂R^A, or S0₂R^A, and

(ii) from zero to 2 substituents are each independently CycG, AryG, HetG, HetH, or C_1-6 alkyl substituted with CycG, AryG, O-AryG, HetG, or HetH; each CycG is independently C3-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, C_1-6 alkyl, OH, O- - C _1-6 alkyl, C_1-6 haloalkyl, or O- - C _1-6 haloalkyl; each AryG is independently phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with from 1 to 5 substituents each of which is independently halogen, CN, N0₂, d.₆ alkyl, C _1-6 haloalkyl, OH, 0- --C_1-6 alkyl, 0- --C_1-6 haloalkyl, C(O)N(R^A)R^B, C(O)R^A, C0₂R^A, SR^A, S(O)R^A, S0₂R^A, S0₂N(R^A)R^B, or S0₂N(R^A)C(O)R^B; each HetG is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein each N is optionally in the form of an oxide, and wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C_1-6 alkyl, C_1-6 haloalkyl, O- - C_1-6 alkyl, O- - C_1-6 haloalkyl, OH, C(O)R^A, C0₂R^A, S0₂R^A, N(R^A)R^B, N(R^A)C(O)N(R^A)R^B, or N(R^A)C0₂R^B; andeach HetH is independently a 4- to 7-membered, saturated or mono-unsaturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or S(O)₂, and wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents, each of which is independently halogen, CN, C_1-6 alkyl, OH, oxo, O- -C_1-6 alkyl, C_1-6 haloalkyl, 0- --C_1-6 haloalkyl, C(O)R^A, C0₂R^A, or S0₂R^A

The compounds can be prepared using the following general schemes:

R

Additional experimental details are provided in U.S. Publication 200900221571.

Still further integrase inhibitor compounds include those disclosed in U.S. Pubikalion No. 20070179196. These compounds are hydroxy polyhydro-2,6-naphthyridine dione compounds of Formula I, and pharmaceutically acceptable salts thereof:

wherein: bond in the ring is a single bond or a double bond; R¹ is — C_1-6 alkyl, R^J, or — C_1-6 alkyl substituted with R^J, wherein R^J is: (A) (i) aryl or (ii) aryl fused to a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S or (iii) aryl substituted on two adjacent ring carbons with alkylenedioxy, wherein the aryl or fused aryl or alkylenedioxy aryl is:

(a) optionally substituted with from 1 to 5 substituents each of which is independently: — C_1-6 alkyl optionally substituted with - -OH, - - O- - C _1-6 alkyl, - - O- - C _1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, - - S0₂N(R^A)R^B, - -N(R^A)C(=O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - - OC(=O)N(R^A)R^B, or - -N(R^A)C(=O)N(R^A)R^B, (2) -O-C^ alkyl, (3) - -C _1-6 haloalkyl,

(4) - -O- -C_1-6 haloalkyl, (5) - -OH, halogen, (7) - -CN, (8) - -N0₂,

(9) - -N(R^A)R^B, (10) - -C(=O)N(R^A)R^B, (11) - -C(=O)R^A, (12) - -C0₂R^A,

(13) - -SR^A, (14) - -S(=O)R^A, (15) - -S0₂R^A, (16) - -S0₂N(R^A)R^B, (17)

N(R^A)S0₂R^B, (18) - -N(R^A)S0₂N(R^A)R^B, (19) - -N(R^A)C(=O)R^B, (20)

N(R^A)C(=O)- -C(=O)N(R^A)R^B, (21) - -N(R^A)C0₂R^B, or (22) - -N(R^A)C(=O)N(R^A)R^B, and

(b) optionally substituted with 1 or 2 substituents each of which is independently:

(1) C₃-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C _1-6 alkyl, OH, O- - C _1-6 alkyl, C _1-6 haloalkyl, O- - C _1-6 haloalkyl, C_1-6 alkylene-CN, C_1-6 alkylene-OH, or C _1-6 alkylene-O- - C_1-6 alkyl, (2) aryl or C_1-6 alkyl substituted with aryl, wherein in either case the aryl is optionally substituted with from 1 to 5 substituents each of which is independently halogen, CN, N0₂, C_1-6 alkyl, C _1-6 haloalkyl, OH, 0- -C_1-6 alkyl, 0- --C_1-6 haloalkyl, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C(O)OR^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, S(O)₂N(R^A)C(O)R^B, C _1-6 alkylene-CN, C _1-6 alkylene- N0₂, C_1-6 alkylene-OH, C_1-6 alkylene-0- -C_1-6 alkyl, C _1-6 alkylene-0- -C _1-6 haloalkyl, C _1-6 alkylene-N(R^A)R^B, C_1-6 alkylene-C(O)N(R^A)R^B, C_1-6 alkylene-C(O)R^A, C_1-6 alkylene- C(O)OR^A, C₁.6 alkylene-SR^A, C _1-6 alkylene-S(O)R^A, C _1-6 alkylene-S(O)₂R^A, C_1-6 alkylene- S(O)₂N(R^A)R^B, or C _1-6 alkylene-S(O)₂N(R^A)C(O)R^B, (3) - -HetA, (4) - -C(=O)- -HetA, or (5) - - HetB; wherein each HetA is independently a C₄-7 azacycloalkyl or a C3-6 diazacycloalkyl, either of which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C_1-6 alkyl, OH, oxo, O- - C_1-6 alkyl, C_1-6 haloalkyl, S(O)₂R^A, C₁.6 alkylene-CN, C_1-6 alkylene-OH, or C _1-6 alkylene-0- -C_1-6 alkyl; and

wherein each HetB is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, N0₂, C_1-6 alkyl, C _1-6 haloalkyl, OH, 0- -C _1-6 alkyl, 0- -C_1-6 haloalkyl, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C(O)OR^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, S(O)₂N(R^A)C(O)R^B, C _1-6 alkylene-CN, C_1-6 alkylene-N0₂, C_1-6 alkylene-OH, C_1-6 alkylene-O- -C_1-6 alkyl, C_1-6 alkylene-0- -C_1-6 haloalkyl, C_1-6 alkylene-N(R^A)R^B, C_1-6 alkylene-C(O)N(R^A)R^B, C_1-6 alkylene-C(O)R^A, C_1-6 alkylene-C(O)OR^A, C_1-6 alkylene-SR^A, C_1-6 alkylene-S(O)R^A, C_1-6 alkylene-S(O)₂R^A, C_1-6 alkylene-S(O)₂N(R^A)R^B, or C_1-6 alkylene- S(O)₂N(R^A)C(O)R^B; or (B) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is:

(a) optionally substituted with from 1 to 4 substituents each of which is independently: (1) — C_1-6 alkyl optionally substituted with - -OH, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, - -CN, - -N0₂, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, - - S0₂N(R^A)R^B, - -N(R^A)C(=O)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, - - OC(=O)N(R^A)R^B, or - -N(R^A)C(=O)N(R^A)R^B, (2) - -0- -C_1-6 alkyl, (3) - -C_1-6 haloalkyl,

(4) - -O- -C_1-6 haloalkyl, (5) - -OH, (6) halogen, (7) - -CN, (8) - -N0₂,

(9) - -N(R^A)R^B, (10) - -C(=O)N(R^A)R^B, (11) - -C(=O)R^A, (12) - -C0₂R^A,

(13) - -SR^A, (14) - -S(=O)R^A, (15) - -S0₂R^A, (16) - -S0₂N(R^A)R^B, (17)

N(R^A)S0₂R^B, (18) - -N(R^A)S0₂N(R^A)R^B, (19) - -N(R^A)C(=O)R^B, (20)

(b) optionally substituted with 1 or 2 substituents each of which is independently: (1) C₃-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C_1-6 alkyl, OH, O- - C_1-6 alkyl, C_1-6 haloalkyl, O- - C_1-6 haloalkyl, C_1-6 alkylene-CN, C_1-6 alkylene-OH, or C_1-6 alkylene-O- - C_1-6 alkyl, (2) aryl or C_1-6 alkyl substituted with aryl, wherein in either case the aryl is optionally substituted with from 1 to 5 substituents each of which is independently halogen, CN, N0₂, C_1-6 alkyl, C_1-6 haloalkyl, OH, O- -d.6 alkyl, 0- - -C_1-6 haloalkyl, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C(O)OR^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, S(O)₂N(R^A)C(O)R^B, C_1-6 alkylene-CN, C_1-6 alkylene-N0₂, C_1-6 alkylene-OH, C_1-6 alkylene-O- - C_1-6 alkyl, C_1-6 alkylene-O- - C_1-6 haloalkyl, C_1-6 alkylene- N(R^A)R^B, C₁.6 alkylene-C(O)N(R^A)R^B, C_1-6 alkylene-C(O)R^A, C_1-6 alkylene-C(O)OR^A, C_1-6 alkylene-SR^A, C_1-6 alkylene-S(O)R^A, C_1-6 alkylene-S(O)₂R^A, C_1-6 alkylene-S(O)₂N(R^A)R^B, or C₁.6 alkylene-S(O)₂N(R^A)C(O)R^B, (3) - -HetA, (4) - -C(=O)- -HetA, or (5) - -HetB; wherein HetA and HetB are each independently as defined above; R² is - - H or— C_1-6 alkyl; R³ independently has the same definition as R⁴, with the proviso that at least one of R³ and R⁴ is - - H or — C_1-6 alkyl; or, as an alternative, when bond is a double bond, R² and R³ together with the carbon atoms to which each is attached form:

(i) a benzene ring which is optionally substituted with a total of from 1 to 4 substituents wherein (a) from zero to 4 substituents are each independently one of substituents (1) to (22) as defined in part (A)(a) of the definition of R¹ and (b) from zero to 2 substituents are each independently one of the substituents (1) to (5) as defined in part (A)(b) of the definition of R¹, or (ii) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with a total of from 1 to 3 substituents wherein (a) from zero to 3 substituents are each independently one of substituents (1) to (22) as defined in part (B)(a) of the definition of R¹ and (b) from zero to 2 substituents are each independently one of the substituents (1) to (5) as defined in part (B)(b) of the definition of R¹; R⁴ is: (1) - -H, (2) - -C_1-6 alkyl,

(3) - -C_1-6 haloalkyl, (4) - -C_1-6 alkyl substituted with - -OH, - -0- -C_1-6 alkyl, - -O- - C_1-6 haloalkyl, - -CN, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -C(=O)- -N(R^A)- - C_1-6 alkylene-OR^B with the proviso that the - - N(R^A)- - moiety and the - - OR^B moiety are not both attached to the same carbon of the - -C_1-6 alkylene-moiety, - -S(O)_nR^A, - -S0₂N(R^A)R^B, - - N(R^A)C(=O)- -R^B, - -N(R^A)C0₂R^B, - -N(R^A)S0₂R^B, - - N(R^A)S0₂N(R^A)R^B, N(R^A)C(=O)N(R^A)R^B, or - -OC(=O)N(R^A)R^B, (5) - -C(=O)R^A, (6) - -C0₂R^A, (7) - -C(=O)N(R^A)R^B, (8) - -C(=O)- -N(R^A)- -C₁_6 alkylene-OR^B with the proviso that the - -

N(R^A)- - moiety and the OR^B moiety are not both attached to the same carbon of the — C_1-6 alkylene-moiety, (9) - -N(R^A)- -C(=O)- -R^B, (10) - -N(R^A)- -C(=O)- -

C(=O)N(R^A)R^B, (11) - -N(R^A)S0₂R^B, (12) - - N(R^A)S0₂N(R^A)R^B, (13)

N(R^A)C(=O)N(R^A)R^B, (14) - -OC(=O)N(R^A)R^B, (15) R^K, (16) - -C(=O)- -R^K,

(17) - -C(=O)N(R^A)- -R^K, (18) - -C(=O)N(R^A)- -C₁.₆ alkylene-R^K, (19) - -C_1-6 alkyl substituted with - -R^K, (20) - -C_1-6 alkyl substituted with - -C(=O)- -R^K, (21) - -C_1-6 alkyl substituted with - -C(=O)N(R^A)- -R^K, (22) - -C_1-6 alkyl substituted with - -

C(=O)N(R^A)- -C₁_6 alkylene-R^K, (23) - -C(=O)N(R^A)R^c, (24) - -CN, (25) halogen, (26) - - N(R^A)R^B, or (27) - -N(R^A)C0₂R^B; wherein R^K is (i)C₃-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C_1-6 alkyl, OH, 0- --C_1-6 alkyl, C_1-6 haloalkyl, 0- -C_1-6 haloalkyl, C_1-6 alkylene-CN, C_1-6 alkylene-OH, or C_1-6 alkylene-O- - C_1-6 alkyl, (ii) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently— C_1-6 alkyl, — C_1-6 alkylene-OH, - -C_1-6 alkylene-O- -C_Le alkyl, - -C_1-6 alkylene-O- -Q.e haloalkyl, - -C_1-6 alkylene-N(R^A)R^B, - -d_ 6 alkylene-C(=O)N(R^A)R^B, - -C_1-6 alkylene-C(=O)R^A, - -C_1-6 alkylene-C0₂R^A, - -C _1-6 alkylene- S(O)_nR^A, - -O- -C_1-6 alkyl, - -C_1-6 haloalkyl, - -0- -C_1-6 haloalkyl, - -OH, halogen, - - N(R^A)R^B, - - C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, or - -S0₂N(R^A)R^B, (iii) HetK, which is a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is:

(a) optionally substituted with from 1 to 6 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, oxo, - -C(=O)N(R^A)R^B, - -C(=O)C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, or - - S0₂N(R^A)R^B; and (b) optionally substituted with: (1) C₃-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C_1-6 alkyl, OH, 0- -C_1-6 alkyl, C_1-6 haloalkyl, Q-C_1-6 haloalkyl, C_1-6 alkylene-CN, C_1-6 alkylene-OH, or C_1-6 alkylene-O- - C_1-6 alkyl, (2) aryl which is optionally substituted with from 1 to 5 substituents each of which is independently halogen, CN, N0₂, C_1-6 alkyl, C_1-6 haloalkyl, OH, 0- -C_1-6 alkyl, 0- --C_1-6 haloalkyl, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C(O)OR^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, S(O)₂N(R^A)C(O)R^B, C_1-6 alkylene-CN, C_1-6 alkylene- N0₂, C_1-6 alkylene-OH, C_1-6 alkylene-0- -C_1-6 alkyl, C_1-6 alkylene-0- -C_1-6 haloalkyl, C_1-6 alkylene-N(R^A)R^B, C_1-6 alkylene-C(O)N(R^A)R^B, C_1-6 alkylene-C(O)R^A, C_1-6 alkylene- C(O)OR^A, C_1-6 alkylene-SR^A, C_1-6 alkylene-S(O)R^A, C_1-6 alkylene-S(O)₂R^A, C_1-6 alkylene- S(O)₂N(R^A)R^B, or C_1-6 alkylene-S(O)₂N(R^A)C(O)R^B, or (3) HetC,

wherein HetC is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally fused with a benzene ring, and the optionally fused heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, N0₂, d.₆ alkyl, C_1-6 haloalkyl, OH, 0- --C_1-6 alkyl, 0- --C_1-6 haloalkyl, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C(O)OR^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, S(O)₂N(R^A)C(O)R^B, C_1-6 alkylene-CN, C_1-6 alkylene-N0₂, C_1-6 alkylene-OH, C_1-6 alkylene-O- -C_1-6 alkyl, C_1-6 alkylene-0- -C_1-6 haloalkyl, C_1-6 alkylene-N(R^A)R^B, C_1-6 alkylene- C(O)N(R^A)R^B, d.₆ alkylene-C(O)R^A, C_1-6 alkylene-C(O)OR^A, C_1-6 alkylene-SR^A, C_1-6 alkylene-S(O)R^A, C_1-6 alkylene-S(O)₂R^A, C_1-6 alkylene-S(O)₂N(R^A)R^B, or C_1-6 alkylene- S(O)₂N(R^A)C(O)R^B, or

(iv) - - HetL, which is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, N0₂, C_1-6 alkyl, C_1-6 haloalkyl, OH, 0- -C_1-6 alkyl, 0- -C_1-6 haloalkyl, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C(O)OR^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, S(O)₂N(R^A)C(O)R^B, C_1-6 alkylene-CN, C_1-6 alkylene-N0₂, C_1-6 alkylene-OH, C_1-6 alkylene-O- -CL6 alkyl, C_1-6 alkylene-O- -C₁.e haloalkyl, C_1-6 alkylene-N(R^A)R^B, d_₆ alkylene- C(O)N(R^A)R^B, C_1-6 alkylene-C(O)R^A, C_1-6 alkylene-C(O)OR^A, C_1-6 alkylene-SR^A, C_1-6 alkylene-S(O)R^A, C_1-6 alkylene-S(O)₂R^A, C_1-6 alkylene-S(O)₂N(R^A)R^B, or C_1-6 alkylene- S(O)₂N(R^A)C(O)R^B;

R⁵ is: (1) - -H, (2) - -C_1-6 alkyl, (3) - -C₃-8 cycloalkyl optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C_1-6 alkyl, OH, 0- -C_1-6 alkyl, C_1-6 haloalkyl, 0- -C_1-6 haloalkyl, C_1-6 alkylene-CN, C_1-6 alkylene-OH, or C_1-6 alkylene-O- - C_1-6 alkyl, (4) — C_1-6 alkyl substituted with C₃-8 cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, C_1-6 alkyl, OH, O- - C_1-6 alkyl, C_1-6 haloalkyl, O- - C_1-6 haloalkyl, C_1-6 alkylene-CN, C_1-6 alkylene-OH, or C_1-6 alkylene-0- -C_1-6 alkyl, (5) - -C_1-6 alkyl substituted with aryl, wherein the aryl is optionally substituted with from 1 to 5 substituents each of which is independently halogen, CN, N0₂, C_1-6 alkyl, C_1-6 haloalkyl, OH, O- - C_1-6 alkyl, 0- -C_1-6 haloalkyl, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C(O)OR^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, S(O)₂N(R^A)C(O)R^B, C_1-6 alkylene-CN, C_1-6 alkylene-N0₂, C_1-6 alkylene-OH, C_1-6 alkylene-O- -C_Le alkyl, C_1-6 alkylene-O- -C₁.e haloalkyl, C_1-6 alkylene-N(R^A)R^B, C_1-6 alkylene-C(O)N(R^A)R^B, C_1-6 alkylene-C(O)R^A, C_1-6 alkylene-C(O)OR^A, C_1-6 alkylene-SR^A, C_1-6 alkylene-S(O)R^A, C_1-6 alkylene-S(O)₂R^A, C_1-6 alkylene-S(O)₂N(R^A)R^B, or C_1-6 alkylene- S(O)₂N(R^A)C(O)R^B, (6) - -C_1-6 alkyl substituted with HetD, wherein HetD is:

(i) a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with from 1 to 5 substituents each of which is independently halogen, — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, oxo, - -C(=O)N(R^A)R^B, - -C(=O)C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, or - - S0₂N(R^A)R^B; or

(ii) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently — C_1-6 alkyl, — C_1-6 haloalkyl, - - O- - C_1-6 alkyl, - - O- - C_1-6 haloalkyl, or hydroxy, (7) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently— C_1-6 alkyl, - - C_1-6 alkylene-OH, — C_1-6 alkylene-O- - C_1-6 alkyl, — C_1-6 alkylene-O- - C_1-6 haloalkyl, — C_1-6 alkylene-N(R^A)R^B, - -C_1-6 alkylene-C(=O)N(R^A)R^B, - -C_1-6 alkylene-C(=O)R^A, - -C_1-6 alkylene- C0₂R^A, - -C_1-6 alkylene-S(O)_nR^A, - -0- -C_1-6 alkyl, - -C_1-6 haloalkyl, - -0- -C_1-6 haloalkyl, - -OH, halogen, - -CN, - -N0₂, - - N(R^A)R^B, - -N(R^A)C(=O)R^B, - -N(R^A)C(=O)- -C_1-6 haloalkyl, - - N(R^A)C(=O)N(R^A)R^B, - -N(R^A)C0₂R^B, - -N(R^A)S(O)_nR^B, - -C(=O)N(R^D)R^E, - -C(=O)R^A, - - C0₂R^A, - -S(O)_nR^A, or - -S0₂N(R^D)R^E, (8) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, CN, N0₂, C_1-6 alkyl, C_1-6 haloalkyl, OH, 0- -C_1-6 alkyl, 0- -C_1-6 haloalkyl, N(R^A)R^B, C(O)N(R^A)R^B, C(O)R^A, C(O)OR^A, SR^A, S(O)R^A, S(O)₂R^A, S(O)₂N(R^A)R^B, S(O)₂N(R^A)C(O)R^B, C_1-6 alkylene-CN, C_1-6 alkylene-N0₂, C_1-6 alkylene-OH, C_1-6 alkylene-O- -C_1-6 alkyl, C_1-6 alkylene-0- -C_1-6 haloalkyl, C_1-6 alkylene-N(R^A)R^B, C_1-6 alkylene-C(O)N(R^A)R^B, C_1-6 alkylene-C(O)R^A, C_1-6 alkylene-C(O)OR^A, C_1-6 alkylene-SR^A, C_1-6 alkylene-S(O)R^A, C_1-6 alkylene-S(O)₂R^A, C_1-6 alkylene-S(O)₂N(R^A)R^B, or C_1-6 alkylene- S(O)₂N(R^A)C(O)R^B, (9) C_1-6 alkyl substituted with - -0- -C_1-6 alkyl, - -0- -C_1-6 haloalkyl, - - CN, - - N(R^A)R^B, - -C(=O)N(R^A)R^B, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, - -S0₂N(R^A)R^B, - - N(R^A)C(=O)- -R^B, - -N(R^A)C0₂R^B, or - -N(R^A)S0₂R^B, or (10) - -C_1-6 haloalkyl; each aryl is independently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fused carbocylic ring system in which at least one ring is aromatic, or

(iii) an 11- to 14-membered tricyclic, fused carbocyclic ring system in which at least one ring is aromatic; each R^A is independently H or C_1-6 alkyl; each R^B is independently H or C_1-6 alkyl; R^c is C_1-6 haloalkyl or C_1-6 alkyl substituted with - -C(=O)N(R^A)R^B, - -C(=O)R^A, - - C0₂R^A, - -S(O)_nR^A, - -S0₂N(R^A)R^B, N(R^A)R^B, - -N(R^A)C(=O)- -R^B, - -N(R^A)C0₂R^B, or - - N(R^A)S0₂R^B; each R^D and R^E are independently H or C_1-6 alkyl, or together with the N atom to which they are attached form a 4- to 7-membered saturated or mono-unsaturated heterocyclic ring optionally containing a heteroatom in addition to the nitrogen attached to R^D and R^E selected from N, O, and S, wherein the S is optionally oxidized to S(O) or S(O)₂, and wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, — CN, - - C_1-6 alkyl, - -OH, oxo, - -O- -C_1-6 alkyl, - --C_1-6 haloalkyl, - -C(=O)R^A, - -C0₂R^A, - -S(O)_nR^A, - -S0₂N(R^A)R^B, - - N(R^A)C(=O)- -R^B, - -N(R^A)C0₂R^B, or - -N(R^A)S0₂R^B; and each n is independently an integer equal to zero, 1, or 2.

The compounds can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples.

Additional experimental details are disclosed in U.S. Publication No. 20070179196. Further integrase inhibitor compounds include those disclosed in U.S. Publication No. 20070123524. The compounds are hydroxypyrimidinone carboxamides of Formula (I):

wherein

R¹ is

(1) - -H,

(2) — C₁-6 alkyl, which is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH,— CN, — O- - C₁-6 alkyl, - - O- - d-6 haloalkyl, - -C(=O)R^a, - -C0₂R^a, - -SR^a, - -S(=O)R^a, - -N(R R^b), - -C(=O)- -C₀-6 alkyl- N(R^aR^b), N(R^a)- -C(=O)- -Co-6 alkyl-N(R^bR^c), - -S0₂R^a, - -N(R^a)S0₂R^b, - -S0₂N(R^aR^b), - -N(R )- -C(=O)R^b,

or - -N(R²)C(=O)C(=O)N(R^aR^b),

(3) - -R^k,

(4) - -C₁-6 alkyl-R^k, wherein:

(i) the alkyl is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono- substituted) each of which is independently halogen, - -OH, — CN, — O- - C_{1- 6} alkyl, - - O- - C_{1- 6} haloalkyl, - -N(R^aR^b), - -N(R^a)C0₂R^b, - -N(R^a)C(=O)- -C₀-6 alkyl-N(R^bR^c), or - -N(R^a)- -C₂-6 alkyl-OH with the proviso that the - -OH is not attached to the carbon alpha to N(R ); and

(ii) the alkyl is optionally mono-substituted with - -R^s, - -C₁-6 alkyl-R^s, - -N(R^a)- - C(=O)- -Co-6 alkyl-R^s, - -N(R^a)- -C₀-6 alkyl-R^s, - -O- -C₀-6 alkyl-R^s, or - -N(R^a)- -C(=O)- -C₀-6 alkyl-R^s; wherein R^s is (a) aryl which is optionally substituted with one or more substituents (e.g., optionally from 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH, — C₁-6 alkyl, - - C₁-6 alkyl-OR^a, - -C₁-6 haloalkyl, - -O- -d-6 alkyl, - -O- -d-6 haloalkyl, methylenedioxy attached to two adjacent carbon atoms, or aryl; (b) a 4- to 8-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the saturated heterocyclic ring is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, — C₁-6 alkyl, — C₁-6 alkyl-OR^a, - -d-6 haloalkyl, - -O- -d-6 alkyl, - -O- -d-6 haloalkyl, - -C(=O)R^a, - -C0₂R^a, - - C(=O)- -Co-6 alkyl-N(R^aR^b), - -S0₂R^a, oxo, aryl, or - -C₁-6 alkyl-aryl; or (c) a 5- to 7- membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heteroaromatic ring is optionally substituted with one or more substituents (e.g., optionally 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, — C₁-6 alkyl, — C₁-6 alkyl-OR , - - C₁-6 haloalkyl, - -O- -d-6 alkyl, - -O- -d-6 haloalkyl, oxo, or aryl; (5) - -C₀-6 alkyl-O- -C₀-6 alkyl-R^k, (6) - -C₀-6 alkyl-S(O)_n- -C₀-6 alkyl-R^k, (7) - -O- -d-6 alkyl-OR^k, (8) - -O- -d-6 alkyl-O- -d-6 alkyl-R^k, (9) - -O- -d-6 alkyl-S(O)_nR^k, (10) - -C₀-6 alkyl-

N(R^a)- -R^k, (11) - -Co-6 alkyl-N(R^a)- -C₁-6 alkyl-R^k, (12) - -C₀-6 alkyl-N(R^a)- -C₁-6 alkyl-OR^k, (13) - -C₀-6 alkyl-C(=O)- -R^k, (14) - -C₀-6 alkyl-C(=O)N(R^a)- -C₀-6 alkyl- R^k, (15) - -Co-6 alkyl-N(R^a)C(=O)- -Co-6 alkyl-R^k, (16) - -C₀-6 alkyl-N(R^a)C(=O)- -0- - Co-6 alkyl-R^k, or (17) - -C₀-6 alkyl-N(R^a)C(=O)C(=O)R^k; R² is - -C_{1- 6} alkyl which is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently (1) halogen, (2) - -OH, (3) - -CN, (4) - -O- -d-6 alkyl, (5) - -0- -C_{1- 6} haloalkyl, (6) - -C(=O)R^a, (7) - -C0₂R^a, (8) - -SR^a, (9) - -S(=O)R^a, (10) - -N(R^aR^b), (11) - -C(=O)N(R^aR^b), (12) - -N(R^a)- -C(=O)- -d-6 alkyl-N(R^bR^c), (13) - -S0₂R^a, (14) - -N(R^a)S0₂R^b, (15) - -S0₂N(R^aR^b), (16) - -N(R^a)- -C(R^b)=O, (17)— d-8 cycloalkyl, (18) aryl, wherein the aryl is optionally substituted with one or more substituents (e.g., optionally from 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, — d-6 alkyl, — d-6 haloalkyl, - -O- -d-6 alkyl, - -O- -d-6 haloalkyl, - -d-6 alkyl-N(R^aR^b), or - -d-6 alkyl substituted with a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently - - d-6 alkyl, oxo, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; or (19) a 5- to 8-membered monocyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S; wherein the heterocycle is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently - -C₁-6 alkyl, - -O- -C₁-6 alkyl, oxo, phenyl, or naphthyl; R³ is — H or— C₁-6 alkyl; R⁴ is (1) H, (2) C₁-6 alkyl which is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH, O- -d-6 alkyl, - -O- -d-6 haloalkyl, - -N0₂, - -N(R^aR^b), - -C(=O)R^a, - -C0₂R^a, - -SR^a, - -S(=O)R^a, - -S0₂R^a, or - -N(R^a)C0₂R^b, (3) C_{1- 6} alkyl which is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH, or alkyl, and which is substituted with 1 or 2 substituents each of which is independently:

