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AU2006262274A1 - HIV-1 protease inhibitors - Google Patents

HIV-1 protease inhibitors Download PDF

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Publication number
AU2006262274A1
AU2006262274A1 AU2006262274A AU2006262274A AU2006262274A1 AU 2006262274 A1 AU2006262274 A1 AU 2006262274A1 AU 2006262274 A AU2006262274 A AU 2006262274A AU 2006262274 A AU2006262274 A AU 2006262274A AU 2006262274 A1 AU2006262274 A1 AU 2006262274A1
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AU
Australia
Prior art keywords
alkyl
heterocyclyl
compound
aralkyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU2006262274A
Inventor
Akbar Ali
Michael D. Altman
Saima Ghafoor Anjum
Hong Cao
Sripriya Chellappan
Miguel X. Fernandes
Kiran Kumar Reddy Garudammagari Sai
Michael Gilson
Visvaldas Kairys
Nancy King
Madhavi Nagga Laxmi Nalam
Ellen Nalivaika
Moses Prabu
Tariq M. Rana
Celia Schiffer
Bruce Tidor
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Massachusetts Institute of Technology
University of Massachusetts Amherst
The University of Maryland Biotechnology Institute
Original Assignee
Massachusetts Institute of Technology
University of Massachusetts Amherst
The University of Maryland Biotechnology Institute
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Publication date
Application filed by Massachusetts Institute of Technology, University of Massachusetts Amherst, The University of Maryland Biotechnology Institute filed Critical Massachusetts Institute of Technology
Publication of AU2006262274A1 publication Critical patent/AU2006262274A1/en
Assigned to THE UNIVERSITY OF MARYLAND BIOTECHNOLOGY INSTITUTE, UNIVERSITY OF MASSACHUSETTS, THE MASSACHUSETTS INSTITUTE OF TECHNOLOGY reassignment THE UNIVERSITY OF MARYLAND BIOTECHNOLOGY INSTITUTE Alteration of Name(s) of Applicant(s) under S113 Assignors: UNIVERSITY OF MASSACHUSETTS
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—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
    • 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
    • C07D213/60—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 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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    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D233/54—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
    • 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
    • C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
    • C07D233/82—Halogen atoms
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    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pyrane Compounds (AREA)
  • Furan Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

WO 2007/002172 PCT/US2006/024108 HIV-1 Protease Inhibitors 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 5 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 rights in the invention. BACKGROUND OF THE INVENTION 10 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 15 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), 20 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 25 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 WO 2007/002172 PCT/US2006/024108 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 5 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 ii culture. 10 The challenge for the research community is therefore to develop drugs, e.g., HIV-1 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 15 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 20 The present invention is based, at least in part, on the discovery of new small molecule protease inhibitors (PIs). 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. 25 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 30 administering a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the methods further include - 2- WO 2007/002172 PCT/US2006/024108 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, Epivir
TM
) and d4T (stavudine, Zerit T M )/3TC, and d-drugs (ddl [didanosine, VidexTM/VidexECTM], ddC [zalcitabine, Hivid T M ], d4T); a nucleotide reverse transcriptase inhibitor, such as tenofovir (VireadTM); and a fusion inhibitor, such as enfuvirtide (FuzeonTM). In some embodiments, 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 Ki 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. Na 2
CO
3 ,
CH
2 Cl 2 , r. t; (c) TFA, CH 2 Cl 2 ; (d) Et 3 N, THF; (e) R4X 2
CO
2 H, EDCI, -3- WO 2007/002172 PCT/US2006/024108 HOBt, DIPEA, 0 'C to r. t.; (f) H2, Pd/C, MeOH, r. t; and (g) aq. NaHCO 3 , EtOAc, 0 0 C to r. t.. Figure 8 depicts the synthesis of protease inhibitors containing an aza hydroxyethylamine (Aza-HEA) core. Key: (a) (CH 3
)
2 CHOH, 80 'C (b) H2, Pd/C, MeOH, 5 r. t; (c) R 4
X
2
CO
2 H, EDCI, HOBt, DIPEA, 0 'C to r. t.; (d) TFA, CH 2 Cl 2 ; and (e)
R
3
X
1
CO
2 H, EDCI, HOBt, DIPEA, 0OC to r. t.; aq. NaHCO 3 , 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 10 dimensional structures that the homodimeric HIV protease can tolerate, to maximize the likelihood that these HIV-I 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. Chen. Bio. 2004, 11, 1333-1338; and 15 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 20 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. 25 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 inhibitors are useful in the treatment of HIV in susceptible mammals, e.g., humans and 30 certain other primates, and can be administered as a monotherapy, or in combination with other therapeutic agents, e.g., as part of a highly active antiretroviral therapy (HAART) regimen. - 4- WO 2007/002172 PCT/US2006/024108 Selected Protease Inhibitors of the Invention. One aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula I: 0 R 2 0 0p
R
3 'X XR4
R
1
R
5 I 5 wherein, independently for each occurrence, X1 is absent, -0-, -S- or -NR-;
X
2 is absent, -0-, -S- or -NR-;
R
1 is -OH, -SH or -NHR; R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl; 10 R 2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R
3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R
4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or 15 heteroaralkyl;
R
5 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 o 0 0 20 provided that when X 1 is absent; R3 is not R3A or '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 1 is absent. 25 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent. - 5- WO 2007/002172 PCT/US2006/024108 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; and X 2 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH. 5 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl. In certain embodiments, the present invention relates to the aforementioned
A
1 A 2
A
3 10 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; and A 1 , A 2 ,
A
3 , A 4 and A 5 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, 15 trifluoromethyl and cyano. In certain embodiments, the present invention relates to the aforementioned
A
1 A 2 /
A
3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; A 1 , A 2 , A 4 and A 5 are hydrogen; and A 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, 20 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
A
1 A 2 / A 3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; A 1 , A 2 , A 3 and A 5 are hydrogen; and A 4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, 25 hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, - 6- WO 2007/002172 PCT/US2006/024108 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, 5 (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 10 compound and any of the attendant definitions, wherein R 4 is alkyl, aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned 15 compound 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 X 1 is absent; X 2 is absent; R 1 is OH; R 2 is aralkyl; R3 is aryl or heteroaryl; R 4 is alkyl, aryl or heteroaryl; and R is alkyl, 20 (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 0 0 0 R3'X N N R4 H OH R II 25 wherein, independently for each occurrence, X1 is absent or -0-; R3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; -7- WO 2007/002172 PCT/US2006/024108
R
4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and
R
6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; /0 provided that when X 1 is absent; R3 is not R3A or N'R 3 A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, 5 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 1 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkenyl, (amino)alkyl, 10 (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 R 3 is aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned 15 compound and any of the attendant definitions, wherein R 4 is alkyl, aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned 20 compound and any of the attendant definitions, wherein R 6 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl. In certain embodiments, the present invention relates to the aforementioned
H
3 C N compound and any of the attendant definitions, wherein R3 is CH 3 H H3C
H
3 C
H
3 C 0 , O , , 8 - 8- WO 2007/002172 PCT/US2006/024108 0
,H
3 CO HC HO N-- OH SCH 3
CF
3 F3C H 3 C F B H F H OH
OH
3 HO \HOe OH S HO , HO
H
3 C "" C Br 5OH 3 Cl HO HO H3C H3C H3C N 5 0OC H F H Opun andan o ,t eHtedn eiiins hri 4i C3 H 3 0 N-- H N C H3 N OH , OHH,H 3 , H 3 orCF \O In certain embodiments, the present invention relates to the aforementioned / OCH 3 compound and any of the attendant definitions, wherein R 4 is F
OH
3 N N
H
3 C N > /> \~ I>-CH 3 - \ N 3 OH, OH 3 , \0 3 ,\ 3, F N ~OCH 3 10 F 0 \0 3
SNH
2
H
3 C 3 2 F3
OH
3 in certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is \z:) 0 -9- WO 2007/002172 PCT/US2006/024108
GH
3
H
3 C A HO HO ,CH3 S"CH3, "CH3 \ CH 3 C H 3 C CH 3
H
3 C CH 3 HC H3OH, OH, 0 CHH or OH In certain embodiments, the present invention relates to the aforementioned 5 compound and any of the attendant definitions, wherein X 1 is absent; and R 3 is
H
3 C N
H
3 C'N H 3 C
H
3 C
OH
3 , 0 0 , ( 0 0
H
3 C H 3 CO H 3 C N O N N HO 1 HH 0 Cl C
OH
3
CF
3 ///
F
3 C
H
3 C N BC F HO 'N[[H 3 OH OH3 F H HO HO& 10 F , HO ,:[(: HO OH
SH
3 C O H 3 CI 'N H 3 0 ,Q C 0 CH 3 7N - 10- WO 2007/002172 PCT/US2006/024108 HO HO H 3 C H 3 C H3C - , OH, OH 3 = OH 3 , 0 CH 3 Or F H In certain embodiments, the present invention relates to the aforementioned
