EP1937655A1 - Inhibitoren der hiv-1-protease und verfahren zu ihrer herstellung und verwendung - Google Patents

Inhibitoren der hiv-1-protease und verfahren zu ihrer herstellung und verwendung

Info

Publication number
EP1937655A1
EP1937655A1 EP06785253A EP06785253A EP1937655A1 EP 1937655 A1 EP1937655 A1 EP 1937655A1 EP 06785253 A EP06785253 A EP 06785253A EP 06785253 A EP06785253 A EP 06785253A EP 1937655 A1 EP1937655 A1 EP 1937655A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
heterocyclyl
aryl
aralkyl
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.)
Withdrawn
Application number
EP06785253A
Other languages
English (en)
French (fr)
Inventor
Tariq M. Rana
Akbar Ali
Hong Cao
Kiran Kumar Reddy Ga Sai
Saima Ghafoor Anjum
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.)
University of Massachusetts UMass
Massachusetts Institute of Technology
University of Maryland at College Park
Original Assignee
University of Massachusetts UMass
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Filing date
Publication date
Application filed by University of Massachusetts UMass filed Critical University of Massachusetts UMass
Publication of EP1937655A1 publication Critical patent/EP1937655A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—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
    • 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • HIV-1 Protease Inhibitors and Methods of Making and Using Them
  • HIV-1 protease plays a critical role in the virus life cycle by processing the viral Gag and Gag-Pol polyproteins into structural and functional proteins essential for viral maturation. Inhibition of HIV-1 protease leads to the production of noninfectious virus particles and hence is a promising therapeutic target for antiviral therapy in AIDS patients, In fact, HIV-1 protease inhibitors represent the most potent anti-AIDS drugs reported to date and are essential components of highly active ant-retroviral therapy (HAART). In the last decade, structures based drug design has led to the discovery of eight PDA approved drugs and several others in advanced clinical trials.
  • HIV-1 protease inhibitors saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, and tipranavir
  • saquinavir indinavir
  • ritonavir nelfinavir
  • amprenavir lopinavir
  • lopinavir atazanavir
  • tipranavir all competitive inhibitors that bind in the active site of the enzyme.
  • all approved inhibitors have been developed based on transition state mimetic concept and contain various noncleavable dipeptide isosteres as core scaffolds to mimic the transition state of HIV-1 protease substrates.
  • the development and clinical, introduction of anti-AIDS HIV-1 protease inhibitors is regarded as major success of structure based drug design.
  • Anti-AIDS chemotherapy based on HIV-1 protease and reverse-transcriptase inhibitors has been remarkably successful in decreasing the mortality rate in HIV-1 infected patients,
  • tube emergences of HlV-1 mutants that are resistant to current drug regimens is a critical factor in the clinical failure of antiviral therapy.
  • drug resistance occurs when mutations in a target protein allow that protein to retain function while in the presence of a drug.
  • drug resistence typically occurs when, even in the presence of protease inhibitors, the enzyme is able to cleave the Gal and Pol polypeptides in at least nine different locations, allowing viral mutation.
  • Viral resistance is regarded as a critical factor in clinical failure of antiviral therapy.
  • the challenge is to develop new classes of protease inhibitors that are less susceptible to drug resistance with an emphasis on broad spectrum activity against MDR mutants.
  • the present invention addresses the challenege.
  • the present invention is based, at least in part, on the discovery of small molecule protease inhibitors (PIs). These inhibitors, and methods of making and using them, are described herein. It is expected that these inhibitors will be less likely to induce the development of resistant strains, because when they are bound to HIV-1 protease, these inhibitors appear not to protrude beyond the enzyme's substrate binding envelope.
  • PIs small molecule protease inhibitors
  • 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.
  • the invention features methods for treating a viral infection, e.g., an HIV infection or AIDS in a subject, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein.
  • the methods further comprise administering a second therapeutic agent, e.g., a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz (SustivaTM), nevirapine (ViramuneTM) and delavirdine (RescriptorTM); a nucleoside reverse transcriptase inhibitor (NRTI), such as AZT (zidovudine, RetrovirTM)/3TC (lamivudine, EpivirTM) and d4T (stavudine, ZeritTM)/3TC; and d-drugs (ddl [didanosine, VidexTM/VidexECTM], ddC [zalcitabine, HividTM], d4T); a nucleotide reverse transcriptase inhibitor (
  • the compound or pharmaceutical composition is administered as part of a highly active antiretroviral therapy (HAART) regimen.
  • HAART highly active antiretroviral therapy
  • FIG 1 depicts the chemical structures of amprenavir (APV) 1, TMCl 14 2 and selected compounds of the invention 3.
  • Figure 2 depicts a scheme showing the synthesis of intermediates N- Phenyloxazolidine-5-carboxylic acids 9 and 10. Key: (a) n-BuLi, THF, -78 oC to r. t. overnight; (b) RuCl 3 -H 2 O, CH 3 CN-CCl 4 -H 2 O (2:2:3), 0 oC to r. t. 4-10 h.
  • Figure 3 depicts a scheme showing the synthesis of inventive compounds 20-29. Key: (a) EtOH, 80 oC, 3-4 h; (b) aq. Na 2 CO 3 , CH 2 C1 2 , 0 oC to r. t, 4-8 h; (c) TFA, CH 2 C1 2 , 1 h; (d) (OCOCl) 2 , r. t, overnight; (e) Et 3 N, THF, 0 oC to r. t, 4-8 h; (f) SnCl 2 .2H 2 O, EtOAc, 70 oC, 2 h.
  • Figure 4 depicts a scheme showing the synthesis of compounds 36-39. Key: (a) /PrOH or EtOH, 80 oC, 3-4 h; (b) aq. Na 2 CO 3 , CH 2 C1 2 , 0 oC to r. t, 4-8 h; (c) TFA, CH 2 C1 2 , 1 h; (d) (OCOCl) 2 , r. t, overnight; (e) Et 3 N, THF, 0 oC to r. t, 4-8 h.