(i) C₃-8 cycloalkyl,

(ii) aryl,

(iii) a fused bicyclic carbocycle consisting of a benzene ring fused to a -7 cycloalkyl,

(iv) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S,

(v) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or

(vi) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic, (4) C₂-5 alkynyl optionally substituted with aryl, (5) C3-8 cycloalkyl optionally substituted with aryl, (6) aryl, (7) a fused bicyclic carbocycle consisting of a benzene ring fused to a C₅-7 cycloalkyl, (8) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S,

(9) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (10) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic; wherein each aryl in (3)(ii) or the aryl (4), (5) or (6) or each fused carbocycle in (3)(iii) or the fused carbocycle in (7) is optionally substituted with one or more substituents (e.g., optionally from 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH, - -C_{1- 6} alkyl, - -C_{1- 6} alkyl-OR^a, - -C_{1- 6} haloalkyl, - -O- -d-6 alkyl, - -O- -C₁-6 haloalkyl, - -CN, - -N0₂, - -N(R^aR^b), - -C_{1- 6} alkyl-N(R^aR^b), - -C(=O)N(R^aR^b), - C(=O)R^a, - -C0₂R^a, - -d-6 alkyl-C0₂R^a, - -OC0₂R^a, - -SR^a, - -S(=O)R^a, - -S0₂R^a, - -N(R^a)S0₂R^b, - -S0₂N(R^aR^b), - -N(R^a)C(=O)R^b, - -N(R^a)C0₂R^b, - -C_{1- 6} alkyl-N(R^a)C0₂R^b, aryl, - -C_{1- 6} alkyl- aryl, - - O-aryl, or - - C₀-6 alkyl-het wherein het is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, and het is optionally fused with a benzene ring, and is optionally substituted with one or more substituents (e.g., optionally from 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently— C₁-6 alkyl, — C₁-6 haloalkyl, - - O- - C₁-6 alkyl, - - O- - C₁-6 haloalkyl, oxo, or - - C0₂R ; each saturated heterocyclic ring in (3)(iv) or the saturated heterocyclic ring in (8) is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, — C₁-6 alkyl, — C₁- 6 haloalkyl, - - O- - C₁-6 alkyl, - - O- - C₁-6 haloalkyl, oxo, aryl, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; and

each heteroaromatic ring in (3)(v) or the heteroaromatic ring in (9) or each fused bicyclic heterocycle in (3)(vi) or the fused bicyclic heterocycle in (10) is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, — C₁-6 alkyl, — C₁-6 haloalkyl, - - O- - C₁-6 alkyl, - - O- - C₁-6 haloalkyl, oxo, aryl, or - - C₁-6 alkyl-aryl; or alternatively R³ and R⁴ together with the N to which both are attached form a C₃-7 azacycloalkyl which is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently - - C_{1- 6} alkyl or oxo; each R^a, R^b, R^c, and R^d is independently— H or— C₁-6 alkyl;

R^k is carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more substituents (e.g., optionally from 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently (1) halogen, (2) - -OH, (3) - -CN, (4) - -C_{1- 6} alkyl, which is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH, - -CN, - -0- -C_{1- 6} alkyl, - -0- -C_{1- 6} haloalkyl, - -C(=O)R^a, - - C0₂R^a, - -SR^a, - -S(=O)R^a, - -N(R^aR^b), - -C(=O)- -(CH₂)₀-2N(R^aR^b), N(R^a)- -C(=O)- -(CH₂)₀- 2N(R^bR^c), - -S0₂R^a, - -N(R^a)S0₂R^b, - -S0₂N(R^aR^b), or - -N(R^a)- -C(R^b)=O, (5) - -0- -C_{1- 6} alkyl, which is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH, - -CN, - -0- -C_{1- 6} alkyl, - -0- -C_{1- 6} haloalkyl, - -C(=O)R^a, - -C0₂R^a, - -SR^a, - -S(=O)R^a, - -N(R^aR^b), - -C(=O)- -(CH₂)₀-2N(R^aR^b), N(R^a)- -C(=O)- -(CH₂)₀- 2N(R^bR^c), - -S0₂R^a, - -N(R^a)S0₂R^b, - -S0₂N(R^aR^b), or - -N(R^a)- -C(R^b)=O, (6) - -N0₂, (7) oxo, (8) - -C(=O)R^a, (9) - -C0₂R^a, (10) - -SR^a, (11) - -S(=O)R^a, (12) N(R^aR^b), (13) - -C(=O)N(R^aR^b), (14) - -C(=O)- -C_{1- 6} alkyl-N(R^aR^b), (15)

N(R^a)C(=O)R^b, (16) - -S0₂R^a, (17) - -S0₂N(R^aR^b), (18) - -N(R^a)S0₂R^b, (19) - -R^m,

(20) - - C₁-6 alkyl-R^m, wherein the alkyl is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH, - - CN, - - C₁- 6 haloalkyl, - -0- -C_{1- 6} alkyl, - -0- -C_{1- 6} haloalkyl, - -C(=O)R^a, - -C0₂R^a, - -SR^a, - -S(=O)R^a, - - N(R^aR^b), - -N(R^a)C0₂R^b, - -S0₂R^a, - -N(R^a)S0₂R^b, - -S0₂N(R^aR^b), or - -N(R^a)- -C(R^b)=O, (21) - -Co-6 alkyl-N(R^a)- -Co-6 alkyl-R^m, (22) - -C₀-6 alkyl-O- -C₀-6 alkyl-R^m, (23) - -C₀-6 alkyl-S- -Co-6 alkyl-R^m, (24) - -C₀-6 alkyl-C(=O)- -C₀-6 alkyl-R^m, (25) - -C(=O)- -0- -

Co-6 alkyl-R^m, (26) - -C(=O)N(R^a)- -C₀-6 alkyl-R^m, (27) - -N(R^a)C(=O)- -R^m,

(28) - -N(R^a)C(=O)- -C₁-6 alkyl-R^m, wherein the alkyl is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, - -OH, - -CN, - -C₁-6 haloalkyl, - -0- -C_{1- 6} alkyl, - -0- -C_{1- 6} haloalkyl, - -C(=O)R^a, - -C0₂R^a, - -SR^a, - - S(=O)R^a, - -N(R^aR^b), - -N(R^a)C0₂R^b, - -S0₂R^a, - -N(R^a)S0₂R^b, - -S0₂N(R^aR^b), or - -N(R^a)- - C(R^b)=O, (29) - -N(R^a)- -C(=O)- -N(R^b)- -C₀-6 alkyl-R^m, (30) - -N(R^a)- -C(=O)- -0- -

Co-6 alkyl-R^m, (31) - -N(R^a)- -C(=O)- -N(R^b)- -SO₂- -C₀-6 alkyl-R^m, (32) - -C(=O)- -

C(=O)- -N(R^aR^b), (33) - -C(=O)- -C_{1- 6} alkyl-S0₂R^a, or (34) - -C(=O)- -C(=O)R^m; carbocycle in R^k is (i) a C₃ to C₈ monocyclic, saturated or unsaturated ring, (ii) a C₇ to C₁2 bicyclic ring system, or (iii) a C₁l to C₁6 tricyclic ring system, wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated; heterocycle in R^k is (i) a 4- to 8-membered, saturated or unsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ring system, or (iii) an 11 to 16-membered tricyclic ring system; wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated; the monocyclic ring, bicyclic ring system, or tricyclic ring system contains from 1 to 6 heteroatoms selected from N, O and S and a balance of carbon atoms; and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally be oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized;

each R^m is independently C₃-₈ cycloalkyl; aryl; a 5- to 8-membered monocyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S; or a 9- to 10-membered bicyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S; wherein any one or more of the nitrogen and sulfur heteroatoms in the heterocycle or bicyclic heterocycle is optionally oxidized and any one or more of the nitrogen heteroatoms is optionally quaternized; and wherein

the cycloalkyl or the aryl defined in R^m is optionally substituted with one or more substituents (e.g., optionally from 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, — C₁-₆ alkyl optionally substituted with - -0- -C_1-4 alkyl, - -C_{1- 6} haloalkyl, - -0- -C_{1- 6} alkyl, - -O- -C₁-6 haloalkyl, - - N(R^aR^b), aryl, or - -C₁-₆ alkyl-aryl; and

the monocyclic or bicyclic heterocycle defined in R^m is optionally substituted with one or more substituents (e.g., optionally from 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 or 2 substituents; or is optionally mono-substituted) each of which is independently halogen, — C₁-6 alkyl, — C₁-6 haloalkyl, - - O- - C₁-6 alkyl, - - O- - C₁-6 haloalkyl, oxo, aryl, — C₁-6 alkyl-aryl, - - C(=O)-aryl, - - C0₂-aryl, - - C0₂- - C₁-6 alkyl-aryl, a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or a 5- or 6- membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S; and

each n is independently an integer equal to zero, 1 or 2;

or a pharmaceutically acceptable salt thereof.

A class of compounds of the present invention includes any compound of Formula (I), wherein

R¹ is - -R^k;

R^k is phenyl which is (a) optionally substituted with from 1 to 3 substituents each of which is independently:

(1) halogen,

(2) — C₁-6 alkyl, which is optionally substituted with 1 or 2 substituents each of which is independently - -0- -C_{1- 6} alkyl, - -0- -C_{1- 6} haloalkyl, - -C(=O)R^a, - -C0₂R^a, - -SR^a, - -S(=O)R^a, - -N(R^aR^b), - -C(=O)- -(CH₂)₀-2N(R^aR^b), N(R^a)- -C(=O)- -(CH₂)₀-2N(R^bR^c), - -S0₂R^a, - - N(R^a)S0₂R^b, - -S0₂N(R^aR^b), or - -N(R^a)- -C(R^b)=O,

(3) - -C₁-6 haloalkyl,

(4) - -O- -C₁-6 haloalkyl,

(5) - -C(=O)R^a,

(6) - -C0₂R^a,

(7) - -C(=O)N(R^aR^b), or

(8) - -C(=O)- -C₁-6 alkyl-N(R^aR^b); and

(b) optionally mono-substituted with

(1) - -C_1-4 alkyl-R^m, or (2) -C_O alkyl-N(R^a)- -C₀^_t alkyl-R^m; wherein R^m is aryl selected from phenyl and naphthyl; a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; or a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; wherein

the aryl defined in R^m is optionally substituted with from 1 to 3 substituents each of which is independently halogen, - -C_1-4 alkyl, - -CF₃, - -0- -C_1-4 alkyl, - -OCF₃, or - -N(R^aR^b); the saturated heterocyclic ring defined in R^m is optionally substituted with from 1 to 3 substituents each of which is independently — C_1-4 alkyl or oxo, and is additionally optionally mono-substituted with phenyl, - -(CH₂)₁-2 -phenyl, - - C(=O)-phenyl, - - C0₂-phenyl, - -C0₂- - (CH₂)₁-2-phenyl, or a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; and

the heteroaromatic ring defined in R^m is optionally substituted with 1 or 2 substituents each of which is independently — C_1-4 alkyl or oxo; and all other variables are as originally defined above; or a pharmaceutically acceptable salt thereof.

A sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (I), wherein R² is methyl; R³ is - - H; R⁴ is: (1) - - CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, - - C_1-4 alkyl, — C_1-4 fluoroalkyl, — O- - C_1-4 alkyl, - - 0- -C_1-4 fluoroalkyl, - -(CH₂)_1-2- -N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- -CO₂R^a, - -(CH₂)₀-2- - N(R^a)C0₂R^b, - -N0₂, - -SR^a, - -N(R^aR^b) or phenyl; or (2) a fused bicyclic carbocycle selected from

wherein Z¹ is — H or - -OH; and each R and R^b is independently is H or — C_1- alkyl; and all other variables are as defined in the class; or a pharmaceutically acceptable salt thereof. Another sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (I), wherein R⁴ is 4-fluorobenzyl or 2,3- dimethoxybenzyl; and all other variables are as defined in the class; or a pharmaceutically acceptable salt thereof.

Still another sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (I), wherein R² is methyl; R³ is— H; R⁴ is 4-fluorobenzyl or 2,3-dimethoxybenzyl; each R and R^b is independently is H or — C_1-4 alkyl; and all other variables are as defined in the class; or a pharmaceutically acceptable salt thereof.

ound of Formula (II):

wherein

Q is:

(1) methyl which is optionally substituted with 1 or 2 of - - O- - C_1-4 alkyl,

(2) phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently — F, - -CI, Br, — C_1-4 alkyl, — CF₃, - -O- -C 14 alkyl, — OCF₃, methylenedioxy attached to two adjacent carbon atoms, or phenyl, or

(3) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; wherein the saturated heterocyclic ring is optionally substituted with 1 or 2 substituents each of which is independently— F, - -CI, - -Br, - - C_1-4 alkyl, oxo, phenyl, or— C(=O)-phenyl;

T is:

(1) - -H,

(2) - -OH,

(3) methyl or ethyl, optionally substituted with - -OH or— O- - C_1-4 alkyl,

(4) - -O- -C₁.4 alkyl

(5) - -N(R^aR^b),

(6) - -N(R^a)- -(CH₂)₂- -OH,

(7) - -N(R^a)- -C0₂R^b,

(8) - -N(R^a)- -C(=O)- -(CH₂)₁-2- -N(R^aR^b), (9) - -R^s,

(10) - -(CH₂)_1-2- -R^s, or

(11) - -(CH₂)₀-2- -N(R^a)- -(CH₂)₀_3- -R^s;

R^s is:

(1) phenyl optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C_1-4 alkyl, — C_1-4 alkyl-OR^a, - - C_1-4 haloalkyl, — O- - C_1-4 alkyl, — O- - C_1- ₄ haloalkyl, or - -N(R^aR^b);

(2) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; which is optionally substituted with from 1 to 4 substituents each of which is independently - -C_H alkyl, - -C_1-4 alkyl-OR^a, - - C_1-4 haloalkyl, - -0- -C_1-4 alkyl, - -0- -C_1-4 haloalkyl, - -C(=O)R^a, oxo, phenyl, or - -CH₂-phenyl; or

(3) a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; which is optionally substituted with from 1 to 4 substituents each of which is independently — C_1-4 alkyl, — C_1-4 alkyl-OR^a, - - C_1-4 haloalkyl, - - O- -C_1-4 alkyl, - - O- - C_1-4 haloalkyl, or oxo;

R² is

(1) - -C_1-4 alkyl,

(2) - -C_1-4 alkyl substituted with - -N(R^aR^b), or

(3) - - C₁-4 alkyl substituted with a 5- or 6-membered saturated monocyclic heterocycle which contains from 1 to 3 heteroatoms selected from 1 to 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; wherein the saturated heterocycle is optionally substituted with from 1 to 4 substituents each of which is independently a— C_1-4 alkyl;

R³ is - -H or - -C_1-4 alkyl;

R⁴ is - - CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, - - C_1-4 alkyl, — C_1-4 fluoroalkyl, - -0- -C_1-4 alkyl, -0-C_1A fluoroalkyl, - -(CH₂)_1-2- -N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- - C0₂R^a, - -(CH₂)₀-2- -N(R^a)C0₂R^b, - -N0₂, - -SR^a, - -N(R^aR^b) or phenyl;

each R^a and R^b is independently is H or— C_1-4 alkyl; and

s is an integer equal to zero, 1, or 2; or a pharmaceutically acceptable salt thereof.

In an aspect of this class, R⁴ is — CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, - -C_1-4 alkyl, - -C_1-4 fluoroalkyl, - -0- -C_1-4 alkyl, - -O- -d-4 fluoroalkyl, - -(CH₂)_1-2- - N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- -C0₂R^a, - -(CH₂)₀-2- -N(R^a)CO₂R^b, - -N0₂, or phenyl.

A sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (II) exactly as defined in the preceding class, except that when R² is - -C_1-4 alkyl substituted with - -N(R^aR^b), it is with the proviso that - -N(R^aR^b) is not attached to the carbon atom in the— C_1-4 alkyl group that is attached to the ring nitrogen (i.e., that the - - N(R R^b) group is not attached to the carbon atom alpha to the ring nitrogen).

Another sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (II), wherein

Q is phenyl;

T is:

(1) - -H,

(2) - -N(R^aR^b),

(3) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; which is optionally substituted with 1 or 2 substituents each of which is independently— C_1-4 alkyl or - - C(=O)R , or

(4) - - N(R )- - (CH₂) 1-2 -he tero aromatic, wherein the heteroaromatic is a 5- or 6- membered ring containing 1 or 2 N atoms;

R² is methyl;

R³ is - -H; and

R⁴ is - - CH₂-phenyl, wherein the phenyl is optionally substituted with 1 or 2 substituents each of which is independently - - F, - -CI, - -Br, — C_1-4 alkyl, - - CF₃, - -O- - C_1-4 alkyl, - -S0₂CH₃, - -SCH₃, - -N(CH₃)₂ or - -OCF₃;

each R and R^b is independently - - H, methyl or ethyl; and

s is an integer equal to zero or 1; or a pharmaceutically acceptable salt thereof. In an aspect of this subclass, R⁴ is - - CH₂-phenyl, wherein the phenyl is optionally substituted with 1 or 2 substituents each of which is independently - - F, - -CI, - -Br,— C_1-4 alkyl, - -CF₃, - -0- -C_1-4 alkyl, or - -OCF₃.

Another class of compounds of the present invention includes any compound of Formula (I), wherein

R¹ is - -R^k;

R^k is (i) a 5- or 6-membered saturated heterocyclic ring containing from 0 to 1 oxygen atoms and from 1 to 3 nitrogen atoms or (ii) a bicyclic heterocycle which is a benzene ring fused to a 5- or 6-membered saturated heterocyclic ring containing from 0 to 1 oxygen atoms and from 1 to 3 nitrogen atoms; wherein the saturated heterocyclic ring or bicyclic heterocycle is optionally substituted with from 1 to 3 substituents each of which is independently

(1) - - C_1-4 alkyl, which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, -0-C_1-4 alkyl, - -0- -C_1-4 haloalkyl, - -C(=O)R^a, - -C0₂R^a, - - SR^a, - -S(=O)R^a, - -N(R^aR^b), - -C(=O)- -(CH₂)₀-2N(R^aR^b), N(R^a)- -C(=O)- -(CH₂)₀-2N(R^bR^c), - - S0₂R^a, - -N(R^a)S0₂R^b, - -S0₂N(R^aR^b), or - -N(R^a)- -C(R^b)=O,

(2) - -OH,

(3) - -C(=O)R^a, (4) - -C0₂R^a,

(5) - -C(=O)N(R^aR^b),

(6) - -C(=O)- -C₁-6 alkyl-N(R^aR^b),

(7) - -SR^a,

(8) - -S(=O)R^a,

(9) - -S0₂R^a,

(10) - -N(R^aR^b),

(Π) - -R^m,

(12) — C_1-4 alkyl-R^m, wherein the alkyl is optionally substituted with from 1 to 4 substituents each of which is independently halogen, - -OH, — CN, - - C_1-4 haloalkyl, - - O- - C_1-4 alkyl, - -0- -C!_4 haloalkyl, - -C(=O)R^a, - -C0₂R^a, - -SR^a, - -S(=O)R^a, - -N(R R^b), - -N(R^a)C0₂R^b, - - S0₂R^a, - -N(R^a)S0₂R^b, - -S0₂N(R^aR^b), or - -N(R^a)- -C(R^b)=O,

(13) - -Co-4 alkyl-N(R^a)- -Co^ alkyl-R^m,

(14) - -Co.4 alkyl-O- -Co.4 alkyl-R^m,

(15) - -Co-4 alkyl-S- -Co-4 alkyl-R^m,

(16) - -Co-4 alkyl-C(=O)- -Co^ alkyl-R^m,

(17) - -C(=O)- -0- -Co-4 alkyl-R^m, or

(18) - -C(=O)N(R^a)- -C₀^ alkyl-R^m; wherein each R^m is independently - -C₃-6 cycloalkyl; aryl selected from phenyl and naphthyl; a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; or a 5- or 6- membered heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, wherein any N is optionally oxidized to form an N-oxide; wherein

the aryl is optionally substituted with from 1 to 3 substituents each of which is independently halogen, - -C_1-4 alkyl, - -CF₃, - -0- -C_1-4 alkyl, - -OCF₃, or - -N(R^aR^b);

the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently - -C_H alkyl or oxo, and is additionally optionally mono- substituted with phenyl, - - (CH₂) ^-phenyl, - - C(=O)-phenyl, - - C0₂-phenyl, or - - C0₂- - (CH₂)₁- ₂-phenyl; and

the heteroaromatic ring is optionally substituted with 1 or 2 substituents each of which is independently halogen, - -C_1-4 alkyl, or oxo; and all other variables are as originally defined above; or a pharmaceutically acceptable salt thereof.

A sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (I), wherein

R¹ is:

R⁸ is:

(1) --H, (2) - - C_1-4 alkyl, which is optionally substituted with 1 or 2 substituents each of which is independently - -OH, - -0- -C_1-4 alkyl, - -OCF₃, - -C(=O)R^a, - -C0₂R^a, - -SR^a, - -N(R^aR^b), or - - C(=O)N(R^aR^b), (3) - -C(=O)R^a,

(4) - -C0₂R^a,

(5) - -C(=O)N(R^aR^b),

(6) - -C(=O)- -(CH₂)₁-2- -N(R^aR^b),

(7) - -S0₂R^a,

(8) - -(CH₂)_1-2- -R^m,

(9) - -(CH₂)₀-2- -C(=O)- -(CH₂)₀-2- -R^m,

(10) - -C(=O)- -0- -(CH₂)₀-2- -R^m, or

(11) - -C(=O)N(R^a)- -(CH₂)₀-2- -R^m;

R¹⁰ is - -H, - -OH, - -C_1-4 alkyl, - -0- -C_1-4 alkyl, - -N(R^aR^b), or - -0- -(CH₂)₁-₂ - -R^m;

R¹² is

(1) - -H,

(2) — C_1-4 alkyl, which is optionally substituted with 1 or 2 substituents each of which is independently - -OH, - -0- -C_1-4 alkyl, - -OCF₃, - -C(=O)R^a, - -C0₂R^a, - -SR^a, - -N(R^aR^b), or - - C(=O)N(R^aR^b), (3) - -C(=O)R^a,

(4) - -C0₂R^a,

(5) - -C(=O)- -(CH₂)₁-2- -N(R^aR^b), or

(6) - -S0₂R^a;

R² is methyl;

R³ is— H or methyl;

R⁴ is — CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, - - C_1-4 alkyl, — C_1-4 fluoroalkyl, - -0- -C_1-4 alkyl, -0-C_1-4 fluoroalkyl, - -(CH₂)_1-2- -N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- - C0₂R^a, - -(CH₂)₀-2- -N(R^a)C0₂R^b, - -N0₂, - -SR^a, - -N(R^aR^b) or phenyl; and

each R^a and R^b is independently— H or— C_1-2 alkyl; or a pharmaceutically acceptable salt thereof.

In an aspect of this subclass, R⁴ is — CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, - -C_1-4 alkyl, - -C_1-4 fluoroalkyl, - -0 - -C_1-4 alkyl, - -0 - -C_1-4 fluoroalkyl, - -(CH,)_!-,- - N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- -C0₂R^a, - -(CH₂)₀-₂- -N(R^a)CO₂R^b, - -N0₂, or phenyl.

Another class of the present invention includes any compound of Formula (III):

wherein R² is:

(1) - -C₁-6 alkyl,

(2) - -C₁-6 alkyl substituted with - -N(R R^b),

(3)— C₁-6 alkyl substituted with phenyl which is:

(a) optionally substituted with from 1 to 4 substituents each of which is independently halogen, — C_1-4 alkyl, — C_1-2 haloalkyl, — O- - C_1-2 alkyl, — O- - C_1-4 haloalkyl, or — C₀-6 alkyl- N(R^aR^b); and

(b) optionally mono-substituted with --C_1-4 alkyl substituted with a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms selected from 1 or 2 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms;

wherein the heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently— C₁-6 alkyl, oxo, or a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms selected from 1 to 3 N atoms, 0 or 1 O atom, and 0 or 1 S atom;

(4) - - C₁-6 alkyl optionally substituted with - -OH and substituted with a 5- or 6- membered saturated monocyclic heterocycle which contains from 1 to 3 heteroatoms selected from 1 to 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; wherein the heterocycle is optionally substituted with from 1 to 4 substituents each of which is independently — C₁-6 alkyl, - - O- - C₁-6 alkyl, oxo, or phenyl; or

(5) - - C₁-6 alkyl substituted with a 5- or 6-membered heteroaromatic ring which contains from 1 to 3 heteroatoms selected from 1 to 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently — C₁-6 alkyl, - - O- - C₁-6 alkyl, oxo, or phenyl; and all other variables are as originally defined above; or a pharmaceutically acceptable salt thereof.

A sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (III) exactly as defined in the preceding class, except that when R² is - -C₁-6 alkyl substituted with - -N(R^aR^b), it is with the proviso that - -N(R^aR^b) is not attached to the carbon atom in the— C₁-6 alkyl group that is attached to the ring nitrogen (i.e., that the - - N(R R^b) group is not attached to the carbon atom alpha to the ring nitrogen).

Another sub-class of the preceding class of compounds of the present invention includes any compounds of Formula (III), wherein

R² is:

(1) - -C_1-4 alkyl,

(2) - -(CH₂)_1-3--N(R^aR^b),

(3) - - (CH₂)₁-3-phenyl, wherein the phenyl is:

(a) optionally substituted with from 1 to 3 substituents each of which is independently fluoro, chloro, bromo, - -C_1-4 alkyl, - -CF₃, - -O- -C^ alkyl, - -O- -CF₃, or - -(CH₂)_1-3- -N(R^aR^b); and

(b) optionally mono-substituted with - - (CH₂)₁-3-saturated heterocycle which is a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms selected from 1 or 2 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms, wherein the heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently — C_1-4 alkyl or pyridyl;

(4) - - (CH₂)₁_3-saturated heterocycle, wherein the — (CH₂)₁_₃- - moiety is optionally substituted with an - -OH and the saturated heterocycle is a 5- or 6-membered saturated monocyclic heterocycle which contains from 1 to 3 heteroatoms selected from 1 to 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; wherein the heterocycle is optionally substituted with from 1 to 3 substituents each of which is independently a— C_1-4 alkyl; or

(5) - -(CH₂)_1-2-pyridyl;

R³ is - - H or methyl;

R⁴ is - - CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, — C_1-4 alkyl, — C_1-4 fluoroalkyl, - -0- -C_1-4 alkyl, -0-C_1-4 fluoroalkyl, - -(CH₂)_1-2- -N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- - C0₂R^a, - -(CH₂)₀-2- -N(R^a)C0₂R^b, - -N0₂, - -SR^a, - -N(R^aR^b) or phenyl; and

each R and R^b is independently is H or— C_1-4 alkyl; or a pharmaceutically acceptable salt thereof.

In an aspect of this subclass, R⁴ is - - CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, - -C_1-4 alkyl, - -C_1-4 fluoroalkyl, -0-C_1-4 alkyl, - -0- -C_1-4 fluoroalkyl, - -(CH₂)_1-2- - N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- -C0₂R^a, - -(CH₂)₀-2- -N(R^a)CO₂R^b, - -N0₂, or phenyl.

R¹ is - -C(=O)NH- -(CH₂)_1-2- -R^k; and

R^k is (i) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, or (ii) a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S; and all other variables are as originally defined above; or a pharmaceutically acceptable salt thereof.

R¹ is - -C(=O)NH- -(CH₂)₁-2- -R^k; and

R^k is (i) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, or (ii) a 5- or 6-membered heteroaromatic ring containing from 1 to 3 heteroatoms independently selected from N, O and S;

R² is methyl;

R³ is - - H or methyl;

R⁴ is - - CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, - - C_1-4 alkyl, — C_1-4 fluoroalkyl, - -0- -C_1-4 alkyl, -0-C₁ fluoroalkyl, - -(CH₂)₁-2- -N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- - C0₂R^a, - -(CH₂)₀-2- -N(R^a)C0₂R^b, - -N0₂, - -SR^a, - -N(R^aR^b) or phenyl; and

each R and R^b is independently— H or --C_1-4 alkyl; or a pharmaceutically acceptable salt thereof.