H
3 C N compound and any of the attendant definitions, wherein Xi is absent; R 3 is CH 3
H
3 C H
H
3 C
H
3 C , \ H 3 C 5 0 , 0 , , 0 0 0
H
3 CO H 3 C N HO N-- OH
SCH
3
CF
3 O ,
F
3 C H 3 C IF OH FFN 11 ,H , ) F__ B F OH
CH
3 HO HO H3C C1 Br
H
3 C C N. HO N. HO 10 0 6H 3 C N
OH
3
H
3 H H F H SN H 3 .- 11 N N
H
3 0 y ,,- 0 OH, OH 3
OH
3 , 0 OH 3 or F( ,and R4is
N-H
3 N H 3 0 N N \110H 3 -" 11- WO 2007/002172 PCT/US2006/024108 F N
OHC
3 ~ -S
OCH
3 , F \ \CH3 OCH3
NH
2
H
3 C F H 3 C For\ H In certain embodiments, the present invention relates to the aforementioned
H
3 C N compound and any of the attendant definitions, wherein X 1 is absent; R 3 is CH 3
H
3 C' N
H
3 C O
H
3 C
H
3 C 5 0 , 0 , 0 0 0 H3CO
H
3 C N HO N , H0F
HH
3
CF
3 H H H3C, 3 0N H 3 N F CI Br OH
HH
3 HO NH .O Li],), HO OH HO HO H3C N H CI B r O3 H 3 N.~e HO N. HO 10 0 C H 3 ,N.
OH
3 H0 H F H H3C N H N
H
3 C o -~-.. H 3 N<.' o OH , OH 3
OH
3 , OH 3 orF ; and R 6 is - 12- WO 2007/002172 PCT/US2006/024108
CH
3
H
3 C C HO HQ1 0 ) O'\ 0H 3 \ S '\I OV H 3 Y CH3,
CH
3 C CH 3
H
3 C HH 3 OH 3 3 , H 3 OH O3H H3 \ , \, , H, H, CH3 I 6 or OH In certain embodiments, the present invention relates to the aforementioned
OCH
3 5 compound and any of the attendant definitions, wherein R 4 is F
CH
3 N N ~ 3 C N 0O /> \> \-CH, N H 3 , OH 3 , H C ,\OCH 3 F F FC OCH 3 CH3/CH S' OH H
N
2
H
3 H H
H
3 o 3
C
H CH3
CH
3 10 H3 Oand R 6 0 CsH r C
OH
3 HO HO H 3 -1 3
H
3
H
3
OH
3 CH3 H 3 03 OH 3 / 0 H H 0~OH 10 , ,O H, H, OHor OH. In certain embodiments, the present invention relates to the aforementioned
H
3 0 N' compound and any of the attendant definitions, wherein X, is absent; R 3 is OH 3
H
3 H3 'N0 , 3 0 Ot !H C0 , 3 0 - 13- WO 2007/002172 PCT/US2006/024108 0
H
3 CO H 3 C N N HO N xN- OH O F 3 C HF 3 OH CH N 0 FC Br 5\H3C CHHO H F
.
H3C H3HH C 3 CH 3 N FF OH
OH
3 HI H:):t XOH S HOO HO N2H 3 C FkJ "\ oa CI Br H.0 HQ CI \, HO,1\: HO -C
H
3 5 0 NH 3 , I,'
OH
3
H
3 H H H HyN HN-1 N4 OH , O 3
O
3 , 0 O 3 or F J 0
OH
3 N OO/ N N H 3 C N NCH /I-.OH 3 N F 0 \ OH 3 , O H 3 ,\S F
OOH
3 , F 0 H OC0H 3
NH
2
H
3 C 3 F or\ O H3;and Ris
OH
3
H
3 0 HO HO 10 0 , \ H 3 , S \ C\H 3
<V-OH
3 , - 14- WO 2007/002172 PCT/US2006/024108
H
3 C H 3 C- CH 3
H
3 C CH 3 CH, ),CH13 OH OH NN N. N. N. , , H, H, 0 0~C " /N' 3 "< -C3 or OH Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of ,CH, PcH, N N S N H 3 C N N- - -So N 3C 0 OH 1 H 1, N /H 3 CHI N N 0 H 0 N H OH I H OH - VCH 3 . a 0 > N1 'sN H 3 CN~ OH - OH - H 0 , 0 0 0 0 H " H3'N S N 0 HOH NO- OH F OCH 3 F I F I F H 0 0 F 0 I 00 H3C N,,l 'S HO _ NNS H1 OF \\ H\ #HO 0 CH 3 OH FHN- OH Y F/ F OH OCH, F OCH 3 I -I - F CHO I 0 0 o o \\ -CPs HO 'S H 0~ H 3 0 N\A F H 0~ OH-b H0 OH )AH OH 10 IS6 s/ ,s - 15- WO 2007/002172 PCT/US2006/024108 F OCH, F CHO N0 F OHO 0 F Is'' HOe IS FaC N N NHN N" N N O F OH HO OH OH
OHH
3 C N C00 OH 00 H 3 00 .j 1 0 5 Cls , HN N HC N N Hy 0 H N CH 3 OH ~CI OH OH OH O Cs a ,CH , N'N N C N NS CH F 0 , Br 0C HC' N N H 3 C 0 N NO N H OH S O H H H H CH 3H
OCH
3 00H 3 N 10 H \ N N 'S N N- H0 0 H OH 0 OH yrOH
OH
3 00H 3 00H 3 HN N3-Y k N'S\ HO N
I
3 NN N'~ 0 OH OHH O 0 5 H 3 I 00H 3 00H, 00H, 0 N 0 o 0 0 H,, NN H NC _)A~ o
H
3 0 N H 3 0 N' N x C 1 kN-YN " N OH HOH L>,IOH H OH
OH
3
OH
3 00H 3 00H 3 I I - - H 3 H 0H 0 H 0 N OH OH OH ,oH 0 OH 3 y0 OH
OH
3
OH
3
OH
3 OH 3 H 00 N 0o. N N Hc N' OH H 3 0 N - \ 3 C' N H N \ o OH "O &J H OH OH 3
OH
3 H CH,6 WO 2007/002172 PCT/US2006/024108 S H 3 CH3 CH, 0,, _ N N4 HaCO ~ H3 O N\HaC CH 0N C N NO C 3 N N N OH 0CH O H O CHH OH CH OH 1 CH , CH 3 HaC N N O Ha N N OC~ H 0 H H O C0a N N
N
3 NS H 3 0 N\ HC( N Ni~c H N~ H 3 NNS\ O ,OHH . OHC H NO N 00
H
3 ~ N N N' \\o~~~ ~ OH N OH -N H OH CH C0 OH OH C
CH
3 CH OH N' 0 .0H 3
O
3
'
0 C N , H- 17 OH OH N N N \ I H OH -Nb HS 0OHY H 3 0 OH H 3 5 OH 3
OH
3 0F 3 0 o I 0 0 Ia HIII fj \' N LIII ' NR\\ N H 0~ H 0 OH y CH3 OH OH 3 H F H 3 0 OH 3 H3C C3 0 - N \# -N OHN NH H,> l O*H 3 0 H CH, 0H s CH, HNx)k Sa H , ~ 0
H
3 N0 H-k.H OH OCH 3 OH OH O H 3
H
3 0' OH 3 N- O. 0H 3 N 0H0 o0Nrk OHO 0 N OHO 0 SS lc H0 Nl-A N N\ OH OH O H 3
CH
3 OH OCH 3
OH
3 H OH O, H 3 OH, OH,
OH
3 - 17- WO 2007/002172 PCT/US2006/024108 I OC CH 3 O N N N N N O O OH CH, 0 OH CH HO ON N SOO O~ HO N sN~ I HCH N~ OH CH 3 H OH CH, HCH N N OCH HOCH N CI O~ CN1a O N N O N N O OH OH 3 , OH OH OH H0 OH 3 Ha O O H N0 N C N NO O H, N 0 OH OH CH OH OH CH 3 OCH , CN OH IH OH C0 HC CH OH C0HC H O Sc N NO N N H 0 -H 0 OH OH CH 3
OH
3 OH CH HO C OCH , NN 0 OH OCH 3 0OH OCH 3
OH
3 3 OH 0 10 1 00H 0 NI~ HO N HO N H- Nb \\ H OH OCH 3 OH OCH 3
H
3 0C , CHH, 0,~j IC H 3
O
0 10'N ::C S H N \b
H
3 0 OH 3 OH C, , .1;C OH OH
OHOH
3 3
OH
3
OH
3 OH
H
3 0 N H 3 0 YH 0 0 OH OH OH 3 OH H OH OCH 3
OH
3 OH 3 WO 2007/002172 PCT/US2006/024108 OCHa N OHO 0 N OH O -_S N N' N N' H( 0 j ,0 CH, OH CH, CH, OH CH CH, CH3 , H OCHI OCH 0 to0 I
F
3 a O\
H
3 C N N H 3 CI N N H 0H N O OH CH 3 OH CH 3 CH, CH, OCHO OCH 00 'al- OCH, 0 OH Hj0 N 1
OH
3 O O\\N
H
3 N N F N N O 6H 3 OH CH, OH CH 3
CH
3 , and CH 3 Another aspect of the present invention relates to a compound, or a 5 pharmaceutically acceptable salt thereof, selected from the group consisting of F SCH0 CHA N N OH 3 O N N' HHO N N N S CH 3 OH -N OH 0 CH -N H OH O O N HHayH HO 0 HO' NOH ,HO 0 H 3 C'N OH HaC N OH F F O NNN N N CH 3 O HO 0s 0 0KKo,0I HN H H OH N CH3 O - H OH 0 - OH 0 Ca HaCNO HO O CH ,COOH~ N OH NH-1
H
3 C' NOH H 3 0 N OH H 3 0-N OH F 0C,0 1-, 0 CH
H
3 00 N S OH 3
H
3 C00-1." N N N CH 3 N 0 H 0 ~ I H NOH C:NN N" N NH OH N HY H3,O OH ,H 3 0' NOH , CH 3 0' NOH F ,-F 0 001CH, 0 N' N " N'C~"H 3 N N ~OO 'NNb % N, H-N OH YO - N OH YO H OH 3
CH
3
H
3 0" NOH ,HO O H 3 HO 0 OH 3 - 19- WO 2007/002172 PCT/US2006/024108 F N0 CH 3 CH, HO OH CH 3 HO OH O C CH, N H OH 0 H N H OH NO CH N H OH 3
CH
3 , CH 3 CH F -F I. I I IN 0 O N N S H 3 0ON N CH H N' N-k H 0 H 3 I H 0 C H 3 OH O N-" OH aO OH 0 CHCH ,CH Ca , OH H3 O3 H 3
OHON
N NO I 'N \ C~ N H 0H. NOH H NCO ~ OH 3 O N-a N HOH~ Na 5H 0 H ,H H NOH N OH 0 OHr CH 3
OH
3
OH
3
OH
3
OH
3 OH OH 3
H
3 0 N N N C( O- 0
OH
3 OH F NF N \ 0 N--CH HC N NCH H OH OHK 0 O" O N-C,7-Ca HOH NNH 5 CH OH OH 3 0 N\ FN N--\ F HCH3) N-CH NN N N N 20 0F H 0H OH 0 F - OH 0 F H~ ~ H,(-~ 0\\ ,I,,Ni N N N NISN\ H I H 0 OH O O 0 H0 N ,kZ-H _, N N I HCH I, OHKA.. 07 OH OH 3 - 20- WO 2007/002172 PCT/US2006/024108 I N::\ 0 -
H
3 0 _Nz 0 )R jzzN-H 3 HONI NAJ / '. N N N I H OH I, 0 NH N.-N OH 0 S N--\ N~ OLN-H, NH O \ ),N-CH 3 H OHKAC<H, 0 H OH N0 OH OH, H,0 N - \\ -\~N OH0 yJH 3 CO1,( No (
CH
3 OH C H, N H OH 1,,o OH OH, , C I. N-\
N-
H 0. k,:,,N-CH, 0\\ )J,,zN-CH 3 H H 0O OH " NH H OH 0 N~ N~\ N\ HO 'N N N I H rjJ\\ Nr H -N OH 0 F 0 OH N F 0 ~ N\ , F 0 ( R , -H 0 0N' r- N N' 0\ N S 0OH O H 3
OH
3 OH F I . F N N~ 0 H 3 C 0 No b0 b H o\ OyN,,,? i S#, S N N'N F N N' N N H OH FH 0 OHH 3 N0 OH, CH, CH, OH 0 OH S 0N,- OH ,) N 10 N ' N CH 0 O~ 0 H0 00, .b CH, 0 b~
F
3 0 A N' N N' OH 3 N H OH 3 OH 0~ OH 3 H N CH, N 0 CH O S OH L S OH 1s) WO 2007/002172 PCT/US2006/024108 F N N OcHa N N O BI H, ~ H 0H N' H OH SOH s s OH S n o OcI HO SS F-c N NC' O N N H OF u H ,and Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, seletedorom thIII: losing R3 2 1I HI F/HN ' OH 0 5hriineednlyfrec occrrece Xiohe is ec abte sent, -O-,tio -S-estacmpud or -N X2amaeuisal abet bl O-, -S- eof orece -NR-;gopositngo 'N OCH 3 O SiOH NI N4 ' 0 3 -O OH OHO
CH
3 0, phaReuicalyrg accepabl aralky theeooafrua orcyl 0H 0 2 0 XN Nf7 N N X H H 1 OH 10 CH,0 wnhern indpendoftel frsn ieah o ocuree oacmono phamaeuial abset bl 0-, theeof or -NR-;aH
X
2 ~~~ is absnt -0- 4S r N
R
1 ~~ is-1,-HoYNR 15 R~~X is hydroen, al0, a rak, he-rarlylorac
R
2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; - 22- WO 2007/002172 PCT/US2006/024108
R
3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R
4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; 5 R 5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R
7 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 0-o 10 provided that when X 1 is absent; R 3 is not R3A or V R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; /0 and provided that when X 2 is absent; R 4 is not R4A or N R 4 A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, 15 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 1 is absent. In certain embodiments, the present invention relates to the aforementioned 20 compound and any of the attendant definitions, wherein X 2 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; and X 2 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH. 25 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl. -23- WO 2007/002172 PCT/US2006/024108 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl. In certain embodiments, the present invention relates to the aforementioned
A
1 A 2
A
3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; and A 1 , A 2 , 5 A 3 , A 4 and A 5 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. 10 In certain embodiments, the present invention relates to the aforementioned
A
1 A 2
A
3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; A 1 , A 2 , A 4 and A 5 are hydrogen; and A 3 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, 15 heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano. In certain embodiments, the present invention relates to the aforementioned
A
1 A 2
A
3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; A 1 , A 2 , A 3 and A 5 are hydrogen; and A4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, 20 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 R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, 25 (heterocyclyl)alkyl, aralkyl or heteroaralkyl. - 24- WO 2007/002172 PCT/US2006/024108 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 R 4 is alkyl, aryl or heteroaryl. 5 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
B
1 B 2
B
3 compound and any of the attendant definitions, wherein R7 is B 5
B
4 ; and B 1 , B 2 ,
B
3 , B 4 and B 5 are independently selected from the group consisting of hydrogen, halogen, 10 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
