WO2008118849A2 - Hiv-1 protease inhibitors - Google Patents

Hiv-1 protease inhibitors Download PDF

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Publication number
WO2008118849A2
WO2008118849A2 PCT/US2008/058004 US2008058004W WO2008118849A2 WO 2008118849 A2 WO2008118849 A2 WO 2008118849A2 US 2008058004 W US2008058004 W US 2008058004W WO 2008118849 A2 WO2008118849 A2 WO 2008118849A2
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WIPO (PCT)
Prior art keywords
alkyl
compound
heterocyclyl
amino
amido
Prior art date
Application number
PCT/US2008/058004
Other languages
French (fr)
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WO2008118849A3 (en
Inventor
Akbar Ali
Michael D. Altman
Saima Ghafoor Anjum
Hong Cao
Sripriya Chellappan
Miguel X. Fernandes
Michael Gilson
Visvaldas Kairys
Nancy King
Ellen Nalivaika
Moses Prabu
Tariq M. Rana
Kiran Kumar Reddy Garudammagari Sai
Celia A. Schiffer
Bruce Tidor
Madhavi Naga Laxmi NALAM
Original Assignee
University Of Massachusetts
University Of Maryland Biotechnology Institute
Massachusetts Institute Of Technology
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Publication date
Application filed by University Of Massachusetts, University Of Maryland Biotechnology Institute, Massachusetts Institute Of Technology filed Critical University Of Massachusetts
Priority to EP08744245A priority Critical patent/EP2139883A4/en
Priority to CA002681718A priority patent/CA2681718A1/en
Priority to CN200880016701A priority patent/CN101702908A/en
Publication of WO2008118849A2 publication Critical patent/WO2008118849A2/en
Publication of WO2008118849A3 publication Critical patent/WO2008118849A3/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • 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
    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors

Definitions

  • HIV-I 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-I protease leads to the production of noninfectious virus particles and hence is a promising therapeutic target for antiviral therapy in AIDS patients.
  • PIs Protease inhibitors
  • IAS-USA International AIDS Society-USA
  • DHHS U.S. Department of Health and Human Services
  • HIV-I protease inhibitors represent the most potent anti-AIDS drugs reported to date and are essential components of highly active antiretro viral therapy
  • HIV-I protease inhibitors saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, and tipranavir
  • saquinavir HIV-I protease inhibitors
  • indinavir HIV-I protease inhibitors
  • ritonavir nelfinavir
  • amprenavir lopinavir
  • lopinavir atazanavir
  • tipranavir are 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-I protease substrates.
  • the development and clinical introduction of anti-AIDS HIV-I protease inhibitors is regarded as major success of structure based drug design.
  • Anti-AIDS chemotherapy based on HIV-I protease and reverse-transcriptase inhibitors has been remarkably successful in decreasing the mortality rate in HIV-I infected patients.
  • HIV-I 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.
  • HIV-I protease inhibitors were designed to inhibit a single variant of HIV-I protease.
  • MDR multi drug resistant
  • HIV protease is a particularly appealing target, as inhibition of its activity is clinical effective; however, it can evolve to tolerate extensive mutation that confers drug resistance while retaining enzymatic function.
  • the present invention is based, at least in part, on the discovery of new small molecule protease inhibitors (PIs). These inhibitors, and methods of making and using them, are described herein. Because these inhibitors do not protrude beyond the substrate binding envelope on the protease, it is expected that these inhibitors will be less likely to induce the development of resistant strains.
  • PIs 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 HIV in a subject, by administering a therapeutically effective amount of a compound or pharmaceutical composition described herein.
  • the methods further include administering a second therapeutic agent, e.g., a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz (SustivaTM), nevirapine (ViramuneTM) and delavirdine (RescriptorTM); an nucleoside reverse transcriptase inhibitor (NRTI) such as AZT
  • NRTI non-nucleoside reverse transcriptase inhibitor
  • NRTI nucleoside reverse transcriptase inhibitor
  • AZT AZT
  • the compound or pharmaceutical composition is administered as part of a highly active antiretro viral therapy (HAART) regimen.
  • HAART highly active antiretro viral therapy
  • Figures la-b depict possible synthetic routes to selected inventive compounds.
  • Figures 2a-k depict anti-HIV drugs by class.
  • Figure 3 depicts the synthesis of protease inhibitors containing [A] a hydroyethylamine (HEA) core or [B] a hydroxyethylene (HE) core.
  • EtOH 70 0 C
  • aq. Na 2 CO 3 CH 2 Cl 2 , r. t
  • (c) TFA, CH 2 Cl 2 ;
  • Et 3 N THF
  • Figure 4 depicts the synthesis of protease inhibitors containing an aza- hydroxyethylamine (Aza-HEA) core. Key: (a) (CH 3 ) 2 CHOH, 80 0 C (b) H 2 , Pd/C, MeOH, r. t; (c) R 4 X 2 CO 2 H, EDCI, HOBt, DIPEA, O 0 C to r. t; (d) TFA, CH 2 Cl 2 ; and (e) R 3 XiCO 2 H, EDCI, HOBt, DIPEA, O 0 C to r. t; aq. NaHCO 3 , EtOAc.
  • Figure 5 depicts a comparison of isobutyl and (5)-2-methylbutyl moieties as Pl' ligands: Inhibitory activities against wild-type and MDR mutant variants of HIV-I protease.
  • Figure 6 depicts selected compounds of formula I and associated K values.
  • FIG. 7 depicts selected compounds of formula I.
  • Figure 8 depicts the chemical structures of amprenavir (APV) 1, TMCl 14 2 and selected compounds of the invention 3.
  • Figure 9 depicts a scheme showing the synthesis of intermediates N- Phenyloxazolidine-5-carboxylic acids 9 and 10. Key: (a) n-BuLi, THF, -78 0 C to r. t. overnight; (b) RuCl 3 -H 2 O, CH 3 CN-CCl 4 -H 2 O (2:2:3), 0 °C to r. t. 4-10 h.
  • Figure 10 depicts a scheme showing the synthesis of inventive compounds 20-29. Key: (a) EtOH, 80 0 C, 3-4 h; (b) aq. Na 2 CO 3 , CH 2 Cl 2 , 0 0 C to r. t, 4-8 h; (c) TFA, CH 2 Cl 2 , 1 h; (d) (OCOCl) 2 , r. t, overnight; (e) Et 3 N, THF, 0 0 C to r. t, 4-8 h; (fj SnCl 2 .2H 2 O, EtOAc, 70 0 C, 2 h.
  • Figure 11 depicts a scheme showing the synthesis of compounds 36-39. Key: (a) zPrOH or EtOH, 80 0 C, 3-4 h; (b) aq. Na 2 CO 3 , CH 2 Cl 2 , 0 °C to r. t, 4-8 h; (c) TFA, CH 2 Cl 2 , 1 h; (d) (OCOCl) 2 , r. t, overnight; (e) Et 3 N, THF, 0 0 C to r. t, 4-8 h.
  • Figure 12 depicts selected compounds of formula XVA/XVB and associated K, values.
  • Figure 13 depicts selected compounds of formula XIIIA/XIIIB and associated K 1 values.
  • Figure 14 depicts selected compounds of formula XVIIA/XVIIB and associated K, values.
  • Figure 15a-b depict possible synthetic routes to selected inventive compounds.
  • Figure 16 depicts inhibitory activities of selected compounds against wild-type and MDR mutant variants of HIV-I protease.
  • Figure 17a-j depicts selected compounds and, in some cases, associated K 1 values.
  • HIV-I protease inhibitors that are less vulnerable to drug resistance and/or more active against current pro tease-resistant HIV-I 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.
  • certain compounds of the invention are competitive inhibitors that appear to bind in the center of the "substrate 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-I protease.
  • 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 antiretro viral therapy (HAART) regime.
  • HAART highly active antiretro viral therapy
  • One aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula I:
  • Xi is absent, -O-, -S-, -NR- or ZA ;
  • X 2 is absent, -O-, -S-, -NR- or
  • 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, (amino)alkyl, amido, amido, (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, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
  • R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
  • Xi is ZA ; or X 2 is ZA ; or R 3 is amino, ,
  • 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
  • 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 Xi is absent; and X 2 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri 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 compound and any of the attendant definitions, wherein R 3 is alkenyl, amino, (amino)alkyl, amido, (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 alkyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula II:
  • Xi is absent, -O- or ZA ;
  • R 3 is alkyl, alkenyl, amino, (amino)alkyl, amido, (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
  • R 3 is wherein
  • R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
  • Xi is ⁇ S ZAc*- H3C .. H 3 C ; or R 3 is amino, ⁇ o
  • 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
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkenyl, amino, (amino)alkyl, amido, (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 alkyl, aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
  • the present invention relates to the aforementioned
  • R 3 is CH 3
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • R 6 is CH 3 or CH s.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; and R 3 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, selected from the group consisting of
  • 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 III:
  • Xi is absent, -O-, -S-, -NR- or l ⁇ ;
  • X 2 is absent, -O-, -S-, -NR- or ⁇ ;
  • Ri 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, (amino)alkyl, amido, (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, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
  • R 3 A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
  • X is ZA ; or X 2 is ZA ; R 3 is amino, ⁇ 00
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xj is absent.
