CA2667445A1 - Hiv-1 protease inhibitors - Google Patents

Hiv-1 protease inhibitors Download PDF

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Publication number
CA2667445A1
CA2667445A1 CA002667445A CA2667445A CA2667445A1 CA 2667445 A1 CA2667445 A1 CA 2667445A1 CA 002667445 A CA002667445 A CA 002667445A CA 2667445 A CA2667445 A CA 2667445A CA 2667445 A1 CA2667445 A1 CA 2667445A1
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alkyl
heterocyclyl
compound
aralkyl
aryl
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CA002667445A
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French (fr)
Inventor
Celia A. Schiffer
Tariq M. Rana
Michael Gilson
Bruce Tidor
Visvaldas Kairys
Nancy King
Madhavi Nagga Laxmi Nalam
Ellen Nalivaika
Moses Prabu
Akbar Ali
Hong Cao
Kiran Kumar Reddy Garudammagari Sai
Saima Ghafoor Anjum
Michael D. Altman
Sripriya Chellappan
Miguel X Fernandes
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Massachusetts Institute of Technology
University of Maryland at College Park
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Individual
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Publication of CA2667445A1 publication Critical patent/CA2667445A1/en
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
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Abstract

Described are novel protease inhibitors and methods for using said protease inhibitors in the treatment of human immunodeficiency virus (HIV) infection.

Description

2 PCT/US2006/024108 HIV-1 Protease Ihzhibitors RELATED APPLICATIONS

The present application claims priority from U.S. provisional patent application serial No. 60/693,134, filed on June 22, 2005, which is hereby expressly incorporated by reference.

GOVERNMENT SUPPORT

This invention was made with support provided by the NIH/NIAID (Grant No. P01 GM 066524); therefore, the government may have certain riglits in the invention.
BACKGROUND OF THE INVENTION

Protease inhibitors (PIs) are potent antiretroviral drugs for the treatment of patients infected with Human Immunodeficiency Virus (HIV). Several known PIs are recommended as part of the "preferred regimen" for patients in the guidelines of International AIDS Society-USA (IAS-USA) and the U.S. Department of Health and Human Services (DHHS). However, use of these drugs has sometimes been associated with the development of irreversible HIV resistance, due to mutation of the virus.

The development of HIV 1 protease inhibitors is regarded as a major success of structure-based drug design; in fact, known protease inhibitors are generally considered to be the most potent drugs currently available for the treatment of AIDS. These agents are often combined with other agents to establish highly active antiretroviral therapy (HAART), which is credited with an approximately three-fold drop in the death rate from AIDS since about 1995. Despite this remarkable success, there is still much concern regarding the treatment of AIDS, largely because of the emergence of HIV mutants that resist current therapy. Drug resistance occurs when mutations in the target protein allow the protein to retain function while no longer being inhibited efficiently by the drug. In the case of HIV-1 protease, drug resistance occurs when, even in the presence of protease inhibitors, the enzyme is able to cleave the Gag and Pol polyproteins in at least nine different locations, allowing viral maturation. Viral resistance is regarded as a critical factor in clinical failure of antiviral therapy. The relatively rapid appearance of resistant viral mutants among treated HIV patients is attributable to the virus's high rate of replication, coupled with a high intrinsic rate of mutation due to the infidelity of the HIV reverse transcriptase. In addition, the current HIV 1 protease inhibitors were designed specifically to inhibit primarily a single variant of HIV-1 protease.

Developing different classes of therapeutic agents is not likely to be an adequate solution to the problem of resistance to protease inhibitors, primarily because the same basic mechanisms readily generate viral strains resistant to other agents.
Thus, resistance is a major clinical problem for the other major class of HIV drugs, the reverse transcriptase inhibitors, and resistance to newer, preclinical agents, such as the fusion inhibitors is readily elicited iri culture.

The challenge for the research community is therefore to develop drugs, e.g., protease inhibitors, that are less vulnerable to drug resistance and/or more active against current protease resistant HIV-1 isolates. The present inventions address this challenge by integrating clinical data, in vitro virology, protein crystallography, computational modeling and chemical design, and high-throughput chemistry and compound screening. HIV
protease is a particularly appealing target, as inhibition of its activity is clinical effective;
however, it can evolve to tolerate extensive mutation that confers drug resistance while retaining enzymatic function. As the design of the initial protease inhibitors was structure based, a huge knowledge reservoir exists for this protein.

SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery of new small molecule protease inhibitors (Pls). These inhibitors, and methods of making and using them, are described herein. Because these inhibitors do not protrude beyond the substrate binding envelope on the protease, it is expected that these inhibitors will be less likely to induce the development of resistant strains.

In one aspect, the invention features PIs described herein, or an enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions for inhibiting HIV protease that include a pharmaceutical carrier and a therapeutically effective amount of a PI described herein.

In another aspect, the invention features methods for treating HIV in a subject, by administering a therapeutically effective amount of a compound or phamiaceutical composition described herein. In some embodiments, the methods further include administering a second therapeutic agent, e.g., a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz (SustivaTM), nevirapine (ViramuneTM) and delavirdine (RescriptorTM); an nucleoside reverse transcriptase inhibitor (NRTI) such as AZT (zidovudine, RetrovirTM)/3TC (lamivudine, EpivirTM) and d4T (stavudine, ZeritTM)/3TC, and d-drugs (ddl [didanosine, VidexTM/VidexECTM], ddC [zalcitabine, HividTM], d4T); a nucleotide reverse transcriptase inhibitor, sucli as tenofovir (VireadTM); and a fusion inhibitor, such as enfuvirtide (FuzeonTM). In some einbodiments, the compound or pharmaceutical composition is administered as part of a highly active antiretroviral therapy (HAART) regimen.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

Figures la-b depict possible synthetic routes to selected inventive compounds.
Figures 2a-f depict selected compounds of formula I and associated K; values.
Figures 3a-d depict selected compounds of formula III.

Figures 4a-c depicts additional selected compounds of formula I.
Figure 5 depicts additional selected compounds of formula I.
Figures 6a-k depict anti-HIV drugs by class.

Figure 7 depicts the synthesis of protease inhibitors containing [A] a hydroyethylamine (HEA) core or [B] a hydroxyethylene (HE) core. Key: (a) EtOH, 70 C; (b) aq.
Na2CO3, CH2C12, r. t; (c) TFA, CHzCIZ; (d) Et3N, THF; (e) R4X2CO2H, EDCI,
-3-HOBt, DIPEA, 0 C to r. t.; (f) H2, Pd/C, MeOH, r. t; and (g) aq. NaHCO3, EtOAc, 0 C to r. t..

Figure 8 depicts the synthesis of protease inhibitors containing an aza-hydroxyethylamine (Aza-HEA) core. Key: (a) (CH3)2CHOH, 80 C (b) H2, Pd/C, MeOH, r. t; (c) R4X2CO2H, EDCI, HOBt, DIPEA, 0 C to r. t.; (d) TFA, CH2C12i and (e) R3X1COZH, EDCI, HOBt, DIPEA, 0 C to r. t.; aq. NaHCO3, EtOAc.
DETAILED DESCRIPTION

The protease inhibitors described herein were designed rationally using an ensemble of HIV-1 protease variant sequences (available online at hivdb.stanford.edu) and three-dimensional structures that the homodimeric HIV protease can tolerate, to maximize the likelihood that these HIV-1 protease inhibitors that will evade mutational resistance.
Recently, a structure-based strategy was proposed to reduce the probability of drug resistance by designing inhibitors that interact only with the same residues that are necessary to recognize substrate. (King, N. M. et al. Chena. Biol. 2004, 11, 1333-1338; and Prabu-Jeyabalan, M. et al. J. Virol. 2003, 77, 1306-1315.) Analysis of the crystal structures of HIV-1 protease in complex with substrate peptides suggested that substrate specificity for HIV-1 protease is based not on a particular amino acid sequence, but on a conserved shape ("substrate envelope"). (Prabu-Jeyabalan, M. et al. Structure 2002, 10, 369-381.) Comparison of the substrate structures with protease inhibitor structures reveal critical differences between inhibitor and substrate binding to the enzyme. In case of substrates, most of the conserved hydrogen bonds occur primarily between the backbone of the protease and the backbone of the substrate. Thus, it was determined that it is important that the inhibitors are designed to form hydrogen bonds with relatively conserved residues and preferably with the backbone atoms of the protease rather than the side chain atoms.

Remarkably, the new compounds are competitive inhibitors that bind in the center of the substrate envelope, which is the active site of the protease molecule.
However, the new compounds are designed such that they do not significantly protrude beyond the substrate envelope, and therefore are less likely to induce escape mutations. The new protease inliibitors are useful in the treatment of HIV in susceptible mammals, e.g., humans and certain other primates, and can be administered as a monotherapy, or in combination with other tlierapeutic agents, e.g., as part of a highly active antiretroviral therapy (HAART) regimen.
- 4-Selected Protease Inhibitors of the Invention. One aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of fonnula I:

Rs, X~N N S X R4~
H~ 2 Rl R5 I
wherein, independently for each occurrence, Xl is absent, -0-, -S- or -NR-;

X2 is absent, -0-, -S- or -NR-;
Rl is -OH, -SH or -NHR;

R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloallcyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;

s' 0O O
N
provided that when Xl is absent; R3 is not R3A or N-R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X, is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X2 is absent.
- 5-In certain embodiinents, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein XI is absent; and X2 is absent.