B
1 B 2
B
3 15 compound and any of the attendant definitions, wherein R 7 is B 5
B
4 ; B 1 , B 2 , B 4 and B 5 are hydrogen; and B 3 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. 20 In certain embodiments, the present invention relates to the aforementioned
B
1
B
2
B
3 compound and any of the attendant definitions, wherein R7 is B 5
B
4 ; B 1 , B 2 , B 3 and B 5 are hydrogen; and B 4 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, 25 heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano. -25- WO 2007/002172 PCT/US2006/024108 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned 5 compound and any of the attendant definitions, wherein R 7 is alkyl, (cycloalkyl)alkyl or aralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X1 is absent; X 2 is absent; R 1 is OH; R 2 is aralkyl; R 3 is aryl or heteroaryl; R 4 is alkyl, aryl or heteroaryl; R 5 is hydrogen; 10 and R 7 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: 0i H R3 x N N R 4 OH R 7 0 IV 15 wherein, independently for each occurrence, X, is absent or -0-;
R
3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R
4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, 20 aralkyl or heteroaralkyl; and
R
7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl; / O>~ O~ provided that when X 1 is absent; R 3 is not R3 or NN'R3; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; - 26- WO 2007/002172 PCT/US2006/024108 and provided that when X 2 is absent; R 4 is not R4A or N'R 4 A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. 5 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 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 10 heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl. In certain embodiments, the present invention relates to the aforementioned 15 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 X 1 is absent; and R3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, 20 (heterocyclyl)alkyl, aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; R3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl 25 (heterocyclyl)alkyl or heterocyclyl; and R7 is alkyl, cycloalkyl or (cycloalkyl)alkyl. In certain embodiments, the present invention relates to the aforementioned
CH
3 compound and any of the attendant definitions, wherein R3 is - 27- WO 2007/002172 PCT/US2006/024108 F
H
3 C Oy CH 3
OCH
3 ONH 0 1 0
H
3 C HO , 0 ,
H
3 C O CH 3
H
3 C 3C
OCH
3 , ,or ,. In certain embodiments, the present invention relates to the aforementioned
OCH
3 compound and any of the attendant definitions, wherein R 4 is F \ /
H
3 C O yCH 3
H
3 C O yCH 3 5OH NH C NH OCH 3
H
3 9 0 yCH3 H 3 9 OyCH3
H
3 C O yCH 3
OH
3 C ,NH H 3 C NH H3C 0 NH
H
3 CjCH 3
H
3 C CH 3 H3C CH3 H3COCH3
H
3 C NH . O CH3, CH 3 O or In certain embodiments, the present invention relates to the aforementioned
CH
3 compound and any of the attendant definitions, wherein R 7 is CH 3 j 10 or3 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; and R 3 is -28- WO 2007/002172 PCT/US2006/024108 F O CH 3
OCH
3 ,HO 0\ 00 -b
H
3 C OyCH 3
H
3 C O CH 3
H
3 C
H
3 C
H
3 C NH , or H 3 , ~ Oo 0,. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; R3 is F 5 O CH 3
H
3 C O CH 3
H
3 C O CH 3
H
3 C
H
3 C CH
H
3 NH0111<"C H3C NH H3C Nor O ;and R iH 3
CH
3 3 3H3C 0 C3 NH3 H3C NH OC3OH3NN HN 14 0_0 H 3 O
R
4 is - -F 0 ~
H
3 O0 yHH 3
H
3 C yH 3
H
3 H3y CH 3 NH HH 3
H
3 I H 3 O NH O3 H H HO 0 CH3 H 3 O OH 3
H
3 0 yH 3
H
3 O 0yOH 3
H
3 4O 3 3 ~ ~XN
H
3 C NH H 3 C NH 0 OOH 3 , 0 00-OH 3 , H
H
3
COCH
3 '<N O N 10 or H. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; R 3 is F O OH 3 OCH 3 HO 0' Q -29 - 29- WO 2007/002172 PCT/US2006/024108
H
3 C O CH 3
H
3 C 0 CH 3
H
3 C
H
3 C NH H 3 C NH O0CH O\ ~O ,or 0;R 7
CH
3 is CH 3 or. In certain embodiments, the present invention relates to the aforementioned OC H 3 compound and any of the attendant definitions, wherein R 4 is F / \q /H 3 C 0 yCH 3
H
3 C O yCH 3 O> 0
H
3 C ,NH
H
3 C NH
OCH
3
H
3 C Oy CH 3
H
3 Oy CH3 H 3 C Oy CH 3
H
3 C - INH
H
3 C NH
H
3 C ,NH H3CCH3CH3
H
3 C CH 3
H
3 C CH 3
H
3 C CH 3
H
3 C N H N NH O"N H OI 0-1-CH, OH - N 0 N 0~ ,H 3 , 3 , H or H ; and O H 3 R 7 is CH 3 or . In certain embodiments, the present invention relates to the aforementioned 10 compound and any of the attendant definitions, wherein X1 is absent; R3 is F
OH
3 CHF O' CH3 \OH 3 O ~ , HO , 0~
H
3 C 0 yCH 3
H
3 C 0 CH 3
H
3 C 0
H
3 C N H 3 C NH 'N NO>
OH
3 , O, or 0;R 4 OCH
H
3 O 0yCH 3 3 0- 0-NH is F , 0 5 H 3 C " -30- WO 2007/002172 PCT/US2006/024108
H
3 C O yCH 3
H
3 9 O CH 3
H
3 C O yCH 3
H
3 C NH OCH 3
H
3 C NH H 3 C NH HCCH3 HCCH3
H
3 C OCH 3
H
3 C OCH3 CH 3
H
3 C NH H 3 C NH O S0OCH 3 , O OCH 3 ,
H
3 C CH 3
H
3 C CH 3 2tIhI N
CH
3 O!<N) 0 ON or ;and R 7 is H 3 or 5 Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
H
3 C O N
H
3 C O. N~ -N OH 0 1 HUH O Ca
H
3 C CH , H 3 C CH , 0 cH C N H O O H "H OH OH O CH H 3C CH3 H O N 0O CH 3 O H FOH 0 HO C FK OH 0 H OH 0 0 H N H NN, e H ) N - H F OH 0 IIF 2H N OH 0 H 10 ,Hc CH, -31- WO 2007/002172 PCT/US2006/024108 OH 0 H 0 OHO O N N H 3 H I H OH NCOHF H OH 0 F OH O OH H H3C ON 'N ~H CH 3 ~. N F HH3 COH , -~~ OH O HH3C CN 3 O C O H O H3 CH N - N N H H( A : H: NN NH F H OH OO C~ OaN F H OH O H F F O 3OH0 HO0OOHO HHC CH3 H HOO 3 H 'N C NN OC'NH NH 0 O I~~3 CH3 , , H OH H OH3ONO~ H N NO NH F 0 O F OH N O FHN 3 -- 32 H H6H 0F H
H
3 CC NCHN,' HO OH 00 H, H,0 OH5 H 3 C CH, N HH N OH0 H I"N HF 00 N OJ5 H 0 'N N - OCH OH0 N~H 3
OH
3 C 'N 0 H H H 0N N0 H. N, 000H 3 6H 0H H0
H
3 00 N % N 0O 0 OH 0 -C 32- WO 2007/002172 PCT/US2006/024108
H
3 Ca O -H NN 0 O O H H H H 3 CO N OH OH 0
H
3 C CH3, O H OH H 3 COr N N N
H
3 CO N N H OH 0 O OH 0 O .. H3C CH 3
H
3 C CH 3 H 0H
H
3 CO N NH H 3 CO N . N H NH H --- , H 0 H O O CHa 0 H OH 0Q CH,
H
3 C CH 3 O
H
3 C CH, H3CO NH O H CH O H H O C N ,'NH OH 0 OHOH 0 OH 3
H
3 C CH 3 O
H
3 C OH 3 H OH 3 N N ' - 0 O CH 3 "' N H 3
H
3 C H3 H N O C H 3C N H 3 N3 CH3 3 , H- H 3 0H C C H 3 N H "'N DCA~ NOHO OH 0 0C 0 OH
H
3 O OH 3 H HO
H
3 H HH SO H OHH N "'NH 0 OH 3 3
H
3 00 N- 6 H OHH H0 0 OH00 -H HC CH3H3-33- WO 2007/002172 PCT/US2006/024108 O H 3 C CH 3 H 3 N - HC 3 3 5 O ON ~ H OH O H O H OH 0 0NH CCH,
H
3 C OH 3 N N H 3 H3C ON H3C ',,HC O OH C CH N 'NH HNH N
H
3 C OH 3 OH H H 3 C H OH O
OH
3
H
3 O & Ci
H
C CH, , H H H3 0 N OH 3 H O H3C H3 O H 0 H 0H
H
3 OH O HC O N
H
3 O'N :H H:I. HT O~~~ N I NO..k OH 0 H OH 0 O
H
3 O O - - H 3 HC , 0 H OH HC0 N H N. CH H3CN H 0 HN:: H OH 0 5 , and Another aspeCt of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula V: 0 R 2 O H3R R4C N N ~ X N 'I ' N _ N H~~ YOH
R
1
R
5 V 10 wherein, independently for each occurrence, X1 is absent, -0-, -S- or -NR-;
X
2 is absent, -0-, -S- or -NR-; - 34- WO 2007/002172 PCT/US2006/024108
R
1 is -OH, -SH or -NHR; R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R
2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; 5 R 3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R
4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R
5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, 10 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; N N provided that when X 1 is absent; R 3 is not R3A or N'R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, 15 cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and provided that when X 2 is absent; R 4 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. 20 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X1 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is -0-. In certain embodiments, the present invention relates to the aforementioned 25 compound and any of the attendant definitions, wherein X 2 is absent. - 35- WO 2007/002172 PCT/US2006/024108 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent or -0-; and X 2 is absent. In certain embodiments, the present invention relates to the aforementioned 5 compound and any of the attendant definitions, wherein R 1 is OH. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl. 10 In certain embodiments, the present invention relates to the aforementioned
A
1 A 2
A
3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; and A 1 , A 2 ,
A
3 , A 4 and A 5 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, 15 alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano. In certain embodiments, the present invention relates to the aforementioned
A
1 A 2
A
3 compound and any of the attendant definitions, wherein R 2 is A5 A 4 ; A 1 , A 2 , A 4 and A 5 are hydrogen; and A 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, 20 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
A
1 A 2
A
3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; A 1 , A 2 , A 3 25 and A 5 are hydrogen; and A 4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, -36- WO 2007/002172 PCT/US2006/024108 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 5 compound and any of the attendant definitions, wherein R 3 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 R 3 is heterocyclyl. 10 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is (heterocyclyl)alkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl. In certain embodiments, the present invention relates to the aforementioned 15 compound and any of the attendant definitions, wherein X 1 is absent or -0-; X 2 is absent;
R
1 is OH; R 2 is aralkyl; R 3 is heterocyclyl; R 4 is alkyl, aryl or heteroaryl; and R 5 is alkyl. Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VI: O Ph O R3'X 1 N N
R
4 H
R
1 R 20 VI wherein, independently for each occurrence,
X
1 is absent or -0-;
R
1 is -OH or -NH 2 ;
R
3 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or 25 heteroaralkyl;
R