  • Figure 5 depicts a table showing the inhibitory activities of selected inventive compounds, amprenavir (APV) and lopinavir (LPV) against wild type HIV-1 Protease.
  • Figure 6 depicts selected structure and inhibitory activities of novel protease inhibitors of the invention.
  • Figure 7 depicts a table showing inhibitory activities of selected compounds of the invention against wild type HIV-1 protease.
  • Figure 8 depicts a table of inhibitory activities of selected compounds of the invention, and known inhibitors, against MDR Mutant Proteases (Wt: Q7K; Ml: LlOI, G48V, I54V, L63P, V82A; M2: D30N, L63P, N88D; M3: LlOI, L63P, A71V, G73S, I84V, L90M; APV: amprenavir; LPV: lopinavir.)
  • Figure 9 depicts a table showing the purity of selected target compounds as determined by HPLC using two different systems.
  • First system column, Waters Nova-Pak RP-C18 (4 ⁇ m, 3.9 mm x 150 mm); mobile phase A, 10 rnM ammonium acetate in water; mobile phase B, acetonitrile. Using a flow rate of 0.8 mL/min, gradient elution was performed from 50% B to 100% B over 10 min.
  • Second system column, Agilent Zorbax 300SB-C8 (5 ⁇ m, 4.6 mm x 250 mm); mobile phase A, 0.1% trifluoroacetic acid in water; mobile phase B, 0.1% trifluoroacetic acid in acetonitrile. Gradient elution was performed from 50% B to 100% B over 10 min at a flow rate of 1 mL/min.
  • Figure 10 depicts graphically HIV protease kinetics in the absence and presence of an inhibitor (Amprenavir).
  • Figure 11 depicts a graph used for the calculation of initial velocities.
  • Figure 12 depicts a graph and equation used to determine binding dissociation constants.
  • Figure 14 depicts various classes of HIV-1 protease inhibitors of the present invention.
  • Figure 15 depicts various embodiments of the cyclic carbamate portion of the HIV-
  • protease inhibitors of the present invention e.g., those represented by any of Formulas I to IX.
  • the present invention expressly encompasses the combination of any of the embodiments depicted in the Figure with any of the other structural features described herein.
  • Figure 16a-k depicts anti-HIV drugs by class.
  • Figure 17 depicts selected compounds of formula VA/VB and associated K i values.
  • Figure 18 depicts selected compounds of formula IIIA/IIIB and associated K i values.
  • Figure 19 depicts selected compounds of formula VIIA/VHB and associated K i values.
  • Figure 20 depict possible synthetic routes to selected inventive compounds.
  • HIV protease inhibitors that are less vulnerable to drug resistance and/or more active against current protease-resistant HIV-1 isolates than other HIV drugs.
  • the present invention addresses this challenge by integrating clinical data, in vitro virology, and high-throughput chemistry and compound screening.
  • HIV protease is a particularly appealing target because inhibiton of its activity is clinically effective; however, it can evolve to tolerate extensive mutations conferring drug resistance while retaining enzymatic function.
  • the invention relates to designed inhibitors based on the (i?)-(hydroxyethylamino)sulfonamide isostere present in 1 and 2 ( Figure 1).
  • amprenavir (APV) 1 fits reasonably well within the substrate envelope ( Figure 1). It has been suggested that the inhibitors designed on the APV template may be less susceptible to drug resistance. (King, N. M. et al. J. Virol. 2004, 78, 12012- 12021.) Protease inhibitor TMCl 14 2, structurally similar to 1, has been recently shown to possess very potent in vitro and in vivo antiviral activity against wild type as well as MDR mutants ( Figure 1). (De Meyer, S. et al. Antimicrob. Agents & Chemother.
  • N-phenyloxazolidine-5-carboxamides were selected to be utilized as P2 ligands in HIV-1 protease inhibitors.
  • the oxazolidines represent a class of synthetic antimicrobial agents that are highly stable and exhibit exceptional bioavailability profiles.
  • Linezolid is an FDA approved antibacterial drug that contains N-phenyloxazolidine nucleus.
  • N-phenyloxazolidine-5-carboxamides were recently reported to possess better antibacterial activities compared to linezolid with enhanced solubility and bioavailability properties.
  • the carbonyl group of the oxazolidine ring would mimic critical hydrogen bond interactions of THF/bis-THF moieties of APV and TMCl 14 in the S2 binding pocket of the protease active site.
  • the phenyl group at the ring nitrogen can be utilized to introduce functional groups to make additional contacts with the protease.
  • the selected heterocyclic moiety can be linked to the (hydroxyethylamino)sulfonamide isostere in stereochemically defined manner using either (R)- or (S)-enantiomer of N- phenyloxazolidine-5-carboxylic acids.
  • N-phenyloxazolidine based cyclic carbamate ligands have not been utilized previously in protease inhibitors.
  • inhibitors containing other cyclic carbamate ligands but with poor protease inhibitory activities. (Salituro, F. G. et al. Bioorg. Med. Chem. Lett.
  • the compounds of the invention are a novel series of HIV-1 protease inhibitors incorporating N-phenyloxazolidine-5-carboxamides as P2 ligands.
  • Certain compounds of the invention are competitive inhibitors that appear to bind in the center of the "substate envelope" (i.e., at the active site of the protease).
  • the compounds of the invention are designed such that when bound they do not significantly protrude beyond the substrate envelope; therefore, they are less likely to induce escape mutations.
  • the protease inhibitors of the invention are useful in the treatment of HIV in susceptible mammals, e.g., humans and certain other primates.