  • 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 Xi is absent; and X 2 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri 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 compound and any of the attendant definitions, wherein R 3 is alkenyl, amino, (amino)alkyl, amido, (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
  • 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
  • R 4 is 1 ⁇ 00 - ⁇ , ,
  • 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 compound and any of the attendant definitions, wherein R 7 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (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.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IV:
  • R 3 is alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is aryl, amino, (amino)alkyl, amido, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl;
  • R 7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl;
  • R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is not R 4A wherein R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
  • Xi is Z ⁇ ; or X 2 is ZA ; R 3 is amino, 1 ⁇ 00 ⁇ ,
  • 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 3 is amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • 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, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl.
  • the present invention relates to the aforementioned
  • 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, wherein Xj is absent; and R 3 is amino, (amino)alkyl, amido, (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 Xi is absent; R 3 is amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is aryl, amino, (amino)alkyl, amido, (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
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • R 7 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 a pharmaceutically acceptable salt thereof, of formula V:
  • Xi is absent, -0-, -S-, -NR- or I ⁇ ;
  • X 2 is absent, -0-, -S-, -NR- or Z ⁇ ;
  • R 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, (amino)alkyl, amido, (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, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
  • R 3 is not xr R 3A wherein
  • R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
  • Xj is Z ⁇ ; or X 2 is l ⁇ ; or R 3 is amino.
  • 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 Xi is -O-.
  • 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 Xi is absent or -O-; and X 2 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri 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 compound and any of the attendant definitions, wherein R 3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • R 3 is heterocyclyl.
  • 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 Xi is absent or -O-; X 2 is absent; Ri is OH; R 2 is aralkyl; R 3 is heterocyclyl; R 4 is alkyl, aryl or heteroaryl; and R 5 is alkyl.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VII:
  • Xi is absent, -O-, -S-, -NR- or ⁇ P:
  • a 7 A X 2 is absent, -O-, -S-, -NR- or Z ⁇ ;
  • Ri 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, (amino)alkyl, amido, (amido)alkyl,
  • R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 5 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
  • R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
  • Xi is Ll ⁇ ; or X 2 is L ⁇ ; or R 3 is amino.
  • 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 X 2 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; and X 2 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri is -OH or -NH 2 . In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl. In certain embodiments, 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 compound and any of the attendant definitions, wherein R 3 is alkenyl, amino, (amino)alkyl, amido, (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 (amido)alkyl or heterocyclyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is (amido)alkyl or heterocyclyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is alkyl or aryl.
  • One aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula XII:
  • 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 6 is ⁇ CH 3 Qr ⁇ CH 3 .
  • the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R 3 is
  • the present invention relates to any of the aforementioned
  • the present invention relates to any of the aforementioned .CH 3 compounds and any of the attendant definitions, wherein R 6 is CH 3.
  • the present invention relates to any of the aforementioned
  • 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
  • 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 a pharmaceutically acceptable salt thereof, of formula XII:
  • 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 any of the aforementioned
  • the present invention relates to any of the aforementioned
  • the present invention relates to any of the aforementioned
  • the present invention relates to any of the aforementioned
  • R 4 is ⁇ />- 0CH 3
  • the present invention relates to any of the aforementioned
  • 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:
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula iso-XII: iso-XII wherein, independently for each occurrence,
  • 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 any of the aforementioned compounds and any of the attendant definitions, wherein R 3 is aryl or heteroaryl.
  • the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R 3 is aryl. hi certain embodiments, the present invention relates to any of the aforementioned
  • the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R 4 is aryl or heteroaryl.
  • the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R 4 is aryl.
  • the present invention relates to any of 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 any of the aforementioned compounds and any of the attendant definitions, wherein R 6 is alkyl, heterocyclyl, aryl or heteroaryl. In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R 6 is alkyl.
  • the present invention relates to any of the aforementioned
  • R 6 is CH 3 , CH 3 s CH 3J o ⁇ > .0 H n
  • V- ⁇ 5 ⁇ _/ , - V ⁇ , or
  • the present invention relates to any of the aforementioned
  • R 6 is CH 3 .
  • the present invention relates to any of the aforementioned
  • the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R 3 is aryl or heteroaryl; and R 4 is aryl or heteroaryl.
  • protease inhibitors I, II, III, IV, V and VII can be synthesized using the synthetic schemes outlined in Figures la-b.
  • Protease inhibitors I, II, and V can be prepared using the synthetic scheme shown in Figure Ia (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, or V.
  • Protease inhibitor III and IV can be prepared using the synthetic scheme shown in Figure Ia (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 Ib. 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. Under certain conditions, further deprotection yields amine 11 followed by reaction with acid chloride yields inhibitor VII.
  • 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.
  • Protease inhibitors XII can be prepared using the synthetic scheme shown in Figure 15a (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 XI, XII, XV or XVI.
  • 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 9. (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.
  • the compounds 23b-f containing A- nitrophenylsulfonamide group at P2' position were transformed to the corresponding A- aminophenylsulfonamide derivatives 25b-f by the reduction of the nitro group.
  • series of compounds were prepared with variations at three different positions.
  • the isobutyl group at PlD position was replaced with three cyclic primary amines.
  • the target compounds were synthesized using an analogous synthetic route ( Figure 11). In brief, ring opening of epoxide 11 with primary amines 30a-c provided amino alcohols 31a-c.
  • 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, hi many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, and/or sodium chloride in the composition.
  • 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.
  • HIV 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
  • 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.
  • These MDR mutant variants are LlOI, G48V, I54V, L63P, V82A (Ml), D30N, L63P, N88D (M2), and LlOI, L63P, A71V, G73S, I84V, L90M (M3).
  • the methods described herein include methods for the treatment or prevention of a viral infection, e.g., an HIV, infection and Acquired
  • 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).
  • severe risk of illness e.g., AIDS-related diseases, such as Kaposi's sarcoma or pneumocystic pneumonia.
  • 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 LD5O/ED5O.
  • 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. Such information can be used to determine more accurately useful doses in humans.
  • 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- retro viral 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, DPCO83, calanolide A, SJ-1366, TSAO, 4"-deaminated TSAO, MVl 50 and MV026048; a nucleoside reverse transcriptase inhibitor (NRTI), such as AZT (zidovudine, RetrovirTM)/3TC (lamivudine, EpivirTM), emtricitabine (EmtrivaTM) and d4T (stavudine, ZeritTM)/3TC
  • 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, CYPl A2, 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 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
  • 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).
  • 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.
  • 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.
  • 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-HIV compounds (e.g. those listed in Figures 6a-k). Additional compounds which may be combined with one or more of the inventive compounds, and further discussion of combination therapy can be found in Yeni, P. G. et al. JAMA 2004, 292(2), 251-265; Pozniak, A. et al.
  • HIV Human Immunodeficiency Virus
  • HIV-I Human Immunodeficiency Virus
  • HIV-2 There are many different strains of HIV-I.
  • the strains of HIV-I 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.
  • clade A 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).
  • the lentiviral genome upon infection by the RNA virus, the lentiviral genome is reverse-transcribed into DNA by a virally encoded reverse transcriptase that is carried as a protein in each retrovirus.
  • the viral DNA is then integrated pseudo-randomly into the host cell genome of the infecting cell, forming a "provirus" which is inherited by daughter cells.
  • the retrovirus genome contains at least three genes: gag codes for core and structural proteins of the virus; ol 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).
  • lentivirus animal lentiviruses
  • infecting cats feline immunodeficiency virus
  • sheep visna virus
  • goats caprine arthritis-encephalitis virus
  • non-human primates non-human primates.
  • 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., Ci-C 3O 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.
  • 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, isobenzo furan, 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
  • Carbocycle 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, -0-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.
  • 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 Nova-Pak RP- C18 (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 selecyed compound is shown in Figure 20.
  • HIV-I 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 0 C. Excitation and emission wavelengths were set at 340 nm 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 niM dithiothreitol (DTT), 2% dimethylsulfoxide (DMSO) and 1 mg/mL bovine serum albumin (BSA) with an adjusted pH 4.7.
  • EDTA ethylenediaminetetraacetic acid
  • DTT niM 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.
  • the designed inhibitors with a hydroxyethylamine (HEA) core isostere can be synthesized in four steps starting with commercially available chiral epoxide ( ⁇ S,2S enantiomer) 12. Ring opening of epoxide 12 with various primary and secondary amines provided compounds 13. Reaction of 13 with various sulfonyl chlorides gave compounds 14. After deprotecting the Boc group, the resulting amines 15 were coupled with either (R) or (S) isomer of activated carboxylic acids to provide the designed inhibitors 16 ( Figure 7A).
  • HOA hydroxyethylamine
  • protease inhibitors containing hydroxyethylene (HE) isostere starts with the synthesis of the core 17, which was obtained from L-phenylalanine in 5 steps. After coupling OfR 4 X 2 CO 2 H to 17, the dibenzyl protection was removed and the free amine 19 was coupled to the an activated acid to provide inhibitors 20 (Figure 7B).