In an aspect of this subclass, R⁴ is — CH₂-phenyl, wherein the phenyl is optionally substituted with from 1 to 3 substituents each of which is independently fluoro, bromo, chloro, - -OH, - -C_1-4 alkyl, - -C_1-4 fluoroalkyl, -0-C₁ alkyl, - -0- -C_1-4 fluoroalkyl, - -(CH₂)_1-2- - N(R^aR^b), - -S0₂R^a, - -(CH₂)₀-2- -C0₂R^a, - -(CH₂)₀-2- -N(R^a)CO₂R^b, - -N0₂, or phenyl.

Specific compounds suitable for use as integrase inhibitors include:

N-(2-ethoxybenzyl)-5-hydroxy-1-methyl-2-(4-methylphenyl)-6-oxo-l,6-dihydr- opyrimidine.₄-carboxamide;

N-(2,3-dimethoxybenzyl)-5-hydroxy- 1 -methyl-2-(4-methylphenyl)-6-oxo- 1 ,6-d- ihydropyrimidine^-carboxamide;

N-(2,3-dimethoxybenzyl)-2- { 4-[(dimethylamino)methyl]phenyl } -5 -hydroxy- 1 -m- ethyl-6-oxo- 1 ,6-dihydropyrimidine.₄-carboxamide;

N-(4-fluorobenzyl)-2- { 4- [(dimethylamino)methyl]phenyl } -5-hydroxy- 1 -methyl- -6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-2-[4-(pyrrolidin-1-ylmet- hyl)phenyl] - 1 ,6-dihydropyrimidine.₄-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-[4-(pyrrolidin- 1 -ylmethyl)p- henyl] - 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-l-methyl-6-oxo-2-[4-(piperidin-1-ylmethyl)ph- enyl]- 1 ,6-dmydropyrirnidine^-carboxarnide; N-(2,3-dimethoxybenzyl)-5-hydroxy- 1 -methyl-2- [4-(morpholin^-ylmethyl)phe- nyl] - 6-oxo- 1,6-dmydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[4-(morpholin^-ylmethyl)phenyl]- - 6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- { 4-[(4-methylpiperazin- 1 -yl)methy- l]phenyl } -6-oxo-l ,6-dihydropyrimidine.₄-carboxamide;

2-{4-[(diethylamino)methyl]phenyl}-N-(2,3-dimethoxybenzyl)-5-hydroxy-1-me- thyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2- { 4- [(diethylamino)methyl]phenyl } -N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl- - 6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2-[(dimethylamino)(phenyl)methyl] -N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-2- [(4-formylpiperazin- 1 -yl)(phenyl)methyl] -5 -hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-{phenyl[(pyridin_3-ylmethyl- )amino]methyl}-1,6-dihydropyrimidine^-carboxamide;

2-benzyl-1-[2-(dimethylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-l,- 6- dihydropyrimidine^-carboxamide;

l-[2-(dimethylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-2-(2-methylphenyl- )-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(4-methylphenyl)-6-oxo- 1 ,6-dihydr- opyrimidine.₄-carboxamide; 2-benzyl-N-(2,3-dimethoxybenzyl)- 1 - [2- (dimethylamino)ethyl]-5-hydroxy-6-o- xo-1,6-dihydropyrimidine^-carboxamide;

2-{4-[(4-ethylpiperazin-1-yl)methyl]phenyl}-N-(4-fluorobenzyl)-5-hydroxy- - 1- methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-{4-[(2-pyridin_3-ylpiperidi- n-1- yl)methyl]phenyl } - 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide; N-(23-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine^-- carboxamide;

N-[4-fluoro-2-(trifluoromethyl)benzyl] -5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihyd- ropyrimidine^-carboxamide;

N-(3-chloro^-methylbenzyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidin- e_₄- carboxamide;

5-hydroxy-N-[(lR,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1-methyl-2-{4-[- (4- methylpiperazin- 1 -yl)methyl]phenyl } -6-oxo- 1 ,6-dihydropyrimidine^-carbo- xamide; N-(4-fluorobenzyl)-5-hydroxy-2-(4- { [(2R)-2-(methoxymethyl)pyrrolidin- 1 -yl- ] methyl} phenyl)- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2-(4- { [(2S)-2-(methoxymethyl)pyrrolid-in- 1 - yl]memyl}phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-2-(4- { [(4-fluorobenzyl)amino]methyl }phenyl)-5- - hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-1-(2-morpholin^-ylethyl)-6-oxo-1,6- dihydropyrimidine^-carboxamide

1- [2-(dimemylamino)ethyl]-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1,6-dihydro- pyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(pyridin_3-ylmethyl)-1,6-dihydropyrimidine- 4-carboxamide;

2- benzyl-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-1-(2-pyrrolidin-1-ylethyl)-l,- 6- dihydropyrimidine^-carboxamide;

2-benzyl-N-(4-fluorobenzyl)-5-hydroxy-6-oxo-l -(2-piperidin- 1 -ylethyl)- 1 ,6- dihydropyrimidine^-carboxamide;

2-(l -benzylpiperidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,- 6- dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(l -methylpiperidin-2-yl)-6-oxo- 1 ,- 6- dihydropyrimidine^-carboxamide;

2-(l -benzylpiperidin_3-yl)-N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,- 6- dihydropyrimidine^-carboxamide;

l-{3-[(dimethylamino)methyl]benzyl)-N-(4-fluorobenzyl}-5-hydroxy-6-oxo-l,- 6- dihydropyrimidine^-carboxamide;

N-(2,3-dimethoxybenzyl)- 1 -[2-(dimethylamino)ethyl] -5-hydroxy-6-oxo- 1 ,6-di- hydropyrimidine.₄-carboxamide ;

N-(2,3-dimethoxybenzyl)-5-hydroxy-6-oxo- 1 -(pyridin.₃-ylmethyl)- 1 ,6-dihydr- opyrimidine.4-carboxamide;

N4-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-N2-(2-morpholin^-ylethyl)-6-oxo- 1 - ,6- dihydropyrimidine-2,4-dicarboxamide;

N-(4-fluorobenzyl)-5-hydroxy-6-oxo- 1 -[3-(pyrrolidin-l -ylmethyl)benzyl]- 1 ,- 6- dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-[3-(morpholin^-ylmethyl)benzyl]-6-oxo-1,6- dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 - { 3-[(4-methylpiperazin- 1 -yl)methyl]benzyl } - -6- oxo- 1 ,6-dihydropyrimidine^-carboxamide; N-(4-fluorobenzyl)-5-hydroxy-6-oxo- 1 - { 3-[(4-pyridin-2-ylpiperazin- 1 -yl)me- thyl]benzyl } - 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 - [2-(morpholin.₄-ylmethyl)benzyl] -6-oxo- 1 ,6- dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-6-oxo- 1 - { 2-[(4-pyridin-2-ylpiperazin- 1 -yl)me- thyl]benzyl } - 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo-2-pyrrolidin-2-yl- 1 ,6-dihydro- pyrimidine^-carboxamide;

N4-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo-N2-(pyridin-2-ylmethyl)- 1 ,6- - dihydropyrimidine-2,4-dicarboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-(2-hydroxy_3-morpholin^-ylpropyl)-6-oxo-1- ,6- dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 - [4-(morpholin.₄-ylmethyl)benzyl] -6-oxo- 1 ,6- dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(2-morpholin^-ylethyl)-6-oxo- 1 ,6- dihydropyrimidine^-carboxamide;

2-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-di- hydropyrimidine.₄-carboxamide ;

2-(2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo- -1,6- dihydropyrimidine^-carboxamide;

2-[2-(4-benzoylpiperazin- 1 -yl)ethyl]-N-(4-fluorobenzyl)-5-hydroxy- 1 -methy- 1-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2-[l-(N,N-dimethylglycyl)piperidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-m- ethyl- 6-oxo-l, 6-dmydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(l-methyl-2,3-dihydro-1H-indol-2- - yl)-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-(1,2,3,4-tetrahydroquinolin- -2-yl)- 1 ,6-dmydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(l -methyl- 1 ,2,3,4-tetrahydroquino- lin-2- yl)-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide;

tert-butyl (2S,4R)^-(benzyloxy)-2-(4-{ [(4-fluorobenzyl)amino]carbonyl}-5-hydroxy- 1 - - methyl-6-oxo- 1 ,6-dihydropyrimidin-2-yl)pyrrolidine- 1 -carboxylate;

tert-butyl (2S,4R)-2-(4-{ [(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-1-methyl-6- oxo- 1 - ,6-dihydropyrimidin-2-yl)^-hydroxypyrrolidine- 1 -carboxylate;

2-[(2S,4R)^-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-m- ethyl-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide; N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)^-hydroxypyrrolidin-2-yl]-1-methy- 1-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2- [(2S,4R)^-hydroxy- 1 -methylpyrrolidin-2-yl- ] - 1 - methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

2-[(2S,4R)-4-(benzyloxy)-1-methylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1- methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

2-[(2S,4R)-1-benzoyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine.₄-carboxamide;

2-[l-(N,N-dimethylglycyl)-2,3-dihydro-1H-indol-2-yl]-N-(4-fluorobenzyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2-( 1 -benzoyl-2,3 -dihydro- 1 H-indol-2-yl)-N-(4-fluorobenzyl)-5 -hydroxy- 1 -methyl-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridin-2-ylcarbonyl)-2- ,3- dihydro- 1 H-indol-2-yl] - 1 ,6-dihydropyrimidine^-carboxamide;

tert-butyl 3-(4- { [(4-fluorobenzyl)amino]carbonyl } -5-hydroxy- 1 -methyl-6-oxo- 1,6- dihydropyrimidin-2-yl)-4-methylpiperazine- 1 -carboxylate;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin_3-yl)-6-oxo-l,- 6- dihydropyrimidine-4-carboxamide;

(+)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin_3-yl)-6-ox- o-1,6- dihydropyrimidine-4 -carboxamide

(-)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin_3-yl)-6-ox- o-1,6- dihydropyrimidine-4 -carboxamide

2-(l-ethyl-2,3-dihydro-1H-indol-2-yl)-N-(4-fluorobenzyl)-5 -hydroxy- 1-meth- yl-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

2-(l-benzoylpiperidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1- ,6- dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridin-2-ylcarbonyl)piperidin- 2-yl] - 1 ,6-dihydropyrimidine_4 -carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(2-methyl- 1 ,2,3,4-tetrahydroisoquinolin_₃- yl)-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2-(l-benzoylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo- - 1,6- dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridin-2-ylcarbonyl)pyrrolidin- 2-yl] - 1 ,6-dihydropyrimidine_4 -carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-( 1 -methylpyrrolidin-2-yl)-6-oxo- 1 - ,6- dihydropyrimidine^-carboxamide; 2-[(2S,4R)^-(benzyloxy)-1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4- fluorobenzyl)-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2- [ 1 -(dimethylamino)-2-phenylethyl] -N-(4-fluorobenzyl)-5-hydroxy- 1 - -methyl-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2-[(2S,4R)- 1 -benzoyl.₄-hydroxypyrrolidin-2-yl] -N-(4-fluorobenzyl)-5-hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2-(l-isobutyl-2,3-dihydro-1H-indol-2-yl)-1-methyl-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2-(l-isopropyl-2,3-dihydro-1H-indol-2-yl)-l- - methyl- 6-oxo-l, 6-dihydropyrimidine^-carboxamide;

2- [ 1 -(N,N-dimethylglycyl)pyrrolidin-2-yl] -N-(4-fluorobenzyl)-5 -hydroxy- 1 - - methyl - 6-oxo- 1,6-dihydropyrimidine-4-carboxamide;

2-{ l-[(6-bromopyridin-2-yl)carbonyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(l-methylpiperazin-2-yl)-6-oxo-l,- 6- dihydropyrimidine-4-carboxamide;

2-(l-benzoyl-4-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methy- 1-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridin-2-ylcarbonyl)-1- ,2,3,4- tetrahydroquinolin-2-yl] - 1 ,6-dihydropyrimidine-4-carboxamide;

2-( 1 -acetylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl- - 6-oxo- 1,6- dihydropyrimidine-4-carboxamide;

2- [ 1 -(cyclopropylcarbonyl)pyrrolidin-2-yl] -N-(4-fluorobenzyl)-5-hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[l-(methylsulfonyl)pyrrolidin-2-y- l]-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- { 1 -[(4-methylmorpholin.₃-yl)carbo- nyl]pyrrolidin-2-yl} -6-oxo-l, 6-dmydropyrimidine-4-carboxamide;

2-(l ,4-dimethylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridin_3-ylcarbonyl)pyrrolidin- 2-yl]-1,6-dihydropyrimidine-4-carboxamide;

2-[(2S,4R)-1-acetyl-4-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2-(l-isonicotinoylpyrrolidin-2-yl)-l -methyl- - 6-oxo- 1 ,6-dmydropyrimidine^-carboxamide; 2- { 1 - [(ethylamino)carbonyl]pyrrolidin-2-yl } -N-(4-fluorobenzyl)-5-hydroxy- - 1 - methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- { 1 - [( 1 -methyl- 1 H-imidazol-2- yl)carbonyl]pyrrolidin-2-yl} -6-oxo- 1,6-dmydropyrimidine-4-carboxamide;

2-[(2S,4R)- 1 -acetyl-4-hydroxypyrrolidin-2-yl] -N-(4-fluorobenzyl)-5-hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

2-[l-(anilinocarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

2-(4-ethyl- 1 -methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5 -hydroxy- 1 -methyl- - 6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- { 1 - [( 1 -oxidopyridin-2-yl)carbonyl- ]pyrrolidin-2-yl} -6-oxo- 1,6-dmydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyrazin-2- ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;

2-[(4R).₃-acetyl- 1 ,3-thiazolidin-4-yl] -N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[l-methyl.₄-(methylsulfonyl)piperazin-2- yl] -6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -memyl-2-(4-methylthiomorpholin_₃-yl)-6-ox- o- 1 ,6- dihydropyrimidine-4-carboxamide;

N-[4-fluoro-2-(methylsulfonyl)benzyl] -5-hydroxy- 1 -methyl-6-oxo-2-[l -(pyrazin-2- ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine^-carboxamide;

2-(l-acetylpyrrolidin-2-yl)-N-[4-fluoro-2-(methylsulfonyl)benzyl]- - 5-hydroxy- 1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

2-(3-acetyl-1,3-thiazolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-l -methyl-6- -oxo- 1 ,6-dmydropyrimidine-4-carboxamide;

2-[l -(acetylamino)- 1 -methylethyl] -N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6- -oxo- 1 ,6-dmydropyrimidine-4-carboxamide;

2-(l-acetylpyrrolidin-2-yl)-N-(2-ethoxybenzyl)-5 -hydroxy- l-methyl-6-oxo-1- ,6- dihydropyrimidine-4-carboxamide;

2-(4-acetyl- 1 -methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl- -6-oxo- 1 ,6-dmydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-[l-methyl.₄-(pyrazin-2-ylcarbonyl- )piperazin-2-yl]-6-oxo-1,6-dmydropyrirnidine.₄-carboxamide;

2-(l-acetylpyrrolidin-2-yl)-5-hydroxy-1-methyl-N-[2-(methylthio)benzyl]-6- -oxo- 1 ,6-dmydropyrimidine-4-carboxamide; N-(4-fluorobenzyl)-5-hydroxy-2-{ l-[(1H-imidazol-5-ylcarbonyl)amino]-l -methylethyl } - 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2-[l-benzoyl^-(pyrazin-2-ylcarbonyl)piperazin-2-yl]-N-(4-fluorobenzyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2-(4-benzoyl- 1 -methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy- - 1 -methyl-6- oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2-[4-(benzyloxy)-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2-(l-acetylpyrrolidin-2-yl)-N-(2,3-dimethoxybenzyl)-5 -hydroxy- l-methyl-6- - oxo- 1 ,6-dmydropyrimidine^-carboxamide;

2-(l-acetylpyrrolidin-2-yl)-5-hydroxy-N-(2-methoxybenzyl)-1-methyl-6-oxo- - 1,6- dihydropyrimidine-4-carboxamide;

Nl -[1 -(4-{ [(4-fluorobenzyl)amino]carbonyl } -5-hydroxy- 1 -methyl-6-oxo- 1 ,6-d- mydropyrimidin-2-yl)-1-methylethyl]-N2,N2-dimethylethanediamide;

2-( 1 -acetylpyrrolidin-2-yl)-N- [2-(dimethylamino)benzyl] -5-hydroxy- 1 -methy- 1-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

2-[(2S)-1-acetylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy- l-methyl-6- - oxo- 1 ,6-dmydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2-[4-hydroxy-1-(pyrazin-2-ylcarbonyl)pyrroli- din-2- yl] - 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

N-[l -(4-{ [(4-fluorobenzyl)amino]carbonyl} -5-hydroxy- 1 -methyl-6-oxo- 1 ,6-di- hydropyrimidin-2-yl)- 1 -methylethyl]imidazo[2, 1 -b] [1 ,3]thiazole-6-carboxamide;

2-[(2S,4S)-1-acetyl.₄-fluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5 -hydroxy- -1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- { 1 -methyl^- [( 1 -methyl- 1 H-imidazo- 1-2- yl)carbonyl]piperazin-2-yl } -6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(l-methyl-1-{ [(5-methyl-1- ,3,4- oxadiazol-2-yl)carbonyl]arrdno}emyl)-6-oxo-1,6-dmydropyrirnidine-4-carboxamide;

Nl-{ l-[4-({ [4-fluoro-2-(methylsulfonyl)benzyl]amino}carbonyl)-5-hydroxy-1- methyl-6-oxo- 1 ,6-dihydropyrimidin-2-yl] - 1 -methylethyl } -N2,N2-dimethylethanediamide;

2-(4-acetyl- 1 ,2-dimethylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy- 1 -me- thyl-6- oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyrimidin^-ylcarbonyl)- pyrrolidin-2-yl]-1,6-dmydropyrirrddine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyrimidin-5-ylcarbonyl)- pyrrolidin-2-yl]-1,6-dmydropyrirrddine-4-carboxamide; N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{ l-methyl-1-[(1H-pyrazol-5-ylcarb- onyl) amino] ethyl } -6-oxo- 1 ,6-dihydropyrirnidine-4-carboxarnide;

2-[(2R,4R)-1-acetyl^-methoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydrox- y-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

2-{ l-[(dimethylamino)(oxo)acetyl]pyrrolidin-2-yl}-N-(4-fluorobenzyl)-5-hy- droxy- 1 -methyl-6-oxo- 1 ,6-dmydropyrirnidine-4-carboxarnide;

N- { 1 - [4-( { [4-fluoro-2-(methylsulfonyl)benzyl] amino } carbonyl)-5 -hydroxy- 1 - - methyl-6-oxo- 1 ,6-dihydropyrimidin-2-yl] - 1 -methylethyl } imidazo[2, 1 -b] [ 1 ,3] thiazole-6- carboxamide;

2-[(2R,4R)-1-benzoyl^-methoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy-1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2-[4-(isopropylsulfonyl)- 1 -methylpiperazin-2- -yl] - 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

2-[1,2-dimethyl.₄-(methylsulfonyl)piperazin-2-yl]-N-(4-fluorobenzyl)-5-hy- droxy- 1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2- [(2S,4R)^-methoxy- 1 -methylpyrrolidin-2-yl- ] - 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{ l-[(methylsulfonyl)acetyl]pyrrol- idin-2- yl} -6-oxo- 1,6-dihydropyrimidine-4-carboxamide;

2-[(2S)- 1 -acetyl-4,4-difluoropyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

2-[(2R,4R)-1-acetyl-4-ethoxypyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hydroxy- -1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

2- [(2S)^,4-difluoro- 1 -methylpyrrolidin-2-yl] -N-(4-fluorobenzyl)-5-hydrox- y- 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(2,3-dimethoxybenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridazin.₃-ylcarb- onyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(l -methyl- 1 - { [morpholin^-yl(oxo)- acetyl] amino } ethyl)-6-oxo- 1 ,6-dmydropyrirnidine-4-carboxarnide;

2- { (2R,4R)- 1 - [(dimethylamino)(oxo)acetyl] ^-methoxypyrrolidin-2-yl } -N-(4- - fluorobenzyl)-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide- ;

2-[(2S)_^t,4-difluoro-1-(pyrazin-2-ylcarbonyl)pyrrolidin-2-yl]-N- - (4-fluorobenzyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxam- ide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- { (2S,4S)- 1 -methyU-[(methylsulfo- nyl)amino]pyrrolidin-2-yl } -6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2- { 1 -[(dimethylamino)sulfonyl]pyrrolidin-2-yl } -N-(4-fluorobenzyl)-- 5-hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide; 2-{ (2R,4R).₄-ethoxy-1-[(methylamino)(oxo)acetyl]pyrrolidin-2-yl}-N-(4- fluorobenzyl)-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2-[(2S) -4,4-difluoro-1-(pyridazin-3-ylcarbonyl)pyrrolidin-2-yl]-N- - (4- fluorobenzyl)-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxam- ide;

2-[(2S)-4,4-difluoro-1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4-fluoro- benzyl)-5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine^-carboxamide;

2-{ (2S)-1-[(dimethylamino)(oxo)acetyl]4,4-difluoropyrrolidin-2-yl}- -N-(4- fluorobenzyl)-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carbo- xamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- { 1 -[morpholin-4-yl(oxo)acetyl]pyr- rolidin-2-yl } -6-oxo-l ,6-dihydropyrimidine-4-carboxamide;

2-{ (2S)- 1 -[(dimethylamino)(oxo)acetyl]pyrrolidin-2-yl } -N-(4-fluorobenzyl)- -5- hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2-{ (2S)- 1 -[(dimethylamino)(oxo)acetyl]pyrrolidin-2-yl } -N-(4-fluoro-2-meth- oxybenzyl)-5 -hydroxy- l-methyl-6-oxo-1,6-dmydropyrirrddine-4-carboxamide;

Nl -[1 -(4-{ [(4-fluorobenzyl)amino]carbonyl } -5-hydroxy- 1 -methyl-6-oxo- 1 ,6- dihydropyrimidin-2-yl)- 1 -methylethyl] -Nl ,N2,N2-trimethylethanediamide;

2-[(2S)- 1 -acetylpyrrolidin-2-yl] -N-(4-fluoro-2-methoxybenzyl)-5- -hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine^-carboxamide;

N-(4-fluorobenzyl)-2-[(2S,4S) -4-fluoro-1-methylpyrrolidin-2-yl]-5-hydroxy- -1- methyl-6-oxo-1,6-dihydropyrimidine-4-carbo xamide;

2-{ (2S,4S)-1-[(dimethylamino)(oxo)acetyl]^-fluoropyrrolidin-2-yl}-N-(4-f- luorobenzyl) -5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

Nl - [ 1 -(4- { [(3-chloro^-fluorobenzyl)amino] carbonyl } -5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidin-2-yl)- 1 -methylethyl]-N2,N2-dimethylethane-diamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyrazin-2- ylcarbonyl)pyrrolidin-2-yl]-1,6-dihydropyrimidine-4-carbo xamide;

2-[(2S,4R)- 1 -benzoyl^-hydroxypyrrolidin-2-yl] -N-(4-fluorobenzyl)-5-hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carbo xamide;

2-(l-acetylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1- ,6- dihydropyrimidine-4-carboxamide;

2-[(2S,4R)^-(benzyloxy)-1-(pyridin-2-ylcarbonyl)pyrrolidin-2-yl]-N-(4- fluorobenzyl)-5 -hydroxy- 1 -methyl-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(4-methylmorpholin-3-yl)-6- -oxo- 1 ,6- dihydropyrimidine-4-carboxamide; (+)-N-(4-fluorobenzyl)-5 -hydroxy- l-methyl-2-(4-methylmorpholin-3-yl)-6-ox- o- 1 ,6-dihydropyrimidine-4-carboxamide

(-)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-ox- o-1,6- dihydropyrimidine-4 -carboxamide

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridin-2-ylcarbonyl)py- rrolidin-2-yl] - 1 ,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridin-2-ylcarbonyl)-1- ,2,3,4- tetrahydroquinolin-2-yl] - 1 ,6-dihydropyrimidine^-carboxamide;

2-[(2S,4R)- 1 -benzoyl^-(benzyloxy)pyrrolidin-2-yl] -N-(4-fluorobenzyl)-5-hydroxy- 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

2-[(2S,4R)-1-acetyl.₄-(benzyloxy)pyrrolidin-2-yl]-N-(4-fluorobenzyl)-5 -hydroxy- 1- methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridine-3-ylcarbonyl)py- rrolidin-2-yl] 1 ,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy-2-(l-isonicotinoylpyrrolidin-2-yl)-l -methyl- - 6-oxo- 1 ,6-dmydropyrimidine-4-carboxamide;

2-( 1 ,4-dimethylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-6-ox- o- 1 ,6- dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- { 1 - [( 1 -methyl- 1 H-imidazol-2-yl)ca- rbonyl]pyrrolidin-2-yl } -6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2-(l-benzoylpyrrolidin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo- - 1,6- dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2- [ 1 -(methylsulfonyl)pyrrolidin-2-y- 1] -6- oxo-1,6-dihydropyrimidine-4-carboxamide;

2-[(4R)_3-acetyl-1,3-thiazolidin^-yl]-N-(4-fluorobenzyl)-5-hydroxy-1-met- hyl-6- oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2- { 1 -[(ethylamino)carbonyl]pyrrolidin-2-yl } -N-(4-fluorobenzyl)-5-hydroxy- - 1 - methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide;

2-(4-ethyl-1-methylpiperazin-2-yl)-N-(4-fluorobenzyl)-5-hydroxy-l -methyl- - 6-oxo- 1 ,6-dmydropyrimidine-4-carboxamide;

2-[(2S,4R)^-(benzyloxy)-1-methylpyrrolidin-2-yl]-N-(4-fluorobenzyl)-5-hy- droxy- 1 -methyl-6-oxo- 1 ,6-dmydropyrimidine-4-carboxamide; [

N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-2-[l-(pyridin-2-ylcarbonyl)-2- ,3- dihydro- 1 H-indol-2-yl] - 1 ,6-dihydropyrimidine-4-carboxamide;

N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(l -methyl- 1 ,2,3,4-tetrahydroquino- lin-2- yl)-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide; N-(4-fluorobenzyl)-5-hydroxy- 1 -methyl-2-(2-methyl- 1 ,2,3,4-tetrahydroisoqu- inolin.

₃- yl)-6-oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

2- [ 1 -(dimethylamino)-2-phenylethyl] -N-(4-fluorobenzyl)-5 -hydroxy- 1 -methyl- -6- oxo-l,6-dihydropyrimidine-4-carboxamide; 2-[(dimethylamino)(phenyl)methyl]-N-(4- fluorobenzyl)-5 -hydroxy- 1 -methyl-6- -oxo- 1 ,6-dihydropyrimidine-4-carboxamide;

N-(2,3-dimethoxybenzyl)-5-hydroxy- 1 -methyl-2- [4-(morpholin^-ylmethyl)phenyl] -6- oxo-1,6-dihydropyrimidine-4-carboxamide; and pharmaceutically acceptable salts thereof.