  • the compounds have shown activity against a panel of multi-drug resistant (MDR) mutant variants of HIV- 1 protease.
  • MDR multi-drug resistant
  • the inhibitors of the invention can be administered as a monotherapy, or in combination with other therapeutic agents, e.g., as part of a highly active antiretroviral therapy (HAART) regime.
  • 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:
  • n 1 or 2;
  • 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 1 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when R 1 is -OH; R 2 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when R 1 is -OH; R 2 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when R 1 is -OH; R 2 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when R 1 is -OH; R 2 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when R 1 is -OH; R 2 is
  • the present invention relates to the aformentioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl.
  • the present invention relates to the aforementioned
  • R 2 and A 1 , A 2 , A3, 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.
  • the present invention relates to the aforementioned
  • R 2 A 1 , A 2 , A 4 and A5 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 2 is A5 A 4 ;
  • Ai, A 2 , A3 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl.
  • the present invention relates to the aforementioned
  • R 3 is B5 B 4 ; and B 1 , B 2 , B 3 , B 4 and B 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.
  • the present invention relates to the aforementioned
  • R 3 is B 5 B 4 ; B I; 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.
  • the present invention relates to the aforementioned
  • Bi, 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl.
  • the present invention relates to the aforementioned
  • R 4 is D 5 D 4 ; and Di, D 2 , D 3 , D 4 and D 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.
  • the present invention relates to the aforementioned
  • Di, D 2 , D 4 and D 5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned
  • R 4 is D 5 D 4 ;
  • Di, D 2 , D 3 and Ds are hydrogen; and
  • D4 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • R 5 is alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH; R 2 is aralkyl or heteroaralkyl; R 3 is aryl or heteroaryl; and R 4 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH; R 2 is aralkyl or heteroaralkyl; R 3 is aryl or heteroaryl; and R 5 is alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R] is OH; R 2 is aralkyl or heteroaralkyl; R 4 is aryl or heteroaryl; and R 5 is alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH; R 3 is aryl or heteroaryl; R 4 is aryl or heteroaryl; and R 5 is alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH; R 2 is aralkyl; R 3 is aryl; R 4 is aryl; and R 5 is alkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH; R 2 is aralkyl; R 3 is aryl; R 4 is aryl; and R 5 is aralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH; R 2 is aralkyl; R 3 is aryl; R 4 is aryl; and R 5 is heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is OH; R 2 is aralkyl; R 3 is aryl; R 4 is aryl; and R 5 is (heterocyclyl)alkyl.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula II:
  • R 3 is alkyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is aryl, heteroaryl, aralkyl or heteroaralkyl
  • R 6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • 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 compound and any of the attendant definitions, wherein R 3 is aryl.
  • the present invention relates to the aforementioned
  • R 3 is and Bi
  • B 2 , B 3 , B 4 and B 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 3 is Bi, 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 3 i 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl. In certain embodiments, the present invention relates to the aforementioned
  • R 4 is D 5 D 4 ; an d Di, D 2 , D 3 , D 4 and D 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.
  • the present invention relates to the aforementioned
  • R 4 Di, D 2 , D 4 and D 5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned
  • R 4 Di, D 2 , D 3 and D 5 are hydrogen; and D4 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl, heterocyclyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl; and R 4 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl; and R 6 is alkyl, heterocyclyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl or heteroaryl; and R 6 is alkyl, heterocyclyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl; R 4 is aryl or heteroaryl; and R 6 is alkyl, heterocyclyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl; and R 4 is aryl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl; and R 6 is alkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl; and R 6 is alkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl; R 4 is aryl; and R 6 is alkyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 )2;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) p N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl;
  • p is 1-10 inclusive; and
  • R 6 is
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl;
  • p is
  • Another aspect of the present invention relates to a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • Another aspect of the present invention relates to a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • W is selected, independently for each occurrence, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected, independently for each occurrence, from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IIIA:
  • n 1 or 2;
  • X 2 is absent, -O-, -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, 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 undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when n is 1; R 1 is -OH; R 2 is 1
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is -OH.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl.
  • the present invention relates to the aforementioned
  • R 2 is A 5 A 4 ; and Ai, 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, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 is and As are hydrogen; and A 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloallcyl, 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.
  • the present invention relates to the aforementioned
  • 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, cycloallcyl, 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.
  • 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.
  • R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • R 3 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is alkyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned
  • R 7 is Bs ⁇ 4 ; and B 1 , B 2 , B 3 , B 4 and B 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.
  • the present invention relates to the aforementioned
  • R 7 is 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.
  • the present invention relates to the aforementioned
  • R 7 is 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is alkyl, (cycloalkyl)alkyl or aralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein 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.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IIIB: wherein, independently for each occurrence, n is 1 or 2; Xi is absent, -O-, -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 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl
  • R 4 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl
  • R 7 is hydrogen, alkyl, (cycloalkyl)alkyl, (arnino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl
  • the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when n is 1; R 1 is -OH; R 2 is
  • Xi is absent; R 3 is is H; R 7 is no
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when n is 1; R 1 is -OH; R 2 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent.
  • the present invention relates to the aforementioned 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl.
  • the present invention relates to the aforementioned
  • R 2 is and Ai, 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, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 is 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned
  • R 2 is A 5 A 4 ;
  • Ai, 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned
  • R 7 is B 5 B4 ; and Bi, B 2 , B 3 , B 4 and B 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.
  • the present invention relates to the aforementioned
  • R 7 is 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.
  • the present invention relates to the aforementioned
  • R 7 Bi, 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is alkyl, (cycloalkyl)alkyl or aralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi 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.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IVA:
  • 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;
  • R 7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl; and the stereochemical configuration at any undefined stereocenter is R or S.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaralkyl.
  • 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 compound and any of the attendant definitions, wherein R 7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.