In certain enlbodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Rl is OH.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is A5 A4 ; and Al, A2, A3, A4 and A5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2, and A5 are hydrogen; and A3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfliydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned Al A2 compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2, and A5 are hydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfliydryl, imino, amido, phosphonate, phosphinate,
- 6-carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloallcyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is aryl or heteroaryl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wlierein R4 is alkyl, aryl or heteroaryl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein RS is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned conipound and any of the attendant definitions, wherein RS is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; X2 is absent; Rl is OH; R2 is aralkyl; R3 is aryl or heteroaryl; R4 is alkyl, aryl or heteroaryl;
and R5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.

Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula II:

Ph R3,X'~'H N.S.R4 N-( OH R

s II

wherein, independently for each occurrence, Xi is absent or -0-;

R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
-7-R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
p provided that when Xl is absent; R3 is not R3A or N-R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is aryl or heteroaryl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is alkyl, aryl or heteroaryl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R6 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R6 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is CH3 H3C~N~~ H3CH3CH3C

O p
- 8-O
H3CO H3C N~ N HO VN N/ N OH ~ e > > s ~

FsC~~ , HsC "-F
N CHs S 11 CH3 HO~ F ~..
/
I \
F
F
OH
HO HO
H
HO HO ~ ~`~ CH3 I ~ I ~ ~ H3C"j/`~
CI Br H3C NI~ CH CI ~`~. HO HO ~~r..
~ 3 I I~

CH >
> > > > H F

CH3 ~ H3C N H3C N N H
\
H3C~ ~ ^ o ~ 0 OH , CH3 CH3, s or F

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is F

p N H3 NI~ NO H3C N
:~O ~N ~ }-CH3 ~ ~ N CH s , CHs , S
OCH3 , F
F

-CH3 S~
,---,/
F o , /\
~,. , ~.. F or 4`'- CH3 .

In certain embodiments, the present invention relates to the aforementioned /~p c compound and any of the attendant definitions, wherein R6 is ~
- 9-(:H3 `'~-CH3 S `~õ~CH3 `V-CH3 CH3 > > > > > > >

H3C CH3 )1,OH 1,,OH
~ H H O CH3or JII-N'CH3 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; and R3 is H3C.N\ H3CCH3 H3C\
CH3 0 , 0 O
~+ 0 H3C\ H3CO I H3C N~ ~ NHO V ON ~ N

>
N ~

cr O
OH O 0\/~ ~`/~/~`' > > > >
N
CH3 CF3 / S S CHCC\ F3C~ H3C~~ >
> > > , , F

HO I~~ F CH3 ~ HO HO OH `~r CH3 ~
F )~ ~~
F HO / HO ~
>
CI

I~
H3C,"\ 0 CH3 ~/~ I / - 10-H
Br ~ ~ HO CH3 `~ H3C N
HO ~4..

~ H3C p ^ y ~
I/ OH CH3 CH3, 0 CH3 or F
N
F I O

In certain embodiments, the present invention relates to the aforementioned ~ \
H3C N~N
Y\
compound and any of the attendant definitions, wherein Xl is absent; R3 is CH3 O
H3C- NFi3CH3C '~ H3C~~
0 , 0 O CH3 \ O~v O O N~ ~.

H
3CO y H3C N\ N HO N~
N/ N~ I/ OH
> > > , O-\ , F3C " \ H3C \ F

S 11 CH3 HO F ~
/ I
S F
~ , Br F OH CH3 OH
HO I ~ ~.. HO ~ ~ ~+ - ~ S HO ~ HO ~ > ~ H3C~<31 > > > >

CI Br H3C N CH CI ~.. HO ~~.. HO ~~..

y 0 CH3 I ~ C F

za~ H3CyN HgCu N N
H3C O /~ II I/ IOI
OH , CH3 CH3 ~ 0 CH3 or F ; and R4 is OCH ~ N H3 N N H3C N
/ N ~CH

~ N S

CH
F > > > > > 3 F
F
N
~/ ~ ~~CH3 I/ S
`~ OCH3 , F , , ~ , ~ OCH NH2 H3C

~ ~CH3 ,~, ~ F or~

In certain embodiments, the present invention relates to the aforementioned il--\
H3C N,N
Y'll compound and any of the attendant definitions, wherein Xl is absent; R3 is CH3 O
H3C,N\ H3C\ O CH3 H3CH3C\ ^/~,.
~O 0 O j0~ _ O N~ ~-N HO VIN-N `+
/ N~ OH
> > > > > >

F3C"I~~~ H3C"J':~~~
F

s S 11 CHci:~~ ~ F ~..
Br/ F F I/
> > > >

H O/v / I~~z HO
HO HOI~~c > = `~ S I
H3C,"I'/"ZI
> >
CI Br H
H3C N CH CI ~~.. HO ~.. HO

O CH3 ~`~ I / , I / CH3 H F

H C ~ H3C II N H3C N N
~ y~

OH CH3 CH3 ~ 0 CH3 or F ; and R6 is H3C I) I HO HO
0 ,"~CH3 ~ S ~KCH3 CH3 a a a a a a a a H3C H3C CH3 H3C CH3 ~
CH3 CH3 ~OH OH ' N
, H H

0 ~N,CH3 CH3 or ~ OH

In certain einbodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is F

o CH3 N NO H3C
N N ~
~ j ~ }-CH3 ~ ~
N \ ~g ~
~O , , CH3, CH3, ~4.. OCH3 F
F
~ N OCH3 ~'\CH3 ( / S
F , O
, ~ ,~.

NH2 H3C H3C ~ H C
/\CH3 ,, 'O 'IO /'CH3 F or ~ and R6 is ~r, ~

yz~, S yt, I `+~~~ `~,.~KCH3 '~~CH3 -CH3 cH3 " a " a a a a a a H3C CH 3 H3C CH3 0 ~CH3 ~OH ~OH JN~ \~ ~CH ~ N
~ ~, ~- H , ~ 3 or OH

In certain embodiments, the present invention relates to the aforementioned / ~

Y'll compound and any of the attendant definitions, wherein Xl is absent; R3 is CH3 H O
H3C.N~A.. H3C~~.. CH3 H3C\ ^/~.. H3C
0 , 0 O 0 a 0 - 13-N N
OH
, a a a a 0~~ F3C~~ a H3C'~~ , F
S NCH HO I~~+ CH3 ~ 11 CU\ (:~~ F Br , F F , I / OH CH3 HO I~, HO I~~ = ~.L S
OH
HO / HO ~ H3C,,-,~~
a a a a a CI Br H3C NCH CI ~~r.. HO ~~`4,. HO

C H F

`~ H3C~N H3C N N
H3C y Jc OH OCH3 CH3 0 CH3 or F 0 ; R4 1s ~ OCH3 N N
H3 N' `~N O ~
> N H3C N CH
~~ }- 3 F a ~ a a a a F
F
~/ O CH3 S
`~ OCH3 , F , , I~ OCH3 NH2 H3C H C
~ / `CH3 .
~ F or ~ - and R61s ~ H3C I~ I ~ HO HO
O O /~CH3 S ~,. ~..~`CH3 ~CH
~ a a a a a 3 H3C H3 C CH3 H3C CHs CH3 H ~OH

H H

O ~N,CH3 '~~CH3 or ~ OH

Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of H 0 Q. ~/ 0 Q~ /~
N NSD N
H3C'N~N NS~ N H3C N' O H OH I/ H OH
$ ~ 'GJ
NC
H, CH, O 0 ~
pq H3C0 I N N S\O N HaC N~ N NS` N

O~/ , ~

\~ N \~ /
O O r~> O ON NN H3C N~ N N'S~ \ OCH3 H OH O ~/ H OH O

/ CH3 p OCH3 b HO\ 0~~~> 0 O H3C N~ H N SO N H3C0 H N-SO
jOj OH N OH
0_/ 0~/

F F
O \lo /~ F 0 o O o H ` \ o \ v \
H3C~N,LH N'S F HO S0 O NS~

51/ , F SJ

0` \ ~ o O\ 0 0 \ ~

I F \ I ~
F N N'SO H3C\ ^\J~N NSO HO e N N
'SO
H OH 0~ H OH F HO H OH
, ~ , ~

F I F
CH3 0 o p` \ OH 0 P p\ \ ~ I O O\
F3C" v N N'S~ HO e N N'S N N'S`
O
H H OH F
~
H OH
I-S o F HO OH
I'~
pCH3 H N\SO \ ~ CH3 O p C l /~ S CH3 p H N~SO CH ~/ H OH N' OH OH 3 \
~ i ~
SJ
, N Br 0 p \ N
CF3 0 Q~ O H C O
H3C" v N N'S 3 N N' p a H3C N N/\
H OH O CH3 H OH \ CI ~H O CH3 0 OH r SI / J~' /
/
H O \ I H O o~ \ I
H C,N~N N.S\ \ H3C'N~H N-S~

H \ I O p /
` \
H3C'N~N N'S H3C N\ N' 0 H OH ~,,OH ~/ H OH O
CH3 ~

b / / o O oO ~ \ I ~ O~~ \ ~
H C I N~ H N~SO H C I N~ H ~S (~ 1 ll N N S`
3 // OH OH 3 OH õOH v`/ `H O
~ OH ~
CH3 ~ C`iH3 OCH3 po, O O \ I H O I O\ ~ N
~H N O ~H 0 H H3C-N~N N-SH3 OH yOH OH , p OH 0 CH3 ~ CH3 H 0 0 I_ N 0 I S\
H3C;N~H N.SO~,{CH3 H3C N~ N N\S~N
0 OH ~,OH ~/ H OH O CH3 CH3 ~