4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and - 37- WO 2007/002172 PCT/US2006/024108 0-0 0 0 provided that when X 1 is absent; R 3 is not R3A or 'R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; 00 --C/ 0 5 and provided that when X2 is absent; R4 is not NR4A 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 10 compound and any of the attendant definitions, wherein R 1 is -OH. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is -NiH 2 . In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is -0-. 15 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is heterocyclyl. In certain embodiments, the present invention relates to the aforementioned 0 0 compound and any of the attendant definitions, wherein R3 is Ii or In certain embodiments, the present invention relates to the aforementioned 20 compound and any of the attendant definitions, wherein X 1 is -0-; and R 3 is heterocyclyl. In certain embodiments, the present invention relates to the aforementioned 0 compound and any of the attendant definitions, wherein X, is -0-; and R3 is . In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is heterocyclyl. - 38- WO 2007/002172 PCT/US2006/024108 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl. n certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is -CH(CH 3
)
2 . 5 Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VII: 0 R 2 H , R3, N X 2
R
1
R
5 0 VII wherein, independently for each occurrence, 10 X 1 is absent, -0-, -S- or -NR-;
X
2 is absent, -0-, -S- or -NR-;
R
1 is -011, -SH or -NHR; R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R
2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, 15 aralkyl or heteroaralkyl;
R
3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R
4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; 20 R 5 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; I O O provided that when X 1 is absent; R 3 is not NR or R 3 A; wherein 25 R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; -39- WO 2007/002172 PCT/US2006/024108 0-, / 0 and provided that when X 2 is absent; R 4 is not R4A or N-R 4 A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. 5 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent. In certain embodiments, the present invention relates to the aforementioned 10 compound and any of the attendant definitions, wherein X 1 is absent; and X 2 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is -OH or -NH 2 . In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl. 15 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl. In certain embodiments, the present invention relates to the aforementioned
A
1 A 2
A
3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; and A 1 , A 2 ,
A
3 , A 4 and A 5 are independently selected from the group consisting of hydrogen, halogen, 20 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
A
1 A 2
A
3 25 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; A 1 , A 2 , A 4 -40- WO 2007/002172 PCT/US2006/024108 and A 5 are hydrogen; and A 3 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. 5 In certain embodiments, the present invention relates to the aforementioned
A
1 A 2
A
3 compound and any of the attendant definitions, wherein R 2 is A 5
A
4 ; A 1 , A 2 , A 3 and A 5 are hydrogen; and A 4 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, 10 heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. 15 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is (amido)alkyl or heterocyclyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is (amido)alkyl or heterocyclyl. In certain embodiments, the present invention relates to the aforementioned 20 compound and any of the attendant definitions, wherein R 5 is alkyl or aryl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; X 2 is absent; R 1 is OH; R 2 is aralkyl; R 3 is (amido)alkyl or heterocyclyl; R 4 is (amido)alkyl or heterocyclyl; and R 5 is alkyl or aryl. 25 Another aspect of the present invention relates to a compound, or a phannaceutically acceptable salt thereof, of formula VIH: -41- WO 2007/002172 PCT/US2006/024108 0 Ph R3 ' NN'N R4 XI N N' H 6 6H R 6 0 VIII wherein, independently for each occurrence,
X
1 is absent or -0-; 5 R 3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R
4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and
R
6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; NN provided that when X1 is absent; R 3 is not R3A or _ R3A; wherein 10 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 X 2 is absent; R 4 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 15 heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X1 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 20 heterocyclyl. -42- WO 2007/002172 PCT/US2006/024108 In certain embodiments, the present invention relates to the aforementioned
H
3
COCH
3 \ NH compound and any of the attendant definitions, wherein R 3 is O OCH3 or
H
3 C CH 3 "'NH 0 OCH 3 . In certain embodiments, the present invention relates to the aforementioned 5 compound and any of the attendant definitions, wherein R 4 is (amino)alkyl, (amido)alkyl or heterocyclyl. In certain embodiments, the present invention relates to the aforementioned
H
3 COj3CH 3 \ NH compound and any of the attendant definitions, wherein R 4 is 0 OCH 3 or
H
3 C CH 3 "'NH o
OCH
3 . 10 In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl or aryl. In certain embodiments, the present invention relates to the aforementioned
CH
3 compound and any of the attendant definitions, wherein R 6 is CH 3 or - N 15 In certain embodiments, the present invention relates to the aforementioned
CH
3 r~
H
3 CQ CH 3 \-''NH compound and any of the attendant definitions, wherein R 3 is 0 OCH 3 , or -43- WO 2007/002172 PCT/US2006/024108 HCCH3CH H 3 C CH 3
H
3 CCH3CH 3 \iNH \$ NH \ NH CH 3 o OCH3; R4 is 0 OCH 3 ,or 0 OCH3; and R6 is CH 3 or
-
N
Synthesis 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 5 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 10 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 l 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. 15 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. 20 As can be seen from Figures la and 1b, 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. Pharmaceutical Compositions. The methods described herein include the 25 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. - 44- WO 2007/002172 PCT/US2006/024108 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 5 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 10 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. Pharmaceutical Sciences 1977, 66: 1-19, incorporated herein by reference. The 15 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 20 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 25 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, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, 30 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, tartrate, thiocyanate, p -45- WO 2007/002172 PCT/US2006/024108 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, 5 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 10 alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety 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 15 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 transformed in vivo to yield the parent compound of the above 20 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. 25 Methods of formulating 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 compositions typically include a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, coatings, antibacterial and 30 antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions. - 46- WO 2007/002172 PCT/US2006/024108 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 5 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 10 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 sodium 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 15 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 EL T M (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 20 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 25 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, 30 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. -47- WO 2007/002172 PCT/US2006/024108 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 5 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. 10 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 15 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 20 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 25 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 30 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 -48- WO 2007/002172 PCT/US2006/024108 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 5 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 10 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 15 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 Compounds of the Invention. HIV protease inhibitor activities were determined by fluorescence resonance energy transfer (FRET) 20 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 25 on Morrison equation. (Greco, W. R. et al. J. Biol. Chem. 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 Treatment. The methods described herein include methods for the 30 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 - 49- WO 2007/002172 PCT/US2006/024108 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 5 are expecting a child (pregnant women) and in whom 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 10 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 15 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 20 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 25 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(l):104-114 (1995); Saah et al. Arch. Pathol. Lab. Med. 121(9):960-2 (1997); Mwaba et al., Lancet 362 1459-60 (2003)). Healthy adults and teenagers generally have a CD4 count of at least 800 cells per 30 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. - 50- WO 2007/002172 PCT/US2006/024108 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 5 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 10 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 15 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 20 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 25 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 30 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 - 51- WO 2007/002172 PCT/US2006/024108 protease inhibitor described herein ranges from about 0.1 to 10 mg per day, or about 0.3 to 5 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, 10 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, Zerit T M )/3TC, and d-drugs (ddl [didanosine, Videx T M /VidexEC