  • HE hydroxyethylene

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Abstract

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

Description

HIV-I Protease Inhibitors
RELATED APPLICATIONS
The present application claims priority to U.S. Provisional Application Serial No. 60/919,896, filed March 23, 2007, U.S. Provisional Application Serial No. 60/919,819, filed March 23, 2007, U.S. Provisional Application Serial No. 60/941,786, filed June 4, 2007, and U.S. Provisional Application Serial No. 60/941,829, filed June 4, 2007, all of which are hereby incorporated by reference in their entirety.
GOVERNMENT SUPPORT
This invention was made with government support under Grant No. POl GM 066524 awarded by the National Institutes of Health/National Institute of Allergy and Infectious Diseases. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION
Human immunodeficiency virus type 1 (HIV-I) 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-I protease leads to the production of noninfectious virus particles and hence is a promising therapeutic target for antiviral therapy in AIDS patients.
Protease inhibitors (PIs) are potent antiretro viral drugs for the treatment of patients infected with Human Immunodeficiency Virus (HIV). Several known PIs are recommended as part of the "preferred regimen" for patients in the guidelines of
International AIDS Society-USA (IAS-USA) and the U.S. Department of Health and Human Services (DHHS). However, use of these drugs has sometimes been associated with the development of irreversible HIV resistance, due to mutation of the virus.
In fact, HIV-I protease inhibitors represent the most potent anti-AIDS drugs reported to date and are essential components of highly active antiretro viral therapy
(HAART). In the last decade, structure based drug design has led to the discovery of eight FDA approved drugs and several others in advanced clinical trials. Currently marketed HIV-I protease inhibitors, saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir, and tipranavir, are all competitive inhibitors that bind in the active site of the enzyme. Except the newly approved drug tipranavir, 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-I protease substrates. The development and clinical introduction of anti-AIDS HIV-I protease inhibitors is regarded as major success of structure based drug design.
Anti-AIDS chemotherapy based on HIV-I protease and reverse-transcriptase inhibitors has been remarkably successful in decreasing the mortality rate in HIV-I infected patients. However, the emergence of HIV-I mutants that are resistant to current drug regimens is a critical factor in the clinical failure of antiviral therapy. In general, drug resistance occurs when mutations in a target protein allow that protein to retain function while in the presence of a drug. In the case of HIV-I protease, 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 relatively rapid appearance of resistant viral mutants among treated HIV patients is attributable to the virus' high rate of replication, coupled with a high intrinsic rate of mutation due to the infidelity of the HIV reverse transcriptase. Further, current HIV-I protease inhibitors were designed to inhibit a single variant of HIV-I protease.
For most of the currently approved protease inhibitors, the emergence of multi drug resistant (MDR) mutants poses a great challenge to the efficacy of these drugs. (Condra, J. H. et al. Nature 1995, 374, 569-571; and Clavel, F. et al. N. Engl. J. Med. 2004, 350, 1023-1035.) Development of next generation HIV-I protease inhibitors active against MDR virus has been the focus of intense research efforts in recent years. (Koh, Y. et al. Antimicrob. Agents Chemother. 2003, 47, 3123-3129; Surleraux, D. L. N. G. et al. J. Med. Chem. 2005, 48, 1813-1822; and Surleraux, D. L. N. G. et al. J. Med. Chem. 2005, 48, 1965-1973.)
Developing different classes of therapeutic agents is not likely to be an adequate solution to the problem of resistance to protease inhibitors, primarily because the same basic mechanisms readily generate viral strains resistant to other agents. Thus, resistance is a major clinical problem for the other major class of HIV drugs, the reverse transcriptase inhibitors, and resistance to newer, preclinical agents, such as the fusion inhibitors is readily elicited in culture. The challenge for the research community is therefore to develop drugs, e.g., HIV-I protease inhibitors, that are less vulnerable to drug resistance and/or more active against current protease resistant HIV-I isolates. The present inventions address this challenge by integrating clinical data, in vitro virology, protein crystallography, computational modeling and chemical design, and high-throughput chemistry and compound screening. HIV protease is a particularly appealing target, as inhibition of its activity is clinical effective; however, it can evolve to tolerate extensive mutation that confers drug resistance while retaining enzymatic function. As the design of the initial protease inhibitors was structure based, a huge knowledge reservoir exists for this protein.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of new small molecule protease inhibitors (PIs). These inhibitors, and methods of making and using them, are described herein. Because these inhibitors do not protrude beyond the substrate binding envelope on the protease, it is expected that these inhibitors will be less likely to induce the development of resistant strains.
In one aspect, the invention features PIs described herein, or an enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions for inhibiting HIV protease that include a pharmaceutical carrier and a therapeutically effective amount of a PI described herein. In another aspect, the invention features methods for treating HIV in a subject, by administering a therapeutically effective amount of a compound or pharmaceutical composition described herein. In some embodiments, the methods further include administering a second therapeutic agent, e.g., a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as efavirenz (Sustiva™), nevirapine (Viramune™) and delavirdine (Rescriptor™); an nucleoside reverse transcriptase inhibitor (NRTI) such as AZT
(zidovudine, Retrovir™)/3TC (lamivudine, Epivir™) and d4T (stavudine, Zerit™)/3TC, and d-drugs (ddl [didanosine, Videx™/VidexEC™], ddC [zalcitabine, Hivid™], d4T); a nucleotide reverse transcriptase inhibitor, such as tenofovir (Viread™); and a fusion inhibitor, such as enfuvirtide (Fuzeon™). In some embodiments, the compound or pharmaceutical composition is administered as part of a highly active antiretro viral therapy (HAART) regimen. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.
BRIEF DESCRIPTION OF DRAWINGS
Figures la-b depict possible synthetic routes to selected inventive compounds. Figures 2a-k depict anti-HIV drugs by class.
Figure 3 depicts the synthesis of protease inhibitors containing [A] a hydroyethylamine (HEA) core or [B] a hydroxyethylene (HE) core. Key: (a) EtOH, 70 0C; (b) aq. Na2CO3, CH2Cl2, r. t; (c) TFA, CH2Cl2; (d) Et3N, THF; (e) R4X2CO2H, EDCI, HOBt, DIPEA, 0 °C to r. t; (f) H2, Pd/C, MeOH, r. t; and (g) aq. NaHCO3, EtOAc, O 0C to r. t.
Figure 4 depicts the synthesis of protease inhibitors containing an aza- hydroxyethylamine (Aza-HEA) core. Key: (a) (CH3)2CHOH, 80 0C (b) H2, Pd/C, MeOH, r. t; (c) R4X2CO2H, EDCI, HOBt, DIPEA, O 0C to r. t; (d) TFA, CH2Cl2; and (e) R3XiCO2H, EDCI, HOBt, DIPEA, O 0C to r. t; aq. NaHCO3, EtOAc.
Figure 5 depicts a comparison of isobutyl and (5)-2-methylbutyl moieties as Pl' ligands: Inhibitory activities against wild-type and MDR mutant variants of HIV-I protease. Figure 6 depicts selected compounds of formula I and associated K values.
Figure 7 depicts selected compounds of formula I.
Figure 8 depicts the chemical structures of amprenavir (APV) 1, TMCl 14 2 and selected compounds of the invention 3. Figure 9 depicts a scheme showing the synthesis of intermediates N- Phenyloxazolidine-5-carboxylic acids 9 and 10. Key: (a) n-BuLi, THF, -78 0C to r. t. overnight; (b) RuCl3-H2O, CH3CN-CCl4-H2O (2:2:3), 0 °C to r. t. 4-10 h.
Figure 10 depicts a scheme showing the synthesis of inventive compounds 20-29. Key: (a) EtOH, 80 0C, 3-4 h; (b) aq. Na2CO3, CH2Cl2, 0 0C to r. t, 4-8 h; (c) TFA, CH2Cl2, 1 h; (d) (OCOCl)2, r. t, overnight; (e) Et3N, THF, 0 0C to r. t, 4-8 h; (fj SnCl2.2H2O, EtOAc, 70 0C, 2 h.
Figure 11 depicts a scheme showing the synthesis of compounds 36-39. Key: (a) zPrOH or EtOH, 80 0C, 3-4 h; (b) aq. Na2CO3, CH2Cl2, 0 °C to r. t, 4-8 h; (c) TFA, CH2Cl2, 1 h; (d) (OCOCl)2, r. t, overnight; (e) Et3N, THF, 0 0C to r. t, 4-8 h.
Figure 12 depicts selected compounds of formula XVA/XVB and associated K, values.
Figure 13 depicts selected compounds of formula XIIIA/XIIIB and associated K1 values. Figure 14 depicts selected compounds of formula XVIIA/XVIIB and associated K, values.
Figure 15a-b depict possible synthetic routes to selected inventive compounds.
Figure 16 depicts inhibitory activities of selected compounds against wild-type and MDR mutant variants of HIV-I protease. Figure 17a-j depicts selected compounds and, in some cases, associated K1 values.
DETAILED DESCRIPTION
One aspect of the present invention addresses the challenge of developing HIV-I protease inhibitors that are less vulnerable to drug resistance and/or more active against current pro tease-resistant HIV-I 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.