I CH3 CH3 CH, 0 O ~N S~ O~ S4 H3C N N NS~ ~l~ O~ ~N H
I H OH OOH CH3 H OH N~SO CH3 OH N OOH CH3 CH, ~ CH3 /
0 p H p o \\ p \
H C'N~~N N'S` \ H3C.N~N N'S~ H3C N S`
o H OH O \

OH `~,,OH ~/ H OH ' 0 ~ 1CH3 ~ / I ~

0 O~ 0~ \ I O O p ~\) H3C I N~ H N.S` ~ N Q \\ ~ ~o/\~f S H N~
/ OH ~111OH H OH , O OH ~1110H

CH3 O p\ CH3 O 0 I_S>
H N.O ~H N~O
0 OH ~ /CH3 0 OH ~ /CH3 CH, H3 I CT H3 N
al OCH3 ocs\
O O~ O p HO \ N N,S` HO \ N N'S`
I/ H' OH OCH3 H OH ~ H3 / F H3C O 0H~~\ OCH3 CF3 O õ pS \ ~ OS \ ~
H3C~~N N' ~p N N' 0 H OH ~/CH3 H OH ~F H3C~CH3 T
J
S ~ CH3 H3 O \ / N OCH3 C
~ p ~
HN N NO H3CCH3 p ~N N'S0 H3C^CHH OH ~/CH3 OH H OH ~/CH3 CH3 ' CT H3 P / N \ ~ OCH3 c N
ps \ ~ SOH O pOH O p S
H3CN N' ~0 ~N N' ~O N N'S\
OH H OH y CH3 CH3 H OH YCH3 CH3 H OH ~,/OCH3 CH3 C H3 , iCH3 CH3 O pS CH3 O ~S~
I S
N N' ``
~`N N' O H OH Q/-ICH3 0 H O H OH Q,~-ICH3 O O ~
P1- OCH, pocr-HOr N
/ O\ ~ N N'S HO \ N N S

H OH ~~CH3 I/ H OH Q,~-ICH3 , , H3pYp p \ 1 p\ / I OCH3 H3C~p p \ p / N
~ \ ~` \ s HN N N~SN HN N N-S`
H3C~CHH OH ~^CH3 H3C~CHH OH ~/~CH3 / OCH, N
CH3 O \ pS a CH3 O pS / \
H3C N N' H3 C~N N' OH H OH Q~-ICH3 OH H OH Q/-ICH3 OH O pS OH 0 pS / ~ s~>
\
H N' ~H N' ~O
CH, OH Q O/~CH3 CH, OH `/-ICH3 CH3 O \ pS / ~ CH3 O \ pS / S~~
J \ \ ~ \
H N ~O ~H N- ~
O
~ O
O OH ~CH3 O OH CH3 CH3 ~ CH3 O \ `` p ~ ~
\ ~ O ` \ S
HO \ N NS~ HO N N'S~
I/ H OH CH3 I\ / H OH CH3 CH, CH, H3C O \ ~ OCH3 H3C O ~N
0 \ ~ ~~ q \ S) HN H N - sO HN H N,sO
H3CIICH3 OH ~CH3 H3CI ~CH3 OH CH3 CH, ~ CH3 CH3 O \ p` \ S / ~ CH3 O \ pS /
~ \ S
H3C H N \O H3C~H N~ ~O
OH OH `'CH3 OH OH ~CH, CH3 , CH, - 18-OH 0 \ pS \ ~ OH 0 pS \ I \~
S
~H N~O H N-~O
CH3 OH ~CH3 CH3 OH ~CH3 CH3 a CH3 0 p\ CF, 3 O O` \ ~
H3C~H N.SO H3C/j\H N.SO
IOI OH ~/CH3 OH ~/CH3 CT H3 ~C"H3 OCH3 / ~ OCH3 H 0 Q, \ CH3 0 \ 0 I
H Cu N~N NS` F \ N N'S\3 O CH3 H OH OCH3 I/ H OH OCH3 TCHa , and TCHa Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of F
CH3 \ I / \ I CH3 H NSCH3 O H N \ CHI HO p N, _N OH O iN OH O 3 N H OH 140 HO O H3C'N'OH , HOI O H3C'N'OH H3C'N'OH
F F

O IO p \ IO CH3 O IO
'J' HO N N'SO N N.S~ CH3 N N~S
I i N H OH YO CH3 N/ H OH ~ OO N/ H OH YO CH3 H3C'N, OH H3C~N', OH H3C'N, OH

I CH3 \ I / \ I CH3 H3CO p p$'j,CH3 H3CO 0 O$ 0 O$''CH3 11\ N N' ~0 ~\ N N' ~O N' N/ H OH ~0 N/ H OH ~O CH3 I iN H OH "40 H3C'N, OH H3C'N'OH a CH3 H3C'N'OH
F F
/
O
O~ O 3 \ p~ 1 p \ I Q~
N NISO N.S`CH3 N NJS\
/N OH ~O 3 3 H CH 'N OH YO I i N H OH ` OO CH
CH3 H3C'N, OH a HO p CH3 HO O C~H3 F
P%li 0 CH3 0/ 0 CH3 ~~ ~ ~\ I CH
HO \ N N'S\ CH3 HO \ N N'S~ N N~O s O I i N H OH O CH3 N H OH O
I N H OH Y~

F
I F
O \~o 1 O CH3 0 O
N NS` H3C0 \ N N SCH3 H3C0 \ N N'Sl N H OH I` 00 CH3 N/ H OH ' vO N/ H OH O CH3 ^~", ~
~,H3 ' l~t'~3 ~ CH3 F

O 3 O~ ~ O O` 1 H 0 0 ~ ~N-CH3 N N'S` CH3 N N.S~ H3C' N~N N'S`
i N H OH YO I i N H OH (O CH3 0 H OH ^/CH3 CH3 CH3 CH3 CH3 OH ,CH3 H3C /N\N O N=~
0~ ~N-CH3 ~A
N N'SO
CH3 H OH ~O`
Iv) O N=~ O~ N-CH3 F OI O~ ~N-CH3 H3CO\~N N'S` N\^~`N N.SO
IN J/'I H OH ONH F O H OH j\ ~CH3 O(H TCH3 ~,~ O`` ~N-CH3 F H _ O~J R, ~N-CH3 H
NSO ~rN ~ /~/\N OH 0 FIOI H OH
v N--\ N=::\
F H O O` ~N-CH3 O ~~ ~N-CH3 \ N\^`~N NSO H3C N,N N'S~
F I/ ~0 H OH 0 I H OH
v , ~ , 0 IO N=\N-CH
H3C N, N N'S` ~ 3 O
H OHj~CH3 OH ~CH3 O \ I N=~N N%~
H C N ~S~-CH3 HO 0 N-CH3 3N N' O I\ N NI' ~Q
I/ H OH ,,, ~NH N H OH
(~~//, /
N
O \ I N~
O`/v 1` -N-CH3 H O R\ ~N-CH3 H N,SO H3C'N~IN N'So OH CHa 0 H OH 1-p`
OH CH3 Iv) 7 !
/~ \l HaC-N,N O \ I N=~ N N=\ ~~ -CH3 0 N-CH3 ~H N.O H3COI\ N N.SO
CH3 OH /T CH3 N/ H OH 1 /, OH CH3 (~/, e e \ I
H OII ~N-CHa OII 0~ ~N-CH3 H3C'N~N N-S`O N'SO
O I H OH NH H OH ~
V ~ lv) e O O~ ~N-CH3 F H 0 0 ' N-CH3 p HO` ^ ~LN I' SD N~N ~ S~
IiNT H OH ~p F I/ 0 H OH /N~{
(~/) 0 F

F
H 0 L,N-CH3 H O O`
H3C'N~N N'S~ OYN~N N'Sb O H OH 1",, ~0_ CHa CHa H OH , F
(~/, F
N N
H 0 O\~ H3C 0 O \ O`~ rV,0 O\/N,, H N.SI / 0 O F OH N O CH3 ~\
3 H N.S/O CH3 C(H3 CH OH S OH S N.No OH S
/ I /

f ) D
N N N

S r,O H3C 0 \ OS I_ O \ CHa Q ~S I_ O
FaC~~~H N\O/ CHa 1 ~I H NOCHa H N0~CHa OH S ~ OH OH

~ e e - ~l-N / ~ rN
F CH3 O \ Q3 \ I OCH S0~ OS~O Br O \ OS I_ O
H N- O H N~ O CH3 H ~O~IfCH3 OH OH S OH
I/ ~/ , ~/ and F
F
#1F

O OS ~H N/ ~OH Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of o H,CS_ -/~
o ,~ ~
H N~ ~/ NH N~~O
F3C-S \ / ;T"~' p O
Oy O OH
,and / ~
O, OCH3 OH O ~

NH NS\O
H3C )-O OH
Z (',H3 O

Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula III:

R3.X~N~NYX2 III
wherein, independently for each occurrence, Xi is absent, -0-, -S- or -NR-;

X2 is absent, -0-, -S- or -NR-;
Rl is -OH, -SH or -NHR;

R is hydrogen, alkyl, aralkyl, heteroarallcyl or acyl;

R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (lceto)alkyl, cycloallcyl, cycloalkenyl, heterocyclyl,- aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, arallcyl or heteroaralkyl;

R5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R7 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;

YO~IrO O-~fO

provided that when Xl is absent; R3 is not R3A or N-R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloallcyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

O~o O-'~O
N
and provided that when X2 is absent; R4 is not R4A or N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (lceto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X2 is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; and X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Rl is OH.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is A5 A4 ; and Al, A2, A3, A4 and A5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, ainino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonainido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.

In certain embodiments, the present invention relates to the aforementioned Al A2 compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2, and A5 are hydrogen; and A3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulflrydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2, and A5 are hydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulflrydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is aryl or heteroaryl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is alkyl, aryl or heteroaryl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein RS is hydrogen.