TM
], ddC [zalcitabine, Hivid T M ], d4T), Abacavir, FTC, DAPD, dOTC, and DPC 817; a nucleotide 15 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 foscarnet and prodrugs; an RNAse H inhibitor, such as SP1093V and PD126338; a 20 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 25 140135, TMC 114 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 30 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 - 52- WO 2007/002172 PCT/US2006/024108 inhibitor of CYP2C19, CYP1A2, 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, 5 methionine enkephalin, 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 10 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. 15 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; 20 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 25 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; Sustiva@). In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is T-20 (Fuzeon@; Enfuvirtide; DP 30 178; Pentafuside; GP41 127-162 AA). - 53- WO 2007/002172 PCT/US2006/024108 In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is TMCC 114, or TMCC 114 in combination with a reverse transcriptase inhibitor. In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic 5 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 10 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, 15 292(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 Chemotherapy 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, 20 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 25 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, 30 H, I, J, and K. A "clade" is a group of organisms, such as a species, whose members share homologous features derived from a common ancestor. Any reference to HIV in this application includes all of these tupes and strains. - 54- WO 2007/002172 PCT/US2006/024108 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 5 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 10 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 immunodeficiency 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, 15 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 20 atoms in its backbone (e.g., C-C 30 for straight chain, C 3
-C
30 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 25 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). 30 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. - 55- WO 2007/002172 PCT/US2006/024108 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 aryl 5 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, 10 sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, CF 3 , -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. 15 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 20 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, 25 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 30 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, -CF 3 , -CN, or the like. - 56- WO 2007/002172 PCT/US2006/024108 The terms "polycyclyl" or "polycyclic group" are art-recognized and refer to two or more rings (e.g., cycloalkyls, 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 5 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, -CF 3 , -CN, or the like. 10 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 -NO 2 ; 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 15 refers to -S0 2 ~. "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: 20 -N(R51)(R50) or [-N(R50)(R52)(R53)]*, wherein R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 )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. 25 In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-R6 1. 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 30 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. -57- WO 2007/002172 PCT/US2006/024108 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. 5 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-(CH 2 )m-R6 1, 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 10 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, -(CH 2 )m-R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R6 1, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an 15 "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 20 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. 25 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 (=0). 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, 30 alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 )m-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 -(CH 2 )m-R61. - 58- WO 2007/002172 PCT/US2006/024108 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 5 renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -0-alkyl, -0-alkenyl, -0-alkynyl, -0-(CH 2 )m-R6 1, 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(=0) 2 0R57, in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl. 10 The term "sulfate" is art recognized and includes a moiety that may be represented by the general formula: -OS(=0) 2 OR57, 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(=0) 2 0R56, in which R50 and R56 are as defined above. 15 The term "sulfamoyl" is art-recognized and refers to a moiety that may be represented by the general formula: -S(=0) 2 N(R50)(R5 1), 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(=0) 2 R58, in which R58 is one of the following: hydrogen, alkyl, 20 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, 25 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, 30 trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by - 59- WO 2007/002172 PCT/US2006/024108 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 5 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 10 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 15 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 20 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 25 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 hydroxyethylamine (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 30 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 - 60- WO 2007/002172 PCT/US2006/024108 14. After deprotecting the Boo 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 5 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 R 4
X
2
CO
2 H to 17, the dibenzyl protection was removed and the free amine 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 10 Series The synthesis of protease inhibitors containing aza-hydroxyethylamine (Aza-HEA) isostere is outlined in Figure 8. The ring opening of chiral epoxide (lS,2R enantiomer) 21 with CBz protected hydrazine derivative 22 provided compound 23. Deprotection of CBz followed by the coupling with R4X 2 C0 2 H gave compounds 24. Removal of the Boc 15 protection and coupling with R 3
X
1
CO
2 H 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 20 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., 25 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. 30 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 -61- WO 2007/002172 PCT/US2006/024108 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 5 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 terns in documents that are incorporated by reference herein conflict with those used herein, the definitions used herein govern. 10 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. 15 - 62-

Claims (122)

1. A compound, or a pharmaceutically acceptable salt thereof, of formula I: 0 R 2 0 0p R3X N N X 2 R4 R 1 R 5 I wherein, independently for each occurrence, X 1 is absent, -0-, -S- or -NR-; X 2 is absent, -0-, -S- or -NR-; R 1 is -OH, -SH or -NHR; R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl; R 2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 5 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; N provided that when X 1 is absent; R 3 is not R3A or N' R 3 A; 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. -63- WO 2007/002172 PCT/US2006/024108
3. The compound of claim 1, wherein X 2 is absent.
4. The compound of claim 1, wherein X 1 is absent; and X 2 is absent.
5. The compound of claim 1, wherein R 1 is -OH.
6. The compound of claim 1, wherein R 2 is aralkyl or heteroaralkyl.
7. The compound of claim 1, wherein R 2 is aralkyl.
8. The compound of claim 1, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, arallyl or heteroaralkyl.
9. The compound of claim 1, wherein R 3 is aryl or heteroaryl.
10. The compound of claim 1, wherein R 4 is alkyl, aryl or heteroaryl.
11. The compound of claim 1, wherein R 5 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
12. The compound of claim 1, wherein R 5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
13. The compound of claim 1, wherein X 1 is absent; X 2 is absent; R 1 is -OH; R 2 is aralkyl; R 3 is aryl or heteroaryl; R 4 is alkyl, aryl or heteroaryl; and R 5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
14. A compound, or a pharmaceutically acceptable salt thereof, of fonnula II: Ph 0 0 X 1 N N R 4 H OH R II wherein, independently for each occurrence, X 1 is absent or -0-; R 3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and - 64- WO 2007/002172 PCT/US2006/024108 R 6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; provided that when X1 is absent; R 3 is not R3A or NR3A; 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 X 1 is absent.
16. The compound of claim 14, wherein R 3 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 R 3 is aryl or heteroaryl.