Additional integrase inhibitors include those disclosed in U.S. Publication No. 20090233964. The '964 application also discloses ways to improve the pharmacokinetics of

4- oxoquinoline compounds. In one embodiment, the integrase inhibitor is 6-(3-chloro-2- fluorobenzyl)- 1-[(2S)-1 -hydroxy _₃-methylbutan-2-yl] -7-metho- xy.₄-oxo- 1 ,4- dihydroquinoline_₃-carboxylic acid. The compounds that increase the pharmacokinetics of the 4-oxoquinoline compounds generally have the formula:

where,

ring Cy is a C3-10 carbon ring group or a heterocyclic group, each group being optionally substituted by 1 to 5 substituents selected from group A; the heterocyclic group is a saturated or unsaturated ring comprising at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; group A is cyano, phenyl, nitro, halogen, C_1-2 alkyl, halo C_1-2 alkyl, halo C_1-4 alkyloxy, - -OR^al, - -SR^al, - -NR^alR^a2, - -CONR^alR^a2, - -S0₂NR^alR^a2, - -COR^a3, - -NR^alCOR^a3, - -S0₂R^a3, NR^alS0₂R^a3, - -COOR^al or - -NR^a2COOR^a3;

R l and R 2 are the same or different and each is H, C_1-4 alkyl or benzyl;

R^a3 is C_1-4 alkyl;

R¹ is selected from group B or is C₁-10 alkyl optionally substituted by 1 to 3 substituents selected from halogen or group B; group B is: a C₃-10 carbon ring optionally substituted by 1 to 5 substituents selected from group A, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A, - -OR^a4, - -SR^a4, - -NR^a4R^a5, - -CONR^a4R^a5, - -S0₂NR^a4R^a5, - -COR^a6, - -

NR^a4COR^a6, - -S0₂R^a6, - -NR^a4S0₂R^a6, - -COOR^a4 or - -NR^a5COOR^a6;

R^a4 and R^a5 are the same or different and each is:

H, C_1-4 alkyl, a C3-10 carbon ring group optionally substituted by 1 to 5 substituents selected from group A or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the group A;

R^a6 is C_1-4 alkyl, a C3-10 carbon ring group optionally substituted by 1 to 5 substituents selected from group A or a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A;

R² is H or C1.4 alkyl;

R³¹ is H, cyano, hydroxy, amino, nitro, halogen, C_{1 -4} alkyl, C_{1 -4} alkoxy, alkylsulfanyl, halo C_{1 -4} alkyl or halo C1.4 alkyloxy group;

X is C- -R³² or N;

Y is C- -R³³ or N;

R³² and R³³ are the same or different and each is: H, cyano, nitro, halogen, a C3- 10 carbon ring group optionally substituted by 1 to 5 substituents selected from group A, a heterocyclic group optionally substituted by 1 to 5 substituents selected from group A, C₁-10 alkyl optionally substituted by 1 to 3 substituents selected from halogen or group B,

OR^a7, - -SR^a7, - -NR^a7COR^a8, - -NR^COR^, - -COOR^a10 or - -N=CH- -NR^a10R^al l ;

R^a7 and R^a8 are the same or different and each is selected from H, group B or Cno alkyl optionally substituted by 1 to 3 substituents selected from halogen or group B;

R^a9 is C_1-4 alkyl; and

R^a10 and R^a11 are the same or different and each is H or C_{1 -4} alkyl.

Compound 1 is a specific compound:

Compound 1 is a HIV integrase inhibitor that is metabolized by cytochrome P450 monooxygenase, particularly, the CYP 3A isoform. It has now been found that ritonavir can be used to boost the pharmacokinetics of compounds of Formula (I) as well as other HIV integrase inhibitors. Ritonavir is particularly useful for boosting the effects of integrase inhibitors that are metabolized by cytochrome P450 monooxygenase (e.g. the CYP 3A isoform). Ritonavir can limit the first-pass effect of these compounds. Ritonavir may also limit the secondary-pass (systemic or hepatic metabolism/clearance) effects of these compounds.

Additional integrase inhibitor compounds include those disclosed in U.S. Publication No. 20080058315 (to Gilead). In one aspect, the compounds are of formula (I):

wherein:

A² and A³ are each independently N or CR_a; each R_a is independently H or C₁-C4 alkyl;

R_b is H or C₁-C4 alkyl;

R_c is H, R_k, -M-R_m, or -Q-R_n;

R_d is H, halo, or C₁-C4 alkyl that is optionally substituted with Rj;

R_f is H or C₁-C4 alkyl;

M is branched C₂-C₄ alkylene;

Q is C₁-C4 alkylene; each R_j is phenyl, optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C₁-C4 alkyl;

R_k is - - S0₂R_r, C₁-C₆ alkyl, C₂-Ce alkenyl, or C₂-Ce alkynyl, each of which is optionally substituted with one or more halo, hydroxy, carboxy, C₁-C₆ alkoxy, dimethylamino, diethylamino, N-ethyl-N-methylamino, morpholino, thiomorpholino, piperidino, C(=O)NR_aaR_ab, - -N(R_aa)S0₂R_ab, - -S0₂R_ab, C_1-C₆ alkanoyl, C₃-C₆ carbocycle, pyrrolidino, 2- oxopyrrolidino, or piperazino;

R_m is phenyl optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C₁-C₄ alkyl; and

R_n is a 5- or 6-membered heteroaryl ring optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C₁-C₄ alkyl; or R_n is a phenyl ring substituted with at least one group selected from hydroxy, trifluoromethyl, R_fS0₂NH- - , or and optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C₁-C₄ alkyl; or R_n is a C₃-C₆ carbocycle; each R_aa and R_ab is independently H or C₁-C₆ alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

In another aspect the invention provides a compound of the invention which is a compound of formula (II): wherein:

A² and A³ are each independently N or CR_a; each R_a is independently H or C₁-C₄ alkyl;

R_c is H, R_k, or -Q-R_n;

R_d is H, halo, or C₁-C₄ alkyl that is optionally substituted with Rj;

R_e is H, halo, or C₁-C₄ alkyl that is optionally substituted with Rj;

Q is C₁-C₄ alkylene;

Z is O or two hydrogens; each R_j is phenyl, optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C₁-C₄ alkyl;

R_k is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, each of which is optionally substituted with one or more halo, hydroxy, C₁-C₆ alkoxy, dimethylamino, diethylamino, N- ethyl-N-methylamino, morpholino, thiomorpholino, piperidino, or piperazino;

R_n is a C₃-C₆ carbocycle, a phenyl ring, or a 5- or 6-membered heteroaryl ring, which phenyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C₁-C₄ alkyl;

R_p is OH, C₁-C4 alkyl, C_1-C₄ alkanoyl, C_1-C₄ alkoxy, C₂-C₆ alkenyl, C₂-C₆ alkynyl, - - C(=O)NR_xR_x, - -C(=NR_ak)R_am, NH₂, - -N(R_a)- -C(=O)NR_xR_x, 4,5-dihydro^,4-dimethyloxazole, or - -N(R_s)- -S(O)₂- -R_t, wherein each C₁-C₄ alkyl of R_p is substituted with - -C(=O)NR_xR_x, - N(R_ag)- -C(=O)- -R_ah, or - -N(R_ag)- -S(O)₂- -R_ah; and wherein each C₁-C4 alkoxy, C₂-C₆ alkenyl and C₂-C₆ alkynyl of R_p is optionally substituted with phenyl, hydroxy, C3-C₆ carbocycle or - - C(=O)NR_xR_x;

R_s is - - S(O)₂- -R_w, and R_t is C₁-C4 alkyl optionally substituted with R_v; or R_s is C₁-C4 alkyl substituted with R_u, and R_t is C₁-C4 alkyl optionally substituted with R_v; or R_s is C₁-C4 alkyl optionally substituted with R_u, and R_t is R_z, NR_XR_X, or C₁-C4 alkyl substituted with R_v; each R_v is fluoro, chloro, phenyl, pyridyl, 1,4 diazepanyl, or piperazino, wherein each phenyl, pyridyl, 1,4-diazepanyl, and piperazino is optionally substituted with one or more fluoro, chloro, bromo, iodo, C₁-C4 alkyl, C₁-C4 alkyl-C(=O)- -, C₁-C4 alkyl-S(O)₂- - , - - C(=O)NR_aR_a, or - -C(=O)OR_a; each R_u is independently dimethylamino, diethylamino, N-ethyl-N-methylamino, or a ring selected from C3-C₆ carbocycle, pyrrolidino, morpholino, thiomorpholino, piperidino, and piperazino, which ring is optionally substituted with one or more C₁-C4 alkyl; and

R_w is C₁-C4 alkyl; each R_x is independently H, C₁-C4 alkyl, C3-C₆ carbocycle, or C₁-C4 alkyl-R_y; or NR_XR_X taken together form a piperidino, morpholino, azetidino, pyrrolidino, or piperazino ring, which ring is optionally substituted with one or more C₁-C4 alkyl or halo; each R_y is independently cyano, phenyl or pyridyl, wherein each phenyl or pyridyl is optionally substituted with one or more fluoro, chloro, bromo, iodo, C₁-C4 alkyl, C₁-C4 alkyl- C(=O)- -, C₁-C4 alkyl-S(O)₂- -, - -C(=O)NR_aR_a, or - -C(=O)OR_a;

R_z is phenyl which is optionally substituted with one or more fluoro, chloro, bromo, iodo, C₁-C4 alkyl, C₁-C4 alkyl-C(=O)- -, C_1-C₄ alkyl-S(O)₂- -, - -C(=O)NR_aR_a, or - -C(=O)OR_a; each R_ag and R_ah is independently H or C₁-C4 alkyl; each R_ak is hydroxy, C₁-C4 alkoxy, or NR_amR_an, each R_ah is independently H or C₁-C4 alkyl; each R_am and R_an is independently H or C₁-C4 alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

In another aspect the invention provides a compound of the invention which is a compound of formula (III): wherein:

A² and A³ are each independently N or CR_g; wherein each R_g is independently H or alkyl;

R_c is H, R_k, or -L-Ar

R_d is H, halo, or C₁-C4 alkyl that is optionally substituted with Rj; R_e is H, halo, or C₁-C4 alkyl that is optionally substituted with Rj;

L is C₁-C4 alkylene;

R_k is C₁-C₆ alkyl, C₂-Ce alkenyl, or C₂-Ce alkynyl, each of which is optionally substituted with one or more halo, hydroxy, C₁-C₆ alkoxy, dimethylamino, diethylamino, N- ethyl-N-methylamino, morpholino, thiomorpholino, piperidino, or piperazino;

X is - -C(=O)- - or - -S(O)₂- -;

Y is - -CH₂- -, or - -CH2--CH2--;

Ar is a C₃-C₁2 carbocycle, a substituted C₃-C₁2 carbocycle, C₆-C₂o aryl, substituted C₆-C₂0 aryl, C₆-C₂₀ heteroaryl, substituted C₆-C₂₀ heteroaryl; each R_j is phenyl, optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C₁-C₄ alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

In another aspect the invention provides a compound of the invention which is a compound of formula (II), wherein:

R_c is H, R_k, or -Q-R_n;

R_d is C₁-C₄ alkyl that is substituted with Rj;

R_e is H, halo, or C₁-C₄ alkyl that is optionally substituted with Rj;

Q is C₁-C₄ alkylene;

R_k is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, each of which is optionally substituted with one or more halo, hydroxy, C₁-C₆ alkoxy, dimethylamino, diethylamino, N- ethyl-N-methylamino, morpholino, thiormorpholino, piperidino, or piperazino;

R_n is a C3-C₆ carbocycle, a phenyl ring, or a 5- or 6-membered heteroaryl ring, which phenyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, - - C(=O)NR_acR_ad, or C₁-C₄ alkyl;

R_P is - -N(R_ae)- -S(O)₂- -R_af;

R_w is C₁-C₄ alkyl; each R_x is independently H, C₁-C₄ alkyl, or C₁-C₄ alkyl-R_y; or NR_XR_X taken together form a piperidino or piperazino ring, which ring is optionally substituted with one or more C₁- C₄ alkyl; each R_y is independently phenyl or pyridyl, wherein each phenyl or pyridyl is optionally substituted with one or more fluoro, chloro, bromo, iodo, C₁-C₄ alkyl, C₁-C₄ alkyl- C(=O)- -, C1-C4 alkyl-S(O)₂- -, - -C(=O)NR_aR_a, or - -C(=O)OR_a;

R_z is phenyl which is optionally substituted with one or more fluoro, chloro, bromo, iodo, C₁-C4 alkyl, C_1-C₄ alkyl-C(=O)- -, d-C₄ alkyl-S(O)₂- -, - -C(- -0)NR_aR_a, or - -C(=O)OR_a; each R_ac and R_ad is independently H or C₁-C₆ alkyl; each R_ae and R_af is independently H or C₁-C₆ alkyl; or a pharmaceutically acceptable salt or prodrug thereof. In another aspect the invention provides a compound of the invention which is a compound of formula (II): wherein:

R_c is H, R_k, or -Q-R_n;

R_d is C₁-C₄ alkyl that is substituted with Rj;

R_e is H, halo, or C₁-C₄ alkyl that is optionally substituted with Rj;

Q is C₁-C₄ alkylene;

R_n is a C₃-C₆ carbocycle, a phenyl ring, or a 5- or 6-membered heteroaryl ring, which phenyl ring or 5- or 6-membered heteroaryl ring is optionally substituted with one or more F, CI, Br, I, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C₁-C₄ alkoxy, - - C(=O)NR_acR_ad, or C₁-C₄ alkyl;

R_p is H, NH₂, - -C(=O)NR_xR_x, C₁-C₄ alkyl, pyridyl, 1,3,4-oxadiazole, 5-methyl- 1,3,4- oxadiazole, or phenyl that is optionally substituted with one or more F, CI, CN, hydroxy, or trifluoromethyl, wherein any C₁-C₄ alkyl of R_p is optionally substituted with one or more hydroxy, cyano, - -C(- -0)NR_xR_x, or - -NR_arR_as;

R_w is C₁-C₄ alkyl; each R_x is independently H, C₁-C₄ alkyl, C₃-C₆ carbocycle, or C₁-C₄ alkyl-R_y; or NR_XR_X taken together form a piperidino, morpholino, azetidino, pyrrolidino, or piperazino ring, which ring is optionally substituted with one or more C₁-C₄ alkyl or halo; each R_y is independently cyano, trifluoromethyl, hydroxy, C₁-C₄ alkoxy, phenyl or pyridyl, wherein each phenyl or pyridyl is optionally substituted with one or more fluoro, chloro, bromo, iodo, C_1-C₄ alkyl, C₁-C₄ alkyl-C(=O)- -, C_1-C₄ alkyl-S(O)₂- -, - -C(=O)NR_aR_a, or - -C(=O)OR_a;

R_z is phenyl which is optionally substituted with one or more fluoro, chloro, bromo, iodo, C₁-C4 alkyl, C₁-C4 alkyl-C(=O)- -, C₁-C4 alkyl-S(O)₂- -, - -C(=O)NR_aR_a, or - -C(- -0)OR_a; each R_ac and R_ad is independently H or C₁-C₆ alkyl; each R_ae and R_af is independently H or C₁-C₆ alkyl; each R_ar and R_as is independently H, C₁-C₆ alkyl, or C₁-C₆ alkanoyl; or a pharmaceutically acceptable salt or prodrug thereof.

Compound Preparation

The compounds of the invention may be prepared by a variety of synthetic routes and methods known to those skilled in the art. The invention also relates to methods of making the compounds of the invention. The compounds may be prepared by any of the applicable techniques of organic synthesis. For example, known techniques are elaborated in: "Compendium of Organic Synthetic Methods", John Wiley & Sons, New York, Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., "Advanced Organic Chemistry", Third Edition, John Wiley & Sons, New York, 1985; "Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry" (9 Volume set) Barry M. Trost, Editor-in-Chief, Pergamon Press, New York, 1993.

A number of detailed exemplary methods for the preparation of the integrase inhibitors described above are provided in U.S. Publication No. 20080058315; a summary of one such procedure is provided below.

To a microwave vial containing 25 mg of the methyl ketone 241 in 1 mL of ethyl alcohol was added 100 μΕ AcOH and 50 μΕ of the hydrazine. This mixture was heated to 150°C for 10 minutes, after which time LC/MS shows that hydrazone formation as well as TIPS solvolysis had proceeded to completion. The resulting products were formed as isomer mixtures which were separable by HPLC. Purification by HPLC on CI 8 provided the final products as pure compounds.

Further integrase inhibitors are disclosed in US Publication No. 20080070920 (to Gilead). The compounds are of Formula (I) or (II):

or a pharmaceutically acceptable salt, solvate, and/or ester thereof, wherein:

X and Y are independently O or S;

A is - -0- -, - -S- -, NR⁵ or - -C(R⁶)₂- -;

D is alkylene or substituted alkylene;

L is a covalent bond, alkylene, substituted alkylene, alkenylene, or substituted alkenylene;

R¹ is carbocyclyl or heterocyclyl;

R² is H, halogen, nitro, cyano, alkyl, substituted alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, alkoxycarbonyl, amino, alkylamino, dialkyamino, alkylcarbamoyl, dialkylcarbamoyl, cycloalkyl, substituted cycloalkyl, arylalkyl, or substituted arylalkyl; R³ is a carbocyclyl or heterocyclyl;

R⁴ is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, arylalkyl, substituted arylalkyl;

R⁸ is H, - -C(O)- -0-alkyl, - -C(O)- -0-(substituted alkyl), - -C(O)-alkyl-, C(O)- (substituted alkyl). R⁵ is H, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, acyl, or substituted acyl; each R⁶ is independently H, alkyl, hydroxyl, alkoxy, cyano, or halo; or

each R⁶, together with the carbon atom to which they are shown attached, form a— C(O)- - , - - C(S)- -, - -C(NR⁷)- -, or cycloalkyl; or

one R⁶, together with R², forms a heterocyclyl or substituted heterocyclyl ring; R⁷ is H, alkyl, substituted alkyl, hydroxyl, or alkoxy; each W and Z is independently selected from the group consisting of halo, nitro, hydroxyl, amino, acetamido, trifluoroacetamido, azido, cyano, formyl, carbamoyl, alkyl, substituted alkyl, alkylcarbamoyl, dialkylcarbamoyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxycarbonyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, oxide; and n and m are independently integers of from 0 to 4;

with the following proviso:

when -O-R¹ (W)_m or -D-R¹(NHR⁸ )-(W)_m is:

then -A-R³(L-CN)-(Z)_n or -A-R³-(Z)_n is not:

o

In another embodiment, the integrase inhibitors are compounds of Formula (ΠΓ):

or pharmaceutically acceptable salt, solvate, and/or ester thereof:

wherein

X and Y are independently O or S;

A is 0-, -S-, NR⁵ or ~C(R⁶)₂-;

D is alkylene or substituted alkylene;

Q is halo or alkoxy;

R¹ is carbocyclyl or heterocyclyl; R² is H, halogen, nitro, cyano, alkyl, substituted alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl, alkoxycarbonyl, amino, alkylamino, dialkyamino, alkylcarbamoyl, dialkylcarbamoyl, cycloalkyl, substituted cycloalkyl, arylalkyl, or substituted arylalkyl; R³ is a carbocyclyl or heterocyclyl;

R⁸ is H, - -C(O)- -0-alkyl, - -C(O)- -0-(substituted alkyl), - -C(O)-alkyl-, C(O)- (substituted alkyl). R⁵ is H, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl; each R⁶ is independently H, alkyl, hydroxyl, alkoxy, or halo; or

each R⁶, together with the carbon atom to which they are shown attached, form a - - C(O)- - or - -C(NR⁷)- -; or

one R⁶, together with R⁷, forms a heterocyclyl or substituted heterocyclyl ring; R⁷ is H, alkyl, substituted alkyl, hydroxyl, or alkoxy;

each W and Z is independently selected from the group consisting of halo, nitro, hydroxyl, amino, acetamido, trifluoroacetamido, azido, cyano, formyl, carbamoyl, alkyl, substituted alkyl, alkylcarbamoyl, dialkylcarbamoyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkoxycarbonyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, oxide; and

n and m are independently integers of from 0 to 4;

with the following provisos:

(a) when D is - - CH₂- -, R³ is carbocyclyl, and n is 2, then R¹ is heterocyclyl; and

(b) when D is - - CH₂- - , R¹ is heterocyclyl, Q is halo, R³ is carbocyclyl, and n is 2, then Z is not alkyl.

In another embodiment of the compounds of Formula (I) or (II), A is A is - - C(R⁶)₂- -. In another embodiment of the compounds of Formula (I) or (II), A is - - C(NR⁵)- - . In another embodiment of the compounds of Formula (I) or (II), A is - - C(N- - OR⁵)- - . In another embodiment of the compounds of Formula (I) or (II), A is - - C(O)- - . In another embodiment of the compounds of Formula (I) or (II), A is - - O- - . In another embodiment of the compounds of Formula (I) or (II), A is - - NR⁵. In another embodiment of the compounds of Formula (I) or (II), R³ is aryl or heteroaryl.

In another embodiment of the compounds of Formula (I) or (II), R³ is phenyl.

In another embodiment of the compounds of Formula (I) or (II), R³ is phenyl and each Z is independently selected from the group consisting of - - CN, alkyl, substituted alkyl, halo, and substituted alkenyl. In another embodiment of the compounds of Formula (I) or (II), R³-(Z)_n or R³(L- CN)-(Z)_n have the following structures:

In another embodiment of the compounds of Formula (I) or (II), each Z is independently selected from the group consisting of - - CN, - - CH₃, - - CH=CH- - CN, - - CH₂CH₂- - CN, CI, and Br.

In another embodiment of the compounds of Formula (I) or (II), R³-(Z)_n is selected from the group consisting of:

In another embodiment of the compounds of Formula (I) or (II), R³ is phenyl and each Z is independently selected from the group consisting of - - CN, alkyl, substituted alkyl, halo, and substituted alkenyl.

In another embodiment of the compounds of Formula (I) or (II), R³-(Z)_n or R³(L- CN)-(Z)_n have the following structures:

In another embodiment of the compounds of Formula (I) or (II), each Z is independently selected from the group consisting of - - CN, - - CH₃, - - CH=CH- - CN, - - CH₂CH₂- CN, CI, and Br.

In another embodiment of the compounds of Formula (I) or (II), R³ is phenyl, R⁵ is H, and each Z is independently selected from the group consisting of - - CN, alkyl, substituted alkyl, halo, and substituted alkenyl.

In another embodiment of the compounds of Formula (I) or (II), D is alkylene or substituted alkylene.

In another embodiment of the compounds of Formula (I) or (II), D is methylene.

In another embodiment of the compounds of Formula (I) or (II), R¹ is aryl or heteroaryl.

In another embodiment of the compounds of Formula (I) or (II), R¹ is phenyl, pyridyl, pyrimidyl, pyridazinyl, and isoxazolyl.

In another embodiment of the compounds of Formula (I) or (II), R¹- - (W)_m is:

In another embodiment of the compounds of Formula (I) or (II), each W is independently selected from the group consisting of halo, hydroxyl, alkoxyl, amino, substituted amino, -amino-C(O)-alkylene-amino, and sulfonamide

In another embodiment of the compounds of Formula (I) or (II), R¹- -(W)_m is selected from the group consisting of:

In another embodiment of the compounds of Formula (I) or (II), R¹- -(W)_m is:

In another embodiment of the compounds of Formula (I) or (II), each W is independently selected from the group consisting of halo, hydroxyl, alkoxy, amino, substituted amino, -amino-C(O)-alkylene-amino, and sulfonamide

In another embodiment of the compounds of Formula (I) or (II), R¹- - (W)_m is:

In another embodiment of the compounds of Formula (I) or (II), W is selected from the group consisting of halo, alkyl, cyano, - - C(O)-amino, alkoxy, hydroxy, and amino.

In another embodiment of the compounds of Formula (I) or (II), R¹- <W)_m is:

In another embodiment of the compounds of Formula (I) or (II), R² is alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, substituted cycloalkyl, halo, or amino.

In another embodiment of the compounds of Formula (I) or (II), R² is alkyl.

In another embodiment of the compounds of Formula (I) or (II), X and Y are both O; A is - - C(O)- - ; D is alkylene; R¹ is aryl or heteroaryl; R² is alkyl; and R³ is aryl.

In another embodiment of the compounds of Formula (I) or (II), X and Y are both O; A is - - C(O)- - ; D is - - CH₂- - ; R¹ is phenyl, pyridyl, pyrimidyl, pyridazyl, or isoxazolyl; R² is 2- propyl; and R³ is phenyl. It is preferred that R¹ is 4-pyridyl. It is also preferred that each W is independently selected from the group consisting of halo, hydroxyl, alkoxy, amino, substituted amino, -amino-C(O)-alkylene-amino, and sulfonamido. It is also preferred that R¹ is phenyl.

In another embodiment of the compounds of Formula (I) or (II), X and Y are both O; A is - -C(R⁶)₂, - -C(N- -OR⁵)- -, or - -C(NR⁵)- -; D is alkylene; R¹ is aryl or heteroaryl; R² is alkyl; and R³ is aryl. Preferably, R⁶ is - - CHOH or R⁶, together with R², forms a heterocyclyl or substituted heterocyclyl.

In another embodiment of the compounds of Formula (I) or (II), the compound is selected from the group consisting of:

In yet another embodiment of the compounds of Formula (III), R¹ is heteroaryl.

In yet another embodiment of the compounds of Formula (III), R¹ is 4-pyridyl.

In yet another embodiment of the compounds of Formula (III), m is 0.

In yet another embodiment of the compounds of Formula (III), R³ is aryl.

In yet another embodiment of the compounds of Formula (III), R³ is phenyl.

In yet another embodiment of the compounds of Formula (III), n is 2.

In yet another embodiment of the compounds of Formula (III), each Z is independently halo or alkyl.

In yet another embodiment of the compounds of Formula (III), R¹ is 4-pyridyl, m is 0, R³ is phenyl, n is 2, and each Z is independently halo or alkyl.

In yet another embodiment of the compounds of Formula (III), the compound is selected from the group consisting of:

The compounds can generally be synthesized using a reaction scheme similar to the following:

Λ

Detailed synthetic protocol for synthesizing the above-described integrase inhibitors are disclosed in U.S. Publication No. 2008/0070920.

Still further integrase inhibitors are disclosed in U.S. Publication No. 20080153783. In one embodiment, the compounds are 4,5-dihydroxypyrimidine, 6-carboxamide phosphonate compounds having Formula I:

I

In another aspect, the invention includes 3-N-substituted, 5-hydroxypyrimidinone, 6- carboxamide phosphonate compounds having Formula II:

R¹ is selected from H, F, CI, Br, I, OH, OR, amino (- -NH₂), ammonium (- -NH₃ ⁺), alkylamino (- - NHR), dialkylamino (- - NR₂), trialkylammonium (- - NR₃₊), carboxyl (- - C0₂H), sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, 4-dialkylaminopyridinium, alkylsulfone (- -S0₂R), arylsulfone (- -S0₂Ar), arylsulfoxide (- -SOAr), arylthio (- -SAr), sulfonamide (- -S0₂NR₂), allylsulfoxide (- -SOR), formyl (- -CHO), ester (- -C0₂R), amido (- - C(=O)NR₂), 5-7 membered ring lactam, 5-7 membered ring lactone, nitrile (--CN), azido (- - N₃), nitro (- -N0₂), C_1-C₈ alkyl, C₁-C₁s substituted allyl, C₂-C₁₈ alkenyl, C₂-C₁₈ substituted alkenyl, C₂-C₁₈ alkynyl, C₂-C₁₈ substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, and C₂-C₂₀ substituted heterocycle, phosphonate, phosphate, polyethyleneoxy, a protecting group, L-A³, and a prodrug moiety.

R² and R⁵ are each independently selected from H, carboxyl (- - C0₂H), sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, 4-dialkylaminopyridinium, alkylsulfone (- - S0₂R), arylsulfone (- - S0₂Ar), arylsulfoxide (- -SOAr), arylthio (- -SAr), sulfonamide (- - S0₂NR₂), alkylsulfoxide (- -SOR), formyl (- -CHO), ester (- -C0₂R), amido (- -C(=O)NR₂), 5-7 membered ring lactam, 5-7 membered ring lactone, nitrile (--CN), azido (- - N₃), nitro (- - N0₂), C₁-C₁s alkyl, C₁-C₁s substituted allyl, C₂-C₁₈ alkenyl, C₂-C₁₈ substituted alkenyl, C₂-C₁₈ alkynyl, C₂-C₁₈ substituted alkynyl, C₁6-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, and C₂-C₂₀ substituted heterocycle, phosphonate, phosphate, polyethyleneoxy, a protecting group, L-A³, and a prodrug moiety.

R^2b, R³, and R⁴ are each independently selected from H, OH, OR, amino (- - NH₂), ammonium (- - NH₃ ⁺), alkylamino (- -NHR), dialkylamino (- - NR₂), trialkylammonium (- - NR₃ ⁺), carboxyl (- - C0₂H), sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, 4 dialkylaminopyridinium, alkylsulfone (- - S0₂R), arylsulfone (- - S0₂Ar), arylsulfoxide (- - SOAr), arylthio (- -SAr), sulfonamide (- -S0₂NR₂), alkylsulfoxide (- -SOR), formyl (- -CHO), ester (- - C0₂R), amido (- - C(=O)NR₂), 5-7 membered ring lactam, 5-7 membered ring lactone, nitrile (--CN), azido (- -N₃), nitro (- -N0₂), C_1-C₁₈ alkyl, C_1-C₁₈substituted alkyl, C₂-C₁₈ alkenyl, C₂-C₁₈ substituted alkenyl, C₂-C₁₈ alkynyl, C₂-C₁₈ substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂o heterocycle, and C₂-C₂o substituted heterocycle, phosphonate, phosphate, polyethyleneoxy, a protecting group, L-A³, and a prodrug moiety.