  • R 3 is aryl or heteroaryl
  • R 4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl
  • R 7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.
  • the present invention relates to the aforementioned
  • R 3 is anc ⁇ D 1 , D 2J D 3 , D 4 and D 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.
  • the present invention relates to the aforementioned
  • R 3 is D 1 , D 2 , D 4 and D 5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned.
  • R 3 is D 1 D 2 , D 3 and Ds are hydrogen; and D 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is -Ph.
  • the present invention relates to the aforementioned
  • R 7 is Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IVB:
  • R 3 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl;
  • R 4 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl; and the stereochemical configuration at any undefined stereocenter is R or S.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is alkyl, cycloalkyl or (cycloalkyl)alkyl .
  • the present invention relates to the aforementioned compound and any of the attendant definitions, R 4 is aryl or heteroaryl; R 3 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl; and R 7 is alkyl, cycloalkyl or (cycloalkyl)alkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, R 4 is aryl or heteroaryl; R 3 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl; and R 7 is alkyl, cycloalkyl or (cycloalkyl)alkyl. In certain embodiments, the present invention relates to the aforementioned
  • R 4 is D 5 D 4 • and D 1 , D 2 , D 3 , D 4 and D 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 4 is Di, D 2 , D 4 and D 5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned
  • R 4 is D 5 D 4 ; Di, D 2 , D 3 and D 5 are hydrogen; and D4 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is -Ph.
  • the present invention relates to the aforementioned
  • R 7 is Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VA:
  • X 2 is absent, -O-, -S- or -NR-;
  • R 1 is -OH, -SH or -NHR;
  • R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
  • R 2 ' is hydrogen, allcyl, 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 undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • 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 compound and any of the attendant definitions, wherein R 1 is -OH.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl.
  • the present invention relates to the aforementioned
  • R 2 is A5 A 4 ; and Ai, 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, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 is A 5 A 4 ;
  • a 1 , A 2 , A 4 and As 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, trifluorornethyl or cyano.
  • the present invention relates to the aforementioned
  • 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is (heterocyclyl)alkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent; R 1 is -OH; R 2 is aralkyl; R 3 is aryl; 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 VB:
  • Xi is absent, -O-, -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 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, 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 undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when n is 1; R 1 is -OH; R 2 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • 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 1 is -OH.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl.
  • the present invention relates to the aforementioned
  • R 2 is A5 A 4 ; and A 1 , A 2 , A 3 , A 4 and A5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 is A 5 A 4 ; Ai, 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 2 is h ⁇ , 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • 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.
  • R 4 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X] is absent; R 1 is -OH; R 2 is aralkyl; R 4 is aryl; R 3 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 VIA:
  • R 1 is -OH or -NH 2 ;
  • 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 aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl;
  • R 6 is alkyl, cycloalkyl, or aryl; and the stereochemical configuration at any undefined stereocenter is R or S.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is -OH.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is -NH 2 . In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is -O-.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is heterocyclyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is -O-; and R 4 is heterocyclyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl.
  • the present invention relates to the aforementioned
  • R 3 is and D 1 , D 2 , D 3 , D 4 and D 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • R 3 is D 1 ; D 2 , D 4 and D 5 are hydrogen; and D 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 3 is Di, D 2 , D 3 and D 5 are hydrogen; and D 4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is -CH(CH 3 ) 2 .
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VIB:
  • R 1 is -OH or -NH 2 ;
  • R 3 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl;
  • R 4 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • Re is alkyl, cycloalkyl, or aryl; and the stereochemical configuration at any undefined stereocenter is R or S.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when n is 1; R 1 is -OH; Xj is -
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is -OH.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is -NH 2 .
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is -O-.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is heterocyclyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is -O-; and R 3 is heterocyclyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl or heteroaryl.
  • the present invention relates to the aforementioned
  • R 4 i j and Di, D 2 , D 3 , D 4 and D5 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.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • R 4 is Di, D 2 , D 4 and D5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned
  • R 4 is Di, D 2 , D 3 and D 5 are hydrogen; and D 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is -CH(CH 3 ) 2 .
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VIIA:
  • X 2 is absent, -O-, -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 undefined stereocenter is R 1 S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when n is 1; R 1 is -OH; R 2 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Rj is -OH or -NH 2 .
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl.
  • 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
  • R 2 is an( j Ai, 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, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 is 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 2 is 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R. 3 is aryl or heteroaryl.
  • 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 compound and any of the attendant definitions, wherein R5 is alkyl or aryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent; R 1 is -OH; R 2 is aralkyl; R 3 is aryl; R 4 is (amido)alkyl or heterocyclyl; and R 5 is alkyl or aryl.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VIIB:
  • Xi is absent, -O-, -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 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is hydrogen, alkyl, alkenyl, (amino)alkyl, (a ⁇ nido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, 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 undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when n is 1; R 1 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 1 is -OH or -NH 2 .
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl.
  • 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
  • R 2 is 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • 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, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 2 is A5 A 4 ;
  • a 1 , A 2 , A 3 and A5 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, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • 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 aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl or aryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; R 1 is -OH; R 2 is aralkyl; R 4 is aryl; R 3 is (amido)alkyl or heterocyclyl; and R 5 is alkyl or aryl.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VIIIA:
  • X 2 is absent or -O-;
  • 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 aryl, heteroaryl, aralkyl or heteroaralkyl
  • R 6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl
  • the stereochemical configuration at any undefined stereocenter is R or S.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when X 2 is absent; R 3 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl.
  • the present invention relates to the aforementioned
  • R 3 is and D 1 , D 2 , D 3 , D 4 and D 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • R 3 D 1 , D 2 , D 4 and D 5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned
  • R 3 D 1 , D 2 , D 3 and D 5 are hydrogen; and D4 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.