18. The compound of claim 14, wherein R 4 is alkyl, aryl or heteroaryl.
19. The compound of claim 14, wherein R 6 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. H 3 C N H H 3 C'N
21. The compound of claim 14, wherein R 3 is CH 3 , 0 0 H3C O H H3C H3C H3CO 0 N. H 3 C N HO 0, CH CF F3C -65- WO 2007/002172 PCT/US2006/024108 F N 1HO OH 3 OH 3 IF \ HO F B r H F , HO OH CH3 HO H3C H OH s [H3 N.. H 3 C \ \\ Hoe H3,i , \, 0 O H 3 CI Br OH 3 CHO HO H3C ~ , OH H FH H3CN HH OH H 3 C H N OCH 3 CH 3 , 0 CH 3 or F O CH3 OCH 3 N I : ! >
22. The compound of claim 14, wherein R 4 is F , O , N F N " o H 3 0 N >-CH 3 I H 0H 3 , 3 CH OCH 3 , F CH3 N OCH 3 NH2 H3CF or CH 3 -66- WO 2007/002172 PCT/US2006/024108 1>H 3 C
23. The compound of claim 14, wherein R is 0 CH 3 S CH 3 HO HO H 3 C CH3 CH 3 CH 3 CH 3 H 3 C OH 3 H 3 OH 3 C OH OH H , N N O, H3 H, or OH H 3 C N
24. The compound of claim 14, wherein X 1 is absent; and R3 is CH 3 H3C' N H 3 C H 3C H 3 C H 3 CO H3C HO O 3 F3COH3C B I HO F\ H OH OH 0 HH 3 OF 3 HF 3 3 H3H 3 F N 11 ~ HO H O H 3 FF OH F HO ,HO OH CH 3 CH HO[ - HO& H 3 OH \ <-\ 0 1 Br H 3 0 O,, H 3 01,[ HO,[ HO O CH 3 7. I OH 3 HO H H 3 ~.< F H OH, OH 3 O:H 3 , 0 OH 3 or F 0 - 67- WO 2007/002172 PCT/US2006/024108 H3C N'
25. The compound of claim 14, wherein X 1 is absent; R 3 is CH 3 H 3 CN H 3 C 0 OH 3 H 3 C H 3 C 0 N H 3 CO H 3 C HOVN B HO F HCOH N C O CH 3 OF 3 H3C=3 H3HHC C F ON N \ H O ,H 3 F S~Br ,- , , F HHOOH OH 3 HO ,HO&- H 3 0 J\ \ H CI Br H 3 0 N O H 3 'N e HO 'N HO H F O H 3 H O H 3 0 N, H~-8 H 3 COI y H 3 yNy 'N ' OH , O 3 O 3 , 0O 3 or F ~"0 ;and R 4 is C H 3 N O 'OCHrS N F>' J 1 N> OH 3 , OH 3 , F H 3 0 N ' S Va OH 3 ," C ~ H 3 -68- WO 2007/002172 PCT/US2006/024108 N OCH 3 NH 2 H 3 CF H 3 C \ CH 3 H 3 C N
26. The compound of claim 14, wherein X 1 is absent; R 3 is CH 3 H H 3 C N 0 3C 0 O H 3 H 3 C 0 H 3 C 0N H 3 CO H 3 C HO B HHF OHC HO HO H 3 C CI Br H 3 C O C HO HO O CHH, # H3C H3 HFCH OH 3 CH HON N O OH , OH 3 OH 3 , OH 3 or F 0 ; andRais CH H F HOH 0H O CH3, \ CH3 CH3, -69- WO 2007/002172 PCT/US2006/024108 H 3 C H 3 0 OH 3 H 3 0 OH 3 O3 OH 1CH 3 H OH ,XI OH "PN',,D 0 NCH 3 CH3 or OH CH3 OCH 3 , o I 1/>
27. The compound of claim 14, wherein R 4 is F , , N F N\ H 3 C N LzjN >-H 3 K OH 3 , OH 3 , H CH3 OCH 3 , F \ CH 3 N OCH 3 NH 2 11 CH3 Laz z HO 3 H 3 C :CH3 \ CH ,CH CH 3 I For an HdRi Z OH 3 HO HO H 3 O OO HCH 3 oCH 3 CH 3 , ',OH3,LH3 H O H 3 CN O H 3 C OCH H3C H3CON H3C HN -70 N HO N N. OH - 70- WO 2007/002172 PCT/US2006/024108 0 CH 3 CF 3 H3C-I F H3HO CH 3 C CH3 N C r FF H 3 C C H 3 OC H 3F \\C H OH CH ;an1Ri H 3 HO HO ,3CH C H H HCI Br H 3 C N___A CHH 3 3 HOC HO O O H 3 ~I C3H H F H O 3 H 3 O N H N N HH 3 O N H 3 O 0 CH 0 OH 3 or : OH ,H 3 H 3 , 3 o 4i CH 3 N OCH 3 0 F O,,\NO 3 , F H 3 C N \>-OH 3 S OnH 3 F \O, 'N OC0H 3 NH 2 H 3 0 vas F or OH 3 H 3 0 H 3 O 3 aHndaR6 is~ ~ 3 \ S\ HO HO H 3 0 3 CH 3 H O-/'H 3 CH 3 ) OH OH, NCH 3 H H or OH - 71- WO 2007/002172 PCT/US2006/024108
29. A compound, or a pharmnaceutically acceptable salt thereof, selected from the group HH 0 0 OH OH consisting of o0'0 Nc PH, 4 NPH, 0 0 0 > N',O HN O 0H LI. O H OH 0 /.1 0N 0 0 "( N /> ' ~ H )-I 1/> Is N 3 N N S N H- N H N' 0 H H N OHH 0 OH OCH, F OCH, 0I O\H 0 \ F ~ 0\ ' 'NC NS' H;C N N"HO 'N N -H ,0 Yl'~ OF I H( NOH 0 6H,' OH O SF O F OCH, F 0 ICH,o o I 0 NS 'NN' N' "N F N N N N N N H OF H 0\ H N- OH -OH 0 OH L, s/ OCH, F OCH, 0 CHI OHO0 'N : Is" 'N" ' H 'N N N' 5 HO ' N N HO H O N" 0 H OI, H N' 0 OHOH HOH o, ,\ H\ OF N N"N' H OH 0 H 0 H OH 0 CH, - 72- WO 2007/002172 PCT/US2006/024108 0! 0 0 N Br 0 Ns C ~ O F 3 0 C-0N H 0 H 3 C- 0 I's ---- NC OH ~ o H 0 O 3 I H OH 1, CI OHH OCH, NCH HC H 00 H \\,b N N\\\ NNNJ( N H 0 OH 3 H,0 N H 3 N\ 0OH H 0 ~ 0 OH OH -0 OHY OCH 3 OCH, OCH 3 N 0N Is0 H , - NS \ N H 3 0 N \ H 3 N NH 3 C &N N N H N N0 0 H OH H 0OH OH K 1 1,1O OH ;Y CH, OH, 00H, OCH, OCH, 0 0\ 00 \\ & N \ b H NJ S O \1HH OH 0H OH , OH OH 3 OH 3 OCOH 3 0 0 SN 0 0 Ob HN N N 3 N H 6NHC a--" i H 0 \OH OH ~OH 03C Y ,H OH 0 OH 3 0 H H OH 3 1 0 HO OH 3 OH 3 C0 3 H 0 N 0 N 0~~ OH-\ H0 N N N- H N 1 N-O H OH H 3 OH N OH 100 OH 3 OH 3 OH 3 0 N 0 s0\ N 00 H 00 N N \ O N N \ H [0 CH 3 H 3 0 '-A N - H N OH *IIOH o H OH 0 0 OH ,\OH 0 OH N 0 0 N 0 \ N 0\ \ 'D / 0 H 3 0 N S - - H 3 0 N \sI H, N N N- N N N \\ H HJ N~ I H H 0 OH ,,OH H0 OHCOH, 3 O -73- WO 2007/002172 PCT/US2006/024108 O C 3 aO H 3 N \\ S N N C N N O C N H( % Hi N\ H OH ,,OH 0 OH CH 0 OH CH, CH 3 , CH, CH 3 F N.100H 3 N F HO N NOHO O\ N N'HC 3 N N O H , H , 0 ~~ N N'O OH CH, H OH CH H OH F CH 3 CH 3 , S , HC CH OH C Oa H 3 C CHN O C OCH HN,kN S s. S> H J( N N N O C NJ N E H 0~ H 0 H 3 N H OH CH 3 CH , OH CH 3 OH OH CH CHa CH, CH, C N O~aNN HON NOOCH O CH, OH Ca O OH 0 O ~ HO O 3 H 3 OH OH 3 NO C HH N HC N N' OC\ N N N N0C\ OH OH 3 CH , H H O H OHCH 3 CH H OH CH , CH3 NH CH0H3 ~ H 3 0, N O H H OH H C N N OCN N OH OH OH 3 OH OH 3 O 3 OH OH 3 OH OH 3 OH N H 3 OCH3 N N-74 O 0 o~ N. OH 3 0x 0, I0 S \\Ns S j HON' HCH NN>C N o -- I HO C N N $ , I N - N' HN H N O H- H OH OH OH 3 OH OH O-IH 3 H O H 3 0 OH CH N~ NCH N\H0 NN\ HH 0 N 0 N -N Nq S( N NyW50 OH 0 OH OH OHO*, N al 0 H OH 0 CH H OH OCH 3 OH 3 OH 3 O, H H 3 H - 74- WO 2007/002172 PCT/US2006/024108 HO N N NC HO NN NC H NNHa H , H I H O OH OH CHa OH OHa HaC OH 3 H ~ H, Ha , C0 , C0 HOC CH, H CCa OH OH CIa O OH CH, CH, CH 3 CH , O, N N HaC N N HaC NNN H 3 N o\ H 3 N 0~ H 3 CH, OH CH 3 OH OH CH 3 OH OH OH 3 OH 3 OH 3 OH 3 OHC 0 OH 0 , Na N N 00 NJN \ NJ - 3 H 0~ NlA ,~ 0 3 NJ N OH 3 OH OH 3 OH 3 H CH r AH N O O H 3 CH 3 CH, CHCCH CF 3 0 O N'H 0\ N ')'WA ) H 3 C NS H3C N O N S'CON N' H H OH 0 H OH OH O H 3 , COH, and -75 -0H F Nk I H 0 OH O H, OH 3