R is independently selected from H, C₁-C₁s alkyl, C₁-C₁s substituted alkyl, C₂-C₁₈ alkenyl, C₂-C₁₈ substituted alkenyl, C₂-C₁₈ alkynyl, C₂-C₁₈ substituted alkynyl, C₆-C₂₀ aryl, C₆- C₂₀ substituted aryl, C₂-C₂₀ heterocycle, C₂-C₂₀ substituted heterocycle, phosphonate, phosphate, polyethyleneoxy, a protecting group, and a prodrug moiety.

Substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, and substituted heterocycle are independently substituted with one or more substituents selected from F, CI, Br, I, OH, amino (- -NH₂), ammonium (- -NH₃ ⁺), alkylamino (- -NHR), dialkylamino (- - NR₂), trialkylammonium (- - NR₃ ⁺), C₁-C₈ alkyl, C₁-C₈ alkylhalide, carboxylate, thiol (- - SH), sulfate (- - OSO₃R), sulfamate, sulfonate (- - S0₃R), 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈ alkylthiol, alkylsulfone (- - S0₂R), arylsulfone (- - S0₂Ar), arylsulfoxide (- -SOAr), arylthio (- -SAr), sulfonamide (- -S0₂NR₂), alkylsulfoxide (- -SOR), ester (- - C(=.0)OR), amido (- - C(=O)NR₂), 5-7 membered ring lactam, 5-7 membered ring lactone, nitrile (--CN), azido (- -N₃), nitro (- -N0₂), C_1-C₈ alkoxy (- -OR), C_1-C₈ alkyl, C_1-C₈ substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heterocycle, and C₂-C₂₀ substituted heterocycle, phosphonate, phosphate, polyethyleneoxy, and a prodrug moiety.

Embodiments of R¹, R^2a, R^2b, R³, R⁴, and R⁵ include - -C(=S)NR₂, - -C(=O)OR, - - C(=O)NR₂, - -C(=O)NRNR₂, - -C(=O)R, - -S0₂NR₂, - -NRS0₂R, - -NRC(=S)NR₂, - -SR, - - S(O)R, - -S0₂R, - -S0₂R, - -P(=O)(OR) ₂, - -P(=O)(OR)(NR₂), - -P(=O)(NR₂) ₂, - -P(=S)(OR) ₂, - - P(=S)(OR)(NR₂), - -P(=S)(NR₂) ₂, and including prodrug substituted forms thereof.

Embodiments of R¹, R^2a, R^2b, R³, R⁴, and R⁵ may also individually or in combination form a ring, e.g. 4-7 membered ring lactam, carbonate, or sultam, or piperazinyl sulfamate:

Embodiments of R¹ also include - -OC(=S)NR₂, - -OC(=O)OR, - -OC(=O)NR₂, - - OC(=O)NRNR₂, - -OC(=O)R, - -OP(=O)(OR) ₂, - -OP(=O)(OR)(NR₂), - -OP(=O)(NR₂) ₂, - - OP(=S)(OR) ₂, - -OP(=S)(OR)(NR₂), - -OP(=S)(NR₂) ₂, and including prodrug substituted forms thereof.

A linker may be interposed between positions R¹, R², R³, R⁴, and R⁵ and substituent A³, as exemplified in some structures herein as "L-A³". The linker L may be O, S, NR, N- - OR, C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂ substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substituted alkynylene, C(=O)NH, C(=O), S(=O) ₂, C(=O)NH(CH₂) n, and (CH₂CH₂0) n, where n may be 1, 2, 3, 4, 5, or 6. Linkers may also be repeating units of allyloxy (e.g. polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, Jeff amine. TM.); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide. For example, the linker may comprise propargyl, urea, or alkoxy groups.

A³ has the structure:

where:

Y¹ is independently O, S, NR^X, N(O)(R^x), N(OR^x), N(O)(OR^x), or N(N(R^X) ₂);

Y² is independently a bond, O, NR^X, N(O)(R^x), N(OR^x), N(O)(OR^x), N(N(R^X) ₂), - - S(O)- - (sulfoxide), - -S(O) ₂- - (sulfone), - -S-(sulfide), or - -S--S-(disulfide);

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

R_y is independently H, C₁-C₁₈ alkyl, C₁-C₁₈ substituted alkyl, C₆-C₂o aryl, C₆-C₂o substituted aryl, or a protecting group, or where taken together at a carbon atom, two vicinal R^y groups form a carbocycle or a heterocycle. Alternatively, taken together at a carbon atom, two vicinal R^y groups form a ring, i.e. a spiro carbon. The ring may be all carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or alternatively, the ring may contain one or more heteroatoms, for example, piperazinyl, piperidinyl, pyranyl, or tetrahydrofuryl.

R_x is independently H, C₁-C₁s alkyl, C₁-C₁s substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, or a protecting group, or the formula:

where Mia, Mlc, and Mid are independently 0 or 1, and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

At least one of R, R_1; R_2a, R_2b, R3, and R₅ in each Formula I and Formula II compound comprises a phosphonate group.

Exemplary embodiments of C₆-C₂₀ substituted aryl groups include halo-substituted phenyl such as 4 -fluorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, and 3,5-difluorophenyl.

Ar groups include:

where a wavy line , in any orientation, indicates the covalent attachment site of the other structural moieties of the compound.

Embodiments of A₃ include where M2 is 0, such as:

and where M12b is 1, Yi is oxygen, and Y is independently oxygen (O) or nitrogen (N(R_X)) such as:

Embodiments of A₃ include where Yi is O, resulting in the structure:

Embodiments of A₃ include Where Y₂ is O, and M2 is 0, resulting in the structure:

Embodiments of A₃ include where R^y is H, and M 12a is 2, resulting in the structure:

Embodiments of A₃ include where A₂is - - N(CH₃)- - , and M12b is 1, resulting in the structure:

where W⁵ is a carbocycle such as phenyl or substituted phenyl, and Y^2c is independently O, N(R.sup.y) or S. For example, R¹ may be H and n may be 1.

W₅ also includes, but is not limited to, aryl and heterocycle groups such as:

Another embodiment of A₃ includes:

Such embodiments include:

where Y^2b is O or N(R^X); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; R^a is H or C₁-C₆ alkyl; and the phenyl carbocycle is substituted with 0 to 3 R_b groups where R_b is C₁-C₆ alkyl or substituted alkyl. Such embodiments of A₃ include phenyl phosphonamidate amino acid, e.g. alanate esters and phenyl phosphonate-lactate esters:

Embodiments of R^x include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups:

The invention includes pharmaceutically acceptable salts of Formulas I and II, and and tautomeric resonance isomers thereof.

Formula I and II compounds are substituted with one or more covalently attached phosphonate groups. The compounds of the invention include at least one phosphonate group covalently attached at any site, i.e. R¹, R²a, R²b, R³, R⁴ or R⁵.

Exemplary compounds of Formula I include:

Exemplary compounds of Formula II include: Ila

Exemplary embodiments of the invention includes phosphonamidate and phosphoramidate (collectively "amidate") prodrug compounds. General formulas for phosphonamidate and phosphoramidate prodrug moieties include:

The phosphorus atom of the phosphonamidate group is bonded to a carbon atom. The nitrogen substituent R⁸ may include an ester, an amide, or a carbamate functional group. For example, R may be - -CR₂C(=O)OR' where R' is H, C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆- C₂o aryl, C₆-C20 substituted aryl, C₂-C₂o heterocycle, or C₂-C₂o substituted heterocycle. The nitrogen atom may comprise an amino acid residue within the prodrug moiety, such as a glycine, alanine, or valine ester (e.g. valacyclovir, see: Beauchamp, etal Antiviral Chem. Chemotherapy (1992) 3: 157-164), such as the general structure:

where R' is the amino acid side-chain, e.g. H, CH₃, CH(CH₃)₂, etc. An exem lary embodiment of a phosphonamidate prodrug moiety is:

Synthesis of Pyrimidine and Pyrimidinone Phosphonate Compounds

The compounds of the invention may be prepared by a variety of synthetic routes and methods known to those skilled in the art. The invention also relates to methods of making the compounds of the invention. The compounds are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in: Compendium of Organic Synthetic Methods, John Wiley & Sons, New York, Vol. 1 Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, John Wiley & Sons, New York, 1985; Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry (9 Volume set) Barry M. Trost, Editor-in-Chief, Pergamon Press, New York, 1993.

A number of exemplary methods for the preparation of the compounds of the invention are provided herein. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods.

Deliberate use may be made of protecting groups to mask reactive functionality and direct reactions regioselectively (Greene, etal (1991) Protective Groups in Organic Synthesis 2nd Ed., John Wiley & Sons). For example, useful protecting groups for the 8-hydroxyl group and other hydroxyl substituents include methyl, MOM (methoxymethyl), trialkylsilyl, benzyl, benzoyl, trityl, and tetrahydropyranyl. Certain aryl positions may be blocked from substitution, such as the 2-position as fluorine.

Dihydroxypyrimidine carboxamide (WO 03/035076A1) and N-substituted hydroxypyrimidinone carboxamide (WO 03/035077A1) compounds have been prepared.

Representative reaction schemes are shown below. Additional details on the synthesis of these compounds can be found in U.S. Publication No. 20080153783.

Still further integrase inhibitor compounds include those disclosed in U.S. Publication No. 20090029939. In one aspect, the compounds have the structure:

wherein:

A¹ and A² are independently selected from O, S, NR, C(R²)₂, CR²OR, CR²OC(=O)R, C(=O), C(=S), CR²SR, C(=NR), C(R²)₂- -C(R³)₂, C(R²)=C(R³), C(R²)₂- -0, NR- -C(R³)₂, N=C(R³), N=N, S0₂- -NR, C(=O)C(R³)₂, C(=O)NR, C(R²)₂- -C(R³)₂- -C(R³)₂, C(R²)=(R³)- - C(R³)₂, C(R²)C(=O)NR, C(R²)C(=S)NR, C(R²)=N- -C(R³)₂, C(R²)=N- -NR, and N=C(R³)- - NR;

Q is N, ⁺NR, or CR⁴;

L is selected from a bond, O, S, S- -S, S(=O), S(=O)₂, S(=O)₂NR, NR, N- -OR, C_1-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂ substituted alkenylene, C₂- C₁₂ alkynylene, C₂-C₁₂ substituted alkynylene, C(=O)NH, OC(=O)NH, NHC(=O)NH, C(=O), C(=O)NH(CH₂)_n, or (CH₂CH₂0)_n, where n may be 1, 2, 3, 4, 5, or 6;

X is selected from O, S, NH, NR, N- -OR, N- -NR₂, N- -CR₂OR and N- -CR₂NR₂;

Ar is selected from C₃-C₁2 carbocycle, C₃-C₁2 substituted carbocycle, C₆-C₂₀ aryl, Ce- C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl;

R¹ R², R³ and R⁴ are each independently selected from H, F, CI, Br, I, OH, - -NH₂, - - NH₃ ⁺, - -NHR, - -NR₂ ⁺, - -NR₃ ⁺, C_1-C₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5- 7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈ alkylthiol, dialkylaminopyridinium, — S0₂R, — S0₂Ar, - - SOAr, - - SAr, - -S0₂NR₂, - -SOR, - -C0₂R, - -C(=O)NR₂5-7 membered ring lactam, 5-7 membered ring lactone, - -CN, - -N₃, - -N0₂, C_1-C₈ alkoxy, C_1-C₈ trifluoroalkyl, C₁-C₈ alkyl, C_1-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety; when taken together on a single carbon, two R² or two R³ may form a spiro ring; and

R is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;

R^X2 is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug, a pharmaceutically acceptable prodrug, a prodrug moiety, a protecting group, and a phosphonate prodrug moiety; and the salts, solvates, resolved enantiomers and purified diastereomers thereof; with the proviso that when Y=Z is C=C(OH), X is O, A¹ is C(=O), A² is C(R²)=C(R³), and Q is CH, then L is not a bond.

In one aspect, the invention is a compound having the structure:

wherein:

A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(=O)R, C(=O), C(=S), CR²SR, and C(=NR),

A² is independently selected from C(R²)₂- -C(R³)₂, C(R²)=C(R³), and C(=O)C(R³)₂; Q is CR⁴;

is

L is selected from a bond, O, S, S- -S, S(=O), S(=O)₂, S(=O)₂NR, NR, N- -OR, C_1-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₂ substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substituted alkynylene, C(=O)NH, OC(=O)NH, NHC(=O)NH, C(=O), C(=O)NH(CH₂)_n, or (CH₂CH₂0)_n, where n is optionally 1, 2, 3, 4, 5, or 6;

Ar is selected from (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl; or (b) a saturated, unsaturated or aromatic ring or ring system having a mono- or bicyclic carbocycle or heterocycle containing 3 to 12 ring atoms;

R², R³ and R⁴ are each independently selected from H, F, CI, Br, I, OH, - - NH₂, - - NH₃ ⁺, - -NHR, - -NR₂, - -NR₃ ⁺, C_1-C₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C_1-C₈ alkylthiol, - -S0₂R, - -S0₂Ar, - -SOAr, - -SAr, - -S0₂R₂, - -SOR, - - C0₂R, - - C(=O)NR₂, 5-7 membered ring lactam, 5-7 membered ring lactone, - -CN, - - N₃, - - N0₂, C₁-C₈ alkoxy, C_1-C₈ trifluoroalkyl, C_1-C₈ alkyl, C_1-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety; when taken together on a single carbon, two R² or two R³ may from a spiro ring; R¹ is independently selected from CR₃, NRS0₂R, OC(=O)NR₂ OC(=O)R, SR, H, F, CI, Br, I, OH, - -NH₂, - -NH₃ ⁺, - -NHR, - -NR₂, - -NR₃ ⁺, C_1-C₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4- dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈ alkylthiol, - - S0₂R, - - S0₂Ar, - - SOAr, - - SAr, - -S0₂NR₂, - -SOR, --C0₂R, --C(=O)NR₂, 5-7 membered ring lactam, 5-7 membered ring lactone, - -CN, - -N₃, - -N0₂, C_1-C₈ alkoxy, C_1-C₈ trifluoroalkyl, C₁-C₈ alkyl, C_1-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;

R^X2 is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl, C₆-C₂0 substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group; and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof,

with the proviso that when Y=Z is C=C(OH), X is O, A¹ is C(=O), A² is C(R²)=C(R³), and Q is CH, then L is not a bond.

In another aspect the invention is a compound having the structure:

wherein:

A¹ is independently selected from C(R²)₂- -C(R³)₂, C(R²)=C(R³), C(=O)C(R³)₂, C(R²)₂- -C(R³)₂- -C(R³)₂, C(R²)=C(R³)- -C(R³)₂, and C(R²)₂- -C(R³)=C(R³);

Y— Z is C=C; L is selected from a bond, O, S, S- -S, S(=O), S(=O)₂, S(=O)₂NR, NR, N- -OR, C_1-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁2 substituted alkenylene, C₂- C₁₂ alkynylene, C₂-C₁₂ substituted alkynylene, C(=O)N- -H, OC(=O)NH, NHC(=O)NH, C(- - O), C(=O)NH(CH₂)_n, or (CH₂CH₂0)_n, where n may be 1, 2, 3, 4, 5, or 6;

X is selected from O, S, NH, NR, N- -OR, N- -NR₉, N- -CR₂OR and N- -CR₉NR₂;

R², R³ and R⁴ are each independently selected from H, F, CI, Br, I, OH, - - NH₂, - - NH₃ ⁺, - -NHR, - -NR₂, - -NR₃ ⁺, C_1-C₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C_1-C₈ alkylthiol, - -S0₂R, - -S0₂Ar, - -SOAr, - -SAr, - -S0₂NR₂, - -SOR, - - C0₂R, - - C(=O)NR₂, 5-7 membered ring lactam, 5-7 membered ring lactone, - -CN, - - N₃, - - N0₂, C₁-C₈ alkoxy, C_1-C₈ trifluoroalkyl, C₁-C₈ alkyl, C_1-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety; when taken together on a single carbon, two R² or two R³ may form a spiro ring;

R¹ is independently selected from CR₃, NRS0₂R, OC(=O)NR₂ OC(=O)R, SR, H, F, CI, Br, I, OH, - -NH₂, - -NH₃ ⁺, - -NHR, - -NR₂, - -NR₃ ⁺, C_1-C₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4- dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈ alkylthiol, - - S0₂R, - - S0₂Ar, - -SOAr, - - SAr, - -S0₂NR₂, - -SOR, - -C0₂R, - -C(=O)NR₂, 5-7 membered ring lactam, 5-7 membered ring lactone, - -CN, - -N₃, - -N0₂, C_1-C₈ alkoxy, C_1-C₈ trifluoroalkyl, C₁-C₈ alkyl, C_1-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂0 aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety;

R^X2 is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂0 aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety, and a protecting group selected from the group consisting of benzyhydryl (CHPh₂), trialkylsilyl (R₃Si), 2-trimethylsilylethyl, alkoxymethyl (CH₂OR), and ester (C(=O)R); and the tautomers, salts, solvates, resolved enantiomers and purified diastereomers thereof.

In one aspect, the invention includes tricyclic compounds represented by the following structure:

The compounds share a tricyclic scaffold and a potential active site or metal binding motif defined by the lower side of the Formula above including the amide-type functionality, i.e. N- - C(=X), of the left ring, the aromatic hydroxyl of the middle ring, and the nitrogen of the right ring. The compounds of the invention have binding functionality, e.g. nitrogen, hydroxyl, and X-carbonyl, in a pre-organized configuration which may confer optimized inhibitory properties against XMRV integrase.

A¹ and A² are each and independently a moiety forming a five, six, or seven membered ring. Q is N, substituted nitrogen (NR), CH, or substituted carbon. L is a bond or a linker connecting a ring atom of Ar to N. X is O, S, NH, or substituted nitrogen (NR). Ar is a carbocycle, aryl or heteroaryl group. R is a substituent including H, alkyl, aryl, heteroaryl and substituted forms thereof, as well as polyethyleneoxy, phosphonate, phosphate, or a prodrug moiety. The 5 and 6 positions are represented in the structure above by Y and Z respectively. The chemical bond between Y and Z may be a single bond, a double bond, or a bond with enolic, tautomeric character, depending on the substituent on Z, i.e. R¹ or X. The Y and Z substructure is represented wherein:

The compounds of the invention may include prodrug moieties covalently attached at any site. The prodrug moiety may be a phosphonate group.

Synthesis of HIV-Integrase Inhibitor Compounds

The compounds described above may be prepared by a variety of synthetic routes and methods known to those skilled in the art. The invention also relates to methods of making the compounds of the invention. The compounds are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in: "Compendium of Organic Synthetic Methods", John Wiley & Sons, New York, Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., "Advanced Organic Chemistry", Third Edition, John Wiley & Sons, New York, 1985; "Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry" (9 Volume set) Barry M. Trost, Editor-in-Chief, Pergamon Press, New York, 1993.

A number of exemplary methods for the preparation of the compounds, Formulas I- IV, of the invention are provided herein. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods.

Formula I Compounds

Exemplary methods of synthesis of Formula I compounds are described below in Schemes 1-10 and 15-17. One method of synthesis of Formula I compounds of the invention is cyclization of a succinimide compound with a pyridine dicarboxylate compound to give tricyclic compounds (Murray and Semple, Synthesis (1996) 11 :80-82; Jones and Jones, Jour. Chem. Soc, Perkin Transactions I (1973) 26-32), according to Scheme 1.

Alternatively, a succinimide with a labile protecting group (P) on the nitrogen may be reacted with a pyridine dicarboxylate compound. P may be an acid-labile protecting group, such as trialkylsilyl. Trialkylsilyl groups may also be removed with fluoride reagents. After P is removed, a variety of Ar-L groups may be covalently attached.

Imide compounds can be reduced with dissolving metal reducing agents, e.g. Zn, or hydride reagents, e.g. NaBH₄, to form a lactam.

Imide compounds may also be reduced to the hydroxylactam under mild conditions. Reductions with sodium borohydride and cerium or samarium salts have been shown to proceed with regioselectivity on asymmetric imides (Mase, et al J. Chem. Soc. Perkin Communication 1 (2002) 707-709), as in Scheme 4, upper. Grignard reagents and acetylenic anions (Chihab-Eddine, et al Tetrahedron Lett. (2001) 42:573-576) may also add with regioselectivity to an imide carbonyl to form alkyl-hydroxylactam compounds. The phenolic oxygen groups may be protected and deprotected as necessary to furnish yield reactions.

Another synthetic route to the compounds of the invention proceeds through substituted quinoline intermediates (Clemence, et al U.S. Pat. No. 5,324,839; Billhardt- Troughton, et al U.S. Pat. No. 5,602,146; Matsumura, J. Amer. Chem. Soc. (1935) 57:124- 128) having the general formula:

The cyclic anhydride below may be regioselectively esterified to give the compounds of the invention, for example

e 6

where MOM is methoxymethyl and X is, for example, C(=O), CRC(=O), C(=O)C(=O), and S0₂. See Ornstein, et al Jour. Med. Chem. (1989) 32:827-833. The same chemistry can be applied to the 5-membered lactam synthesis to control the regiochemistry as in Scheme 7:

A cyclic imide may be conveniently alkylated, acylated, or otherwise reacted to form a broad array of compounds with Ar-L groups:

The Ar-L group may be attached as one reactant group, for example as an alkylating reagent like benzyl bromide (Ar=phenyl, L=CH₂) or a sulfonating reagent, like 4- methoxyphenyl sulfonyl chloride (Ar=4-methoxyphenyl, L=S(=O)₂. Alternatively, the Ar-L group may be attached by a multi step process. For example, the imide nitrogen may react with a sulfurizing reagent such as 2,2-dipyridyl disulfide to form an N-sulfide intermediate (Ar=2-pyridyl, L=S). Such an intermediate may be further elaborated to a variety of Ar-L groups where L is S, S(=O) or S(=O)₂.

Another synthetic route to the compounds of the invention proceeds through 7- substituted, 8-quinolinol intermediates (Zhuang, et al WO 02/36734; Vaillancourt, et al U.S. Pat. No. 6,310,211; Hodel, U.S. Pat. No. 3,113,135) having the general formulas, including aryl substituted compounds:

Annulation of the third, 5-7 membered ring can be conducted by appropriate selection of aryl substituents on the quinoline ring system, utilizing known synthetic transformations to give compounds of Formula I. For example, methods for coupling carboxylic acids and other activated acyl groups with amines to form carboxamides are well known in the art (March, J. Advanced Organic Chemistry, 3rd Edition, John Wiley & Sons, 1985, pp. 370-376).

One can cyclize a 2-O-protected, 3 halo-aniline compound with an (a,.beta.- unsaturated carbonyl compound to give a functionalized quinoline. The a,.beta. -unsaturated carbonyl compound may be, for example, an aldehyde (X=H), ketone (X=R), ester (X=OR), amide (X=NR₂), acyl halide (X=C1), or anhydride. Carbonylation via palladium catalysis can give an ester which may be elaborated to the amide functionality and cyclization to form a 5, 6, or 7 membered ring. The R group of phenolic oxygen may be a labile protecting group, e.g. trialkylsilyl or tetrahydropyranyl, which may be removed at a step in the synthetic route, or it may be a substituent which is retained in the putative integrase inhibitor compound.

Halo quinoline intermediates may undergo a flexible array of nucleophilic aromatic substitutions and Suzuki-type reactions. Suzuki coupling of aryl halide compounds with acetylenic and vinylic palladium complexes are carbon-carbon bond forming reactions under relatively mild conditions. In some instances it may be necessary to block the 2 position to direct reaction at the desired aryl position.

Formula I compounds with a 5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione were prepared by selective protection of the C9 phenol in 5,9-dihydroxy-pyrrolo[3,4-g]quinolinie- 6,8-dione. The C9 phenol was protected with a TIPS group and the C5 phenol could then be alkylated or acylated.

Additional experimental details are provided in U.S. Publication 2009 029939.

III. Stereoisomerism and Polymorphism

The compounds described herein may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present invention. Compounds of the present invention having a chiral center can exist in and be isolated in optically active and racemic forms. Some compounds can exhibit polymorphism. The present invention encompasses racemic, optically-active, polymorphic, or stereoisomeric forms, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein. The optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution. One can either purify the respective nucleoside, then derivatize the nucleoside to form the compounds described herein, or purify the nucleotides themselves.

Optically active forms of the compounds can be prepared using any method known in the art, including but not limited to by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct;

ii) simultaneous crystallization: a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state;

iii) enzymatic resolutions: a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme;

iv) enzymatic asymmetric synthesis: a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis: a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries;

vi) diastereomer separations: a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer;

vii) first and second order asymmetric transformations: a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer;

viii) kinetic resolutions: this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non- racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis;

x) chiral liquid chromatography: a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;

xi) chiral gas chromatography: a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;

xii) extraction with chiral solvents: a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent;

xiii) transport across chiral membranes: a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.

Chiral chromatography, including but not limited to simulated moving bed chromatography, is used in one embodiment. A wide variety of chiral stationary phases are commercially available.

IV. Salt or Prodrug Formulations

In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate and a-glycerophosphate. Suitable inorganic salts can also be formed, including but not limited to, sulfate, nitrate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid, affording a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made.

The prodrugs described herein can be administered to additionally increase the activity, bioavailability, stability or otherwise alter the properties of the nucleotide monophosphate.

A number of prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the antiretroviral compounds described herein will increase their stability.

In situations where the antiretroviral compounds are nucleotides, examples of substituent groups that can replace one or more hydrogens on the monophosphate moiety are alkyl, aryl, steroids, carbohydrates, including but not limited to sugars, 1,2- diacylglycerol and alcohols. Many are described in R. Jones & N. Bischofberger, Antiviral Research, 1995, 27, 1-17 and S.J. Hecker & M.D. Erion, J. Med. Chem., 2008, 51, 2328-2345. Any of these can be used in combination with such nucleotides to achieve a desired effect.

Nucleotides can also be provided as a 5'-phosphoether lipid as disclosed in the following references, which are incorporated by reference: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C. Piantadosi, "Novel membrane interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation," AIDS Res. Hum. Retroviruses, 1990, 6, 491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S. Ishaq, L.S. Kucera, N. Iyer, C.A. Wallen, S. Piantadosi, and E.J. Modest, "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV activity," J. Med. Chem., 1991, 34, 1408-14; Hosteller, K.Y., D.D. Richman, D.A. Carson, L.M. Stuhmiller, G.M. T. van Wijk, and H. van den Bosch, "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymidine," Antimicrob. Agents Chemother., 1992, 36, 2025-29; Hostetler, K.Y., L.M. Stuhmiller, H.B. Lenting, H. van den Bosch, and D.D. Richman, "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides." J. Biol. Chem., 1990, 265, 61127.

Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably at R2 and/or R3 position of the nucleotides described herein, or lipophilic preparations, include US Pat. Nos. 5,149,794 (Yatvin et al.); 5,194,654 (Hostetler et al.), 5,223,263 (Hostetler et al.); 5,256,641 (Yatvin et al.); 5,411,947 (Hostetler et al.); 5,463,092 (Hostetler et al.); 5,543,389 (Yatvin et al.); 5,543,390 (Yatvin et al.); 5,543,391 (Yatvin et al.); and 5,554,728 (Basava et al.), all of which are incorporated by reference. Foreign patent applications that disclose lipophilic substituents that can be attached to nucleosites of the present invention, or lipophilic preparations, include WO 89/02733, WO 90/00555, WO 91/16920, WO 91/18914, WO 93/00910, WO 94/26273, WO 96/15132, EP 0 350 287, EP 93917054.4, and WO 91/19721.

V. Methods of Treatment

Persons infected with XMRV, including those where the infection might or has already led to the development of prostate cancer, can be treated by administering to the subject an effective amount of one or more of the active anti-XMRV compounds described herein, or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. The compounds can also be used to treat other disorders mediated by XMRV or other MLV infection, such as chronic fatigue syndrome, other neuroimmune diseases where XMRV is involved, and malignancies associated with chronic fatigue syndrome.

This invention also relates to a method of and to a pharmaceutical composition for inhibiting abnormal cellular proliferation in the tissues of a patient, which comprises an amount of an anti-XMRV compound described herein, or a pharmaceutically acceptable salt or prodrug thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.

VI. Methods of Prevention At present the mode of transmission of XMRV remains controversial. While not wishing to be bound by a particular theory, based on other retroviral systems, it is believed that transmission is through exposure to blood and other body fluids, for example, needle exposure, skin cuts, and sexual or vertical transmission. Vertical transmission, i.e., from mother to child, is well documented in the case of both HIV infection and also HTLV-1 and HTLV-2 infection, retroviruses that cause human T cell leukemia/ lymphoma. In the case of HIV-1, vertical transmission can happen during pregnancy or lactation, but takes place mostly during childbirth.