In certain embodiments, the present invention relates to the aforementioned Bi B2 compound and any of the attendant definitions, wherein R7 is B5 B4 ; and B1, B2, B3, B4 and B5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.

In certain embodiments, the present invention relates to the aforementioned g3 compound and any of the attendant definitions, wherein R7 is B5 B4 ; B1, B2, and B5 are hydrogen; and B3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfliydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned Bi B2 compound and any of the attendant definitions, wherein R7 is B5 B4 ; B1, B2, and B5 are hydrogen; and B4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R7 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R7 is alkyl, (cycloalkyl)alkyl or aralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; X2 is absent; Rl is OH; R2 is aralkyl; R3 is aryl or heteroaryl; R4 is alkyl, aryl or heteroaryl;
R5 is hydrogen;
and R7 is alkyl, (cycloalkyl)alkyl or aralkyl.

Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IV:

O Ph R3.XJ~N NuRq.
~ H II

IV

wherein, independently for each occurrence, XI is absent or -0-;

R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and R7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl;

O~ ~s O--fO
N s' provided that when XI is absent; R3 is not R3A or N-R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

.~~N O ~ OO

and provided that when X2 is absent; R4 is not R4A or N- R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; and R3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, arallcyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; R3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl; and R7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.
In certain einbodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is 'CO

F
~_ \ / H3C OyCH3 OCH3 O\ / -~ O H3C~ ,,NH
HO , ~ O ~

H C O~CH3 H3C , I
H3C3 NH <~O o 0l CH3, or _O .

In certain embodiments, the present invention relates to the aforementioned com ound and any p of the attendant definitions, wherein R4 is F
H3C Oy CH3 H3C O y CH3 O \ / C~ H3C~H ry-5, H3C Oy CH3 H3C OyCH3 H3C Oy CH3 H3C NH H3C\ NH H3C\ ~ NH
O, H3CCH3CH3 H3CTCH3 H3C CH3 H3C,---ICH3 O~CH3 H3C NH NH `~, NH ~ ~~ ~
O~O O N O N
CH3, O OCH3, H or H
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R7 is ~CH3, w P -\0 10 orI

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X, is absent; and R3 is F

, O
O \ / , H3C O~CH3 H3C OCH3 H3C
H3C ~,,NH H3C
o clq 0,CHsor 0, In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X, is absent; R3 is ~ ~ j/' O OCH3 \ / - , rl~ 5 O O \ / F~O
, , H3C Oy CH3 H3C O~CH3 H3C
O\
H3C ~,,NH H3C
CH3, or 0; and ~ ~ 3 O) O \ / H3 ,,,,,,,, C~``
is F o ~ > > >
H3C O`\/CH3 H3C O\/CH3 H3C Oy CH3 H3C~NH ^ /OCH3 H3C NH H3CNH

O cO H3CCH3CH3 H3CTCH3 H3C CH3 H3C O~CH3 H3C O~CH3 = XN
H3C NH H3C NH NH "NH
O--OCH OOCH O~ N
3, 3, H
H3C,---,CH3 D
O N
or H .

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; R3 is O ry O \ / ~-CO
HO 0 , , , H3C O~CH3 H3C O~CH3 H3C
H3C~ NH H3C j CH3~ or O >=R

is CH3, In certain embodiments, the present invention relates to the aforementioned I ~ OCH3 compound and any of the attendant v\
definitions, wherein R4 is F
~ ~ / H3C Oy CH3 H3C Oy CH3 O\ O - H3C~ ,,NH H3C~NH ryOCH3 ~ O/ ~ / , O

H3C Oy CH3 H3_ C Oy CH3 H3C Oy CH3 H3C NH H3C\ NH H3C\ NH
0, HCCH33 H3CTCH3 H3C CH3 H3C~CH3 O\/CH3 JCH3 '( - ~ , H3C NH NH `~õNH ~ ~~ O ~~ N
O N
O~ OCH3, O OCH3, H or H and R7 is CH3, or In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; R3 is a ~ \ / OCH3 O~ / -O
, ~ ~~0 , HO , - 0 O~CH3 H3C OCH3 H3C

H3C~,,NH H3C O ~i0 , ~H3, / V O! OT `O .

O~ CH3 OCH3 ~ ~ O - H3C ~ NH
I ~ > O / H3C~
is F O

H3C O\/CH3 H3C O`\/CH3 H3C O\'CH3 NH OCH3 ~__C H3C NH H3C NH
H3C ry- O ~, H3CCH3CH3 H3C~CH3 H3C O ~ H3C
H3C\ NH H3C\ NH NH "NH
O~OCH3~ OOCH3, H3C CH3 H3C"---.CH3 ``~,.
~ N CH3 I ~~ )N O H or O H ; and R7 is ~CH3, or Another aspect of the present invention relates to a compound, or a pharrnaceutically acceptable salt thereof, selected from the group consisting of H3C / \ I H3C I H3C CH3 O O N NH
O N \ ~
N \ ~ N
H OH O H OH O O--J--CH

H3C CH3 H3C CH, H3C / 0 H3C CH3 \ I O~H NNH
H
\ OH N NH OH O O--CH3 OH rOl O-~-CH3 \ I / ~
OH O H ~ I OH O
\ N N \ O N N \ I O

H,C CH3 \ , \ I
I
OH O H i I

H
OH O b N N CH3 F H OH ~

OH 0 H O \ N N1~CHa \ N NCH3 F,JI / H OH 0 F I/ H OH O

o ~
OH 0 HaC O /

H _ N- \ I O' N N \ I O
H
FI\ ~ OH 0 OH 0 / If H3C CHa \

\ I /
OH 0 H~O H3C CHa OH 0 H \ N_ N OH 0 H
\ N N F/ I/ H OH 0 N _ N NH
~/ H H OH 0 O~CH
F~ O H 0 F a 7 ~ H3C CHa /
OH O \ I H3C CHa OH 0 H3C CHa \ N _ NNH
H H
I\ H _ NNH F / OH CHa F~ OH 0 O')-CH

f 7 O H / O / O
H3CO~N N \ I O HaCO~N N \ I
H

H3C CHa I
f f o H3C0\ ^~LN N \ O O H O
0~ OH O b H3CON _ N~OCHa H3C CHa I

0 H 0 N O H O HaCO'lf'-" KH N~,OCH3 H3CO~N NOCH3 0 OH 0 0 H (65 H 0 HaC / O %O:Ho ~ I I O 0I H O

H a HaCON N
0 H (65 H 0 H3C CHa O H O HaCO~H = N
H3C0^AN N 0 OH O
j0~ H OH 0 0 H3C CHa H7NH
O
H
H3CON N ~ 'NH HaCO~N N O H OH 0 O~CH 0 H OH O
3 O--l-CHa H3C CH3 O ~ I H3C CH3 ~ O

C0~ N N NH I/ \ I HaC
H3 H = 0 N
O OH O O~CH , N _ CHa rN
3 H OH 0 O/j-CHa H3C CHa p 0 HaC CHa O NaC CH3 O ~ H _ N NN
O ~ N H I/ OH O O~CH
a H
I / OH 0 O-~-CH
a HaC / O 0 0 ~ I HaC CH
I a v'O" v`H N~OCHa H3CO~H N 'NH
OH 0 0 OH 0 O-~-CH

H3C CH3 H3C CHa / I
0 H 3C CHa 0 HaC CH HaCO~H _ N N

H3CO,r,,_AN N NH 0 OH O O I^CH
O H OH O--CH
a 7 ~

f.::r I!a"; .,1i". " -i...l~ ~~~ :i~ II::;!Ã i!'mi~ ., ` ~u:'~ tr:.{['.~li..
~~;;I! ,1~ l~

O H CH3 O \ H3C CH3 N NH
H = N II "H N N NH O H OH O O~CH3 O OH O H =H O O~CH O O

H3C CH3 > > >

y O CH3 H3Cy O O H3C CH3 HN,, N N HN,, N õ'NH
~H OH IOI H =
H C' 'CH O~CH OH O~

H3C CH3 7 f H'CyO O \ I HC CH3 \ I H'C / C I O
HN,, H = N O' v'H _ N1~OCH3 H3C" 'CH3 OH O OCH3 OH O

7 ) H3C / O \ I O H 3 C / O I O
H N \{ O~H = N
OH LO OH O
H3C CH3 ~ H3C CH3 H3C / 0 {

H3C O O \ I O~N N~
N H OH O
H OH O
, and Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula V:

R3, X'HN~X2R4 I
Rl R5 V

wherein, independently for each occurrence, Xl is absent, -0-, -S- or -NR-;

X2 is absent, -0-, -S- or -NR-;

Rl is -OH, -SH or -NHR;

R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R2 is"hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, arallcyl or heteroaralkyl;

R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloallcyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, arallcyl or heteroaralkyl;

R5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;

~~0 O ~O
N
provided that when Xl is absent; R3 is not RsA or N-R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
O~i O

and provided that when X2 is absent; R4 is not N 1 R4A or ~N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, arallcyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is -0-.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X2 is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent or -0-;
and X2 is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Rl is OH.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is A5 A4 ; and AI, A2, A3, A4 and A5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.