Remarkably, certain compounds of the invention are competitive inhibitors that appear to bind in the center of the "substrate envelope" (i.e., at the active site of the protease). Importantly, 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. In addition the compounds have shown activity against a panel of multi-drug resistant (MDR) mutant variants of HIV-I protease. Moreover, as mentioned above, 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 antiretro viral 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:
H Ri R5
I wherein, independently for each occurrence,
Xi is absent, -O-, -S-, -NR- or ZA ;
X2 is absent, -O-, -S-, -NR- or
Figure imgf000007_0001
Figure imgf000007_0002
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
provided that when Xi is absent; R3
Figure imgf000008_0001
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that Xi is ZA ; or X2 is ZA ; or R3 is amino,
Figure imgf000008_0002
,
CH3 Cl u CH3 CH3
H3C γ^v α> 1 γ HN^V H3CO ' H3CO ≡ J QJ C^H3 J QJ C^H3
O , 0 , 0 , 0 , H3°ϋ / , Ha00 / ,
Figure imgf000008_0003
In certain embodiments, 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 Xi is ZA
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; and X2 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri is OH. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is aryl or heteroaryl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is alkyl, aryl or heteroaryl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R5 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula II:
Figure imgf000009_0001
II wherein, independently for each occurrence,
Xi is absent, -O- or ZA ; R3 is alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
provided that when Xi is absent; R3 is
Figure imgf000010_0001
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
CH3 CH,
provided that Xi is <S ZAc*- H3C .. H3C ; or R3 is amino, ό o
Figure imgf000010_0002
.
In certain embodiments, 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 Xi is IΛ . In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is aryl or heteroaryl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is alkyl, aryl or heteroaryl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R6 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R6 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is
Figure imgf000011_0001
CH3 ,
Figure imgf000011_0002
Figure imgf000012_0001
In certain embodiments, the present invention relates to the aforementioned
CH,
H,CΎ compound and any of the attendant definitions, wherein R3 is O
CH3 Cl CH, CH,
H,c H3C OO C CHH, O C oHn3
Cl y HaCOyAy o O O O H3CO Λ- Λ y' H3Co
Figure imgf000012_0002
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is
Figure imgf000012_0003
F
Figure imgf000012_0004
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R6 is
Figure imgf000013_0001
,
Figure imgf000013_0002
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R6 is
Figure imgf000013_0003
CH3 or CHs.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; and R3 is
Figure imgf000013_0004
Figure imgf000014_0001
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure imgf000014_0002
Figure imgf000015_0001
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure imgf000015_0002
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure imgf000026_0002
Figure imgf000027_0001
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula III:
Figure imgf000028_0001
in wherein, independently for each occurrence,
Xi is absent, -O-, -S-, -NR- or lΛ ;
X2 is absent, -O-, -S-, -NR- or ΔΛ ;
Ri is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl; R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R7 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
Figure imgf000028_0002
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
provided that when X2 is absent; R4
Figure imgf000029_0001
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that X is ZA ; or X2 is ZA ; R3 is amino, ^00
Figure imgf000029_0002
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xj is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; and X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri is OH. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is aryl or heteroaryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is ^
Figure imgf000030_0001
00
Figure imgf000030_0002
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is alkyl, aryl or heteroaryl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R4 is 1
Figure imgf000030_0003
^00 -^, ,
Figure imgf000030_0004
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R5 is hydrogen.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R7 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R7 is alkyl, (cycloalkyl)alkyl or aralkyl.
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IV:
Figure imgf000031_0001
IV wherein, independently for each occurrence, Xi is absent or -0-; R3 is alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is aryl, amino, (amino)alkyl, amido, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and
R7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl;
provided that when Xi is absent; R3
Figure imgf000031_0002
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
provided that when X2 is absent; R4 is
Figure imgf000031_0003
not R4A
Figure imgf000031_0004
wherein R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that Xi is ZΛ ; or X2 is ZA ; R3 is amino, 1^00 ^ ,
Figure imgf000032_0001
In certain embodiments, 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 R3 is amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is
Figure imgf000032_0002
Figure imgf000032_0003
Figure imgf000033_0001
.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is aryl, amino, (amino)alkyl, amido, (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 R4 is
Figure imgf000033_0002
Figure imgf000033_0003
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xj is absent; and R3 is amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; R3 is amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R4 is aryl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl; and R7 is alkyl, cycloalkyl or (cycloalkyl)alkyl. In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R3 is
Figure imgf000034_0001
Figure imgf000034_0002
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is
Figure imgf000034_0003
Figure imgf000034_0004
Figure imgf000035_0001
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R7 is
Figure imgf000035_0002
Figure imgf000035_0003
In certain embodiments, the present invention relates to the aforementioned
compound and any of the attendant definitions, wherein R7 is
Figure imgf000035_0004
:
Another aspect of the present invention relates to a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure imgf000035_0005
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula V:
Figure imgf000038_0002
V wherein, independently for each occurrence,
Xi is absent, -0-, -S-, -NR- or IΛ ;
X2 is absent, -0-, -S-, -NR- or ZΛ ; R, is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
provided that when Xi is absent; R3 is not xr R3A
Figure imgf000039_0001
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
provided that when X2 is absent; R4 is not xr R4A
Figure imgf000039_0002
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that Xj is ZΛ ; or X2 is lΛ ; or R3 is amino.
In certain embodiments, 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 Xi is -O-.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent or -O-; and X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri is OH. hi certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is (heterocyclyl)alkyl. hi certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R5 is alkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent or -O-; X2 is absent; Ri is OH; R2 is aralkyl; R3 is heterocyclyl; R4 is alkyl, aryl or heteroaryl; and R5 is alkyl.
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VII:
Figure imgf000040_0001
VII wherein, independently for each occurrence,
Xi is absent, -O-, -S-, -NR- or ^P:
A7A X2 is absent, -O-, -S-, -NR- or ZΛ ;
Ri is -OH, -SH or -NHR; R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R3 is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl,
(keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
Figure imgf000041_0001
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
Figure imgf000041_0002
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that Xi is Ll \ ; or X2 is L\ ; or R3 is amino.
In certain embodiments, 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 X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; and X2 is absent.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri is -OH or -NH2. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl or heteroaralkyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R2 is aralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R3 is (amido)alkyl or heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R4 is (amido)alkyl or heterocyclyl.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R5 is alkyl or aryl.
One aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula XII:
Figure imgf000042_0001
XII wherein, independently for each occurrence,
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000043_0002
wherein, independently for each occurrence, W is selected, from the group consisting of -NHR7 or -NHR(CH2)PN(R7)2; R7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and p is 1-10 inclusive; and
CH3 CH3
R6 is ^CH3 Qr ^CH3.
In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R3 is
Figure imgf000044_0001
Figure imgf000044_0002
In certain embodiments, the present invention relates to any of the aforementioned
OCH3 compounds and any of the attendant definitions, wherein R4 iiss KJ J- OCH3.
Figure imgf000044_0003
In certain embodiments, the present invention relates to any of the aforementioned .CH3 compounds and any of the attendant definitions, wherein R6 is CH3.
In certain embodiments, the present invention relates to any of the aforementioned
CH3 compounds and any of the attendant definitions, wherein R6 is CH3.
Another aspect of the present invention relates to a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Another aspect of the present invention relates to a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure imgf000056_0002
Figure imgf000057_0001
Another aspect of the present invention relates to a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula XII:
Figure imgf000061_0002
XII wherein, independently for each occurrence,
Figure imgf000061_0003
Figure imgf000062_0001
Figure imgf000062_0002
wherein, independently for each occurrence, W is selected, from the group consisting of -NHR7 or -NHR(CH2)PN(R7)2; R7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and p is 1-10 inclusive; and
Figure imgf000062_0003
In certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R3 is
Figure imgf000062_0004
,
Figure imgf000062_0005
In certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R3 is
Figure imgf000063_0001
Figure imgf000063_0002
In certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R3 i
Figure imgf000063_0003
Figure imgf000063_0004
In certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R4 is
Figure imgf000063_0005
\\ />-0CH3
Figure imgf000063_0006
In certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R6 is CH3.
Another aspect of the present invention relates to a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Another aspect of the present invention relates to a compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure imgf000068_0002
Figure imgf000069_0001
Figure imgf000070_0001
Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula iso-XII:
Figure imgf000071_0001
iso-XII wherein, independently for each occurrence,
R3 is alkyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and
R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R3 is aryl or heteroaryl.
In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R3 is aryl. hi certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R3 is
Figure imgf000071_0002
Figure imgf000071_0003
Figure imgf000072_0001
In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R4 is aryl or heteroaryl.
In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R4 is aryl.
In certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R4 is
Figure imgf000072_0002
\\ /hOCH3
Figure imgf000072_0003
Figure imgf000072_0004
wherein, independently for each occurrence, W is selected, from the group consisting of -NHR7 or -NHR(CH2)PN(R7)2; R7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and p is 1-10 inclusive.
In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R6 is alkyl, heterocyclyl, aryl or heteroaryl. In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R6 is alkyl.
In certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R6 is
Figure imgf000073_0001
CH3 , CH3 s CH3J
Figure imgf000073_0002
o~^> .0 H n
N- "-0
V-^ , 5 \_/ , - V^ , or
In certain embodiments, the present invention relates to any of the aforementioned
compounds and any of the attendant definitions, wherein R6 is CH3.