This last mode of transmission can be prevented by administering antiretroviral agents to the mother in the period before delivery. AZT administered a few weeks before delivery is very effective at preventing viral transmission to the infant. Accordingly, in those cases where XMRV might be vertically transmitted, the use of antiretrovirals for a small period before delivery can effectively prevent viral transmission, and thus all its consequences, such as chronic fatigue syndrome (CFS) or other neuroimmune disorders, prostate cancer, breast cancer, lymphoma, leukemia, and hematologic and other malignancies.

Viral infection is also known to cause other disorders, and the occurrence of the disorders can be prevented by prophylactic administration of antiviral therapy. In addition to the prophylactic HIV treatment to expectant HIV-infected mothers, it is also known to administer lamivudine to patients with chronic hepatitis B and advanced liver disease (Liaw et al., N Engl J Med 2004 Oct 7;351(15): 1521-31). Liaw et al. disclosed the effectiveness of antiviral therapy in preventing disease progression in persons with chronic hepatitis B and advanced fibrosis or cirrhosis. Patients with chronic hepatitis B who had histologically confirmed cirrhosis or advanced fibrosis were randomly assigned in a 2: 1 ratio to receive lamivudine (100 mg per day) or placebo for a maximum of five years. Of 651 patients, 436 were assigned to receive lamivudine and 215 to receive placebo. The primary end point was time to disease progression, defined by hepatic decompensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. An independent data and safety monitoring board monitored the progress of the study and performed interim analyses of the data.

The study was terminated after a median duration of treatment of 32.4 months (range, 0 to 42), owing to a significant difference between treatment groups in the number of end points reached. End points were reached by 7.8 percent of the patients receiving lamivudine and 17.7 percent of those receiving placebo (hazard ratio for disease progression, 0.45; P = 0.001). The Child-Pugh score increased in 3.4 percent of the patients receiving lamivudine and 8.8 percent of those receiving placebo (hazard ratio, 0.45; P = 0.02), whereas hepatocellular carcinoma occurred in 3.9 percent of those in the lamivudine group and 7.4 percent of those in the placebo group (hazard ratio, 0.49; P = 0.047). Genotypic resistance YMDD mutations developed in 49 percent of the patients treated with lamivudine, and the Child-Pugh score was more likely to increase in patients with these mutations than in the other patients treated with lamivudine. Thus, Laiw et al. showed that continuous treatment with lamivudine delayed clinical progression in persons with chronic hepatitis B and advanced fibrosis or cirrhosis by significantly reducing the incidence of hepatic decompensation and the risk of hepatocellular carcinoma.

Thus, in the case of XMRV or other MLV infection, methods of preventing disorders are as important, or perhaps even more important, than the treatment of the disorders. That is, disorders associated with XMRV or other MLV infection may take considerable time to develop after exposure to XMRV, so prophylactic treatment with anti-XMRV compounds can prevent the onset of the disorders. Thus, active antiretroviral therapy (i.e., treatment) can prevent the development of the disease (prevention). Where the disorder is already present, treatment of the underlying disorder (for example, cancer treatment) may be successful in treating cancer that is already present, but may not be effective to prevent recurrence if the patient still has an active XMRV or other MLV infection. Accordingly, for some patients already suffering from a disorder associated with XMRV, it can be desirable to both treat the disorder, and the underlying cause of the disorder (the XMRV or other MLV infection).

To determine whether a patient is infected with XMRV, and/or is suffering from a disorder mediated by XMRV, it is useful to conduct a diagnostic test to confirm the presence of an active XMRV or other MLV infection. Those patients suffering from an active infection can be screened for the existence of a disorder associated with XMRV, or indicia suggestive of a high risk for developing such a disorder (i.e., elevated PSA levels, abnormal cells or tissue, abhorrent staining, and the like). Where a patient has an active XMRV or other MLV infection and a risk of developing the disorder, the patient can be treated with anti-XMRV therapy. Where a patient has an active XMRV or other MLV infection and a disorder associated with an XMRV infection, the person can then treated be with anti-XMRV therapy, as well as treatment for the disorder.

Accordingly, the treatment of XMRV or other MLV infection in a general sense thus is linked to the prevention of disorders where the etiology is linked to replication of XMRV or other MLVs in the host. This includes chronic fatigue syndrome and also other diseases with neuroimmune symptoms, and the prevention of cancer, including prostate cancer, breast cancer, lymphomas and leukemias in patients with Chronic fatigue syndrome. Persons with chronic fatigue syndrome associated with XMRV or other MLV infection may be treated in a similar manner as HIV- infected patients, for example, for the remainder of their lives, to keep virus replication at low levels. The prevention of lymphomas and leukemias would be a further benefit to these patients.

In a further embodiment, the administration of anti-XMRV agents (or anti- MLV agents, such as anti-PMRV or anti-MPMV agents) is used to prevent infection in patients subjected to organ transplantation or blood transfusion. In one aspect of this embodiment, stored blood is treated for XMRV or other MLV infection, for example, by exposure to a dye such as methylene blue and the appropriate source of light to activate the dye, before being administered to a patient. Blood samples can be screened for XMRV or other MLV infection using the techniques described herein to determine whether such an antiviral treatment is necessary or appropriate. In this embodiment, appropriate prophylaxis can prevent transmission of the disease.

VII. Combination or Alternation Therapy

The antiretroviral compounds described herein can also be administered along with partial or radical removal of tissue, radiation therapy, hormonal therapy, androgen ablation therapy, and cytotoxic chemotherapy.

In one embodiment, the antiretroviral compounds described herein can be employed together with at least one other antiviral agent, chosen from entry inhibitors, reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and immune- based therapeutic agents.

For example, when used to treat or prevent an XMRV or other MLV infection, the active compound or its prodrug or pharmaceutically acceptable salt can be administered in combination or alternation with another antiviral agent, including, but not limited to, those of the formulae above. Combination therapy can be particularly useful where the drug resistant XMRV or other MLV has developed, or to prevent the transmission or the selection of the XMRV or other MLV mutants.

In general, in combination therapy, effective dosages of two or more agents are administered together, whereas during alternation therapy, an effective dosage of each agent is administered serially. The dosage will depend on absorption, inactivation and excretion rates of the drug, as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

Nonlimiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include those in the tables below.

HIV Therapies: Nucleoside/Nucleotide Reverse

Transcriptase Inhibitors (NRTIs)

HIV Therapies: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Cellular Inhibitors

Entry Inhibitors (including Fusion Inhibitors)

In another embodiment, anti-cancer compounds are administered in combination or alternation with the antiviral compounds described herein. Thus, while the antiviral compounds inhibit viral replication, the anti-cancer compounds can inhibit prostate cancer via another mechanism.

Prostate cancer is frequently treated with anti-androgenic compounds, which are believed to function by lowering the concentration of testosterone. Representative anti-androgenic compounds include those described, for example, in U.S. Patent No. 7,550,450 (3P-acetoxyandrost-1,5-diene-17-ethylene ketal and 3 -hydroxyandrost- 1,5-diene-17-ethylene ketal). When anti-androgenic therapy is the only therapy, the majority of patients eventually develop symptomatic recurrences, termed "androgen- independent" or "hormone-refractory" prostate cancer. Using a combination of the anti-retroviral compounds described herein, and the anti-androgenic compounds, one can possibly either prevent, or delay the development of, androgen-independent prostate cancer.

The antiretroviral compounds described herein can also be administered in combination or alternation with an effective amount of an anti-prostate specific membrane antigen (PSMA) antibody, or fragment thereof. Such antibodies are described, for example, in U.S. Patent No. 7,514,078, and specifically include the light chain variable region amino acid sequence of the antibody produced by the NSO cell line having ATCC Accession Number PTA-3709 and the light chain variable region amino acid sequence of the antibody produced by the NSO cell line having ATCC Accession Number PTA-4174, and fragments thereof.

The antiretroviral compounds described herein can also be administered in combination or alternation with an effective amount of MDV3100 (Medivation, Inc.) or abiraterone (Cougar Biotechnology) treatments.

The antiretroviral compounds described herein can also be administered in combination or alternation with antibodies used in treatment of hematological malignancies. Such an antibody preparation could be Rituximab, a chimeric monoclonal antibody against B cells surface protein CD20, and used in the treatment of many lymphomas, leukemias, and some autoimmune disorders.

The antiretroviral compounds described herein can also be administered in combination or alternation with radiotherapy. Compounds that emit radiation (i.e., radioactive isotopes) include alpha-emitters, beta-emitters, a gamma-emitters, and combinations thereof. Representative radioactive isotopes include iodine (¹³¹I), iodine (¹²⁵I), yttrium (⁹⁰Y), lutetium (¹⁷⁷Lu), actinium (²²⁵Ac), praseodymium, bismuth (²¹²Bi), bismuth (²¹³Bi), astatine (²¹¹At), rhenium (¹⁸⁶Re), and rhodium (¹⁸⁸Rh). Frequently, radioisotopes are present in small rods inserted directly into the prostate gland, as is known in the art.

The antiretroviral compounds described herein can also be administered in combination or alternation with a cytotoxic agent. Representative cytotoxic agents are selected from the group consisting of antimetabolites, alkylating agents, antibiotics, anthracyclines, and antimitotic agents. Specific cytotoxic agents include taxane, cytochalasin B, vincristine, vinblastine, colchicin, topoisomerase, tenoposide, and maytansinoid. Other specific cytotoxic agents include mitomycin, etoposide, doxorubicin, daunorubicin, mitoxantrone, mithramycin, cisplatin, actinomycin D, and lenalidomide. Still further cytotoxic agents include cyclophosphamide, busulfan, 1- dehydrotestosterone, streptozotocin, dibromomannitol, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, gramicidin D, ethidium bromide, emetine, and dihydroxy anthracin dione. The anti-retroviral compounds described herein can also be administered in combination or alternation with immunomodulatory agents such as IL-1, IL-2, IL-4, IL-6, IL-12, interferon alpha, interferon gamma, GM-CSF and GCSF.

The anti-retroviral compounds described herein can also be administered in combination or alternation with other anti-cancer agents, such as the proteasome inhibitor, bortezomib, or the thalidomide derivative, lenalidomide.

VIII. Diagnostic and Theranostic Applications

The presence of XMRV or other MLV infection can be determined, for example, using the techniques disclosed in Schlaberg et al., PNAS September 22, 2009 vol. 106 no. 38 16351-16356. The techniques involve one or more of a quantitative PCR assay and immunohistochemistry (1HC) with an anti-XMRV specific antiserum, or an antiserum for other MLV. Once the presence of the XMRV or other MLV infection is determined, appropriate therapy can be initiated, as described above.

IX. Pharmaceutical Compositions

Persons infected with XMRV or other MLV can be treated by administering to the patient an effective amount of one or more of the active anti-XMRV (or anti- MLV) compounds described herein, or a pharmaceutically acceptable prodrugs or salts thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form.

A preferred dose of the compound for will be in the range of between about 0.1 and about 100 mg/kg, more generally, between about 1 and 50 mg/kg, and, preferably, between about 1 and about 20 mg/kg, of body weight of the recipient per day. In the case of Entecavir, 0.5 to 1 mg per day is the preferred dose. The effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art. The compound is conveniently administered in unit any suitable dosage form, including but not limited to but not limited to one containing 7 to 3,000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form. An oral dosage of 50- 1 ,000 mg is usually convenient.

Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound from about 0.2 to 70 μΜ, preferably about 1.0 to 15 μΜ. This can be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient.

The concentration of active compound in the drug composition will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time.

A preferred mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.

The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.

The compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup can contain, in addition to the active compound(s), sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

The compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, antiinflammatories or other antivirals, including but not limited to other nucleoside compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including, but not limited to implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid. For example, enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially.

Liposomal suspensions (including but not limited to liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811 (incorporated by reference). For example, liposome formulations can be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.

The present invention will be better understood with reference to the following non-limiting examples.

Example 1: Evaluation of Anti-Retroviral Compounds For Their Ability to Treat XMRV or other MLV Infection

Testing compounds known to inhibit HIV-1 replication for their effects on XMRV replication

Fifteen compounds that are known to inhibit HIV- 1 replication were tested for their effects on replication of XMRV. Because of the homology among MLV, it is believed that compounds that are effective at treating XMRV will also treat other MLV. In brief, cells were inoculated with XMRV, and grown in the presence of a series of different concentrations of the compounds for 8 days. Every 24 hours, supernatants from the infected cells were collected to measure reverse transcriptase (RT) activity. The level of RT activity in the supernatant measured the amount of XMRV released by the cells in the presence of the compounds. A more detailed description of the method and the results is given below.

MCF-7 cells, from a breast cancer cell-line, were grown to 50% confluence in DMEM supplemented with 10% fetal calf serum, L-glutamine (2.2 mM), penicillin (100 units/mL), and streptomycin (100 μg/mL). Cells were washed twice with Dulbecco' s Phosphate Buffered Saline (DPBS, Gibco), and inoculated with XMRV at approximately 10 infectious units per cell, in DMEM containing 8μg/ml of Polybrene. Cells were incubated with the virus for 1.5 hours at 37°C in a humidified incubator with a 95% air/5% carbon dioxide mix. Cells were then washed twice with DPBS to remove viral inoculum, trypsinized and plated in 96 well trays, with each well receiving 1000 cells. Each well contained the compound to be tested at two-fold the final desired concentration, with the final concentration being attained by the addition of an equal volume of cells.

Compounds A, B, C, D, E, F, G, H, I, J, K, L, M, N, and O were tested in a manner that their identities were unknown to the persons carrying out the test (see Table 1 for compound identities). Each compound was dissolved in DMSO (Sigma) and tested in duplicate at the following concentrations: 100 μΜ, 10 μΜ, 1 μΜ, 0.1 μΜ, and 0.01 μΜ. The diluent DMSO (at 0.5% v/v final concentration) served as a negative control. Every 24 hours, 20 μΐ of supernatant was collected from each well and stored at -20°C. At the end of 8 days of collection, these supernatants were assayed for reverse transcriptase (RT) activity using 01igo(dT)-poly(rA) primer- template assays performed in the presence of radiolabeled [a-³²P]dTTP and Mn²⁺ (reference 1, protocol attached)(see Fig. 1, for data from days 5 to 8 following infection).

The level of RT activity in the cell supernatant indicated the amount of XMRV released from the cells. An absence of RT activity in the supernatant would have two likely reasons. First, the compound being tested efficiently suppressed XMRV replication. Second, the compound being tested was toxic to cells, and it was the cell-toxicity that resulted in lack of virus production. To rule out this second possibility, cells were carefully observed under a microscope every 24 hours to monitor cell health and confluence (see Tables 2-9).

Compounds B, C, G and H inhibited viral release at sufficiently low concentrations to be of use as potential drugs. Compound G was cell-toxic, but compounds B, C and H were tested again in duplicate, using a protocol identical to the one above. Supernatants were collected every 24 h for 6 days. Cell toxicity was monitored and RT activity measured as before (see Fig. 2, Tables 10-12).

The data show that the integrase inhibitors Raltegravir (RAL) and L- 000870812 were the most active anti-XMRV compounds, showing efficacy even at dilutions of up to 0.01 μΜ, which was significantly higher activity than compounds C or H. Its median effective concentration (EC₅₀) was less than 0.01 micromolar. Tenofovir DF (TDF; compound C) also showed considerable anti-XMRV activity (EC₅₀ = 0.07 μΜ). AZT (Compound H) showed sufficient antiviral activity, but was less potent than RAL or TDF (see Tables above).

Additional experiments were performed using additional compounds P (tenofovir) and Q (L-000870812 (Merck)). Compounds B, C, P, Q, and AZT were compared, and the data is shown in Figures 8 and 9.

References:

Telesnitsky, A., S. Blain, and S. P. Goff. 1995. Assays for retroviral reverse transcriptase. Methods Enzymol. 262:347-362.

Protocol for measuring XMRV RT activity in supernatants from infected cells

Materials

• Master Mix "A"

• Master Mix "B"

• a -P³² (10 mCi/ml; 400 to 800 Ci/mmol) *added when performing assay

• 0.1M MnCl₂ *added when performing assay

• DMEM only

• 96 well plate

• Viral supernatants

• Blot paper

• 2x SSC (made from 20x SSC pH 7.0)

• Phosphoimager

Procedure

*Done in hood and on ice

1. Thaw MMA and MMB and viral supernatants and keep on ice

2. Label appropriate wells in 96 well plate and aliquot 10.95 μΐ MMA to each well

3. Add 5 μΐ of each viral "sup" into designated wells

*Wear lab coat, radiation badge, and protective eye wear

4. Turn on Geiger counter, check to see if counter is working by detecting radioactive "chip" (record value) and then check area for radiation and record background value

5. Add MnCl₂ and a -P³² to an aliquot of MMB and aliquot 14.05 μΐ of MMB to each designated well

6. Incubate at 37°C for 1 hr in protective Nalgene container

7. Transfer container to radioactive area and blot 5 μΐ of each reaction onto blot paper over layers of paper towels (to prevent contamination) and allow blot to dry 10-15 min

8. Wash blot paper in 2x SSC (During the SSC washes, blank the phosphoimager by exposing the white surface to light for at least 10 min):

a. lx for 5 min on rotary shaker

b. 2x for 15 min on rotary shaker

c. Rinse w/ 95% EtOH 2x and allow paper to dry with heat lamp or hair dryer

i. Be sure to keep waste from washes in separate 50 mL Falcon tubes

9. Wrap blot paper in saran wrap, position on phosphoimager grid, and expose for at least 1 hr or overnight

10. Scan phosphoimager plate and quantify 20x SSC (3 M NaCl, 0.3 M sodium citrate, pH 7.0)

175.4 g NaCl

88.2 g sodium citrate dihydrate

Adjust pH to 7.0 with Hcl

QS to 1 L with water

Autoclave

Sources of material:

DEAE paper: DE-81 Whatman, Inc.

Poly (r A): Sigma

Oligo(dT): pd(T)12-18, Parmacia, -20 A260 units/mg

In the examples described herein, the compounds identified as compounds A- shown in Table 1 :

Table 1:

The following are graphs and tables with actual numbers from an RT assay. The first graph shows the raw numbers for RT activity of drugs B, C and H on day 8 after infection. Each number represents an arithmetic mean of two duplicate data points. DMSO controls are also shown. The next three graphs show each drug individually with the values represented as percentages - with DMSO alone being 100%. The data are also shown in Figures 1-4. Compound

B C H

DMSO 3210.74 2501.923 3343.457

100 138.789 -1.8945 -21.127

10 74.4385 32.487 211.03

1 57.633 204.113 656.075

0.1 238.4695 739.591 2177.092

0.01 899.8805 2260.482 2410.8295

B %

DMSO 3210.74 100

100 138.789 4.32264836

10 74.4385 2.31842192

1 57.633 1.79500676

0.1 238.4695 7.42724419

0.01 899.8805 28.0271993 c %

DMSO 100

100 -0.0757218

10 1.29848121

1 8.15824468

0.1 29.5609018

0.01 90.3497829

H %

DMSO 100

100 -0.6318909

10 6.31173064

1 19.622654

0.1 65.1149992

0.01 72.1058922 RT levels shown in Figure 2 were quantified on a phosphorimager. Values shown in tables above and represented graphically in Figures 3-6.

A side by side comparison of the amounts of virus released (in relative RT units) in the presence of compounds B, C and H (each tested individually is shown in Figure 3. Concentration of compounds tested shown on x-axis. DMSO controls on left.

To compare the results from this assay with what would be seen in live cells, cell confluence and health of the cells was evaluated on each day of the experiment. This is for comparison with RT levels in supernatant. Low RT levels could be due to inhibition of viral release caused by the compound or due to cell toxicity. The data in the table below together with the results of the RT assays allows the distinction between these two processes. Numbers refer to percentage of confluence seen in each well. For example in Table 2, the well containing 100 micromolar of Compound A has cells that are 15% confluent, and all cells in the well containing 100 micromolar of Compound F are dead.

Cell confluence and health on each day of experiment

(Confirmation Experiment)

These data demonstrate that compounds B and H did not cause cell death at any of the concentrations tested, and compound C only resulted in cell death at concentrations of 100 μΜ. The EC5₀ and EC9₀ information for compounds B, C, and H is shown below:

Antiviral EC5₀ and EC9₀ values for Compounds B, C, and H (including slope of the log dose response curve)

Example 2: Alignment of XMRV with other retroviral integrase sequences.

To determine the degree of homology between XMRV and HIV and other retroviruses, the alignment of the IN protein was analyzed. The alignment of XMRV with HIV was poor.

Example 3: Evaluation of Anti-HIV Compounds for Their Ability to Inhibit XMRV

Background

Xenotropic murine leukemia-related retrovirus (XMRV) is a recently discovered retrovirus that has been linked to human prostate cancer and chronic fatigue syndrome (CFS). Both diseases affect a large fraction of the world population, with prostate cancer affecting one in six men, and CFS affecting an estimated 0.4 to 1% of the population.

Principal Findings

Forty-five compounds including twenty-eight drugs approved for use in humans were evaluated against XMRV replication in vitro. We found that the retroviral integrase inhibitor, raltegravir, was potent and selective against XMRV at submicromolar concentrations, in MCF-7 and LNCaP cells, a breast cancer and prostate cancer cell line, respectively. Another integrase inhibitor, L-000870812, and two nucleoside reverse transcriptase inhibitors, zidovudine (ZDV), and tenofovir disoproxil fumarate (TDF) also inhibited XMRV replication. When combined, these drugs displayed mostly synergistic effects against this virus, suggesting that combination therapy may delay or prevent the selection of resistant viruses. Introduction

Xenotropic murine leukemia-related retrovirus (XMRV) is a recently discovered infectious agent [85] that has been linked to human prostate cancer [86] and chronic fatigue syndrome (CFS) [87]. Both diseases affect a large fraction of the world population, with prostate cancer affecting one in six men, and CFS affecting an estimated 0.4 to 1% of the population [88], [89]. XMRV nucleic acid or proteins are found in 27% of prostate cancers and in 68% of chronic fatigue syndrome patients, and in less than 4-6% of normal controls, suggesting an association between the virus and human disease [86,87]. CFS, a disease characterized by severe debilitating fatigue, has had an uncertain etiology since its recognition. While a series of viral agents and environmental toxins have been proposed to be associated with CFS, no clear evidence for these has ever been presented (reviewed in [90]). The recent association of XMRV with CFS from the Whittemore Peterson Institute in Reno, Nevada, while far from being proven causal, is the strongest viral association to be made yet. Three recent reports, using plasmid DNA as positive controls, did not find XMRV in CFS patients in Europe [91] [92] [93]. The prevalence of XMRV in prostate cancer in Europe is uncertain, with one German group reporting the presence of XMRV in human prostates [94], and the other not detecting any [95]. However, the notion that a retrovirus might be involved in both cancer and a neuroimmune illness in humans is not without precedence. Human T-cell lymphotrophic virus, type 1 (HTLV-1), another retrovirus, causes both T-cell lymphoma/leukemia as well as tropical spastic paraparesis, a myelopathy due to immune defects resulting from the viral infection.

Infectious XMRV has been isolated from sera of CFS patients [87]. The presence of circulating infectious retrovirus particles in the blood invokes a scenario not unlike infection with another retrovirus, human immunodeficiency virus type 1 (HIV-1). Since there is no effective treatment for this profoundly debilitating illness, the use of antiretroviral agents that have proven to be reasonably safe for human use, might be of benefit. The discovery of effective antiretroviral agents against XMRV would allow for rational design of clinical trials to prevent progression of prostate cancer or to treat CFS. In this study, we report the effect of 45 compounds on XMRV replication in MCF-7 and LNCaP cells, cell lines generated from human breast and prostate cancers, respectively. We studied drugs used in the treatment of HIV-1 infections, as well as compounds used to treat other viral infections in humans. XMRV is a gammaretro virus, closely related to the murine leukemia viruses (MLV) [85]. At the amino acid level, it shares considerable identity with sequences of Moloney murine leukemia virus (MoMLV), a prototype MLV. The maximum similarity between XMRV and MoMLV proteins is found in the sequences for viral protease (96% identity), and the least similarity is between the two envelope proteins (66% identity) [85]. Unfortunately, not many actively-used antiretroviral agents have been tested for activity against MLV, with the exception of ZDV, which effectively suppresses MLV [96], and was recently demonstrated to be effective against XMRV as well [97]. In contrast, while there is a lot of information on antiviral activity against essential HIV-1 proteins, there is very little similarity between HIV-1 and XMRV proteins, with the proteases (PR) of the two viruses sharing 28% identity at the amino acid level, the reverse transcriptase proteins (RT) sharing 17% and the integrase (IN) proteins sharing just 14% identity. This low sequence similarity makes it difficult to predict which, if any, of the antiretroviral agents that are effective against HIV-1 would be effective against XMRV. Several drugs from each major class of antiretroviral agents: nucleoside and non-nucleoside RT inhibitors (NRTIs and NNRTIs), IN inhibitors, and PR inhibitors (PI) were chosen. The envelope proteins of the XMRV and HIV-1 are widely divergent in size (70 kD and 160 kD respectively), utilize different receptors for viral entry and do not share any significant similarity. Therefore, peptidomimetics that act on the HIV-1 envelope protein to prevent viral entry were not included in our study. A few inhibitors that are known to inhibit replication of viruses other than retroviruses were also evaluated. A significant number of compounds tested in our study, viz. 28 out of a total of 45, are already FDA-approved for the treatment of infection with HIV-1 or other viruses. The integrase inhibitor, raltegravir (RAL), is extremely potent and selective against XMRV, when used at low submicromolar concentrations in both cell culture systems.

Another IN inhibitor, L-000870812, and two NRTIs, ZDV and tenofovir disoproxil fumarate (TDF), also inhibit XMRV replication, but at higher concentrations. When combined, these compounds display synergistic effects, suggesting combined modalities to treat XMRV infection, thus delaying or preventing the selection of resistant viruses.

Results

A total of 45 compounds, belonging to different classes of HIV-1 inhibitors and a few inhibitors of viruses other than retroviruses, were evaluated for their ability to inhibit XMRV replication in cultured cells. LNCaP and MCF-7 cells were chosen for their ability to support robust in vitro replication of XMRV. MCF-7 cells, because of their better growth properties in culture were initially used to test all 45 compounds (Figure 10). Compounds with anti-XMRV activity were subsequently tested in both LNCaP and MCF-7 cells (Table SI). To determine if a reduction in viral release might be due to toxicity of the compound and not due to specific antiretroviral activity, cellular morphology was monitored every 24 h by microscopic examination, and an MTT [3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide] colorimetric assay was used to measure potential cytotoxicity produced by the compounds. Supernatants were collected every 24 h and assayed for viral release by measuring RT activity. Inhibition of RT activity (see Figure 11) was averaged over 3-6 experiments, each performed in duplicate, and used to calculate the median (EC5₀) and 90% effective concentrations (EC9₀) for each compound (Figure 10). For comparison purposes, all compounds evaluated in these studies were also tested against HIV-1LAI in primary human lymphocytes.

Inhibitors of HIV-1 reverse transcriptase

The following NRTI inhibitors of HIV-1 RT were tested in our XMRV replication assays:

ZDV, 3'-azido-3'-deoxyadenosine (AZA), 3'-azido-3'-deoxyguanosine (AZG), 3'- azido-3'-deoxy-5-methyl-cytidine (CS-92), lamivudine (3TC), emtricitabine [(-)- FTC], tenofovir (TNV) and its prodrug form TDF, 9-( -D-1,3-dioxolan-4-yl)guanine (DXG) and its prodrug form, amdoxovir (DAPD, AMDX), (-)-carbovir (CBV), stavudine (D4T) and its corresponding cytosine analog (D4C), videx (ddl), zalcitabine (ddC), and 3'-fluoro-3'- deoxythymidine (FLT). The NNRTIs efavirenz, and a TIBO derivative that was shown to be effective in a murine system [98], were also tested. Among these, the most potent XMRV inhibitors were ZDV and TDF (Figure 11 , A, B). The EC5₀ and EC₉₀ in MCF-7 cells were 0.11 μΜ and 7.3 μΜ for ZDV, and 0.24 μΜ and 15.3 μΜ for TDF respectively (see Figure 10). The EC5₀ and EC9₀ values were also determined in LNCaP cells, a prostate cancer cell line, and there was a consistent difference of up to 5 fold between the two cell lines, which may be related to their differing rates of nucleoside uptake and bioconversion to the active nucleoside triphosphate analog. The EC5₀ and EC9₀ in LNCaP cells were 0.14 μΜ and 1.1 μΜ for ZDV, and 0.9 μΜ and 4.2 μΜ for TDF, respectively. CBV, AZA, FLT and D4T all showed greater than 70% inhibition of XMRV replication (see Table SI), but at the much higher concentration of 100 μΜ. AZG, CS- 92, (-)-FTC, 3TC, ddl, DAPD and DXG were essentially inactive at 100 μΜ (Figure 10). TFV was also ineffective against XMRV, probably due to its polar nature, which may not allow sufficient drug to penetrate into the cells. The NNRTIs efavirenz (EFV) and the TIBO derivative, did not demonstrate any major activity against XMRV.