In certain embodiments, the present invention relates to the aforementioned Al A2 compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2, and A5 are hydrogen; and A3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is A5 A4 ; Al, A2, and A5 are hydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfliydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is heterocyclyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is (heterocyclyl)alkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R5 is alkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein XI is absent or -0-; X2 is absent;
R, is OH; R2 is aralkyl; R3 is heterocyclyl; R4 is alkyl, aryl or heteroaryl;
and R5 is alkyl.
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VI:
0 Ph o R3, X~H N N~R4 RI R

vi wherein, independently for each occurrence, Xl is absent or -0-;

Rl is -OH or -NH2;

R3 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, arallcyl or heteroaralkyl; and O p ~
provided that when XI is absent; R3 is not ~.N R3A or ~ R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aiyl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

/O
Y~--OrO O--and provided that when X2 is absent; R4 is not N R4A or N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)allcyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned conipound and any of the attendant definitions, wherein Rl is -OH.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Rt is -NH2.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is -0-.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is heterocyclyl.

In certain embodiments, the present invention relates to the aforementioned O C) ~.~
compound and any of the attendant defimtions, wherein R3 is or In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is -0-; and R3 is heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xt is -0-; and R3 is ~-In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is heterocyclyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R6 is alkyl.

n certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R6 is -CH(CH3)2.

Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VII:

R3.X'~'H~N.NyX2 Rl R5 0 VII
wherein, independently for each occurrence, Xl is absent, -0-, -S- or -NR-;

X2 is absent, -0-, -S- or -NR-;
Rl is -OH, -SH or -NHR;

R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;

O-~
N
provided that when Xt is absent; R3 is not R3A or N-R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

0 O-'~/ p N
and provided that when X2 is absent; R4 is not R4A or N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X2 is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent; and X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Rl is -OH or -NH2.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl.

In certain embodiments, the present invention relates to the aforementioned Al A2 compound and any of the attendant definitions, wherein R2 is A5 A4 ; and AI, A2, A3, A4 and A5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, allcynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.

In certain embodiments, the present invention relates to the aforementioned coinpound and any of the attendant definitions, wherein R2 is A5 A4 ; AI, A2, and A5 are hydrogen; and A3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned "S', A1 A2 As compouiid and any of the attendant definitions, wherein R2 is A5 A4 ; AI, A2, and A5 are liydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkyltliio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is (amido)alkyl or heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is (amido)alkyl or heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein RS is alkyl or aryl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xt is absent; X2 is absent; RI is -OH; R2 is aralkyl; R3 is (amido)alkyl or heterocyclyl; R4 is (amido)alkyl or heterocyclyl;
and R5 is alkyl or aryl.

Another aspect of the present invention relates to a compound, or a phanizaceutically acceptable salt thereof, of formula VIII:

O Ph H
R3.X~H N.NUR4 OH ~R IOI

YIII

wherein, independently for each occurrence, Xi is absent or -0-;

R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
s~0 -_CIr0 / O--~ O
N
provided that when Xl is absent; R3 is not R3A or N-R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
~00 ~ O-~
/'O
N
and provided that when X2 is absent; R4 is not R4A or N-R4A;
wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xl is absent.

In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is (amino)alkyl, (amido)alkyl or heterocyclyl.

In certain embodiments, the present invention relates to the aforementioned H3C~CH3 V'NH
compound and any of the attendant definitions, wherein R3 is O4-1-OCH3 or ~
`~ NH
O--l-OCH3, In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is (amino)alkyl, (amido)alkyl or heterocyclyl.

In certain embodiments, the present invention relates to the aforementioned H3C~CH3 VNH

compound and any of the attendant definitions, wherein R4 is 0--l-OCH3 or ~
`~ NH

O-~-OCH3110 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R6 is alkyl or aryl.

In certain embodiments, the present invention relates to the aforementioned ~--( ~
compound and any of the attendant definitions, wherein R6 is CH3 or - N-~
In certain embodiments, the present invention relates to the aforementioned H3C~CH3 compound and any of the attendant definitions, wherein R3 is OOCH3 , or H3CCH3CH3 H3C~CH3 H3CCH3CH3 ~
`~. NH `~~'NH NH CH3 O-)-OCH3; R4 is O-~IOCH3 , or O-~IOCH3; and R6 is CH3 or N

Syntlaesis of Selected Compounds of the Invention. The protease inhibitors I-VIII
can be synthesized using the synthetic schemes outlined in Figures la-b. The definition of each of the variables may be the same as shown in formulae I-VIII above.

Protease inhibitors I, II, V and VI can be prepared using the synthetic scheme shown in Figure 1 a (top). As shown therein, an epoxide, for example, can be reacted with an amine in a stereoselective manner to yield amine 2. Amine 2 is reacted with sulfonyl chloride or an acyl chloride to yield 3. Deprotection followed by reaction with an acid chloride, for example, yields inhibitor I, II, V or VI.

Protease inhibitor III and IV can be prepared using the synthetic scheme shown in Figure 1 a (bottom). Amino acid 5 can be converted to amine 6 using standard synthetic procedures. Reaction with an acid yields amide 7. Deprotection followed by reaction with an acid chloride yields inhibitor III or IV.

Protease inhibitor IV can be prepared using the synthetic scheme in Figure lb.
As shown in the scheme, an epoxide, for example, can be reacted with a protected hydrazine in a stereoselective manner to yield hydrazine 9, after deprotection. Hydrazine 9 is reacted with an acid to yield amide 10. Further deprotection yields amine 11 followed by reaction with acid chloride yields inhibitor VII or VIII.

As can be seen from Figures la and lb, the R groups of the inhibitors are determined by choosing suitable reagents and starting material. Similarly, the stereochemistry of the inhibitors is determined by choosing appropriate starting material and reagents.

Phaf maceutical Compositions. The methods described herein include the manufacture and use of pharmaceutical compositions, which include the protease inhibitors described herein as active ingredients. Also included are the pharmaceutical compositions themselves. These compositions can be administered using routes of administration and dosages similar to those used for known HIV protease inhibitors.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Plzannaceutical Sciences 1977, 66: 1-19, incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fuinarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, taztrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
Additionally, as used herein, the term "pharmaceutically acceptable ester"
refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl nioiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug"
refers to compounds that are rapidly transfomied in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

Methods of forniulating pharmaceutical compositions are known in the art; see, e.g., Remington: The Science and Practice of Pharmacy, 20th Ed. (Baltimore, MD:
Lippincott Williams & Wilkins, 2000). Pharmaceutical coinpositions typically include a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions.

Pharmaceutical compositions are typically formulated to be compatible with their intended route(s) of administration. Examples of routes of administration include parenteral, e.g., by intravenous, intradermal, or subcutaneous injection; or mucosal (e.g., by oral ingestion, inhalation, or rectal or vaginal administration) administration. Compositions intended for parenteral administration 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. pH can be adjusted with acids or bases, such as hydrochloric acid or sodiuni hydroxide, as appropriate. A parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where the active ingredient is water soluble) or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent necessary to allow administration via syringe. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, and/or sodium chloride in the composition.
Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an edible carrier. 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, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.
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.

For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in U.S. Patent No. 6,468,798; hereby incorporated by reference.

Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. The pharmaceutical compositions can also be prepared in the form of suppositories (e.g., with conventional suppository bases, such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers.
These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811; hereby incorporated by reference.

The pharmaceutical compositions can be included in a container, kit, pack, or dispenser, optionally with instructions for administration. A kit may comprise one or more compounds described herein and/or one or more other therapeutic compounds and/or a device for their administration, e.g., a syringe.

Biological Evaluation of Selected Cornpounds of the Invention. HIV protease inhibitor activities were determined by fluorescence resonance energy transfer (FRET) method. (Matayoshi, E. D. et al. Science 1990, 247, 954-958.) Protease substrate (Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys(DABCYL)-Arg) was labeled with the energy transfer donor (EDANS) and acceptor (DABCYL) dyes at its two ends to perform FRET. Inhibitor binding dissociation constant (Ki value) was obtained by nonlinear regression fitting to the plot of initial velocity as a function of inhibitor concentration based on Morrison equation. (Greco, W. R. et al. J. Biol. Chenz. 1979, 254, 12104-12109.) The activities of all the synthesized inhibitors against wild type HIV-1 protease (Q7K) were determined in triplicate. Chemical structures of inhibitors and their inhibitory activities (Ki values) are presented in the Figures.

Methods of Ti=eatnaent. The methods described herein include methods for the treatment or prevention of a viral infection, e.g., an HIV, infection and Acquired Immunodeficiency Syndrome (AIDS) or AIDS Related Complex (ARC). Generally, the methods include administering a therapeutically effective amount of a protease inhibitor described herein, to a subject (e.g., a human or other primate) in need thereof, or who has been determined to be in need of, such treatment, e.g., a subject who is (or is determined to be) infected with HIV. A subject who is likely to be infected with HIV, e.g., a person in a high risk group, may also be treated as indicated herein. Subjects also include women who are expecting a child (pregnant women) and in wliom a treatment reduces the liklihood of transmission of HIV to the child.

In addition to HIV-1 infections, the methods described herein are also expected to be beneficial for treating or preventing HIV-2 infections. Among HIV 1 viruses, it is expected that the methods will be effective against any HIV 1 strain, such as those of group M, 0 and N, and subtypes A, B, C, D, E, F, G, H, I, J and K and "circulating recombinant forms" or CRFs thereof. The compounds described herein may also be used for treating any other viral infections in which the viral agent has a protease inhibitor that can be inhibited by the compounds described herein.