In certain embodiments, the present invention relates to any of the aforementioned
CH3 CH3 compounds and any of the attendant definitions, wherein R6 is CH3 Or CH3,
In certain embodiments, the present invention relates to any of the aforementioned compounds and any of the attendant definitions, wherein R3 is aryl or heteroaryl; and R4 is aryl or heteroaryl.
Synthesis of Selected Compounds of the Invention. The protease inhibitors I, II, III, IV, V and VII can be synthesized using the synthetic schemes outlined in Figures la-b.
The definition of each of the variables may be the same as shown in formulae shown above.
Protease inhibitors I, II, and V can be prepared using the synthetic scheme shown in Figure Ia (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, or V.
Protease inhibitor III and IV can be prepared using the synthetic scheme shown in Figure Ia (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 Ib. 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. Under certain conditions, further deprotection yields amine 11 followed by reaction with acid chloride yields inhibitor VII.
As can be seen from Figures Ia and Ib, 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.
Protease inhibitors XII can be prepared using the synthetic scheme shown in Figure 15a (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 XI, XII, XV or XVI.
As can be seen from Figures 15a and 15b, 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.
For example, 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 9. (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. The reaction of CBZ protected anilines 4a-g with either (R)- or (5)-enantiomer of glycidyl butyrate promoted by n-BuLi provided chiral alcohols 7a and 8a-g. This one pot, three step cascade reaction involves the initial ring opening of chiral epoxide with N- lithium species followed by an intramolecular cyclization and finally an in situ ester hydrolysis. (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673-679.) Oxidation of the resulting chiral alcohols using catalytic ruthenium chloride provided the desired N- phenyloxazolidine-5-carboxylic acids 9a and 10a-g (Scheme 1). In case of unsubstituted phenyloxazolidines, both (R)- and (S)- enantiomers, 9a and 10a respectively, were prepared from the corresponding chiral epoxide. All other compounds with substituted phenyl ring, lOb-g, were prepared only as (5)-enantiomers. The synthetic route applied for the preparation of designed protease inhibitors is illustrated in Figure 10. The Boc protected intermediate (R)-
(hydroxyethylamino)sulfonamides 14-19 were prepared following literature procedure. (Koh, Y. et al. Antimicrob. Agents Chemother. 2003, 47, 3123-3129; and Surleraux, D. L. N. G. et al. J. Med. Chem. 2005, 48, 1813-1822.) Briefly, ring opening of commercially available chiral epoxide, (15,25)-(l-oxiranyl-2-phenylethyl)carbamic acid tert-butyl ester, 11 with isobutylamine provided the amino alcohol 12. Reactions of substituted phenylsulfonyl chlorides with 12 afforded the sulfonamides 14-19 that were coupled with phenyloxazolidine fragments. Initially, four compounds were synthesized using either unsubstituted (R)- or (5)-3-phenyloxazolidine-5-carboxylic acid 9a or 10a attached to the (i?)-(hydroxyethylamino)-sulfonamide isostere at P2 position. Previously optimized phenylsulfonamides, 4-methoxyphenylsulfonamide and 4-aminophenylsulfonamide, were utilized as P2' ligands. Thus, removal of the Boc protection of sulfonamides 14-15 followed by the reactions of the resulting amino alcohols with either (R)- or (iS)-enantiomer of the activated carboxylic acids 9a or 10a provided the target compounds 20a-23a (Figure 10). In the case of compounds 22a and 23a, the nitro group was reduced using tin chloride to afford the corresponding amino derivatives 24a and 25a. It has to be noted that attempts to use the standard amide coupling conditions, EDCI/HOBt/DIEA, were not very successful and resulted in poor yields mainly because of very slow reactions even with DMF as solvent. In all subsequent reactions the carboxylic acids 9 and 10 were converted to the corresponding acid chlorides using oxalyl chloride.
Series of inhibitors were synthesized using substituted (S)-phenyloxazolidines at P2 and different phenylsufonamide groups at P2' position for structure-activity relationship (SAR) studies. Following the deprotection of sulfonamide intermediates 14-19, the resulting amines were reacted with (<S)-N-phenyloxazolidine-5-carbonyl chlorides obtained by the activation of the corresponding carboxylic acids lOb-g to afford the target compounds 21 and 25-29 (Figure 10). The compounds 23b-f containing A- nitrophenylsulfonamide group at P2' position were transformed to the corresponding A- aminophenylsulfonamide derivatives 25b-f by the reduction of the nitro group. In addition to the compounds described above, series of compounds were prepared with variations at three different positions. The isobutyl group at PlD position was replaced with three cyclic primary amines. Again, starting from commercially available chiral epoxide 11, the target compounds were synthesized using an analogous synthetic route (Figure 11). In brief, ring opening of epoxide 11 with primary amines 30a-c provided amino alcohols 31a-c. Reactions of various substituted phenylsulfonyl chlorides with 31a- c provided sulfonylamides 32-35. After deprotection of intermediate compounds 32-35, the resulting amines were reacted with (S)-N-phenyloxazolidine-5-carbonyl chlorides prepared from the corresponding carboxylic acids 10 to afford the target compounds 36-39 (Figure 11).
Pharmaceutical Compositions. The methods described herein include the manufacture and use of pharmaceutical compositions, which include the protease inhibitors described herein as active ingredients. Also included are the pharmaceutical compositions themselves. These compositions can be administered using routes of administration and dosages similar to those used for known HIV protease inhibitors.
It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or a pro-drug or other adduct or derivative of a compound of this invention which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences 1977, 66: 1-19, incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting a free base or free acid function with a suitable reagent, as described generally below. For example, a free base function can be reacted with a suitable acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, 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, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
Additionally, as used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
Furthermore, the term "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the issues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Methods of formulating pharmaceutical compositions are known in the art; see, e.g., Remington: The Science and Practice of Pharmacy, 20th Ed. (Baltimore, MD: Lippincott Williams & Wilkins, 2000). Pharmaceutical compositions typically include a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions.
Pharmaceutical compositions are typically formulated to be compatible with their intended route(s) of administration. Examples of routes of administration include parenteral, e.g., by intravenous, intradermal, or subcutaneous injection; or mucosal {e.g., by oral ingestion, inhalation, or rectal or vaginal administration) administration. Compositions intended for parenteral administration can include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates and agents for the adjustment of tonicity, such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide, as appropriate. A parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
Pharmaceutical compositions suitable for injectable use can include sterile aqueous solutions (where the active ingredient is water soluble) or dispersions and sterile powders for the preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent necessary to allow administration via syringe. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like, hi many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, and/or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin; or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring.
For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Such methods include those described in U.S. Patent No. 6,468,798; hereby incorporated by reference.
Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. The pharmaceutical compositions can also be prepared in the form of suppositories (e.g., with conventional suppository bases, such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
In one embodiment, the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations can be prepared using standard techniques. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811; hereby incorporated by reference.
The pharmaceutical compositions can be included in a container, kit, pack, or dispenser, optionally with instructions for administration. A kit may comprise one or more compounds described herein and/or one or more other therapeutic compounds and/or a device for their administration, e.g., a syringe.
Biological Evaluation of Selected Compounds of the Invention. HIV protease inhibitor activities were determined by fluorescence resonance energy transfer (FRET) method. (Matayoshi, E. D. et al. Science 1990, 247, 954-958.) Protease substrate (Arg- 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. Inhibitor binding dissociation constant (Ki value) was obtained by nonlinear regression fitting to the plot of initial velocity as a function of inhibitor concentration based on Morrison equation. (Greco, W. R. et al. J. Biol. Chem. 1979, 254, 12104-12109.) The activities of all the synthesized inhibitors against wild type HIV-I protease (Q7K) were determined in triplicate. Chemical structures of inhibitors and their inhibitory activities (Ki values) are presented in the figures.
In addition, a small set of 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-I Drug Resistance Database
(http://hivdb.stanford.edu) of HIV-I 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. 2003, 77, 4836^1847.) These MDR mutant variants are LlOI, G48V, I54V, L63P, V82A (Ml), D30N, L63P, N88D (M2), and LlOI, L63P, A71V, G73S, I84V, L90M (M3). The inhibitory activities of selected protease inhibitors against M1-M3 mutant HIV-I proteases were examined. For comparison two currently marketed drugs amprenavir (APV) and lopinavir (LPV) were also studied against the selected panel of mutant proteases.
Methods of Treatment. The methods described herein include methods for the treatment or prevention of a viral infection, e.g., an HIV, infection and Acquired
Immunodeficiency Syndrome (AIDS) or AIDS Related Complex (ARC). Generally, the methods include administering a therapeutically effective amount of a protease inhibitor described herein, to a subject (e.g., a human or other primate) in need thereof, or who has been determined to be in need of, such treatment, e.g., a subject who is (or is determined to be) infected with HIV. A subject who is likely to be infected with HIV, e.g. , a person in a high risk group, may also be treated as indicated herein. Subjects also include women who are expecting a child (pregnant women) and in whom a treatment reduces the liklihood of transmission of HIV to the child. hi addition to HIV-I infections, the methods described herein are also expected to be beneficial for treating or preventing HIV-2 infections. Among 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.