30. A compound, or a pharmaceutically acceptable salt thereof, selected from the group OH 3 F N N H 0\ OH 0 NH, -N OH 0 q Nr OH 0O N, N, consisting of HO 0 HC0 OH HO 0 H 3 0 O0H -75- WO 2007/002172 PCT/US2006/024108 F 0 o\ HO e CNN. H 3 HO N' NS\ R N OH H 0~ 'el H OH 0OCH, H 0 N N N..O Y H 3 C0 NOH H 3 C NOH H 3 0'N OH F ~. F N0 1 k\o O HN0 N NJ N- H H0 N n N, H 0 N.- H 0 N. H 0H H 3 O' NOH H 3 0' NOH H 3 O-N OH 0 I0CH 0 oH 0 0\ N4J \ S H 0s Is C N N NN H 3 N N N \ N N \OH -NHOH 0 qCN 'HO 0 CHK-NHO CH 3 0'N OH , CH, 3 0 NOH HO 0 OH 3 F F 0 IN CH 3 N I N N \\HO, \\ C3 NOI -N H OH H N 0 0 HCH 3 0 ..-N OH 0O H- OH 0O F O H 3 N' 0 N OH 3 S OH, Is HCS OH, N JN N~ \\N N- N\ 300 N NJ N - \\ H 0 I H 0 OH 3 , OH 0 Nx O 0 N,- OH 0 F F ~N OH 3 N H 0 1~I \ 0 0 I( 0 HOCO s S CH 3 N N N>\ N N S OH N N H0 OH 3 NI ) H N I H ,0 OH 3 NX H .- N OH 0.-N OH 0 OH 3 , OHCH 3 OH 3 OH 3 H 9\) N-OH 3 3 N' 0 HJ \,N O\ ,L N-CH 3 0 H OH C..<H3 OH 3 H OH 0 OH OH 3 - 76- WO 2007/002172 PCT/US2006/024108 a N N \ FN= o\ 0 O0 -~ F H 0 N-CHa H 3 CO Ns N N N H OH NH F O OHrAO CH, OH CH, R ),zN-CH, F H 0 N N N Ca N N N-CNa OH 0 F 0 OH F 0\ N \ H 0 tN-CHa HNN-CH 3 N N N N N SOH OH N \ N-\ N HO N N -CN H-C N H N CH H 3 O OH -CH CNH OH C N OH I H OH 0 OH OH 3 'C N \H N \ O OHNCa H O OCN-CH 3 -O N-C'N S N \ N'N \ N, -C3 H0 N-H 3 N"A - N H0 N -- ,N \\ o HOH 0 HH OH H H OOH NH OHCH N N\ NN N 0 N-CH 3 H 0 N O O H - N7 N-' H 0 - -J OH 0 FH H" H N 1""- 3 HN H H H F 0\ -CH'~ H, 0 OH H, 'C) "C), , ""ANJ(~~~ N77- JN S WO 2007/002172 PCT/US2006/024108 F N F 0 Fa N\ N.0 H O 0 NO N F N NN a N H H H OH CH, OH HH OH 0 OH S B N N N NOON 0 0a CH, 0 b HC 0 b ' H N H 3 F3 N 0 OH 3 H N 0 OH 3 OH S OH OH O R 3 CH 3 X CHs t - - o an -O-, -S- or OCH-NR H 0 OHO H 0 H -H oCH OH OH 8- S OH S F N F Br 0 b\~ 0 o N \ N N'S# \ s H OH ,~ O H 3 H OH \ sF 1-'/ , and I!b
31. A compound, or a pharmaceutically acceptable salt thereof, of formula III: 0 R 2 R 5 R 4 R 3 ,. lj N X2 X 1 N N X 2 R 1 R 7 0 III wherein, independently for each occurrence, X, is absent, -0-, -S- or -NR-; X 2 is absent, -0-, -S- or -NR-; R, is -OH, -SH or -NHR; R is hydrogen, alkcyl, aralkyl, heteroaralkyl or acyl; R 2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkcyl, aralkyl or heteroaralkcyl; -78- WO 2007/002172 PCT/US2006/024108 R 3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralcyl or heteroaralkyl; R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl; R 7 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)allyl, (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 X 1 is absent; R 3 is not R3A or 'R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; S0o and provided that when X 2 is absent; R 4 is not R4A or R 4 A; 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 X 1 is absent.
33. The compound of claim 31, wherein X 2 is absent.
34. The compound of claim 31, wherein X 1 is absent; and X 2 is absent.
35. The compound of claim 31, wherein R 1 is -OH.
36. The compound of claim 31, wherein R 2 is aralkyl or heteroarallyl.
37. The compound of claim 31, wherein R 2 is aralkyl. - 79- WO 2007/002172 PCT/US2006/024108
38. The compound of claim 31, wherein R 3 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 R 3 is aryl or heteroaryl.
40. The compound of claim 31, wherein R 4 is alkyl, aryl or heteroaryl.
41. The compound of claim 31, wherein R 5 is hydrogen.
42. The compound of claim 31, wherein R 7 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
43. The compound of claim 31, wherein R 7 is alkyl, (cycloalkyl)alkyl or aralkyl.
44. The compound of claim 31, wherein X 1 is absent; X 2 is absent; R 1 is -OH; R 2 is aralkyl; R 3 is aryl or heteroaryl; R 4 is alkyl, aryl or heteroaryl; R 5 is hydrogen; and R 7 is alkyl, (cycloalkyl)alkyl or aralkyl.
45. A compound, or a pharmaceutically acceptable salt thereof, of formula IV: Ph H R3X 1 N R 4 OH R 7 O IV wherein, independently for each occurrence, X 1 is absent or -0-; R 3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and R 7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl; - 80- WO 2007/002172 PCT/US2006/024108 ro 0-- 0 provided that when X 1 is absent; R 3 is not R3A or 'R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; 0 and provided that when X 2 is absent; R4 is not NR4A or R4A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
46. The compound of claim 45, wherein X 1 is absent.
47. The compound of claim 45, wherein R 3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
48. The compound of claim 45, wherein R 4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl.
49. The compound of claim 45, wherein R 7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.
50. The compound of claim 45, wherein X 1 is absent; and R 3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
51. The compound of claim 45, wherein X 1 is absent; R 3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl; and R 7 is alkyl, cycloalkyl or (cycloalkyl)alkyl. - 81- WO 2007/002172 PCT/US2006/024108 F O . CH 3
52. The compound of claim 45, wherein R 3 is -, HO H3C O CH 3 H3C O CH 3 OCH 3 O O H 3 C NH H 3 C NH H 3 C OCH 3 , O0 ,or 0. OCH 3 O
53. The compound of claim 45, wherein R 4 is F H 3 C O CH3 H 3 CO CH3 OOH3C NH H3C NH OCH3 O H 3 O yCH 3 H 3 C O CH 3 H 3 O H 3 0 CH3 H 3 C NH H 3 C NH H 3 C ,NH H 3 CO NH H3H 3 H 3 C CH 3 H 3 C ,CH 3 H 3 O$OH 3 H 3 OQ-0H 3 NIIII H ONHN'< NH O OCH 3 , 0 003, H or H /OH 3
54. The compound of claim 45, wherein R 7 is CH 3 , or - 82- WO 2007/002172 PCT/US2006/024108 CH 3
55. The compound of claim 45, wherein X1 is absent; and R3 is F H 3 0 y CH 3 00 yOH 3 0HC NH HO O\ 0 H 3 0 H3CO CH 3 H 3 C H 3 C N H C ,O 0 o OH 3 , -~ or 0. F CH 3
56. The compound of claim 45, wherein X1 is absent; R 3 is - , HO H 3 C O CH 3 H 3 C O CH 3 OCH 3 O O H3C NH H3C NH H 3 C OOCH 3 CH 3 , O ,or O ; and R 4 is F H 3 C O CH 3 H 3 C O CH 3 O 0 H 3 C ,NH H 3 0C NH OCH3 H3CO CH 3 H30 O CH 3 H3C O CH 3 H3C NH H3C NH H3C NH H 3 CCH3CH3 H 3 CTCH 3 H 3 C CH 3 H 3 COCH 3 H0 yH 3 AN )II H 3 C N H \ N \ N H<O 0 H 0H 3 , 0 OCH 3 , H or H. -83- WO 2007/002172 PCT/US2006/024108 F CH 3 Oja
57. The compound of claim 45, wherein X 1 is absent; R 3 is , HO H 3 C O CH3 H 3 0 y CH 3 OCH 3 O H3C NH 3C NH H3C '0 OH 3 OCH 3 , O ,or O ;R 7 is H 3 or~ OCH 3 0
58. The compound of claim 45, wherein R 4 is F , 0 H 3 C O yCH 3 H 3 C Oy CH 3 O H 3 C NH H 3 C NH OCH 3 H 3 9 O CH 3 H 3 C O CH 3 H 3 C O CH 3 H 3 C O CH 3 H 3 C ,NH H 3 C NH H 3 C NH H 3 C NH H 3 C CH 3 H 3 C CH 3 H 3 C CH 3 4t2IC 3 H 3 CT4CH 3 \NH \ <NHO O- -N 0 N 0 'OCH 3 , 0 OCH 3 , H or H ;and R 7 is OH 3 CH3, - or. - 84- WO 2007/002172 PCT/US2006/024108 F CH 3
59. The compound of claim 45, wherein X 1 is absent; R 3 is , HO H 3 C O yCH 3 H 3 C O yCH 3 OCH 3 O O H3C NH H3C NH H3C 0 ,-Z 0 0 OC 3 OH 3 ,or O ;R 4 is F O H 3 C O yCH 3 H 3 C O CH3 O H 3 C ~NH H 3 C NH OCH 3 O H 3 9 O yCH 3 H 3 O yCH 3 H 3 C O yCH 3 H 3 C 0 CH 3 H 3 C ,NH H 3 C NH H 3 C NH H 3 C NH H 3 CH CH 3 H3C CH 3 H 3 C CH 3 H 3 C CH 3 \NH \<'NHO O- N 0 N O OCH 3 , 0 OCH 3 , H or H ;and R 7 is OH 3 b d. CH 3 , or.