Inhibitors of HIV-1 Integrase

IN inhibitors raltegravir (RAL or MK-0518) and L-000870812 [99] were also evaluated for their ability to inhibit XMRV in the two cell systems (Figure 10, Figure l l C and D). Of all the compounds tested, RAL was the most potent, with an EC5₀ of 0.005 μΜ and an EC₉₀ of 3.5 μΜ in MCF-7 cells, and an EC₅₀ of 0.03 μΜ and an EC90 of 0.46 μΜ in LNCaP cells (Table SI). L-000870812, showed activity against XMRV replication at considerably higher concentrations, with an EC5₀ and EC9₀ of 0.16 μΜ and 26.9 μΜ in MCF-7 cells, and 0.7 μΜ and 4.5 μΜ in LNCaP cells, respectively.

Inhibitors of HIV-1 Protease

Nine known HIV-1 Pis were evaluated for activity against XMRV (Figure 10). The most effective was nelfinavir, albeit with an EC₅₀ of 34.3 μΜ. The following Pis had very modest anti-XMRV activities: atazanavir (EC₅₀ of 64.8 μΜ), amprenavir (EC₅₀ of 68.0 μΜ), lopinavir (EC₅₀ of 72.2 μΜ), and ritonavir (EC₅₀ of 76.4 μΜ). Darunavir, indinavir, 8 saquinavir and tipranavir were essentially ineffective against XMRV in vitro, when tested up to 100 μΜ.

Inhibitors of viruses other than HIV-1

A select number of antiviral agents known to inhibit viruses other than retroviruses were also evaluated. These included the anti-herpetic drugs acyclovir (ACV), ganciclovir (GCV), vidarabine (ara-A), 5-Iodo-2'-deoxyuridine (IdUrd), penciclovir (PCV), foscarnet (PFA), vistide (HPMPC); the anti-hepatitis drugs entecavir (ETV), telbivudine (LdT), and ribavirin (RBV). ETV was also selected because it was recently reported to inhibit HIV-1 replication, both in vitro and in humans [100]. Other compounds claimed to be effective against XMRV, MLV, HIV- 1 and other viruses, such as chloroquine [101], dehydroepiandrosterone (DHEA) [102], methylene blue and aspirin were also evaluated for anti-XMRV activity in vitro. Methylene blue is known to have antiherpetic activity and also can inactivate HIV-1 [103]. Unfortunately, most of the compounds listed above, except IdUrd were ineffective against XMRV, or were effective at toxic concentrations (Figure 10). IdUrd demonstrated a low therapeutic index (TI, the ratio of CC₅₀/EC₅₀) and cannot be considered as a specific antiviral agent against XMRV.

Combination effects of active compounds on XMRV replication

Binary combinations of the most potent compounds, viz. RAL, L-000870812, TDF and ZDV were tested for activity against XMRV in LNCaP cells. Compounds were tested at increasing concentrations, in three different sets, with the ratio of the two compounds kept constant. The data were analyzed using the CalcuSyn method originally described by Chou and Talalay [104]. A summary of results for all combinations evaluated in LNCaP cells is presented in Figure 12.

For the combinations tested (RAL with TDF or ZDV or L-000870812; TDF with ZDV or L-000870812; L-000870812 with ZDV), an additive or mostly synergistic interaction was noted at all effect levels without apparent cytotoxicity at the highest concentrations used. In the computational analysis for either one of the four drugs (RAL, TDF, L- 000870812, or ZDV), the linear correlation coefficient (r values) of the median-effect plot or for their constant ratio combinations ranged from 0.92 to 0.99 (data not shown), matching the law of mass-action. The in vitro effect of the combination of RAL with either TDF or ZDV, showed a favorable dose reduction at all ratios. In addition, all Combination Index (CI) values (see Materials and Methods) were less than 1, suggesting synergy when the combination ratios of either TDF or ZDV and RAL were analyzed (Figure 12). In addition, dual combinations of either ZDV and L-000870812 or TDF were also tested. The weighted CI (Clwt) values of 0.1 to 0.5 for TDF + ZDV, indicated synergistic effects at all ratios tested (Figure 12). Moreover, the dual combination of L-000870812 and ZDV at ratio 1 :2 indicated a nearly additive effect (Clwt of 1.0); however at ratio of 1:0.4, the CI value was 0.3, indicating synergism (Figure 12). Of significance was that all dual combinations containing RAL, the most potent antiviral agent against XMRV, demonstrated marked synergy at all effect levels without any apparent cytotoxicity. Interestingly, the combination of the two IN inhibitors was not antagonistic or additive, but was found to be synergistic, suggesting that these two compounds may have different antiviral mechanisms (see discussion).

Discussion

In the absence of a clear etiology, the treatment of CFS has been both empirical and unconventional. Therapies have included immunostimulant therapy through injections of staphylococcus toxoid [105], intravenous immunoglobulin therapy [106] [107] [108], and hydrocortisone [109] each with uneven results. Interferon-β and TNF-a inhibitors have been tried in very small numbers of patients. Anti-depressants, NSAIDs, anxiolytic drugs, stimulants, anti-allergy drugs and anti- hypotensive drugs have all been used, but are not universally beneficial [110]. The lack of effective therapy has led to use of plant extracts [111], homeopathy [112,113], hypnosis [114], acupuncture [115], and whole body periodic acceleration stress [116], none with sustained benefits. The only modalities of treatment that have any proven benefits are cognitive behavioral therapy and graded exercise programs, both of which appear to aid by improving coping skills rather than reduce symptoms [117]. If, XMRV proves to have a causal association with human disease, then the knowledge that certain antiretroviral agents inhibit XMRV at submicromolar concentrations in vitro, and have synergistic effects when combined, as shown in this study, might lead to clinical trials. The data show that RAL, L-000870812, ZDV, and TDF strongly inhibit XMRV in cell culture, with RAL being the most potent, at an EC₅₀ of 0.005 μΜ, and others such as L-000870812 (EC50 = 0.16 μΜ), ZDV (EC₅₀ = 0.11 μΜ) and TDF (EC₅₀ = 0.24 μΜ) being quite effective as well. In addition, these compounds had high therapeutic indices, with values for ZDV = 591 ; TDF = 218; RAL = 18,460 and L-000870812 = 378, indicating that it should be possible to achieve therapeutic antiviral levels with minimal toxicity. Several compounds that we evaluated had a limited effect on XMRV replication in vitro. Some of these effects can be explained by currently understood mechanisms. For example, both 3TC and (-)-FTC need a functional YMDD motif in RT to be active. The Ml 84V mutation in HIV-1 RT makes the virus resistant to 3TC and (-)-FTC [117]. These drugs are ineffective against MoMLV, because in MoMLV RT, V is the natural residue in this motif in place of M. Similarly, V is also the natural residue at this location in XMRV RT, making 3TC and (-)-FTC ineffective. Why none of the HIV-1 Pis were effective against XMRV (a finding that has been reported for selected Pis before [97]) remains unclear at this time, but could be related to the size of the PI pocket as well as other biochemical and structural factors. There was a difference in activities of compounds when tested in different cell types, which may be related to drug uptake by cells, the different levels of natural dNTP in the cells, as well as different intracellular phosphorylation capacity [118]. In general, the EC5₀ for the active compounds listed above were lower in MCF-7 than LNCaP cells suggesting greater potency. Relative to HIV-1, the compounds were generally less potent against XMRV than HIV-1, especially at the EC9₀ level. The use of monotherapy for treating HIV infections has lead to the appearance of drug resistant virus [119,120]. The finding that RAL, L- 000870812, TDF and ZDV have strong synergistic effects when combined in dual combination bodes well for combination therapy in case of XMRV infection. If XMRV infection parallels other retroviral nfections, then the use of combination antiretro viral therapy might maintain XMRV suppression, prevent the emergence of resistance to antiretroviral agents and possibly also cause amelioration of disease. For HIV-1, combination therapy works especially well when the combined drugs have different viral protein targets, or in the case of nucleosides, utilize different kinases for their activation to NTP analogs [115]. Therefore, drug combinations that inhibit XMRV, such as RAL with ZDV or TDF or L-000870812, were judiciously selected. When the data were analyzed using the robust method of Chou and Talalay, additive or synergistic interactions were found at all effect levels when these agents were tested in LNCaP cells. Of significance was that no antagonism was noted for any of the combinations evaluated in these cells. Surprisingly, even the two IN inhibitors displayed a synergistic effect. Both IN inhibitors act by inhibiting the strand transfer reaction, but if their mechanism of action were to be identical, they would display an additive effect in combination. A synergistic effect suggests that there might be subtle mechanistic differences in the actions of these two IN inhibitors, a finding corroborated by unpublished biochemical experiments. It is important to note here, that XMRV differs from HIV-1 in one aspect that is significant for these studies: XMRV isolates show very limited sequence diversity compared to HIV-1 or MLV. Of all the sequenced XMRV isolates that currently exist, both from cases with prostate cancer as well as CFS, obtained from geographically distant parts of the United States, the two least related genomes differ from each other in only 27 out of a total of over 8,100 nucleotides. A similar degree of limited genetic diversity has been found for HTLV-1 [121], another retrovirus implicated in both cancer and neuroimmune illness. It has been suggested that this lack of diversity in XMRV sequences implies that the number of replication cycles within one infected individual is limited [122]. This would suggest that XMRV has a considerably lower potential for developing drug- resistant mutations, as compared to HIV-1. Furthermore, it is likely that a combination of just two drugs might be sufficient for preventing the emergence of drug-resistant mutant virus, though this would need to be tested before any therapeutic recommendations can be made. We have attempted to select for RAL resistant viruses in culture for several months now, and have not yet been successful at isolating drug resistant viruses. When an assay to measure XMRV viral loads becomes available, virus levels in the blood might become an objective surrogate marker for an effective response to antiviral drugs, in addition to clinical outcomes. While not wishing to be bound by any particular theory, the data indicates that XMRV infections might be prevented or treated with specific antiviral agents.

Materials and Methods

MRV, Cells and Infection with XMRV

93T cells (ATCC, CRL-11268) were transfected with pXMRVl, an infectious clone of XMRV [86]. Virus released in the supernatant was harvested and titrated by inoculating MCF-7 cells, a breast cancer cell line (ATCC, HTB-22) at 70% confluence, with a series of ten-fold dilutions of XMRV in serum-free medium, followed 36-48 hrs later by fixation of cells in paraformaldehyde and processing for immunofluorescence using a rabbit antiserum developed against inactivated XMRV [86]. Typical virus preparations gave titers of approximately 2-5 x 10⁶ infectious units/ml. Virus was diluted in serum-free medium and used to inoculate cells at a multiplicity of infection (MOI) of approximately 3, in the presence of various antiviral compounds as described below. LNCaP, a prostate cancer cell line (ATCC, CRL-1740) and MCF-7 cells were grown to about 50% confluence in DMEM containing 10% heat inactivated fetal bovine serum, 100 μg/ml penicillin, and 100 IU/ml streptomycin. Cells were washed twice with Dulbecco's phosphate buffered saline (DPBS, Gibco), and incubated with the viral inoculum for 90 min at 37°C in the presence of 95% air and 5% C02, cells were washed twice with DPBS, detached with Trypsin-EDTA (0.25% Trypsin; Cellgro), and counted.

One thousand cells were added to each well of a 96-well plate, along with an equal volume of medium containing the retroviral inhibitor at 2-fold the desired concentration. Inhibitors were dissolved in DMSO or water, depending on their solubility, and were all tested at 0.01 to 100 μΜ in 10-fold increments. Where the drug was found to be active at 0.01 μΜ, further dilutions from 1 nM to 0.01 nM were tested. Each inhibitor was tested in duplicate a minimum of three separate times in MCF-7 cells in a completely blind fashion using coded compounds, and the results averaged. Active compounds were also evaluated for antiviral activity in LNCaP cells to confirm activity in a secondary cell line known to support XMRV replication. For controls, wells containing water or DMSO at appropriate concentrations were used.

Assays for cytotoxicity and XMRV replication

Each well was carefully monitored for signs of cellular toxicity due to the inhibitors by microscopic observation every 24 h. In addition, cell viability was measured using the CellTiter 96 AQueous One Solution cell proliferation assay according to the manufacturer (Promega, Madison, Wis). Viral release from the cells was assayed by measuring RT activity in the supernatant. For this, supernatant from each well was collected every 24 h and frozen at -20°C until it was analyzed by RT assay for viral release as described previously [123]. In brief, oligo(dT)-poly(rA) primer-template assays were performed in the presence of radiolabeled [a-32P]dTTP and Mn2+. After incubating the viral supernatants with the RT reaction mix for 1 h at 37 °C, samples were spotted onto DE81 DEAE cellulose paper (Whatman) and unincorporated label washed away with 2x SSC (lx SSC = 0.15 M NaCl and 0.015 M sodium citrate). Virion-associated RT was analyzed using a Typhoon 9410 Phosphorlmager (GE Healthcare) and quantified with the Image J software (http://rsbweb.nih.gov/ij/). Inhibition of viral release as measured on day 6 after inoculation was averaged over 3-5 experiments and plotted.

The antiviral EC₅₀ and cytotoxic concentrations (CC₅₀,) was determined from the concentration- -response curve using the median effect method [104]. HIV-1 replication assays were performed as described previously using peripheral blood mononuclear cells (PBMC) obtained from the American Red Cross, Atlanta, GA, that were stimulated with phytohemagglutinin (PHA) for 72 hr [124].

Combination studies

To evaluate whether the antiviral effects of dual drug combinations of: RAL with TDF or ZDV or L-000870812; TDF with ZDV or L-000870812; L-000870812 with ZDV were synergistic, additive or antagonistic, drug combinations at several constant ratios were evaluated. RAL, L-000870812, ZDV and TDF were first tested alone to determine the EC5₀ and EC9₀ values, at least three times, each in duplicate. For the median-effect analysis, the compounds were combined at several ratios based on multiples of their EC5₀ or EC9₀ values. For each drug (alone or in combination), three to four independent experiments were performed and all samples were processed in duplicate. Analysis was performed using the software CalcuSyn (Biosoft, Ferguson, MO, USA) (see Figure 12 for CI values), which allows automated simulation of synergism and antagonism at all dose and effect levels and displays the methods of Chou and Talalay [104], including median effect plot and CI values. Because the high degree effects are more therapeutically relevant than the low degree of effects, the additional weighted average CI (Clwt) was calculated, which uses the formula: Clwt = [CI50 + 2CI₇₅ + 3CI₉₀ + 4CI₉₅]/10, where CI50, CI75, CI90, CI95 are the CI values at 50%, 75%, 90% and 95% inhibition, respectively. [104,125].

References

1. Acha-Orbea, H., and H. R. MacDonald. 1995. Superantigens of mouse mammary tumor virus. Annu Rev Immunol 13:459-86.

2. Alin, K., and S. P. Goff. 1996. Amino acid substitutions in the CA protein of Moloney murine leukemia virus that block early events in infection. Virology 222:339-51.

3. Auerbach, M. R., K. R. Brown, A. Kaplan, D. de Las Nueces, and I. R.

Singh. 2006. A small loop in the capsid protein of Moloney murine leukemia virus controls assembly of spherical cores. J Virol 80:2884-93.

4. Auerbach, M. R., C. Shu, A. Kaplan, and I. R. Singh. 2003. Functional characterization of a portion of the Moloney murine leukemia virus gag gene by genetic footprinting. Proc Natl Acad Sci U S A 100: 11678-83.

5. Battini, J. L., J. E. Rasko, and A. D. Miller. 1999. A human cell-surface receptor for xenotropic and polytropic murine leukemia viruses: possible role in G protein-coupled signal transduction. Proc Natl Acad Sci U S A 96: 1385-90.

6. Berns, A. J., M. H. Lai, R. A. Bosselman, M. A. McKennett, L. T.

Bacheler, H. Fan, E. C. Maandag, H. V. van der Putten, and I. M. Verma. 1980. Molecular cloning of unintegrated and a portion of integrated moloney murine leukemia viral DNA in bacteriophage lambda. J Virol 36:254-63.

Bhowmick, N. A., E. G. Neilson, and H. L. Moses. 2004. Stromal fibroblasts in cancer initiation and progression. Nature 432:332-7.

Blain, S. W., and S. P. Goff. 1995. Effects on DNA synthesis and translocation caused by mutations in the RNase H domain of Moloney murine leukemia virus reverse transcriptase. J Virol 69:4440-52.

Bright, R. K., C. D. Vocke, M. R. Emmert-Buck, P. H. Duray, D. Solomon, P. Fetsch, J. S. Rhim, W. M. Linehan, and S. L. Topalian. 1997. Generation and genetic characterization of immortal human prostate epithelial cell lines derived from primary cancer specimens. Cancer Res 57:995-1002.

Carpten, J., N. Nupponen, S. Isaacs, R. Sood, C. Robbins, J. Xu, M. Faruque, T. Moses, C. Ewing, E. Gillanders, P. Hu, P. Bujnovszky, I. Makalowska, A. Baffoe-Bonnie, D. Faith, J. Smith, D. Stephan, K. Wiley, M. Brownstein, D. Gildea, B. Kelly, R. Jenkins, G. Hostetter, M. Matikainen, J. Schleutker, K. Klinger, T. Connors, Y. Xiang, Z. Wang, A. De Marzo, N. Papadopoulos, O. P. Kallioniemi, R. Burk, D. Meyers, H. Gronberg, P. Meltzer, R. Silverman, J. Bailey- Wilson, P. Walsh, W. Isaacs, and J. Trent. 2002. Germline mutations in the ribonuclease L gene in families showing linkage with HPC1. Nat Genet 30: 181-4.

Carter, B. S., T. H. Beaty, G. D. Steinberg, B. Childs, and P. C. Walsh. 1992. Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89:3367-71.

Casey, G., P. J. Neville, S. J. Plummer, Y. Xiang, L. M. Krumroy, E. A. Klein, W. J. Catalona, N. Nupponen, J. D. Carpten, J. M. Trent, R. H. Silverman, and J. S. Witte. 2002. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat Genet 32:581-3. Clark, L. C, B. Dalkin, A. Krongrad, G. F. Combs, Jr., B. W. Turnbull, E. H. Slate, R. Witherington, J. H. Herlong, E. Janosko, D. Carpenter, C. Borosso, S. Falk, and J. Rounder. 1998. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. Br J Urol 81:730-4.

Coffin, J. M., S. H. Hughes, and H. E. Varmus (ed.). 1997. Retroviruses. Cold Spring Harbor Press, Cold Spring Harbor, NY.

Colicelli, J., and S. P. Goff. 1985. Mutants and pseudorevertants of Moloney murine leukemia virus with alterations at the integration site. Cell 42:573-580.

Colicelli, J., and S. P. Goff. 1988. Sequence and spacing requirements of a retrovirus integration site. J. Mol. Biol. 199:47-59.

Danilkovitch-Miagkova, A., F. M. Duh, I. Kuzmin, D. Angeloni, S. L. Liu, A. D. Miller, and M. I. Lerman. 2003. Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. Proc Natl Acad Sci U S A 100:4580-5.

De Marzo, A. M., V. L. Marchi, J. I. Epstein, and W. G. Nelson. 1999. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 155: 1985-92.

Dennis, L. K., and D. V. Dawson. 2002. Meta-analysis of measures of sexual activity and prostate cancer. Epidemiology 13:72-9.

Fan, H., M. Palmarini, and J. C. DeMartini. 2003. Transformation and oncogenesis by jaagsiekte sheep retrovirus. Curr Top Microbiol Immunol 275: 139-77.

Fan, P. D., and S. P. Goff. 2000. Abl interactor 1 binds to sos and inhibits epidermal growth factor- and v-Abl-induced activation of extracellular signal-regulated kinases. Mol Cell Biol 20:7591-601.

Felsenstein, K. M., and S. P. Goff. 1992. Mutational analysis of the gag- pol junction of Moloney murine leukemia virus: Requirements for expression of the gag-pol fusion protein. J. Virol. 66:6601-6608.

Friend, C, and J. R. Haddad. 1960. Tumor formation with transplants of spleen or liver from mice with virus-induced leukemia. J Natl Cancer Inst 25: 1279-85.

Goff, S., P. Traktman, and D. Baltimore. 1981. Isolation and properties of Moloney murine leukemia virus mutants: use of a rapid assay for release of virion reverse transcriptase. J. Virol. 38:239-248.

Goff, S. P. 2001. Retroviridae: The Retroviruses and Their Replication, p. 1871-1939. In D. M. Knipe and P. M. Howley (ed.), Fields Virology, Fourth Edition ed. Lippincott Williams & Wilkins, Philadelphia, PA. Goff, S. P., E. Gilboa, O. N. Witte, and D. Baltimore. 1980. Structure of the Abelson murine leukemia virus genome and the homologous cellular gene: studies with cloned viral DNA. Cell 22:777-85.

Goff, S. P., C. J. Tabin, J. Y. Wang, R. Weinberg, and D. Baltimore.

1982. Transfection of fibroblasts by cloned Abelson murine leukemia virus DNA and recovery of transmissible virus by recombination with helper virus. J Virol 41:271-85.

Golovkina, T. V., J. P. Dudley, and S. R. Ross. 1998. B and T cells are required for mouse mammary tumor virus spread within the mammary gland. J Immunol 161:2375-82.

Gonzalgo, M. L., and W. B. Isaacs. 2003. Molecular pathways to prostate cancer. J Urol 170:2444-52.

Granowitz, C., J. Colicelli, and S. P. Goff. 1991. Analysis of mutations in the envelope gene of Moloney murine leukemia virus: Separation of infectivity from superinfection resistance. Virology 183:545-554.

Gross, L. 1961. Viral etiology of mouse leukemia. Adv Cancer Res 6: 149- 80.

Hardin, J. D., S. Boast, M. Mendelsohn, K. de los Santos, and S. P. Goff. 1996. Transgenes encoding both type I and type IV c-abl proteins rescue the lethality of c-abl mutant mice. Oncogene 12:2669-77.

Hayes, R. B., L. M. Pottern, H. Strickler, C. Rabkin, V. Pope, G. M. Swanson, R. S. Greenberg, J. B. Schoenberg, J. Liff, A. G. Schwartz, R. N. Hoover, and J. F. Fraumeni, Jr. 2000. Sexual behaviour, STDs and risks for prostate cancer. Br J Cancer 82:718-25.

Hevezi, P., K. Alin, and S. P. Goff. 1993. Transforming activity and tissue tropism of hybrid retroviral genomes containing portions of the v-abl and v- src oncogenes. Oncogene 8:2413-23.

Hevezi, P., and S. P. Goff. 1991. Generation of recombinant murine retroviral genomes containing the y-src oncogene: Isolation of a virus inducing hemangiosarcomas in the brain. J. Virol. 65:5333-5341.

Hughes, C., A. Murphy, C. Martin, O. Sheils, and J. O'Leary. 2005. Molecular pathology of prostate cancer. J Clin Pathol 58:673-84.

Kalpana, G. V., S. Marmon, W. Wang, G. R. Crabtree, and S. P. Goff. 1994. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science 266:2002-6.

Katz, E., M. H. Lareef, J. C. Rassa, S. M. Grande, L. B. King, J. Russo, S. R. Ross, and J. G. Monroe. 2005. MMTV Env encodes an IT AM responsible for transformation of mammary epithelial cells in three- dimensional culture. J Exp Med 201:431-9.

Khan, A. S., and M. A. Martin. 1983. Endogenous murine leukemia proviral long terminal repeats contain a unique 190-base-pair insert. Proc Natl Acad Sci U S A 80:2699-703.

Kita, N., J. Mitsushita, S. Ohira, Y. Takagi, T. Ashida, M. Kanai, T. Nikaido, and I. Konishi. 2003. Expression and activation of MAP kinases, ERK1/2, in the human villous trophoblasts. Placenta 24:164-72.

Li, J. P., A. D. D Andrea, H. F. Lodish, and D. Baltimore. 1990. Activation of cell growth by binding of Friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor. Nature 343:762-4.

Li, J. P., H. O. Hu, Q. T. Niu, and C. Fang. 1995. Cell surface activation of the erythropoietin receptor by Friend spleen focus-forming virus gp55. J Virol 69:1714-19.

Li, X., B. McDermott, B. Yuan, and S. P. Goff. 1996. Homomeric interactions between transmembrane proteins of Moloney murine leukemia virus. J Virol 70: 1266-70.

Lowy, D. R., E. Rands, and E. M. Scolnick. 1978. Helper-independent transformation by unintegrated Harvey sarcoma virus DNA. J Virol 26:291- 8.

Luban, J., K. L. Bossolt, E. K. Franke, G. V. Kalpana, and S. P. Goff.

1993. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 73: 1067-78.

Lucia, M. S., and K. C. Torkko. 2004. Inflammation as a target for prostate cancer chemoprevention: pathological and laboratory rationale. J Urol 171:S30-4; discussion S35.

Moloney, J. B. 1960. Biological studies on a lymphoid-leukemia virus extracted from sarcoma 37. I. Origin and introductory investigations. J Natl Cancer Inst 24:933-51.

Naghavi, M. H., T. Hatziioannou, G. Gao, and S. P. Goff. 2005. Overexpression of fasciculation and elongation protein zeta-1 (FEZl) induces a post-entry block to retroviruses in cultured cells. Genes Dev 19: 1105-15.

Nelson, J. E., and R. E. Harris. 2000. Inverse association of prostate cancer and non-steroidal anti-inflammatory drugs (NSAIDs): results of a case-control study. Oncol Rep 7: 169-70.

Nelson, W. G., A. M. De Marzo, T. L. DeWeese, and W. B. Isaacs. 2004. The role of inflammation in the pathogenesis of prostate cancer. J Urol 172.S6-11 ; discussion Sl l-2.

Orlova, M., A. Yueh, J. Leung, and S. P. Goff. 2003. Reverse transcriptase of Moloney murine leukemia virus binds to eukaryotic release factor 1 to modulate suppression of translational termination. Cell 115:319- 31.

Palapattu, G. S., S. Sutcliffe, P. J. Bastian, E. A. Platz, A. M. De Marzo, W. B. Isaacs, and W. G. Nelson. 2005. Prostate carcinogenesis and inflammation: emerging insights. Carcinogenesis 26:1170-81.

Platz, E. A., and A. M. De Marzo. 2004. Epidemiology of inflammation and prostate cancer. J Urol 171:S36-40.

Price, D. T., G. D. Rocca, C. Guo, M. S. Ballo, D. A. Schwinn, and L. M. Luttrell. 1999. Activation of extracellular signal-regulated kinase in human prostate cancer. J Urol 162: 1537-42.

Raisch, K. P., M. Pizzato, H. Y. Sun, Y. Takeuchi, L. W. Cashdollar, and S. E. Grossberg. 2003. Molecular cloning, complete sequence, and biological characterization of a xenotropic murine leukemia virus constitutively released from the human B-lymphoblastoid cell line DG-75. Virology 308:83-91.

Rauscher, F. J. 1962. A virus-induced disease of mice characterized by erythrocytopoiesis and lymphoid leukemia. J Natl Cancer Inst 29:515-43. Risser, R., J. M. Horowitz, and J. McCubrey. 1983. Endogenous mouse leukemia viruses. Annu Rev Genet 17:85-121.

Ross, S. R., J. J. Schofield, C. J. Farr, and M. Bucan. 2002. Mouse transferrin receptor 1 is the cell entry receptor for mouse mammary tumor virus. Proc Natl Acad Sci U S A 99: 12386-90.

Roth, M. J., N. Tanese, and S. P. Goff. 1985. Purification and characterization of murine retroviral reverse transcriptase expressed in Escherichia coli. J. Biol. Chem. 260:9326-9335.

Schwartzberg, P., J. Colicelli, and S. P. Goff. 1984. Construction and analysis of deletion mutations in the pol gene of Moloney murine leukemia virus: a new viral function required for productive infection. Cell 37:1043- 1052.

Schwartzberg, P., J. Colicelli, and S. P. Goff. 1983. Deletion mutants of Moloney murine leukemia virus which lack glycosylated gag protein are replication competent. J. Virol. 46:538-546.