As used in this context, to "treat" means to ameliorate at least one clinical symptom or parameter of HIV infection or preventing it from worsening or preventing the transmission of HIV, e.g. , from mother to child. For example, a treatment can result in a reduction in viral load, and/or an increase in number of CD4+ T cells ("CD4 count"). When a subject has achieved a reduction in viral load, and/or an increase in CD4 count, then treatment may also include maintaining the reduction in viral load, and/or the increased CD4 count, e.g., preventing a resurgence of viral load and/or a decrease in CD4 count. These, and other clinically relevant parameters, can be measured using methods known in the art. For example, viral load can be measured, e.g., using PCR or branched DNA (bDNA) assays known in the art. CD4 counts can be measured, e.g., using hematology, DYNAbeads™ (Dynal Biotech/Invitrogen Corp., Brown Deer, WI), flow cytometry (e.g., FACSCount™, 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. 2(l):104-114 (1995); Saah et al. Arch. Pathol. Lab. Med. 121(9):960-2 (1997); Mwaba et al., Lancet 362 1459-60 (2003)). Healthy adults and teenagers generally have a CD4 count of at least 800 cells per cubic millimeter of blood; a CD4 count below 200 is associated with severe risk of illness (e.g., AIDS-related diseases, such as Kaposi's sarcoma or pneumocystic pneumonia).
Current guidelines suggest treatment for HIV should be started when the CD4 count is less than about 350 and/or the viral load is greater than about 50,000.
A "therapeutically effective amount" is an amount sufficient to effect a desired therapeutic effect, e.g., a reduction in viral load, and/or an increase in number of CD4+ T cells. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition may depend on the composition selected. The compositions can be administered once, one or more times per day, and/or one or more times per week; including once every other day. In certain embodiments, the compositions will be administered two or three times per day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to treat effectively a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and any other indications present. Treatment of a subject with a therapeutically effective amount of a protease inhibitor described herein can include a single treatment or a series of treatments.
Dosage, toxicity and therapeutic efficacy of the compounds can be determined, e.g., by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD5O/ED5O. Compounds that exhibit high therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to select a dose and administration schedule that minimizes severe side effects while maximizing therapeutic efficacy.
The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in a method described herein, a therapeutically effective dosage range can be estimated initially from cell culture assays. A dose can be further formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to determine more accurately useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. In some embodiments, a therapeutically effective amount of a new protease inhibitor described herein ranges from about 0.1 to 10 mg per day, or about 0.3 to 5 mg/day.
In some embodiments, one or more of the protease inhibitors described herein will be administered in combination with one or more other therapeutic agents, e.g., as part of a highly active antiretroviral therapy (HAART) regimen that includes one or more other anti- retro viral agents. For example, the methods may include administration of one or more of a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz (Sustiva™), nevirapine (Viramune™) and delavirdine (Rescriptor™), 8 and 9-Cl TIBO (tivirapine), loviride, TMC- 125, dapivirine, MKC-442, UC 781, UC 782, Capravirine, DPC 961, DPC963, DPC082, DPCO83, calanolide A, SJ-1366, TSAO, 4"-deaminated TSAO, MVl 50 and MV026048; a nucleoside reverse transcriptase inhibitor (NRTI), such as AZT (zidovudine, Retrovir™)/3TC (lamivudine, Epivir™), emtricitabine (Emtriva™) and d4T (stavudine, Zerit™)/3TC, and d-drugs (ddl [didanosine, Videx™/VidexEC™], ddC [zalcitabine, Hivid™], d4T), Abacavir, FTC, DAPD, dOTC, and DPC 817; a nucleotide reverse transcriptase inhibitor, such as tenofovir (Viread™) and PMEA; a fusion inhibitor, such as enfuvirtide (Fuzeon™), T20, T1249, 5-helix and D-peptide ADS-Jl; an entry inhibitor; a co-receptor binding inhibitor, such as AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams), TAK 779; SHC-C (SCH351125), SHC-D, PRO-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, nelfmavir, saquinavir, indinavir, lopinavir, palinavir, BMS 186316, atazanavir, DPC 681, DPC 684, tipranavir, AGl 776, mozenavir, GS3333, KNI-413, KNI-272, L754394, L756425, LG-71350, PD161374, PD173606, PD177298, PD178390, PD178392, PNU 140135, TMC114 maslinic acid and U-140690; a glycosylation inhibitor, such as castanospermine, deoxynojirimycine; or a binding inhibitor, such as dextran sulfate, suramine, polyanions, soluble CD4, PRO-542 and BMS-806. Other drugs include those set forth at http://aidsinfo.nih.gov/, hereby incorporated by reference.
Other therapeutic agenets that may be coadministered with with one or more agents described herein are agents that inhibit metabolic enzymes, e.g., inhibitors of cytochrome P450 (CYP450) enzymes. For example, a compound described herein may be administered, simultaneously or not, with an inhibitor of CYP3A4, e.g., Ritonavir, or an inhibitor of CYP2C19, CYPl A2, CYP2D6, or CYP2C9. Exemplary inhibitors of 2C9 are described, e.g., in U.S. publication No. 2006.0069042, hereby incorporated by reference. The compounds of the present invention may also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, methionine enkephalin, interferon alpha, HE-2000 and naltrexone), antibiotics (e.g., pentamidine isothiorate), cytokines (e.g. Th2), modulators of cytokines, chemokines or the receptors thereof (e.g. CCR5) or hormones (e.g. growth hormone), to ameliorate, combat, or eliminate HIV infection and its symptoms.
In some embodiments, the methods further comprise administering a second 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.
In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is ritonavir (Kaletra®; LPV). hi some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of zidovudine (AZT; Azidothymidine; Retrovir®), didanosine (Dideoxyinosine; 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) .
In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is selected from the group consisting of nevirapine (BI-RG-587; Viramune®), delavirdine (BHAP; U-90152; Rescriptor®), and (efavirenz; DMP-266; Sustiva®).
In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is T-20 (Fuzeon®; Enfuvirtide; DP- 178; Pentafuside; GP41 127-162 AA). In some embodiments, the methods further comprise administering a second therapeutic agent, wherein the second therapeutic agent is 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. In certain embodiments the compounds of the invention can be combined with one or more of any anti-HIV compounds (e.g. those listed in Figures 6a-k). Additional compounds which may be combined with one or more of the inventive compounds, and further discussion of combination therapy can be found in Yeni, P. G. et al. JAMA 2004, 292(2), 251-265; Pozniak, A. et al. Business Briefing: Clinical Virology & Infectious Disease 2004, 1-7; and Chittick, G. E. et al. Antimicrobial Agents and Chemotherapy 2006, 1304-1310; all of which are hereby incorporated by reference. Definitions. All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and/or ordinary meanings of the defined terms.
The indefinite articles "a" and "an," as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean "at least one."
The term "HIV" is known to one skilled in the art to refer to Human Immunodeficiency Virus. There are two types of HIV: HIV-I and HIV-2. There are many different strains of HIV-I. The strains of HIV-I 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.
Within the M-group there are at least ten subtypes or clades: e.g., clade A, B, C, D, E, F, G, H, I, J, and K. A "clade" is a group of organisms, such as a species, whose members share homologous features derived from a common ancestor. Any reference to HIV in this application includes all of these tupes and strains. As known to one skilled in the art, "retroviruses" are diploid positive-strand RNA viruses that replicate through an integrated DNA intermediate (proviral DNA). In particular, upon infection by the RNA virus, the lentiviral genome is reverse-transcribed into DNA by a virally encoded reverse transcriptase that is carried as a protein in each retrovirus. The viral DNA is then integrated pseudo-randomly into the host cell genome of the infecting cell, forming a "provirus" which is inherited by daughter cells. The retrovirus genome contains at least three genes: gag codes for core and structural proteins of the virus; ol codes for reverse transcriptase, protease and integrase; and env codes for the virus surface proteins. Within the retrovirus family, HIV is classified as a lentivirus, having genetic and morphologic similarities to animal lentiviruses such as those infecting cats (feline immunodeficiency virus), sheep (visna virus), goats (caprine arthritis-encephalitis virus), and non-human primates (simian immunodeficiency virus). The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., Ci-C3O for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
Unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.
The term "aralkyl" is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The term "aryl" is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those 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, - CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively. For example, the names 1 ,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
The terms "heterocyclyl", "heteroaryl", or "heterocyclic group" are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroa toms. Heterocycles may also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzo furan, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
The terms "polycyclyl" or "polycyclic group" are art-recognized and refer to two or more rings (e.g., 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, -CF3, -CN, or the like.
The term "carbocycle" is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon. The term "nitro" is art-recognized and refers to -NO2; the term "halogen" is art- recognized and refers to -F, -Cl, -Br or -I; the term "sulfhydryl" is art-recognized and refers to -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is art-recognized and refers to -SO2 ". "Halide" designates the corresponding anion of the halogens, and "pseudohalide" has the definition set forth on page 560 of "Advanced Inorganic Chemistry" by Cotton and Wilkinson.
The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas: -N(R51)(R50) or [-N(R50)(R52)(R53)]+, wherein R50, R51, R52 and R53 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, or R50 and R51 or R52, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-R61. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
The term "acylamino" is art-recognized and refers to a moiety that may be represented by the general formula: -N(R50)-C(=O)R54, wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are as defined above.