60. A compound, or a pharmaceutically acceptable salt thereof, selected from the group H,C 0o Hac N H O N6 0 N0 consisting of Hc CH , - 85- WO 2007/002172 PCT/US2006/024108 H 3 C N HaC CH 3 H 3 C< . HaC CH 3 H H S N 'NH O N N "'NH H 5H OO CHa H OH 0O O CH, HaC CHa H 3C H, HC HCH, O HO N FF H 0 H HO N.H CN 0 F ' H H C HaC CH3 F H O 0 1N1. N4 OHO0 H NH H H CNN H 3 F H H 0H F F F OHO H N. H O OH 0 H N.N H N CH H N. N N ' HaC CH, F H -H 86 OH 0H H 3 O OH 3 H 3 O 0~ o N OH N. H N. N N.N N N H H 0H 0 O0H -" F OH 0 H, 0H H, N.' N N NH H HOH OE OH 0 N. N - "'NH N. N '- 'N F F H OH O OHH OH O H H 3 0 OH 3 - 86- WO 2007/002172 PCT/US2006/024108 . O OHaC CH, 'N HOOOOHO OHO0 H H, H H 3 0 N - 'N OHH OH HCO N O F H0 NOCH H OH O O OH O HH. HaC CHa H3ON OH 3 0O NN'NO H O O HCO O N O-0 OH 0 H HCO N O NO H 3 0O HaC CH 3 HHC0C N Y -,H : N - CH 0 OH 0H 0 OH 0 HCONH 3 O N H 3 0 N OCH 'N -A.N - N 'N 0 0O H 0 O C0a N 6- H 0 HC CHaHN 1 0 87 0 N H 0 OH 0 HH 00 HH H0 0 H 'N0 OH 'N H3 C OH 3 -'N "NHO N - NH o--, H6H " N 0 L~H H0 HH 00~" H 3 O OH 3 0~~~~ 87-HHC H WO 2007/002172 PCT/US2006/024108 O H 3 C CH, NaCNNH OH O H OH O O C N OO N ",NH CO N .. N HOH H O H3 0H H H H O HH3C OH 3 C~ ON OHC 0 N 'N H OOH 0 O CH OHC C O HC CN H O NH OH O OH O H CC N OHN.).. N , H N0 N HHCH 3 OHH 0 0 H H 3 C C H 3 OH 3 HN, OH 3 HN , H H " H 0 OH 3 O O C HaH O H , H CHH OONC' H HC HOKO HHOH 0 H3 C OH 3 NOH 3 , 0 N H 3 OH 3 N N FNH N HH H N - NH N N "'NH 0O o H O~H HOH O~ H C<H3 O D A O H 3 0 O H 3 H , 0 1 H H0 0 - - H HC0 0 N H 3 0 C H O 3 H 3 ~ N H 3 0 0OC HC ~ 0 N H 3 0 HN~l N yH O 3 O 0-H 3 "'N T N 'H N ,I H H 'NH HN::, N "'NH HO OH 3 OH 0 C H I ;r H3 O0H OH -)CH C H,0 OH 3 0 OHH 3 H 00H H 3 0 OH 3 - 88- WO 2007/002172 PCT/US2006/024108 H,C 0 0 HaC NrHH 3 ~ HF OH OCH, Ha O N N H OH 0 H 3 C CH, OH 0 H OH O HC CHa , , and HC O N ) H N N a O"- N j H OH 0
61. A compound, or a pharmaceutically acceptable salt thereof, of formula V: o R 2 0 R 3 .. R4 H ~ x R 1 R 5 wherein, independently for each occurrence, X 1 is absent, -0-, -S- or -NR-; X 2 is absent, -0-, -S- or -NR-; R 1 is -OH, -SH or -NHR; R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl; R 2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; -89- WO 2007/002172 PCT/US2006/024108 R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 5 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; R 3 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; and provided that when X2 is absent; R4 is not R4A or N -R 4 A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
62. The compound of claim 61, wherein X 1 is absent.
63. The compound of claim 61, wherein X 1 is -0-.
64. The compound of claim 61, wherein X 2 is absent.
65. The compound of claim 61, wherein X 1 is absent or -0-; and X 2 is absent.
66. The compound of claim 61, wherein R 1 is -OH.
67. The compound of claim 61, wherein R 2 is aralkyl or heteroaralkyl.
68. The compound of claim 61, wherein R 2 is aralkyl.
69. The compound of claim 61, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
70. The compound of claim 61, wherein R 3 is heterocyclyl. - 90- WO 2007/002172 PCT/US2006/024108
71. The compound of claim 61, wherein R 4 is (heterocyclyl)alkyl.
72. The compound of claim 61, wherein R 5 is alkyl.
73. The compound of claim 61, wherein X1 is absent or -0-; X 2 is absent; R 1 is OH; R 2 is aralkyl; R 3 is heterocyclyl; R 4 is alkyl, aryl or heteroaryl; and R 5 is alkyl.
74. A compound, or a pharmaceutically acceptable salt thereof, of formula VI: O Ph O X 1 N N R 4 H R 1 R VI wherein, independently for each occurrence, X 1 is absent or -0-; R1 is -OH or -NH 2 ; R 3 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and R 6 is alkyl, cycloalkyl, or aryl; ~ >o/ o provided that when X 1 is absent; R 3 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; NN and provided that when X 2 is absent; R 4 is not R4A or 'R4A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. -91- WO 2007/002172 PCT/US2006/024108
75. The compound of claim 74, wherein R 1 is -OH.
76. The compound of claim 74, wherein R 1 is -NH 2 .
77. The compound of claim 74, wherein X 1 is -0-.
78. The compound of claim 74, wherein R3 is heterocyclyl. 0 0
79. The compound of claim 74, wherein R 3 is \ or N .
80. The compound of claim 74, wherein X 1 is -0-; and R 3 is heterocyclyl. 0
81. The compound of claim 74, wherein X 1 is -0-; 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(CH 3 ) 2 .
85. A compound, or a pharmaceutically acceptable salt thereof, of formula VII: 0 R 2 R4 R 3 H R 1 R 5 0 VII wherein, independently for each occurrence, X 1 is absent, -0-, -S- or -NR-; X 2 is absent, -0-, -S- or -NR-; R 1 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; - 92- WO 2007/002172 PCT/US2006/024108 R 3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 5 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' _O /O o-C provided that when X 1 is absent; R 3 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; s - Olo 0-o N and provided that when X 2 is absent; R 4 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.
86. The compound of claim 85, wherein X 1 is absent.
87. The compound of claim 85, wherein X 2 is absent.
88. The compound of claim 85, wherein X 1 is absent; and X 2 is absent.
89. The compound of claim 85, wherein R 1 is -OH or -NH 2 .
90. The compound of claim 85, wherein R 2 is aralkyl or heteroaralkyl.
91. The compound of claim 85, wherein R 2 is aralkyl.
92. The compound of claim 85, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. - 93- WO 2007/002172 PCT/US2006/024108
93. The compound of claim 85, wherein R 3 is (amido)alkyl or heterocyclyl.
94. The compound of claim 85, wherein R 4 is (amido)alkyl or heterocyclyl.
95. The compound of claim 85, wherein R 5 is alkyl or aryl.
96. The compound of claim 85, wherein X1 is absent; X 2 is absent; R 1 is -OH; R 2 is aralkyl; R 3 is (amido)alkyl or heterocyclyl; R 4 is (amido)alkyl or heterocyclyl; and R 5 is alkyl or aryl.
97. A compound, or a pharmaceutically acceptable salt thereof, of formula VIII: Ph R3'X NkG N R4 XI N N' H OH R6O VIII wherein, independently for each occurrence, X 1 is absent or -0-; R 3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is aryl, heteroaryl, aralkyl or heteroarallyl; and R 6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; / O0 O / O.K 0 N N provided that when X 1 is absent; R 3 is not R3A or I R3A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; s OO/ OO and provided that when X 2 is absent; R 4 is not R4A or N R 4 A; wherein R3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. - 94- WO 2007/002172 PCT/US2006/024108
98. The compound of claim 97, wherein X1 is absent.
99. The compound of claim 97, wherein R 3 is (amino)alkyl, (amido)alkyl or heterocyclyl. H 3 C 5CH 3 H 3 C CH3 \'NH \ NH
100. The compound of claim 97, wherein R 3 is O OCH 3 or O <OCH 3 .
101. The compound of claim 97, wherein R 4 is (amino)alkyl, (amido)alkyl or heterocyclyl. OCH 3 0
102. The compound of claim 97, wherein R 4 is F , O 0 H 3 C j3CH 3 H 3 C H3 \- NH \' N H o OCH 3 or O OCH 3 .
103. The compound of claim 97, wherein R 6 is alkyl or aryl. CH 3
104. The compound of claim 97, wherein R 6 is OH 3 or H 3 C CH3CH H3C$,JCH3 H3CCHCH3 ' NH \ NH
105. The compound of claim 102, wherein R 3 is 0 'OCH 3 , or O "OCH 3 ; R 4 is H 3 C J;CH 3 H3C CH3 \ONH \ NH CH 3 N o OCH3 ,or O OCH3; and R 6 is CH 3 or - 95- WO 2007/002172 PCT/US2006/024108
106. A compound, or a pharmaceutically acceptable salt thereof, selected from the group 00 FCSac- N/'N SN'OcN'a 0 o OH consisting of Ha N Nc- N N' OHO HcH OHY 00 HCS Z0H 0 and CH,
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 (SustivaTm), nevirapine (ViramuneTM), delavirdine (Rescriptofrm), AZT (zidovudine, RetrovirTM)/3TC (lamivudine, Epivirm), d4T - 96- WO 2007/002172 PCT/US2006/024108 (stavudine, Zerit TM )/3TC, ddI (didanosine, VidexTM/VidexECTM), ddC (zalcitabine, HividTM), d4T, tenofovir (VireadTM), and enfuvirtide (FuzeonTM).
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 TMCC 114.
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. - 97-
AU2006262274A 2005-06-22 2006-06-21 HIV-1 protease inhibitors Abandoned AU2006262274A1 (en)

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