  • the present invention relates to the aforementioned 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
  • the present invention relates to the aforementioned
  • W is anc ⁇ D 1 , D 2 , D 3 , D 4 and D 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.
  • the present invention relates to the aforementioned
  • W is D 1 , D 2 , D 4 and D 5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned
  • W is D 1 ., D 2 , D 3 and D 5 are hydrogen; and D4 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.
  • 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
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VIIIB:
  • R 3 is aryl, heteroaryl, aralkyl or heteroaralkyl
  • R 4 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R ⁇ is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl; and the stereochemical configuration at any undefined stereocenter is R or S.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, provided that when n is 1; R] is -OH; R 2 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned
  • D 2 , D 3 , D 4 and D 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • Di, D 2 , D 4 and D 5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned
  • R 4 is D 1 , D 2 , D 3 and D5 are hydrogen; and D4 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is (amino)alkyl, (amido)alkyl or heterocyclyl. In certain embodiments, the present invention relates to the aforementioned
  • R 3 is and W is aryl or heteroaryl.
  • the present invention relates to the aforementioned
  • D 2 , D 3 , D 4 and D 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.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is D 1 , D 2 , D 4 and D 5 are hydrogen; and D 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.
  • the present invention relates to the aforementioned
  • W is Di, D 2 , D 3 and D 5 are hydrogen; and D4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl or aryl.
  • the present invention relates to the aforementioned
  • Another aspect of the present invention relates to a copmpound, or a of
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IX:
  • n is 1 or 2;
  • 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; and the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1. In certain embodiments, the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • n is 1 or 2;
  • 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 hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 7 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is hydrogen or alkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is methyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is hydrogen.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula XI:
  • n 1 or 2;
  • 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 hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is hydrogen.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula XII: wherein, independently for each occurrence, n is 1 or 2; Z is hydrogen, R 4 , or OR 4 ;
  • 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 hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Z is hydrogen.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Z is R 4 . i
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Z is OR 4 . In certain embodiments, the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula XIII: wherein, independently for each occurrence, n is 1 or 2; m is 1 or 2;
  • 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 hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein m is 1.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • n is 1 or 2;
  • 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 hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • 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 hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any undefined stereocenter is R, S, or a mixture of these configurations.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • W is selected, from the group consisting of -NHR 7 or -NHR(CH 2 ) P N(R 7 ) 2 ;
  • R 7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and
  • p is 1-10 inclusive.
  • Protease inhibitors I, II, V and VI can be prepared using the synthetic scheme shown in Figure 20a (top). As shown therein, an epoxide, for example, can be reacted with an amine in a stereoselective manner to yield amine 2. Amine 2 is reacted with sulfonyl chloride or an acyl chloride to yield 3. Deprotection followed by reaction with an acid chloride, for example, yields inhibitor I, II, V or VI.
  • Protease inhibitor III and IV can be prepared using the synthetic scheme shown in Figure 20a (bottom). Amino acid 5 can be converted to amine 6 using standard synthetic procedures. Reaction with an acid yields amide 7. Deprotection followed by reaction with an acid chloride yields inhibitor III or IV.
  • Protease inhibitor IV can be prepared using the synthetic scheme in Figure 20b. 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 VQ or VIII.
  • 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.
  • chiral N-phenyloxazolidine-5-carboxylic acids 9 and 10 used in the synthesis of designed inhibitors were prepared following the literature procedure as outlined in Figure 2. (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673-679; Hester, J. B. WO 2003/006440, hereby incorporated by reference; and Thomas, R. C. et al. WO 2003/072553, hereby incorporated by reference).
  • the intermediate chiral alcohols, 5- (hydroxymethyl)-3-aryl-oxazolidine-2-ones 7-8, were obtained from substituted anilines in two steps.
  • compositions comprising the manufacture and use of pharmaceutical compositions, which include the protease inhibitors described herein as active ingredients. Also included are the pharmaceutical compositions themselves. These compositions can be administered using routes of administration and dosages similar to those used for known HIV protease inhibitors.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, 66: 1-19, incorporated herein by reference.
  • suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • 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, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • compositions typically include a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions.
  • compositions are typically formulated to be compatible with their intended route(s) of administration.
  • routes of administration include parenteral, e.g., by intravenous, intradermal, or subcutaneous injection; or mucosal (e.g., by oral ingestion, inhalation, or rectal or vaginal administration) administration.
  • compositions intended for parenteral administration can include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates and agents for the adjustment of tonicity, such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide, as appropriate.
  • a parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use can include sterile aqueous solutions (where the active ingredient is water soluble) or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent necessary to allow administration via syringe. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols, such as mannitol, sorbitol, and/or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin; or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring.
  • 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
  • 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.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the pharmaceutical compositions can also be prepared in the form of suppositories (e.g., with conventional suppository bases, such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Such formulations can be prepared using standard techniques.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811; hereby incorporated by reference.
  • kits 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.
  • HTV protease inhibitor activities were determined by fluorescence resonance energy transfer (FRET) method.
  • FRET fluorescence resonance energy transfer
  • Protease substrate (Arg- GIu(ED ANS)-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.
  • Ki value Inhibitor binding dissociation constant was obtained by nonlinear regression fitting to the plot of initial velocity as a function of inhibitor concentration based on Morrison equation. (Greco, W. R. et al J. Biol. 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 Figure 5.
  • protease inhibitors with potent activities against wild type protease was studied against a panel of multidrug-resistant (MDR) mutants of HIV-I proteases each representing different paradigms of resistance.
  • the mutant variants were selected by examining the Stanford HIV-1 Drug Resistance Database (http://hivdb.stanford.edu) of HIV-1 infected-patient sequences of viral isolates.
  • the three selected protease variants represent the pattern of resistance mutations that occur under the selective pressure of three or more currently prescribed protease inhibitors. (Wu, T. D. et al. J. Virol.