The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula: -C(=O)N(R50)(R51), wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.
The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like. The term "carboxyl" is art recognized and includes such moieties as may be represented by the general formulas: -C(=O)-X50-R55 or -X50-C(=O)-R56, wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61 or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an "ester". Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thiolester." Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiolcarboxylic acid." Where X50 is a sulfur and R56 is hydrogen, the formula represents a "thiolformate." On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a "ketone" group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde" group.
The term "carbamoyl" refers to -0(C=O)NRR', where R and R' are independently H, aliphatic groups, aryl groups or heteroaryl groups.
The term "oxo" refers to a carbonyl oxygen (=0).
The terms "oxime" and "oxime ether" are art-recognized and refer to moieties that may be represented by the general formula: -C(R75)(=NOR), wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2)m-R61. The moiety is an "oxime" when R is H; and it is an "oxime ether" when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2)m-R61.
The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -0-alkynyl, -O-(CH2)m-R61, where m and R61 are described above.
The term "sulfonate" is art recognized and refers to a moiety that may be represented by the general formula: -S(=O)2θR57, in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
The term "sulfate" is art recognized and includes a moiety that may be represented by the general formula: -OS(=O)2OR57, in which R57 is as defined above. The term "sulfonamido" is art recognized and includes a moiety that may be represented by the general formula: -N(R50)-S(=O)2OR56, in which R50 and R56 are as defined above.
The term "sulfamoyl" is art-recognized and refers to a moiety that may be represented by the general formula: -S(=O)2N(R50)(R51), in which R50 and R51 are as defined above.
The term "sulfonyl" is art-recognized and refers to a moiety that may be represented by the general formula: -S(=O)2R58, in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. The term "sulfoxido" is art-recognized and refers to a moiety that may be represented by the general formula: -S(=O)R58, in which R58 is defined above.
Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls. The definition of each expression, e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, />-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.
It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, "Handbook of Chemistry and Physics", 67th Ed., 1986-87, inside cover.
EXEMPLIFICATION
The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention
General Experimental Procedures. 1H and 13C NMR spectra were recorded on a Varian 400 MHz NMR spectrometer, operating at 400 MHz for 1H and 100 MHz for 13C. Chemical shifts are reported in ppm relative to the solvent signal, and coupling constant (J) values are reported in Hertz (Hz). Thin-layer chromatography (TLC) was performed on E. Merck silica gel 60-F-254 plates and spots were visualized with UV light. Flash column chromatography was performed using 230-400 mesh silica gels (E-Merck). High resolution mass spectra (HRMS) were recorded on Waters Q-TOF Premier mass spectrometer by direct infusion of solutions of each compound using electrospray ionization (ESI) in positive mode. Low resolution mass spectra were obtained using Waters Alliance HT/Micromass ZQ system (ESI). Tetrahydrofuran was distilled from sodium/benzophenone. Anhydrous Dichloromethane, Λf./V-dimethylformamide, benzene, and toluene were purchased from Aldrich and used as such. All reagents and chemicals were purchased from commercial vendors and used as received.
Analytical reversed-phase high performance liquid chromatography (HPLC) 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 Nova-Pak RP- C18 (4 μm, 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 selecyed compound is shown in Figure 20.
EXAMPLE 1
GENERAL PROCEDURE FOR THE CBZ PROTECTION OF SUBSTITUTED ANILINES
Solid NaHCO3 (32.65 g, 388.5 mmols) was added to an ice-cooled solution of aniline derivative (185 mmols) in acetone-water mixture (2:1) (300 mL) followed by the slow addition of benzyl chloroformate (27 mL, 190 mmols). The resulting slurry was warmed to ambient temperature and stirred overnight. Reaction mixture was poured onto ice and the resulting precipitate was filtered, washed with water and dried. Product was purified by recrystallization from a mixture of hexanes and ethylacetate to provide the pure product as crystalline solid. Compounds 4a-g were prepared following this general procedure.
EXAMPLE 2 GENERAL PROCEDURE FOR THE SYNTHESIS OF 5 -(H YDROXYMETHYL)- OXAZOLIDINONES 7 AND 8
A solution of CBZ protected aniline derivative 4 (34.7 mmols) in dry THF (150 mL) was cooled to -78 °C under dry N2 atmosphere. A solution of n-BuLi (1.6 M in hexanes; 25 mL, 40 mmols) was slowly added keeping the temperature below -70 0C. After stirring the reaction mixture at -78 °C for 45 minutes, a solution of chiral glycidyl butyrate (5 g, 34.7 mmols) in dry THF was slowly added. The resulting mixture was stirred at -78 0C for 2 hours and then slowly warmed to room temperature and stirred overnight. Reaction was quenched by the addition of saturated aqueous NH4Cl solution. Ethyl acetate and water were added and layers separated. The aqueous layer was further extracted with ethyl acetate (3 times). Combined organic extract was washed with saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated to yield a pale yellow solid. This solid was triturated with a mixture of chloroform and hexanes and filtered to provide pure alcohol as off white solid. Compounds 8a-g were prepared following this general procedure.
EXAMPLE 3
GENERAL PROCEDURE FOR THE SYNTHESIS OF PHENYLLOXAZOLIDINONE-5- CARBOXYLIC ACIDS 9 AND 10.
To an ice-cooled solution OfNaIO4 (35 mmols) in water (75 mL) was added a solution of the alcohol 7 or 8 (10 mmols) in a mixture of CH3CN and CCl4 (1:1) (100 mL). Solid RuCl3-H2O (0.5 mmol) was added and the reaction mixture was stirred at 0 0C for 30 minutes, warmed to room temperature and stirred for 4-6 hours. Reaction was quenched by adding CH2Cl2 and layers were separated. The aqueous layer was further extracted with CH2Cl2, combined organic extract was dried (Na2SO4) and evaporated to provide a gummy solid. Crude product was purified by column chromatography on silica gel using a mixture of 25% CH3CN in CH2Cl2 + 1% HCO2H as eluent. This method provided the desired phenyloxazolidine-5-carboxylic acids as solids in excellent yields. The following compounds were prepared by this general procedure:
EXAMPLE 4
GENERAL PROCEDURE FOR THE RING OPENING OF EPOXIDE WITH AMINES.
A solution of the chiral epoxide 11 (l-Oxiranyl-2-phenylethyl)carbamic acid tert- butyl ester) (10 mmol) in EtOH (75 mL) was added to isobutyl amine (10 mL; large excess) and the mixture was heated at 80 °C for 3 hours. After cooling to room temperature, solvents were removed under reduced pressure. Product was purified by recrystallization from ethyl acetate-hexanes mixture to provide the product as white solid in excellent yield.
EXAMPLE 5
GENERAL PROCEDURE FOR THE SYNTHESIS OF (HYDROXYETHYLAMINO)- SULFONAMIDES
To an ice-cooled solution of the secondary amine 12 (5 mmol) in CH2Cl2 (20 mL) was added an aqueous solution OfNa2CO3 (8 mmol in 5 mL H2O) followed by the slow addition of sulfonyl chloride (5 mmol) solution in CH2Cl2 (5 mL). After 15 minutes the reaction mixture was warmed to ambient temperature and stirred till no starting material was detected by tic. Reaction mixture was diluted with CH2Cl2 and layers were separated. Organic extract was washed with saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated. Product was purified by flash chromatography on silica gel using mixture of ethyl acetate and hexanes as eluent to afford pure product.
The following compounds were prepared by this general procedure: N-[(lS,2R)-l- Benzyl-2-hydroxy-3-[isobutyl[(4-methoxyphenyl)sulfonyl]amino]propyl]carbamic acid tert-butyl ester (14); Λ4(lS,2i?)-l-Benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]- ammo]propyl]carbamic acid tert-butyl ester (15); N-[(15',2i?)-3-[[(Benzo-[l,3]-dioxole-5- sulfonyl)](isobutyl)amino]-l-benzyl-2-hydroxypropyl]carbamic acid tert-butyl ester (16); N-[( 1 S, 2R)- 1 -Benzyl-3 - [[(3 -fluoro-4-methoxyphenyl)sulfonyl] (isobutyl)amino] -2- hydroxypropylj-carbamic acid tert-butyl ester (17); N-[(15',2i?)-l-Benzyl-2-hydroxy-3- [isobutyl[[(4-trifluoro-methoxy)phenyl]sulfonyl]amino]propyl]carbamic acid tert-butyl ester (18); N-[(15,2i?)-l-Benzyl-2-hydroxy-3-[isobutyl[(3- methoxyphenyl)sulfonyl]amino]propyl]carbamic acid tert-butyl ester (19); iV- [(15,2.R)-I- Benzyl-3-[(cyclopropylmethyl)[(3-methoxyphenyl)sulfonyl]-amino]-2- hydroxypropyl]carbamic acid tert-butyl ester (32); N-[(lS,2R)-l-Benzy\-2-hyάτoxy-3-[[(3- methoxyphenyl)sulfonyl] (2-thiophenylmethyl)] amino]propyl] carbamic acid tert-butyl ester (33); N-[(l1S,2i?)-l-Benzyl-2-hydroxy-3-[(2-thiophenylmethyl)[(2,4,5- trifluorophenyl)sulfonyl]-amino]propyl]carbamic acid tert-butyl ester (34); and
Figure imgf000095_0001
l-Benzyl-2-hydroxy-3-[[(3-methoxyphenyl)sulfonyl][(i?)-(tetrahydro-2- furanyl)methyl]amino]propyl]carbamic acid tert-butyl ester (35). EXAMPLE 6
GENERAL PROCEDURE FOR THE COUPLING REACTION.