As used in this context, to "treat" means to ameliorate at least one clinical symptom or parameter of HIV infection or preventing it from worsening or preventing the transmission of HIV, e.g., from mother to child. For example, a treatment can result in a reduction in viral load, and/or an increase in number of CD4+ T cells ("CD4 count").
When a subject has achieved a reduction in viral load, and/or an increase in CD4 count, then treatment may also include maintaining the reduction in viral load, and/or the increased CD4 count, e.g., preventing a resurgence of viral load and/or a decrease in CD4 count. These, and other clinically relevant parameters, can be measured using methods known in the art. For example, viral load can be measured, e.g., using PCR or branched DNA (bDNA) assays known in the art. CD4 counts can be measured, e.g., using hematology, DYNAbeadsTM (Dynal Biotech/Invitrogen Corp., Brown Deer, WI), flow cytometry (e.g., FACSCountTM, BD Biosciences, Franklin Lakes, NJ) or enzyme-linked immunosorbent assay (ELISA) methods (see, e.g., Lyamuya et al., J. Immunol.
Methods 195(1-2):103-12 (1996); Paxton et al., Clin. Diagn. Lab. Immunol. 2(1):104-114 (1995);
Saah et al. Arch. Pathol. Lab. Med. 121(9):960-2 (1997); Mwaba et al., Lancet (2003)). Healthy adults and teenagers generally have a CD4 count of at least 800 cells per cubic millimeter of blood; a CD4 count below 200 is associated with severe risk of illness (e.g., AIDS-related diseases, such as Kaposi's sarcoma or pneumocystic pneumonia).
Current guidelines suggest treatment for HIV should be started when the CD4 count is less than about 350 and/or the viral load is greater than about 50,000.

A "therapeutically effective amount" is an amount sufficient to effect a desired therapeutic effect, e.g., a reduction in viral load, and/or an increase in number of CD4+ T
cells. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition may depend on the composition selected. The compositions can be administered once, one or more times per day, and/or one or more times per week; including once every other day. In certain embodiments, the compositions will be administered two or three times per day.
The skilled artisan will appreciate that certain factors may influence the dosage and timing required to treat effectively a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and any other indications present. Treatment of a subject with a therapeutically effective amount of a protease inhibitor described herein can include a single treatment or a series of treatments.

Dosage, toxicity and therapeutic efficacy of the compounds can be determined, e.g., by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
Compounds that exhibit high therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to select a dose and administration schedule that minimizes severe side effects while maximizing therapeutic efficacy.

The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in a method described herein, a therapeutically effective dosage range can be estimated initially from cell culture assays. A dose can be further formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to determine more accurately useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. In some embodiments, a therapeutically effective amount of a new protease inhibitor described herein ranges from about 0.1 to 10 mg per day, or about 0.3 to mg/day.

In some embodiments, one or more of the protease inhibitors described herein will be administered in combination with one or more other therapeutic agents, e.g., as part of a 5 highly active antiretroviral therapy (HAART) regimen that includes one or more other anti-retroviral agents. For example, the methods may include administration of one or more of a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz (SustivaTM), nevirapine (ViramuneTM) and delavirdine (RescriptorTM), 8 and 9-Cl TIBO
(tivirapine), loviride, TMC-125, dapivirine, MKC-442, UC 781, UC 782, Capravirine, DPC 961, DPC963, DPCO82, DPCO83, calanolide A, SJ-1366, TSAO, 4"-deaminated TSAO, MV150 and MV026048; a nucleoside reverse transcriptase inhibitor (NRTI), such as AZT
(zidovudine, RetrovirTM)/3TC (lamivudine, EpivirTM), emtricitabine (EmtrivaTM) and d4T
(stavudine, ZeritTM)/3TC, and d-drugs (ddl [didanosine, VidexTM/VidexECTM], ddC
[zalcitabine, HividTM], d4T), Abacavir, FTC, DAPD, dOTC, and DPC 817; a nucleotide reverse transcriptase inhibitor, such as tenofovir (VireadTM) and PMEA; a fusion inhibitor, such as enfuvirtide (FuzeonTM), T20, T1249, 5-helix and D-peptide ADS-Jl; an entry inhibitor; a co-receptor binding inhibitor, such as AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams), TAK 779; SHC-C (SCH351125), SHC-D, PRO-14ORT inhibitors, such as foscamet and prodrugs; an RNAse H inhibitor, such as SP1093V and PD126338; a TAT inhibitor, such as RO-5-3335, K12 and K37; an integrase inhibitor, such as L 708906, L 731988 and S-1360; another protease inhibitor, such as amprenavir and prodrug GW908, nelfinavir, saquinavir, indinavir, lopinavir, palinavir, BMS 186316, atazanavir, DPC 681, DPC 684, tipranavir, AG1776, mozenavir, GS3333, KNI-413, KNI-272, L754394, L756425, LG-71350, PD161374, PD173606, PD177298, PD178390, PD178392, PNU
140135, TMC114 maslinic acid and U-140690; a glycosylation inhibitor, such as castanospermine, deoxynojirimycine; or a binding inhibitor, such as dextran sulfate, suramine, polyanions, soluble CD4, PRO-542 and BMS-806. Other drugs include those set forth at http://aidsinfo.nih.gov/, hereby incorporated by reference.

Other therapeutic agenets that may be coadministered with with one or more agents described herein are agents that inhibit metabolic enzymes, e.g., inhibitors of cytochrome P450 (CYP450) enzymes. For example, a compound described herein may be administered, simultaneously or not, with an inhibitor of CYP3A4, e.g., Ritonavir, or an inhibitor of CYP2C 19, CYP 1A2, CYP2D6, or CYP2C9. Exemplary inhibitors of 2C9 are described, e.g., in U.S. publication No. 2006.0069042, hereby incorporated by reference.

The compounds of the present invention may also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, methionine enlcephalin, interferon alpha, HE-2000 and naltrexone), antibiotics (e.g., pentamidine isothiorate), cytokines (e.g. Th2), modulators of cytokines, chemokines or the receptors thereof (e.g. CCR5) or hormones (e.g. growth hormone), to ameliorate, combat, or eliminate HIV infection and its symptoms.

In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of amprenavir (Agenerase ; APV), tipranavir (Aptivus ; TPV), indinavir (Crixivan ; IDV), saquinavir (Invirase ; SQV), lopinavir and ritonavir (Kaletra ; LPV), fosamprenavir (Lexiva ; FPV), ritonavir (Norvir ; RTV), atazanavir (Reyataz ;
ATZ), nelfinavir (Viracept ; NFV), brecanavir, and darunavir.

In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is ritonavir (Kaletra ; LPV).
In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of zidovudine (AZT; Azidothymidine; Retrovir ), didanosine (Dideoxyinosine;
ddI; Videx ), zalcitabine (Dideoxycytidine; ddC; Hivid ), lamivudine (3TC;
Epivir ), stavudine (2',3'-didehydro-3'-deoxythymidine; D4T; Zerit ), abacavir succinate (1592U89 succinate; Ziagen ABC), Combivir (lamivudine & zidovudine; (-)-3TC & AZT), and Trizivir (abacavir & lamivudine & zidovudine; ABC & (-)-3TC & AZT).

In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of nevirapine (BI-RG-587; Viramune ), delavirdine (BHAP; U-90152;
Rescriptor ), and (efavirenz; DMP-266; SustivaOO ).

In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic, agent is T-20 (Fuzeon ;
Enfuvirtide; DP-178; Pentafuside; GP41 127-162 AA).

In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is TMCC114, or TMCC114 in combination with a reverse transcriptase inhibitor. In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is Lipinavir, or Lupanivir in combination with a reverse transcriptase inhibitor.
Combination therapy in different formulations may be administered simultaneously, separately or sequentially. Alternatively, such combination may be administered as a single formulation, whereby the active ingredients are released from the formulation simultaneously or separately. Compositions comprising at least two inhibitors described herein and/or one or more other protease inhibitors and/or other therapeutic agents are also provided herein. In certain embodiments the compounds of the invention can be combined with one or more of any anti-HIV compounds (e.g. those listed in Figures 6a-k). Additional compounds which may be combined with one or more of the inventive compounds, and further discussion of combination therapy can be found in Yeni, P. G. et al.
JAMA 2004, 292(2), 251-265; Pozniak, A. et al. Business Briefing: Clinical Virology &
Infectious Disease 2004, 1-7; and Chittick, G. E. et al. Antimicrobial Agents and Chenzotherapy 2006, 1304-1310; all of which are hereby incorporated by reference.

Definitions. All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.

The indefinite articles "a" and "an," as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean "at least one."

The term "HIV" is known to one skilled in the art to refer to Human Immunodeficiency Virus. There are two types of HIV: HIV-1 and HIV-2. There are many different strains of HIV-1. The strains of HIV-1 can be classified into three groups: the "major" group M, the "outlier" group 0 and the "new" group N. These three groups may represent three separate introductions of simian immunodeficiency virus into humans.
Within the M-group there are at least ten subtypes or clades: e.g., clade A, B, C, D, E, F, G, H, I, J, and K. A"clade" is a group of organisms, such as a species, whose members share homologous features derived from a conunon ancestor. Any reference to HIV in this application includes all of these tupes and strains.

As known to one skilled in the art, "retroviruses" are diploid positive-strand RNA
viruses that replicate through an integrated DNA intermediate (proviral DNA).
In particular, upon infection by the RNA virus, the lentiviral genome is reverse-transcribed into DNA by a virally encoded reverse transcriptase that is carried as a protein in each retrovirus. The viral DNA is then integrated pseudo-randomly into the host cell genome of the infecting cell, forming a "provirus" which is inherited by daughter cells.
The retrovirus genome contains at least three genes: gag codes for core and structural proteins of the virus;
pol codes for reverse transcriptase, protease and integrase; and env codes for the virus surface proteins. Within the retrovirus family, HIV is classified as a lentivirus, having genetic and morphologic similarities to animal lentiviruses such as those infecting cats (feline immunodeficiency virus), sheep (visna virus), goats (caprine arthritis-encephalitis virus), and non-human primates (simian immunodef ciency virus).