  • MDR mutant variants are LlOI, G48V, I54V, L63P, V82A (Ml), D30N, L63P, N88D (M2), and LlOI, L63P, A71 V, G73S, I84V, L90M (M3).
  • the inhibitory activities of selected protease inhibitors against M1-M3 mutant HIV-1 proteases were examined.
  • two currently marketed drugs amprenavir (APV) and lopinavir (LPV) were also studied against the selected panel of mutant proteases.
  • protease inhibitors based on hydroxyethylamine isostere incorporating unsubstituted iV-phenyloxazolidine-5-carboxamide were prepared and tested for their inhibitory activities against wild type HIV-I protease. It was also critical to determine which stereoisomer of phenyloxazolidine based P2 ligand will bind more favorably to the protease.
  • the inhibitor series 21 and 25-29 were prepared using small set of mainly substituted (S)-N-phenyloxazolidine-5-carboxylic acids lOb-g, linked to the (R)- (hydroxyethylamino)sulfonamides 14-19 as P2 ligands (Figure 3). AU the compounds were evaluated for their activities against wild type HIV-1 protease and Ki values are presented in Figure 5; Ki values of 21a and 25a are also included.
  • Ki values of 21b and 21c are 80 pM and 66 pM, respectively.
  • Introduction of polar groups, trifluoromethyl, acetyl and methoxy, at positions 3 and 4 of the phenyl ring resulted in significant increase in the potency of the inhibitors.
  • the Ki value of compound 21d with 3- trifluoromethyl group is 6 pM and the 3-methoxy analog 21g showed Ki value of 45 pM.
  • Inhibitors 21e and 21f with 3- and 4-acetyl groups are the most potent HIV-1 protease inhibitors discovered in our studies with Ki values of 0.8 pM and 4 pM, respectively.
  • Inhibitors with 3- fluoro (25b), 3,4-di-fluoro (25c) and 4-acetyl (25f) groups at the phenyl ring showed relatively small improvement in activities compared to 25a ( Figure 5, entries 9-10 & 13).
  • inhibitors with 3- trifluoromethyl (26d), 3-acetyl (26e) and 4-acetyl (26f) groups at the phenyl ring of oxazolidine were the most potent against HIV-1 protease with Ki values of 16 pM, 6 pM and 16 pM, respectively.
  • Ki values of 16 pM, 6 pM and 16 pM were the most potent against HIV-1 protease with Ki values of 16 pM, 6 pM and 16 pM, respectively.
  • Selected primary amines 30a-c include small hydrophobic group cyclopropylmethylamine as well as polar saturated (S)-(2- tetrahydrofuranyl)methylamine and unsaturated 2-(thiophenyl)methylamine heterocyclic groups.
  • Sulfonyl chlorides utilized at R position are all substituted benzene derivatives containing functional groups at various positions.
  • Ki values of 36b (257 pM), 36c (580 pM) and 36f (80 pM) are about 3, 9 and 200 fold higher than the corresponding inhibitors with isobutyl group at Pl ' position.
  • Inhibitors 37-39 with (2- thiophenyl)methyl, and (S)-(2-tetrahydrofuranyl)methyl groups at Pl' position all showed very weak inhibitory activities against HIV-1 protease (Table 2 entries 4-11).
  • Selected Inhibitor Activities against MDR Mutants Selected inhibitors that exhibited potent activities against wild type HIV-1 protease were further evaluated for their activities against a panel of MDR mutant variants. At least one compound was selected from each of the series incorporating different phenyloxazolidine based P2 ligands. In some cases, different functional group variations on benzenesulfonamide fragment were selected in preference to compounds with lowest Ki values in that series. The Ki values of selected inhibitors against M1-M3 MDR mutant protease are presented in Figure 8. Two known drugs, amprenavir (APV, a structurally related compound) and lopinavir (LPV) were also studied for comparisons.
  • AAV amprenavir
  • LDV lopinavir
  • the activity of the most potent protease inhibitor from this series, 21e was less affected by drug resistance mutations and showed quite potent activity against Ml and M2 MDR enzymes and inhibited Ml and M2 MDR enzymes with a Ki values of 160 pM and 39 pM, respectively.
  • Methods of Treatment include methods for the treatment or prevention of a viral infection, e.g., an HIV, infection and Acquired Immunodeficiency Syndrome (AIDS) or AIDS Related Complex (ARC).
  • the methods include administering a therapeutically effective amount of a protease inhibitor described herein, to a subject (e.g., a human or other primate) in need thereof, or who has been determined to be in need of, such treatment, e.g., a subject who is (or is determined to be) infected with HIV.
  • a subject who is likely to be infected with HIV e.g., a person in a high risk group, may also be treated as indicated herein.
  • Subjects also include women who are expecting a child (pregnant women) and in whom a treatment reduces the liklihood of transmission of HIV to the child.
  • the methods described herein are also expected to be beneficial for treating or preventing HIV-2 infections.
  • HIV-I viruses it is expected that the methods will be effective against any HIV-I strain, such as those of group M, O and N, and subtypes A, B, C, D, E, F, G, H, I, J and K and "circulating recombinant forms" or CRFs thereof.
  • the compounds described herein may also be used for treating any other viral infections in which the viral agent has a protease inhibitor that can be inhibited by the compounds described herein.
  • to "treat” means to ameliorate at least one clinical symptom or parameter of HIV infection or preventing it from worsening or preventing the transmission of HIV, e.g., from mother to child.
  • a treatment can result in a reduction in viral load, and/or an increase in number of CD4+ T cells ("CD4 count").
  • CD4 count When a subject has achieved a reduction in viral load, and/or an increase in CD4 count, then treatment may also include maintaining the reduction in viral load, and/or the increased CD4 count, e.g., preventing a resurgence of viral load and/or a decrease in CD4 count.