Shergill, I. S., A. R. Rao, F. H. Anjum, M. Arya, H. R. Patel, and A. R. Mundy. 2006. Tissue microarrays and their relevance to the urologist. J Urol 175: 19-26.

Shikova, E., Y. C. Lin, K. Saha, B. R. Brooks, and P. K. Wong. 1993. Correlation of specific virus-astrocyte interactions and cytopathic effects induced by tsl, a neurovirulent mutant of Moloney murine leukemia virus. J Virol 67: 1137-47.

Shoemaker, C, S. Goff, E. Gilboa, M. Paskind, S. W. Mitra, and D. Baltimore. 1980. Structure of a cloned circular Moloney murine leukemia virus DNA molecule containing an inverted segment: implications for retrovirus integration. Proc Natl Acad Sci U S A 77:3932-6.

Silverman, R. H. 2003. Implications for RNase L in prostate cancer biology. Biochemistry 42: 1805-12.

Singh, I. R., R. A. Crowley, and P. O. Brown. 1997. High-resolution functional mapping of a cloned gene by genetic footprinting. Proc Natl Acad Sci U S A 94: 1304-9.

Smith, J. R., D. Freije, J. D. Carpten, H. Gronberg, J. Xu, S. D. Isaacs, M. J. Brownstein, G. S. Bova, H. Guo, P. Bujnovszky, D. R. Nusskern, J. E. Damber, A. Bergh, M. Emanuelsson, O. P. Kallioniemi, J. Walker- Daniels, J. E. Bailey- Wilson, T. H. Beaty, D. A. Meyers, P. C. Walsh, F. S. Collins, J. M. Trent, and W. B. Isaacs. 1996. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274:1371-4.

Tailor, C. S., A. Nouri, C. G. Lee, C. Kozak, and D. Kabat. 1999. Cloning and characterization of a cell surface receptor for xenotropic and polytropic murine leukemia viruses. Proc Natl Acad Sci U S A 96:927-32. 69. Tanese, N., and S. P. Goff. 1988. Domain structure of the Moloney murine leukemia virus reverse transcriptase: Mutational analysis and separate expression of the DNA polymerase and RNase H activities. Proc. Natl. Acad. Sci. U.S.A. 85: 1777-1781.

70. Tanese, N., M. J. Roth, and S. P. Goff. 1986. Analysis of retroviral pol gene products with antisera raised against fusion proteins produced in Escherichia coli. J. Virol. 59:328-340.

71. Tang, Y., U. Winkler, E. O. Freed, T. A. Torrey, W. Kim, H. Li, S. P.

Goff, and H. C. Morse, 3rd. 1999. Cellular motor protein KIF-4 associates with retroviral Gag. J Virol 73:10508-13.

72. Tlsty, T. D., and P. W. Hein. 2001. Know thy neighbor: stromal cells can contribute oncogenic signals. Curr Opin Genet Dev 11:54-9.

73. Urisman, A., R. J. Molinaro, N. Fischer, S. J. Plummer, G. Casey, E. A.

Klein, K. Malathi, C. Magi-Galluzzi, R. R. Tubbs, D. Ganem, R. H. Silverman, and J. L. DeRisi. 2006. Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant. PLOS Pathogens 2:1-15.

74. Wang, M. Q., and S. P. Goff. 2003. Defects in virion production caused by mutations affecting the C-terminal portion of the Moloney murine leukemia virus capsid protein. J Virol 77:3339-44.

75. Wang, M. Q., W. Kim, G. Gao, T. A. Torrey, H. C. Morse, 3rd, P. De Camilli, and S. P. Goff. 2003. Endophilins interact with Moloney murine leukemia virus Gag and modulate virion production. J Biol 3:4.

76. Wolf, P., D. Gierschner, P. Buhler, U. Wetterauer, and U. Elsasser- Beile. 2006. A recombinant PSMA-specific single-chain immunotoxin has potent and selective toxicity against prostate cancer cells. Cancer Immunol Immunother.

77. Wootton, S. K., C. L. Halbert, and A. D. Miller. 2005. Sheep retrovirus structural protein induces lung tumours. Nature 434:904-7.

78. Yang, Y. L., L. Guo, S. Xu, C. A. Holland, T. Kitamura, K. Hunter, and J. M. Cunningham. 1999. Receptors for polytropic and xenotropic mouse leukaemia viruses encoded by a single gene at Rmcl. Nat Genet 21:216-9.

79. Yoshimura, A., A. D. D'Andrea, and H. F. Lodish. 1990. Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism. Proc Natl Acad Sci U S A 87:4139-43.

80. Yuan, B., A. Fassati, A. Yueh, and S. P. Goff. 2002. Characterization of Moloney murine leukemia virus pl2 mutants blocked during early events of infection. J Virol 76: 10801-10.

81. Yuan, B., X. Li, and S. P. Goff. 1999. Mutations altering the Moloney murine leukemia virus pl2 Gag protein affect virion production and early events of the virus life cycle. EMBO J. 18:in press.

82. Yueh, A., and S. P. Goff. 2003. Phosphorylated serine residues and an arginine-rich domain of the moloney murine leukemia virus pl2 protein are required for early events of viral infection. J Virol 77: 1820-9.

83. Zhang, Q. K., S. Boast, K. de los Santos, M. Begemann, and S. P. Goff.

1996. Transforming activity of retroviral genomes encoding Gag-Axl fusion proteins. J Virol 70:8089-97.

84. Zhou, A., J. Paranjape, T. L. Brown, H. Nie, S. Naik, B. Dong, A.

Chang, B. Trapp, R. Fairchild, C. Colmenares, and R. H. Silverman.

1997. Interferon action and apoptosis are defective in mice devoid of 2', 5'- oligoadenylate-dependent RNase L., Embo J 16:6355-63.

85. Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, et al. (2006)

Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. PLoS Pathog 2: e25.

86. Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR (2009) XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proc Natl Acad Sci U S A 106: 16351- 16356.

87. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, et al. (2009)

Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 326: 585-589.

88. Hayat MJ, Howlader N, Reichman ME, Edwards BK (2007) Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 12: 20-37.

89. Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, et al.

(1999) A community-based study of chronic fatigue syndrome. Arch Intern Med 159: 2129- 2137. 90. Devanur LD, Kerr JR (2006) Chronic fatigue syndrome. J Clin Virol 37: 139-

150.

91. Erlwein O, Kaye S, McClure MO, Weber J, Wills G, et al. (2010) Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One 5: e8519.

92. Groom HCT, Boucherit VC, Makinson K, Randal E, Baptista S, et al. (2010)

Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Retrovirology 7: 10.1186/1742-4690-1187- 1110.

93. van Kuppeveld FJ, Jong AS, Lanke KH, Verhaegh GW, Melchers WJ, et al.

(2010) Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort. BMJ 340: cl018.

94. Fischer N, Hellwinkel O, Schulz C, Chun FK, Huland H, et al. (2008)

Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. J Clin Virol 43: 277- 283.

95. Hohn O, Krause H, Barbarotto P, Niederstadt L, Beimforde N, et al. (2009)

Lack of evidence for xenotropic murine leukemia virus-related virus(XMRV) in German prostate cancer patients. Retrovirology 6: 92.

96. Ruprecht RM, O'Brien LG, Rossoni LD, Nusinoff-Lehrman S (1986)

Suppression of mouse viraemia and retroviral disease by 3'-azido-3'- deoxy thymidine. Nature 323: 467-469.

97. Sakuma R, Sakuma T, Ohmine S, Silverman RH, Ikeda Y (2009) Xenotropic murine leukemia virus-related virus is susceptible to AZT. Virology.

98. Ho W, Kukla MJ, Breslin HJ, Ludovici DW, Grous PP, et al. (1995) Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo-[4,5,l- jk][1,4]benzodiazepin- 2(1H)-one (T1BO) derivatives. 4. J Med Chem 38: 794- 802.

99. Markowitz M, Morales-Ramirez JO, Nguyen BY, Ko acs CM, Steigbigel RT, et al. (2006) Antiretroviral activity, pharmacokinetics, and tolerability of MK- 0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1 -infected individuals. J Acquir Immune Defic Syndr 43: 509-515. 100. Yamada A, Sako A, Nishimura S, Nakashima R, Ogami T, et al. (2009) [A case of HIV coinfected with hepatitis B virus treated by entecavir]. Nippon Shokakibyo Gakkai Zasshi 106: 1758-1763.

101. Naarding MA, Baan E, Pollakis G, Paxton WA (2007) Effect of chloroquine on reducing HIV-1 replication in vitro and the DC-SIGN mediated transfer of virus to CD4+ T-lymphocytes. Retro virology 4: 6.

102. Schinazi RF (1990) Antiviral activity of dehydroepiandrosterone. In: Regelson

MKaW, editor. The Biological Role of Dehydroepiandrosterone (DHEA). Berlin, New York: Walter de Gruyter & Co. pp. 157-177.

103. Floyd RA, Schinazi RF (1998) Thiazine dyes used to inactivate HIV in biological fluids In: Office USPaT, editor. USPTO Patent Full-Text and Image Database. USA: Oklahoma Medical Research Foundation.

104. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22: 27- 55.

105. Zachrisson O, Regland B, Jahreskog M, Jonsson M, Kron M, et al. (2002)

Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome— a randomised controlled trial. Eur J Pain 6: 455-466.

106. Lloyd A, Hickie I, Wakefield D, Boughton C, Dwyer J (1990) A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Am J Med 89: 561-568.

107. Peterson PK, Shepard J, Macres M, Schenck C, Crosson J, et al. (1990) A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Am J Med 89: 554-560.

108. Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, Tymms K, Wakefield D, et al.

(1997) Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med 103: 38-43.

109. Cleare AJ (2003) The neuroendocrinology of chronic fatigue syndrome. Endocr

Rev 24: 236-252.

110. Afari N, Buchwald D (2003) Chronic fatigue syndrome: a review. Am J

Psychiatry 160: 221-236.

11. Tharakan B, Manyam BV (2006) Botanical therapies in chronic fatigue.

Phytother Res 20: 91-95. 112. Weatherley- Jones E, Nicholl JP, Thomas KJ, Parry GJ, McKendrick MW, et al. (2004) A randomised, controlled, triple-blind trial of the efficacy of homeopathic treatment for chronic fatigue syndrome. J Psychosom Res 56: 189-197.

113. Ernst E (2004) A randomised, controlled, triple-blind trial of the efficacy of homeopathic treatment for chronic fatigue syndrome. J Psychosom Res 57: 503; author reply 504.

114. Gregg VH (1997) Hypnosis in chronic fatigue syndrome. J R Soc Med 90: 682-

683.

115. Mears T (2005) Acupuncture in the treatment of post viral fatigue syndrome- - a case report. Acupunct Med 23: 141-145.

116. Sackner MA, Gummels EM, Adams JA (2004) Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise. Med Hypotheses 63: 118-123. 33. Reid S, Chalder T, Cleare A, Hotopf M, Wessely S (2000) Chronic fatigue syndrome. BMJ 320: 292-296.

117. Schinazi RF, Lloyd RM, Jr., Nguyen MH, Cannon DL, McMillan A, et al.

(1993) Characterization of human immunodeficiency viruses resistant to oxathiolanecytosine nucleosides. Antimicrob Agents Chemother 37: 875-881.

118. Schinazi RF, Hernandez- Santiago BI, Hurwitz SJ (2006) Pharmacology of current and promising nucleosides for the treatment of human immunodeficiency viruses. Antiviral Res 71 : 322-334.

119. Volberding PA, Lagakos SW, Grimes JM, Stein DS, Balfour HH, Jr., et al.

(1994) The duration of zidovudine benefit in persons with asymptomatic HIV infection. Prolonged evaluation of protocol 019 of the AIDS Clinical Trials Group. JAMA 272: 437-442.

120. Land S, McGavin C, Lucas R, Birch C (1992) Incidence of zidovudine- resistant human immunodeficiency virus isolated from patients before, during, and after therapy. J Infect Dis 166: 1139-1142.

121. Van Dooren S, Pybus OG, Salemi M, Liu HF, Goubau P, et al. (2004) The low evolutionary rate of human T-cell lymphotropic virus type-1 confirmed by analysis of vertical transmission chains. Mol Biol Evol 21: 603-611.

122. Coffin JM, Stoye JP (2009) Virology. A new virus for old diseases? Science

326: 530-531. 123. Telesnitsky A, Blain S, Goff SP (1995) Assays for retroviral reverse transcriptase. Methods Enzymol 262: 347-362.

124. Schinazi RF, Sommadossi JP, Saalmann V, Cannon DL, Xie MY, et al.

(1990) Activities of 3'-azido-3'-deoxythymidine nucleotide dimers in primary lymphocytes infected with human immunodeficiency virus type 1. Antimicrob Agents Chemother 34: 1061-1067.

125. Bassit L, Grier J, Bennett M, Schinazi RF (2008) Combinations of 2'-

Cmethylcytidine analogues with interferon- alpha2b and triple combination with ribavirin in the hepatitis C virus replicon system. Antivir Chem Chemother 19: 25-31.

The contents of each of the references referred to herein, including the references listed immediately above, and those throughout the specification, are hereby incorporated by reference for all purposes.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

1. A method for treating or preventing XMRV infection, comprising administering to a person in need thereof an effective anti-XMRV amount of an integrase inhibitor or a reverse transcriptase inhibitor.

2. The method of Claim 1 , wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir.

3. The method of Claim 1, further comprising the co-administration of one or more additional active agents, selected from the group consisting of antiretro viral agents and pharmacokinetic (PK) boosters.

4. The method of Claim 3, wherein the additional antiretro viral agent is tenofovir or tenofovir DF.

5. A pharmaceutical composition for use in treating or preventing XMRV infection, comprising an effective anti-XMRV amount of an integrase inhibitor, and a pharmaceutically acceptable carrier or excipient.

6. The composition of Claim 5, wherein the integrase inhibitor is L- 000870812, Raltegravir or Elvitegravir.

7. The composition of Claim 5, further comprising one or more additional anti-retro viral agents.

8. The composition of Claim 7, wherein the additional anti-retroviral agent is tenofovir or tenofovir DF.

9. A method for treating or preventing XMRV infection, comprising administering to a patient in need thereof an effective anti-XMRV amount of tenofovir or tenofovir DF.

10. The method of Claim 9, further comprising the co-administration of at least one additional antiretroviral agent.

11. A pharmaceutical composition for use in treating or preventing XMRV infection, comprising an effective anti-XMRV amount of tenofovir or tenofovir DF, and a pharmaceutically acceptable carrier or excipient.

12. The composition of Claim 11, further comprising at least one additional anti-retroviral agent.

13. A method for diagnosing and treating disorders resulting, at least in part, from XMRV infection, comprising:

a) determining the presence or absence of XMRV infection in a patient, b) if the patient tests positive for XMRV infection, determining the presence or absence of a disorder resulting, at least in part, from XMRV infection,

c) if the patient tests positive for XMRV infection, but negative for disorder resulting, at least in part, from XMRV infection, treating the underlying infection with an anti-XMRV compound, and

d) if the patient tests positive for both XMRV infection and the disorder resulting, at least in part, from XMRV infection, treating the underlying infection with an anti-XMRV compound and treating the disorder with agents specific for that disorder.

14. The method of Claim 13, wherein the anti-XMRV agent is selected from the group consisting of integrase inhibitors, tenofovir and tenofovir DF.

15. The method of Claim 13, wherein the method involves the coadministration of more than one anti-XMRV agent.

16. The method of Claim 13, wherein the disorder associated with XMRV infection is a cancer selected from the group consisting of prostate cancer, breast cancer, lymphoma, leukemia, and myelodysplastic disease.

17. The method of Claim 13, wherein the disorder associated with XMRV infection is prostate cancer.

18. The method of Claim 17, wherein the diagnosis of prostate cancer involves one or more of the detection of elevated PSA levels, and the detection of abnormal cells or tissue by punch biopsy.

19. The method of Claim 17, wherein the prostate cancer is treated by coadministration of an anti-XMRV agent and one or more treatment regimens selected from the group consisting of total or partial surgical excision of the prostate gland, treatment with anti-cancer drugs, treatment with radioisotopes, and treatment with anti- androgenic compounds.

20. The method of Claim 13, wherein the diagnosis of XMRV is performed by one or more of a quantitative PCR assay and immunohistochemistry (1HC) with an anti-XMRV specific antiserum.

21. The method of Claim 20, wherein the diagnosis of XMRV is coupled with a diagnostic step of looking for one or more indicia associated with cancer.

22. The method of Claim 13, wherein the diagnosis of XMRV is coupled with a diagnostic step of looking for one or more indicia associated with chronic fatigue syndrome or other diseases with neuroimmune symptoms.

23. The method of Claim 22, wherein upon a positive diagnosis of both chronic fatigue syndrome or another other disease with neuroimmune symptoms, and XMRV infection, the patient is treated with an anti-XMRV agent.

24. The method of Claim 23, wherein the anti-XMRV agent is selected from the group consisting of integrase inhibitors, tenofovir, and tenofovir DF.

25. The method of claim 23, wherein the patient is treated with a combination of more than one anti-XMRV agent.

26. A method for treating or preventing disorders resulting from XMRV infection, comprising administering to a patient in need thereof an effective anti- XMRV amount of an integrase inhibitor.

27. The method of Claim 26, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir.

28. The method of Claim 27, further comprising the co-administration of at least one additional anti-XMRV agent.

29. The method of Claim 28, wherein the additional anti-XMRV agent is tenofovir or tenofovir DF.

30. The method of Claim 26, wherein the disorder is a cancer.

31. The method of Claim 30, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lymphoma, leukemia, thymomas and myelodysplastic disease.

32. The method of Claim 26, wherein the integrase inhibitor is administered in combination or alternation with an anti-androgenic agent, an anti-cancer agent, or a radioisotope.

33. A method for treating or preventing disorders resulting from XMRV infection, comprising administering to a patient in need thereof an effective anti- XMRV amount of an tenofovir or tenofovir DF.

34. The method of Claim 33, further comprising the co-administration of at least one additional anti-XMRV agent.

35. The method of Claim 33, wherein the disorder is cancer.

36. The method of Claim 35, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lymphoma, leukemia, thymomas and myelodysplastic disease.

37. The method of Claim 33, wherein the tenofovir or tenofovir DF is administered in combination or alternation with an anti-androgenic agent, an anticancer agent, or a radioisotope.

38. A pharmaceutical composition for use in treating or preventing disorders resulting from XMRV infection, comprising an effective anti-XMRV amount of an integrase inhibitor, and a pharmaceutically acceptable carrier or excipient.

39. The composition of Claim 38, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572,

S/GSK1265744, Raltegravir and Elvitegravir.

40. The composition of Claim 39, further comprising an anti-androgenic agent, an anti-cancer agent, or a radioisotope.

41. The composition of Claim 38, further comprising at least one additional anti-XMRV agent.

42. The composition of Claim 41, wherein the additional anti-XMRV agent is tenofovir or tenofovir DF.

43. A pharmaceutical composition for use in treating or preventing disorders resulting from XMRV infection, comprising an effective anti-XMRV amount of tenofovir or tenofovir DF, and a pharmaceutically acceptable carrier or excipient.

44. The composition of Claim 43, further comprising an anti-androgenic agent, an anti-cancer agent, or a radioisotope.

45. The composition of Claim 44, further comprising at least one additional anti-XMRV agent.

46. A method for treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms resulting from XMRV infection, comprising administering to a patient in need thereof an effective anti-XMRV amount of an integrase inhibitor.

47. The method of Claim 46, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir.

48. The method of Claim 46, further comprising the co-administration of one or more additional anti-XMRV agents.

49. The method of Claim 46, wherein the additional anti-XMRV agent is tenofovir or tenofovir DF.

50. A method for treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms resulting from XMRV infection, comprising administering to a patient in need thereof an effective anti-XMRV amount of tenofovir or tenofovir DF.

51. The method of Claim 50, further comprising the co-administration of one or more additional anti-XMRV agents.

52. A pharmaceutical composition for use in treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms, comprising an effective anti-XMRV amount of one or more of an integrase inhibitor, tenofovir, and tenofovir DF, and a pharmaceutically acceptable carrier or excipient.

53. The composition of Claim 52, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir.

54. A pharmaceutical composition for use in treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms, comprising an effective anti-XMRV amount of tenofovir or tenofovir DF, and a pharmaceutically acceptable carrier or excipient.

55. A pharmaceutical composition for use in treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms, comprising:

a) an effective anti-XMRV amount of AZT

b) one or more of tenofovir, tenofovir DF, or an integrase inhibitor, and c) a pharmaceutically acceptable carrier or excipient.

56. A pharmaceutical composition for use in treating or preventing XMRV infection, comprising:

a) an effective anti-XMRV amount of AZT

57. A method for treating or preventing infection by a murine leukemia virus (MLV) other than XMRV, comprising administering to a person in need thereof an effective anti-MLV amount of an integrase inhibitor or a reverse transcriptase inhibitor.

58. The method of Claim 57, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir.

59. The method of Claim 57, further comprising the co-administration of one or more additional active agents, selected from the group consisting of antiretroviral agents and pharmacokinetic (PK) boosters.

60. The method of Claim 59, wherein the additional antiretroviral agent is tenofovir or tenofovir DF.

61. A pharmaceutical composition for use in treating or preventing an infection of an MLV other than XMRV, comprising an effective anti-MLV amount of an integrase inhibitor, and a pharmaceutically acceptable carrier or excipient.

62. The composition of Claim 61, wherein the integrase inhibitor is L- 000870812, Raltegravir or Elvitegravir.

63. The composition of Claim 61, further comprising one or more additional anti-retro viral agents.

64. The composition of Claim 63, wherein the additional anti-retroviral agent is tenofovir or tenofovir DF.

65. A method for treating or preventing an infection by an MLV other than XMRV, comprising administering to a patient in need thereof an effective anti-MLV amount of tenofovir or tenofovir DF.

66. The method of Claim 65, further comprising the co-administration of at least one additional antiretroviral agent.

67. A pharmaceutical composition for use in treating or preventing infection by an MLV other than XMRV, comprising an effective anti-MLV amount of tenofovir or tenofovir DF, and a pharmaceutically acceptable carrier or excipient.

68. The composition of Claim 67, further comprising at least one additional anti-retroviral agent.

69. A method for diagnosing and treating disorders resulting, at least in part, from infection by an MLV other than XMRV, comprising:

a) determining the presence or absence of infection by MLV, other than XMRV, in a patient,

b) if the patient tests positive for infection, determining the presence or absence of a disorder resulting, at least in part, from such infection,

c) if the patient tests positive for infection, but negative for disorder resulting, at least in part, from such infection, treating the underlying infection with an anti- MLV compound, and d) if the patient tests positive for both the infection and the disorder resulting, at least in part, from the infection, treating the underlying infection with an anti-MLV compound and treating the disorder with agents specific for that disorder.

70. The method of Claim 69, wherein the anti-MLV agent is selected from the group consisting of integrase inhibitors, tenofovir and tenofovir DF.

71. The method of Claim 69, wherein the method involves the coadministration of more than one anti-MLV agent.

72. The method of Claim 69, wherein the disorder associated with MLV infection is a cancer selected from the group consisting of prostate cancer, breast cancer, lymphoma, leukemia, and myelodysplastic disease.

73. The method of Claim 69, wherein the disorder associated with MLV infection is prostate cancer.

74. The method of Claim 73, wherein the diagnosis of prostate cancer involves one or more of the detection of elevated PSA levels, and the detection of abnormal cells or tissue by punch biopsy.

75. The method of Claim 73, wherein the prostate cancer is treated by coadministration of an anti-MLV agent and one or more treatment regimens selected from the group consisting of total or partial surgical excision of the prostate gland, treatment with anti-cancer drugs, treatment with radioisotopes, and treatment with anti- androgenic compounds.

76. The method of Claim 69, wherein the diagnosis of MLV is performed by one or more of a quantitative PCR assay and immunohistochemistry (1HC) with an anti-MLV specific antiserum.

77. The method of Claim 76, wherein the diagnosis of MLV infection is coupled with a diagnostic step of looking for one or more indicia associated with cancer.

78. The method of Claim 69, wherein the diagnosis of MLV infection is coupled with a diagnostic step of looking for one or more indicia associated with chronic fatigue syndrome or other diseases with neuroimmune symptoms.

79. The method of Claim 78, wherein upon a positive diagnosis of both chronic fatigue syndrome or another other disease with neuroimmune symptoms, and MLV infection, the patient is treated with an anti-MLV agent.

80. The method of Claim 79, wherein the anti-MLV agent is selected from the group consisting of integrase inhibitors, tenofovir, and tenofovir DF.

81. The method of claim 79, wherein the patient is treated with a combination of more than one anti-MLV agent.

82. A method for treating or preventing disorders resulting from an infection from an MLV other than XMRV, comprising administering to a patient in need thereof an effective anti-MLV amount of an integrase inhibitor.

83. The method of Claim 82, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir.

84. The method of Claim 83, further comprising the co-administration of at least one additional anti-MLV agent.

85. The method of Claim 84, wherein the additional anti-MLV agent is tenofovir or tenofovir DF.

86. The method of Claim 83, wherein the disorder is a cancer.

87. The method of Claim 86, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lymphoma, leukemia, thymomas and myelodysplastic disease.

88. The method of Claim 83, wherein the integrase inhibitor is administered in combination or alternation with an anti-androgenic agent, an anti-cancer agent, or a radioisotope.

89. A method for treating or preventing disorders resulting from infection by an MLV other than XMRV, comprising administering to a patient in need thereof an effective anti-MLV amount of an tenofovir or tenofovir DF.

90. The method of Claim 89, further comprising the co-administration of at least one additional anti-MLV agent.

91. The method of Claim 89, wherein the disorder is cancer.

92. The method of Claim 91, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, lymphoma, leukemia, thymomas and myelodysplastic disease.

93. The method of Claim 89, wherein the tenofovir or tenofovir DF is administered in combination or alternation with an anti-androgenic agent, an anticancer agent, or a radioisotope.

94. A pharmaceutical composition for use in treating or preventing disorders resulting from an infection by an MLV other than XMRV, comprising an effective anti-MLV amount of an integrase inhibitor, and a pharmaceutically acceptable carrier or excipient.

95. The composition of Claim 94, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572,

S/GSK 1265744, Raltegravir and Elvitegravir.

96. The composition of Claim 95, further comprising an anti-androgenic agent, an anti-cancer agent, or a radioisotope.

97. The composition of Claim 96, further comprising at least one additional anti-MLV agent.

98. The composition of Claim 97, wherein the additional anti-MLV agent is tenofovir or tenofovir DF.

99. A pharmaceutical composition for use in treating or preventing disorders resulting from an MLV infection other than an XMRV infection, comprising an effective anti-MLV amount of tenofovir or tenofovir DF, and a pharmaceutically acceptable carrier or excipient.

100. The composition of Claim 99, further comprising an anti-androgenic agent, an anti-cancer agent, or a radioisotope.

101. The composition of Claim 100, further comprising at least one additional anti-MLV agent.

102. A method for treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms resulting from an infection by an MLV other than infection, comprising administering to a patient in need thereof an effective anti- MLV amount of an integrase inhibitor.

103. The method of Claim 102, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572, S/GSK 1265744, Raltegravir and Elvitegravir.

104. The method of Claim 102, further comprising the co- administration of one or more additional anti-MLV agents.

105. The method of Claim 104, wherein the additional anti-MLV agent is tenofovir or tenofovir DF.

106. A method for treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms resulting from an infection by an MLV other than XMRV infection, comprising administering to a patient in need thereof an effective anti-MLV amount of tenofovir or tenofovir DF.

107. The method of Claim 106, further comprising the co-administration of one or more additional anti-MLV agents.

108. A pharmaceutical composition for use in treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms, comprising an effective anti-MLV amount of one or more of an integrase inhibitor, tenofovir, and tenofovir DF, and a pharmaceutically acceptable carrier or excipient.

109. The composition of Claim 108, wherein the integrase inhibitor is selected from the group consisting of globoidnan A, L-000870812, S/GSK1349572, S/GSK1265744, Raltegravir and Elvitegravir.

110. A pharmaceutical composition for use in treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms, comprising an effective anti-MLV amount of tenofovir or tenofovir DF, and a pharmaceutically acceptable carrier or excipient.

111. A pharmaceutical composition for use in treating or preventing chronic fatigue syndrome or other diseases with neuroimmune symptoms, comprising:

a) an effective anti-MLV amount of AZT

112. A pharmaceutical composition for use in treating or preventing an infection by an MLV other than XMRV, comprising:

a) an effective anti-MLV amount of AZT