The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., Ci-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.

Unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl"
and "lower alkynyl" have similar chain lengths.

The term "aralkyl" is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term "aryl" is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aiyl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions with such substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms "heterocyclyl", "heteroaryl", or "heterocyclic group" are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroa toms. Heterocycles may also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like.
The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

The terms "polycyclyl" or "polycyclic group" are art-recognized and refer to two or more rings (e.g., cycloallcyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged"
rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

The term "carbocycle" is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

The term "nitro" is art-recognized and refers to -NO2; the term "halogen" is art-recognized and refers to -F, -Cl, -Br or -I; the term "sulfhydryl" is art-recognized and refers to -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is art-recognized and refers to -S02 ."Halide" designates the corresponding anion of the halogens, and "pseudohalide" has the definition set forth on page 560 of "Advanced Inorganic Chemistry"
by Cotton and Wilkinson.

The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:
-N(R51)(R50) or [-N(R50)(R52)(R53)]+, wherein R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, or R50 and R51 or R52, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2),,; R61. Thus, the term "alkylamine"
includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.

The term "acylamino" is art-recognized and refers to a moiety that may be represented by the general formula: -N(R50)-C(=O)R54, wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m R61, where m and R61 are as defined above.

The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula: -C(=O)N(R50)(R5 1), wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.

The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2),t,-R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.

The term "carboxyl" is art recognized and includes such moieties as may be represented by the general formulas: -C(=O)-X50-R55 or -X50-C(=O)-R56, wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CHa)m R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are defined above.
Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an "ester". Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula represents a"formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thiolester." Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiolcarboxylic acid." Where X50 is a sulfur and R56 is hydrogen, the formula represents a"thiolformate." On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a "ketone" group.
Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde"
group.

The term "carbamoyl" refers to -O(C=O)NRR', where R and R' are independently H, aliphatic groups, aryl groups or heteroaryl groups.

The term "oxo" refers to a carbonyl oxygen (=O).

The terms "oxime" and "oxime ether" are art-recognized and refer to moieties that may be represented by the general formula: -C(R75)(=NOR), wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2)n,-R61. The moiety is an "oxime"
when R is H; and it is an "oxime ether" when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2)n,-R61.

The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -0-alkyl, -0-alkenyl, -0-alkynyl, -O-(CH2)n; R61, where m and R61 are described above.
The term "sulfonate" is art recognized and refers to a moiety that may be represented by the general formula: -S(=O)20R57, in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term "sulfate" is art recognized and includes a moiety that may be represented by the general formula: -OS(=O)20R57, in which R57 is as defined above.

The term "sulfonamido" is art recognized and includes a moiety that may be represented by the general formula: -N(R50)-S(=O)20R56, in which R50 and R56 are as defined above.

The term "sulfamoyl" is art-recognized and refers to a moiety that may be represented by the general formula: -S(=O)2N(R50)(R51), in which R50 and R51 are as defined above.

The term "sulfonyl" is art-recognized and refers to a moiety that may be represented by the general formula: -S(=O)2R58, in which R58 is one of the following:
hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term "sulfoxido" is art-recognized and refers to a moiety that may be represented by the general formula: -S(=O)R58, in which R58 is defined above.

Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

The definition of each expression, e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.

It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, "Handbook of Chemistry and Physics", 67th Ed., 1986-87, inside cover.

EXEMPLIFICATION
The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Example 1 -- Synthesis of protease inhibitors containing a hydrox e~thylamine (HEA core The designed inhibitors with a hydroxyethylamine (HEA) core isostere can be synthesized in four steps starting with commercially available chiral epoxide (1S,2S
enantiomer) 12. Ring opening of epoxide 12 with various primary and secondary amines provided compounds 13. Reaction of 13 with various sulfonyl chlorides gave compounds 14. After deprotecting the Boc group, the resulting amines 15 were coupled with either (R) or (S) isomer of activated carboxylic acids to provide the designed inhibitors 16 (Figure 7A).
Example 2 -- Synthesis of protease inhibitors containing cyclic carbamates: HE
Series The synthesis of protease inhibitors containing hydroxyethylene (HE) isostere starts with the synthesis of the core 17, which was obtained from L-phenylalanine in 5 steps.
After coupling of R4X2CO2H to 17, the dibenzyl protection was removed and the free aniine 19 was coupled to the an activated acid to provide inhibitors 20 (Figure 7B).
Example 3 -- Synthesis of protease inhibitors containing cyclic carbamates:
Aza-HEA
Series The synthesis of protease inhibitors containing aza-hydroxyethylamine (Aza-HEA) isostere is outlined in Figure 8. The ring opening of chiral epoxide (1S,2R
enantiomer) 21 with CBz protected hydrazine derivative 22 provided compound 23. Deprotection of CBz followed by the coupling with R4X2CO2H gave compounds 24. Removal of the Boc protection and coupling with R3X1CO2H provided the desired inhibitors 27.
Example 4 -- Synthesis of designed HIV- 1 protease inhibitor libraries The syntheses of designed protease inhibitor libraries can be carried out using the general reaction scheme described herein.

Example 5 -- Inhibition of HIV- 1 Protease HIV 1 protease inhibitor activities were determined using a standard fluorescence resonance energy transfer (FRET) method, using a protease substrate that becomes fluorescent upon cleavage of a specific peptide sequence separating a fluorescent donor and a nonfluorescent acceptor. Protease substrate 1 was labeled with energy transfer donor (EDANS) and acceptor (DABCYL) at its two ends, respectively (see, e.g., Maggiora et al., J. Med. Chem. 35:3727-3730 (1992); Shakhsher and Seitz, Anal. Chem.
62(17):1758-1762 (1990); Wang et al., Tetrahedron Lett. 31(45):6493-6496 (1990); the labeled substrates are available from Molecular Probes/Invitrogen (cat. No H2930)). The general methodology is described in Science 247:954 (1990).

Measurements were performed on a PTI fluorescence spectrophotometer.
Excitation and emission wavelengths were set at 340 and 490 nm, respectively.
All incubations were carried on at room temperature for 10-20 min. Protease concentration was around 50 nM and substrate concentration was fixed at 1mM. Ki was obtained by fitting the plot of initial velocity as a function of inhibitor concentrations based on Morrison equation. The results are shown in the Figures.

INCORPORATION BY REFERENCE

The contents of all cited references (including literature references, issued patents, published patent applications and GenBank Accession numbers as cited throughout this application) are hereby expressly incorporated by reference. When definitions of tenns in documents that are incorporated by reference herein conflict with those used herein, the definitions used herein govern.

EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (123)

We claim:
1. A compound, or a pharmaceutically acceptable salt thereof, of formula I:

wherein, independently for each occurrence, X1 is absent, -O-, -S- or -NR-;
X2 is absent, -O-, -S- or -NR-;
R1 is -OH, -SH or -NHR;

R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R5 is hydrogen, alkyl, (cycloalkyl)alkyl; (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
provided that when X1 is absent; R3 is not wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
2. The compound of claim 1, wherein X1 is absent.
3. The compound of claim 1, wherein X2 is absent.
4. The compound of claim 1, wherein X1 is absent; and X2 is absent.
5. The compound of claim 1, wherein R1 is -OH.
6. The compound of claim 1, wherein R2 is aralkyl or heteroaralkyl.
7. The compound of claim 1, wherein R2 is aralkyl.
8. The compound of claim 1, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
9. The compound of claim 1, wherein R3 is aryl or heteroaryl.
10. The compound of claim 1, wherein R4 is alkyl, aryl or heteroaryl.
11. The compound of claim 1, wherein R5 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
12. The compound of claim 1, wherein R5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
13. The compound of claim 1, wherein X1 is absent; X2 is absent; R1 is -OH; R2 is aralkyl; R3 is aryl or heteroaryl; R4 is alkyl, aryl or heteroaryl; and R5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
14. A compound, or a pharmaceutically acceptable salt thereof, of formula II:

wherein, independently for each occurrence, X1 is absent or -O-;

R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;

provided that when X1 is absent; R3 is not wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
15. The compound of claim 14, wherein X1 is absent.
16. The compound of claim 14, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
17. The compound of claim 14, wherein R3 is aryl or heteroaryl.
18. The compound of claim 14, wherein R4 is alkyl, aryl or heteroaryl.
19. The compound of claim 14, wherein R6 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
20. The compound of claim 14, wherein R6 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
21. The compound of claim 14, wherein R3 is
22. The compound of claim 14, wherein R4 is
23. The compound of claim 14, wherein R6 is
24. The compound of claim 14, wherein X1 is absent; and R3 is
25. The compound of claim 14, wherein X1 is absent; R3 is and R4 is
26. The compound of claim 14, wherein X1 is absent; R3 is and R6 is
27. The compound of claim 14, wherein R4 is
28. The compound of claim 14, wherein X1 is absent; R3 is
29. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
30. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
31. A compound, or a pharmaceutically acceptable salt thereof, of formula III:

wherein, independently for each occurrence, X1 is absent, -O-, -S- or -NR-;
X2 is absent, -O-, -S- or -NR-;
R1 is -OH, -SH or -NHR;