  • viral load can be measured, e.g., using PCR or branched DNA (bDNA) assays known in the art.
  • CD4 counts can be measured, e.g., using hematology, DYNAbeadsTM (Dynal Biotech/Invitrogen Corp., Brown Deer, WI), flow cytometry (e.g., FACSCountTM, BD Biosciences, Franklin Lakes, NJ) or enzyme-linked immunosorbent assay (ELISA) methods (see, e.g., Lyamuya et al., J. Immunol. Methods 195(l-2):103-12 (1996); Paxton et al., Clin. Diagn. Lab. Immunol.
  • Healthy adults and teenagers generally have a CD4 count of at least 800 cells per cubic millimeter of blood; a CD4 count below 200 is associated with severe risk of illness (e.g., AIDS-related diseases, such as Kaposi's sarcoma or pneumocystic pneumonia).
  • Current guidelines suggest treatment for HIV should be started when the CD4 count is less than about 350 and/or the viral load is greater than about 50,000.
  • a “therapeutically effective amount” is an amount sufficient to effect a desired therapeutic effect, e.g., a reduction in viral load, and/or an increase in number of CD4+ T cells.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a composition may depend on the composition selected.
  • the compositions can be administered once, one or more times per day, and/or one or more times per week; including once every other day. In certain embodiments, the compositions will be administered two or three times per day.
  • Treatment of a subject with a therapeutically effective amount of a protease inhibitor described herein can include a single treatment or a series of treatments.
  • Dosage, toxicity and therapeutic efficacy of the compounds can be determined, e.g., by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds that exhibit high therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to select a dose and administration schedule that minimizes severe side effects while maximizing therapeutic efficacy.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective dosage range can be estimated initially from cell culture assays.
  • a dose can be further formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC50 i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • a therapeutically effective amount of a new protease inhibitor described herein ranges from about 0.1 to 10 mg per day, or about 0.3 to 5 mg/day.
  • 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 highly active antiretroviral therapy (HAART) regimen that includes one or more other anti- retroviral agents.
  • HAART highly active antiretroviral therapy
  • the methods may include administration of one or more of a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz (SustivaTM), nevirapine (ViramuneTM) and delavirdine (RescriptorTM), 8 and 9-Cl TIBO (tivirapine), loviride, TMC-125, dapivirine, MKC-442, UC 781, UC 782, Capravirine, DPC 961, DPC963, DPC082, DPC083, calanolide A, SJ-1366, TSAO, 4"-deaminated TSAO, MV150 and MV026048; a nucleoside reverse transcriptase inhibitor (NRTI), such as AZT (zidovudine, RetrovirTM)/3TC (lamivudine, EpivirTM), emtricitabine (EmtrivaTM) and d4T (stavudine, ZeritTM)/3TC, and
  • AMD3451 (Bicyclams), TAK 779; SHC-C (SCH351125), SHC-D, PRO-140RT inhibitors, such as foscarnet and prodrugs; an RNAse H inhibitor, such as SP1093V and PD126338; a TAT inhibitor, such as RO-5-3335, K12 and K37; an integrase inhibitor, such as L 708906, L 731988 and S-1360; another protease inhibitor, such as amprenavir and prodrug GW908, nelf ⁇ navir, 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, PD17839
  • agents that inhibit metabolic enzymes e.g., inhibitors of cytochrome P450 (CYP450) enzymes.
  • CYP450 cytochrome P450
  • a compound described herein may be administered, simultaneously or not, with an inhibitor of CYP3A4, e.g., Ritonavir, or an inhibitor of CYP2C19, CYP1A2, CYP2D6, or CYP2C9.
  • CYP3A4 e.g., Ritonavir
  • Exemplary inhibitors of 2C9 are described, e.g., in U.S. publication No. 2006.0069042, hereby incorporated by reference.
  • the compounds of the present invention may also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, methionine 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.
  • immunomodulators e.g., bropirimine, anti-human alpha interferon antibody, IL-2, methionine enkephalin, interferon alpha, HE-2000 and naltrexone
  • antibiotics e.g., pentamidine isothiorate
  • cytokines e.g. Th2
  • the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of amprenavir (Agenerase®; APV), tipranavir (Aptivus®; TPV), indinavir (Crixivan®; IDV), saquinavir (Invirase®; SQV), lopinavir and ritonavir (Kaletra®; LPV), fosamprenavir (Lexiva®; FPV), ritonavir (Norvir®; RTV), atazanavir (Reyataz®; ATZ), nelfmavir (Viracept®; NFV), brecanavir, and darunavir.
  • amprenavir Amrenavir
  • APV tipranavir
  • TPV tipranavir
  • IDV indinavir
  • saquinavir Invirase®
  • lopinavir and ritonavir Kaletra®
  • the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is ritonavir (Kaletra®; LPV).
  • the second therapeutic agent is ritonavir (Kaletra®; LPV).
  • 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; ddl; 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) .
  • the second therapeutic agent is selected from the group consisting of zidovudine (AZ
  • the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of nevirapine (BI-RG-587; Viramune®), delavirdine (BHAP; U-90152; Rescriptor®), and (efavirenz; DMP-266; Sustiva®).
  • 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®).
  • the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is T-20 (Fuzeon®; Enfuvirtide; DP- 178; Pentafuside; GP41 127-162 AA).
  • T-20 Filon®; Enfuvirtide; DP- 178; Pentafuside; GP41 127-162 AA.
  • the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is TMCCl 14, or TMCCl 14 in combination with a reverse transcriptase inhibitor. In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is Lipinavir, or Lupanivir in combination with a reverse transcriptase inhibitor.
  • Combination therapy in different formulations may be administered simultaneously, separately or sequentially. Alternatively, such combination may be administered as a single formulation, whereby the active ingredients are released from the formulation simultaneously or separately.
  • Compositions comprising at least two inhibitors described herein and/or one or more other protease inhibitors and/or other therapeutic agents are also provided herein.
  • the compounds of the invention can be combined with one or more of any anti-HTV compounds (e.g. those listed in Figure 16). Additional compounds which may be combined with one or more of the inventive compounds, and further discussion of combination therapy can be found in Yeni, P. G. et al. JAMA 2004, 292(2), 251-265; Pozniak, A. et al. Business Briefing: Clinical Virology & Infectious
  • HIV Human Immunodeficiency Virus
  • HIV-1 HIV-1
  • HIV-2 HIV-2
  • the strains of HIV-1 can be classified into three groups: the "major” group M, the "outlier” group O and the "new” group N. These three groups may represent three separate introductions of simian immunodeficiency virus into humans.
  • M-group there are at least ten subtypes or clades: e.g., clade A, B, C, D, E, F, G, H, I, J, and K.
  • a "clade” is a group of organisms, such as a species, whose members share homologous features derived from a common ancestor. Any reference to HIV in this application includes all of these tupes and strains.
  • retroviruses are diploid positive-strand RNA viruses that replicate through an integrated DNA intermediate (proviral DNA).
  • proviral DNA DNA intermediate
  • the lentiviral genome is reverse-transcribed into DNA by a virally encoded reverse transcriptase that is carried as a protein in each retrovirus.
  • the viral DNA is then integrated pseudo-randomly into the host cell genome of the infecting cell, forming a "provirus” which is inherited by daughter cells.
  • the retrovirus genome contains at least three genes: gag codes for core and structural proteins of the virus; pol codes for reverse transcriptase, protease and integrase; and env codes for the virus surface proteins.
  • HIV is classified as a lentivirus, having genetic and morphologic similarities to animal lentiviruses such as those infecting cats (feline immunodeficiency virus), sheep (visna virus), goats (caprine arthritis-encephalitis virus), and non-human primates (simian immunodeficiency virus).
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • 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.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone ⁇ e.g., C 1 -C 3 0 for straight chain, C 3 -C 30 for branched chain), and alternatively, about 20 or fewer.
  • 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.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • aralkyl is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • 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.
  • 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.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF 3 , -CN, or the like.
  • 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.
  • 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.
  • heterocyclyl refers to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroa toms.
  • Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • 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 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.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
  • carrier is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro is art-recognized and refers to -NO 2 ;
  • halogen is art- recognized and refers to -F, -Cl, -Br or -I;
  • sulfhydryl is art-recognized and refers to -SH;
  • hydroxyl means -OH;
  • sulfonyl is art-recognized and refers to -SO 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.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: -N(R51)(R50) or [-N(R50)(R52)(R53)] + , wherein R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, -(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.
  • R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) m -R61.
  • 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.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH 2 ) m -R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 ) m -R61.
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 ) m -R61.
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH 2 ) m
  • alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH 2 ) m -R61, where m and R61 are described above.
  • Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • the definition of each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, />-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations .
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • 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.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, "Handbook of Chemistry and Physics", 67th Ed., 1986-87, inside cover.
  • Analytical reversed-phase high performance liquid chromatography was performed on a Waters Separation Module 2695 system equipped with an auto sampler and a Waters 996 photodiode array detector. Purity of the final compounds was determined using two different chromatographic systems. First system: column, Waters ⁇ ova-Pak RP- Cl 8 (4 ⁇ m, 3.9 mm x 150 mm); mobile phase A, 10 mM ammonium acetate in water; mobile phase B, acetonitrile. Using a flow rate of 0.8 mL/min, gradient elution was performed from 50% B to 100% B over 10 min.
  • Second system column, Agilent Zorbax 300SB-C8 (5 Dm, 4.6 mm x 250 mm); mobile phase A, 0.1% trifluoroacetic acid in water; mobile phase B, 0.1% trifluoroacetic acid in acetonitrile. Gradient elution was performed from 50% B to 100% B over 10 min at a flow rate of 1 mL/min. A table containing the retention time and purity of each final compound is shown in Figure 9.
  • HIV-1 protease inhibitor activities were determined by fluorescence resonance energy transfer (FRET) method (Matayoshi, E. D.; Wang, G. T.; Krafft, G. A.; Erickson, J. Novel fluorogenic substrates for assaying retroviral proteases by resonance energy transfer. Science 1990, 247, 954-958.)
  • FRET fluorescence resonance energy transfer
  • Protease substrate (Arg-Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro- Ile-Val-Gln-Lys(DABCYL)-Arg) was purchased from Molecular Probe.
  • the energy transfer donor (EDANS) and acceptor (DABCYL) were labeled at its two ends respectively to perform FRET. Fluorescence measurements were carried out on PTI fluorescence spectrophotometer (Photon Technology International) at 30 oC. Excitation and emission wavelengths were set at 340 run and 490 nm, respectively. Each reaction was recorded for about 10 min.
  • Substrate buffer is composite of 0.1 M sodium acetate, 1 M sodium chloride, 1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM dithiothreitol (DTT), 2% dimethylsulfoxide (DMSO) and 1 mg/niL bovine serum albumin (BSA) with an adjusted pH 4.7.
  • EDTA ethylenediaminetetraacetic acid
  • DTT dithiothreitol
  • BSA bovine serum albumin
  • Inhibitor binding dissociation constant (Ki) was obtained by nonlinear regression fitting (GraFit 5, Erithacus software) to the plot of initial velocity as a function of inhibitor concentrations based on Morrison equation. (Greco, W. R.; Hakala, M. T. Evaluation of methods for estimating the dissociation constant of tight binding enzyme inhibitors. J. Biol. Chem. 1979, 254, 12104-12109.) The initial velocities were derived from the linear range of reaction curves.

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