R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R7 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;

provided that when X1 is absent; R3 is not wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

and provided that when X2 is absent; R4 is not wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
32. The compound of claim 31, wherein X1 is absent.
33. The compound of claim 31, wherein X2 is absent.
34. The compound of claim 31, wherein X1 is absent; and X2 is absent.
35. The compound of claim 31, wherein R1 is -OH.
36. The compound of claim 31, wherein R2 is aralkyl or heteroaralkyl.
37. The compound of claim 31, wherein R2 is aralkyl.
38. The compound of claim 31, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
39. The compound of claim 31, wherein R3 is aryl or heteroaryl.
40. The compound of claim 31, wherein R4 is alkyl, aryl or heteroaryl.
41. The compound of claim 31, wherein R5 is hydrogen.
42. The compound of claim 31, wherein R7 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
43. The compound of claim 31, wherein R7 is alkyl, (cycloalkyl)alkyl or aralkyl.
44. The compound of claim 31, wherein X1 is absent; X2 is absent; R1 is -OH;
R2 is aralkyl;
R3 is aryl or heteroaryl; R4 is alkyl, aryl or heteroaryl; R5 is hydrogen; and R7 is alkyl, (cycloalkyl)alkyl or aralkyl.
45. A compound, or a pharmaceutically acceptable salt thereof, of formula IV:
wherein, independently for each occurrence, X1 is absent or -O-;

R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and R7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl;

provided that when X1 is absent; R3 is not or ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

and provided that when X2 is absent; R4 is not or ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
The compound of claim 45, wherein X1 is absent.
The compound of claim 45, wherein R3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
The compound of claim 45, wherein R4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl.
The compound of claim 45, wherein R7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.
The compound of claim 45, wherein X1 is absent; and R3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
The compound of claim 45, wherein X1 is absent; R3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl; and R7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.
52. The compound of claim 45, wherein R3 is
53. The compound of claim 45, wherein R4 is
54. The compound of claim 45, wherein R7 is
55. The compound of claim 45, wherein X1 is absent; and R3 is
56. The compound of claim 45, wherein X1 is absent; R3 is
57. The compound of claim 45, wherein X1 is absent; R3 is
58. The compound of claim 45, wherein R4 is ; and R7 is
59. The compound of claim 45, wherein X1 is absent; R3 is ; and R7 is
60. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of , and
61. A compound, or a pharmaceutically acceptable salt thereof, of formula V:
wherein, independently for each occurrence, X1 is absent, -O-, -S- or -NR-;
X2 is absent, -O-, -S- or -NR-;
R1 is -OH, -SH or -NHR;

R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;

provided that when X1 is absent; R3 is not or ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

and provided that when X2 is absent; R4 is not or ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
The compound of claim 61, wherein X1 is absent.
The compound of claim 61, wherein X1 is -O-.
The compound of claim 61, wherein X2 is absent.
The compound of claim 61, wherein X1 is absent or -0-; and X2 is absent.
The compound of claim 61, wherein R1 is -OH.
The compound of claim 61, wherein R2 is aralkyl or heteroaralkyl.
The compound of claim 61, wherein R2 is aralkyl.
The compound of claim 61, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
The compound of claim 61, wherein R3 is heterocyclyl.
71. The compound of claim 61, wherein R4 is (heterocyclyl)alkyl.
72. The compound of claim 61, wherein R5 is alkyl.
73. The compound of claim 61, wherein X1 is absent or -O-; X2 is absent; R1 is OH; R2 is aralkyl; R3 is heterocyclyl; R4 is alkyl, aryl or heteroaryl; and R5 is alkyl.
74. A compound, or a pharmaceutically acceptable salt thereof, of formula VI:

wherein, independently for each occurrence, X1 is absent or -O-;
R1 is -OH or -NH2;

R3 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and R6 is alkyl, cycloalkyl, or aryl;

provided that when X1 is absent; R3 is not ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

and provided that when X2 is absent; R4 is not ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
75. The compound of claim 74, wherein R1 is -OH.
76. The compound of claim 74, wherein R1 is -NH2.
77. The compound of claim 74, wherein X1 is -O-.
78. The compound of claim 74, wherein R3 is heterocyclyl.
79. The compound of claim 74, wherein R3 is .
80. The compound of claim 74, wherein X1 is -O-; and R3 is heterocyclyl.
81. The compound of claim 74, wherein X1 is -O-; and R3 is .
82. The compound of claim 74, wherein R4 is heterocyclyl.
83. The compound of claim 74, wherein R6 is alkyl.
84. The compound of claim 74, wherein R6 is -CH(CH3)2.
85. A compound, or a pharmaceutically acceptable salt thereof, of formula VII:

wherein, independently for each occurrence, X1 is absent, -O-, -S- or -NR-;
X2 is absent, -O-, -S- or -NR-;
R1 is -OH, -SH or -NHR;

R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;

R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;

provided that when X1 is absent; R3 is not ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

and provided that when X2 is absent; R4 is not ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
86. The compound of claim 85, wherein X1 is absent.
87. The compound of claim 85, wherein X2 is absent.
88. The compound of claim 85, wherein X1 is absent; and X2 is absent.
89. The compound of claim 85, wherein R1 is -OH or -NH2.
90. The compound of claim 85, wherein R2 is aralkyl or heteroaralkyl.
91. The compound of claim 85, wherein R2 is aralkyl.
92. The compound of claim 85, wherein R3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
93. The compound of claim 85, wherein R3 is (amido)alkyl or heterocyclyl.
94. The compound of claim 85, wherein R4 is (amido)alkyl or heterocyclyl.
95. The compound of claim 85, wherein R5 is alkyl or aryl.
96. The compound of claim 85, wherein X1 is absent; X2 is absent; R1 is -OH;
R2 is aralkyl;
R3 is (amido)alkyl or heterocyclyl; R4 is (amido)alkyl or heterocyclyl; and R5 is alkyl or aryl.
97. A compound, or a pharmaceutically acceptable salt thereof, of formula VIII:

wherein, independently for each occurrence, X1 is absent or -O-;

R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
provided that when X1 is absent; R3 is not ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;

and provided that when X2 is absent; R4 is not ; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
98. The compound of claim 97, wherein X1 is absent.
99. The compound of claim 97, wherein R3 is (amino)alkyl, (amido)alkyl or heterocyclyl.
100. The compound of claim 97, wherein R3 is .
101. The compound of claim 97, wherein R4 is (amino)alkyl, (amido)alkyl or heterocyclyl.
102. The compound of claim 97, wherein R4 is .
103. The compound of claim 97, wherein R6 is alkyl or aryl.
104. The compound of claim 97, wherein R6 is .
105. The compound of claim 102, wherein R3 is is and R6 is .
106. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of .
107. A pharmaceutical composition, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of any one of claims 1-106.
108. A method for treating an HIV infection, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-106.
109. A method for treating an HIV infection, comprising administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 107.
110. The method of claim 108, wherein the compound is administered as part of a highly active antiretroviral therapy (HAART) regimen.
111. The method of claim 109, wherein the pharmaceutical composition is administered as part of a highly active antiretroviral therapy (HAART) regimen.
112. The method of any one of claims 108-111, further comprising administering a second therapeutic agent.
113. The method of claim 112, wherein the second therapeutic agent is a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a nucleotide reverse transcriptase inhibitor, an entry inhibitor, an integrase inhibitor, a fusion inhibitor, a protease inhibitor, or an inhibitor of a metabolic enzyme.
114. The method of claim 112, wherein the second therapeutic agent is selected from the group consisting of efavirenz (Sustiva.TM.), nevirapine (Viramune.TM.), delavirdine (Rescriptor.TM.), AZT (zidovudine, Retrovir.TM.)/3TC (lamivudine, Epivir.TM.), d4T

(stavudine, Zerit.TM.)/3TC, ddI (didanosine, Videx.TM./VidexEC.TM.), ddC
(zalcitabine, Hivid.TM.), d4T, tenofovir (Viread.TM.), and enfuvirtide (Fuzeon.TM.).
115. The method of claim 112, wherein the second therapeutic agent is selected from the group consisting of amprenavir (Agenerase®; APV), tipranavir (Aptivus®; TPV), indinavir (Crixivan®; IDV), saquinavir (Invirase®; SQV), lopinavir and ritonavir (Kaletra®; LPV), fosamprenavir (Lexiva®; FPV), ritonavir (Norvir®;
RTV), atazanavir (Reyataz®; ATZ), nelfinavir (Viracept®; NFV), brecanavir, and darunavir.
116. The method of claim 112, wherein the second therapeutic agent is ritonavir (Kaletra®;
LPV).
117. The method of claim 112, wherein the second therapeutic agent is selected from the group consisting of zidovudine (AZT; Azidothymidine; Retrovir®), didanosine (Dideoxyinosine; ddI; Videx®), zalcitabine (Dideoxycytidine; ddC;
Hivid®), lamivudine (3TC; Epivir®), stavudine (2',3'-didehydro-3'-deoxythymidine; D4T;
Zerit®), abacavir succinate (1592U89 succinate; Ziagen® ABC), Combivir® (lamivudine &
zidovudine;
(-)-3TC & AZT), and Trizivir® (abacavir & lamivudine & zidovudine; ABC & (-)-3TC
& AZT).
118. The method of claim 112, wherein the second therapeutic agent is selected from the group consisting of nevirapine (BI-RG-587; Viramune®), delavirdine (BHAP;
U-90152;
Rescriptor®), and (efavirenz; DMP-266; Sustiva®).
119. The method of claim 112, wherein the second therapeutic agent is T-20 (Fuzeon®;
Enfuvirtide; DP-178; Pentafuside; GP41 127-162 AA).
120. The method of claim 112, wherein the second therapeutic agent is TMCC114.
121. The method of claim 120, further comprising administering a reverse transcriptase inhibitor.
122. The method of claim 112, wherein the second therapeutic agent is lupinavir.
123. The method of claim 122, further comprising administering a reverse transcriptase inhibitor.
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