Excess oxalyl chloride was added to solid phenyloxazolidinone-5-carboxylic acid (0.5 mmols) and the resulting mixture was stirred at room temperature overnight. Oxalyl chloride was removed by distillation under reduced pressure and residue dried under high vacuum for 30 minutes. A solution of the resulting acid chloride in dry THF (5 mL) was used in the coupling reaction.
To an ice-cooled mixture of the Boc deprotected amine (0.5 mmols) in dry THF (5 mL) was added Et3N (1.1 mmols) followed by slow addition of the acid chloride solution. After 15 minutes the reaction mixture was warmed to room temperature and stirred until reaction was complete (monitored by tic). Small amount of water and ethyl acetate were added and layers were separated. The organic extract was washed with saturated aqueous NaCl solution, dried (Na2SO4), filtered and evaporated. Flash chromatography on silica gel using mixture of ethyl acetate and hexanes (in some cases, methanol/chloroform mixture) as eluent, provided the target compound as solid.
EXAMPLE 7
GENERALPROCEDURE FORTHEREDUCTION OF THENITRO GROUP A mixture of the nitro compound (0.4 mmols) and SnCl2.2H2O (0.45 g, 2 mmols) in ethyl acetate (10 mL) was heated at 80 °C for 2-3 hours. Reaction mixture was allowed to cool to ambient temperature and treated with saturated aqueous NaHCO3 solution (10 m). It was diluted with ethyl acetate and layers were separated, aqueous layer was further extracted with ethyl acetate (2 x). Combined organic extract was washed with saturated aqueous NaCl solution, dried (Na2SO4) and evaporated to yield a foamy solid. Flash chromatography on silica gel using mixture of methanol in chloroform as eluent, provided the target compound as solid.
EXAMPLE 9
BIOLOGICAL EVALUATION OF HIV-I PROTEASE INHIBITORS HIV-I 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.) 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 0C. Excitation and emission wavelengths were set at 340 nm and 490 nm, respectively. Each reaction was recorded for about 10 min. Wide type HIV-I protease (Q7K) and its MDR mutants Ml (LlOI, G48V, I54V, L63P, V82A), M2 (D30N, L63P, N88D), and M3 (LlOI, L63P, A71V, G73S, I84V, L90M) were desalted through PD-10 columns (Amersham Biosciences). Sodium Acetate (20 mM, pH 5) was used as elution buffer. Apparent protease concentrations were around 50 nM estimated by UV spectrophotometer (Shimadzu) at 280 nm. AU inhibitors were dissolved in DMSO and diluted to appropriate concentrations. Protease (2 μL) and inhibitor (2 μL) or DMSO were mixed and incubated for 20-30 min at room temperature before initialing substrate cleavage reaction. Throughout this work, 150 μL of 1 μM substrate was used. Substrate buffer is composite of 0.1 M sodium acetate, 1 M sodium chloride, 1 mM ethylenediaminetetraacetic acid (EDTA), 1 niM dithiothreitol (DTT), 2% dimethylsulfoxide (DMSO) and 1 mg/mL bovine serum albumin (BSA) with an adjusted pH 4.7. 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.
EXAMPLE 10 SYNTHESIS OF PROTEASE INHIBITORS CONTAINING A HYDROXYETHYLAMINE (HEA) CORE
The designed inhibitors with a hydroxyethylamine (HEA) core isostere can be synthesized in four steps starting with commercially available chiral epoxide (\S,2S enantiomer) 12. Ring opening of epoxide 12 with various primary and secondary amines provided compounds 13. Reaction of 13 with various sulfonyl chlorides gave compounds 14. After deprotecting the Boc group, the resulting amines 15 were coupled with either (R) or (S) isomer of activated carboxylic acids to provide the designed inhibitors 16 (Figure 7A).
EXAMPLE I l SYNTHESIS OF PROTEASE INHIBITORS CONTAINING CYCLIC CARBAMATES : HE SERIES
The synthesis of protease inhibitors containing hydroxyethylene (HE) isostere starts with the synthesis of the core 17, which was obtained from L-phenylalanine in 5 steps. After coupling OfR4X2CO2H to 17, the dibenzyl protection was removed and the free amine 19 was coupled to the an activated acid to provide inhibitors 20 (Figure 7B).
EXAMPLE 12
SYNTHESIS OF PROTEASE INHIBITORS CONTAINING CYCLIC CARBAMATES:
AZA-HEA SERIES
The synthesis of protease inhibitors containing aza-hydroxyethylamine (Aza-HEA) isostere is outlined in Figure 8. The ring opening of chiral epoxide (\S,2R enantiomer) 21 with CBz protected hydrazine derivative 22 provided compound 23. Deprotection of CBz followed by the coupling with R4X2CO2H gave compounds 24. Removal of the Boc protection and coupling with R3XiCO2H provided the desired inhibitors 27.
INCORPORATION BY REFERENCE
The contents of all cited references (including literature references, issued patents, published patent applications and GenBank Accession numbers as cited throughout this application) are hereby expressly incorporated by reference. When definitions of terms in documents that are incorporated by reference herein conflict with those used herein, the definitions used herein govern.
EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim:
1. A compound, or a pharmaceutically acceptable salt thereof, of formula I:
Figure imgf000099_0001
I wherein, independently for each occurrence,
X1 is absent, -O-, -S-, -NR- or AA ;
X2 is absent, -O-, -S-, -NR- or ΔΛ ;
R1 is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
provided that when Xi is absent; R3 is
Figure imgf000099_0002
not ^3A
Figure imgf000099_0003
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and provided that X --A ; or X2 is --A ; or R3 is amino,
Figure imgf000100_0001
Figure imgf000100_0002
2. The compound of claim 1, wherein X1 is absent.
3. The compound of claim 1, wherein X1 is --A
4. The compound of claim 1, wherein X2 is absent.
5. The compound of claim 1, wherein Xi is absent; and X2 is absent.
6. The compound of claim 1, wherein Ri is OH.
7. The compound of claim 1, wherein R2 is aralkyl or heteroaralkyl.
8. The compound of claim 1, wherein R2 is aralkyl.
9. The compound of claim 1, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
10. The compound of claim 1 , wherein R3 is aryl or heteroaryl.
11. The compound of claim 1 , wherein R4 is alkyl, aryl or heteroaryl.
12. The compound of claim 1, wherein R5 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
13. The compound of claim 1, wherein R5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
14. A compound, or a pharmaceutically acceptable salt thereof, of formula II:
Figure imgf000101_0001
II wherein, independently for each occurrence,
Xi is absent, -O- or Z-A ;
R3 is alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and
R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
Figure imgf000101_0002
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that Xi is
Figure imgf000101_0003
Figure imgf000101_0004
15. The compound of claim 14, wherein Xi is absent.
16. The compound of claim 14, wherein Xi is /IA .
17. The compound of claim 14, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
18. The compound of claim 14, wherein R3 is aryl or heteroaryl. 19. The compound of claim 14, wherein R4 is alkyl, aryl or heteroaryl. 20. The compound of claim 14, wherein R6 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
21. The compound of claim 14, wherein R6 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
22. The compound of claim 14, wherein R3 is
Figure imgf000102_0001
Figure imgf000102_0002
Figure imgf000103_0001
24. The compound of claim 14, wherein R4 is
Figure imgf000103_0002
Figure imgf000103_0003
25.
Figure imgf000104_0001
The compound of claim 14, wherein R6 is X °
26.
Figure imgf000104_0002
The compound of claim 14, wherein R6 is or
27. The compound of claim 14, wherein Xi is absent; and R3 is
Figure imgf000104_0003
Figure imgf000104_0004
Figure imgf000105_0001
CH, QH3 Cl CH3 QH3
H3C H3C Cl H3CCv A^ H3CO A1,
O O O O
Figure imgf000105_0002
28. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
Figure imgf000105_0003
Figure imgf000105_0004
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
29. A compound, or a pharmaceutically acceptable salt thereof, of formula III:
Figure imgf000118_0002
III wherein, independently for each occurrence,
Xi is absent, -0-, -S-, -NR- or ~2T: X2 is absent, -O-, -S-, -NR- or ZA ;
Ri is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R7 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
provided that when Xi is absent; R3 is
Figure imgf000119_0001
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
Figure imgf000119_0002
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
Figure imgf000120_0001
30. The compound of claim 29, wherein Xi is absent.
31. The compound of claim 29, wherein X2 is absent.
32. The compound of claim 29, wherein Xi is absent; and X2 is absent.
33. The compound of claim 29, wherein Ri is OH.
34. The compound of claim 29, wherein R2 is aralkyl or heteroaralkyl.
35. The compound of claim 29, wherein R2 is aralkyl.
36. The compound of claim 29, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
37. The compound of claim 29, wherein R3 is aryl or heteroaryl. 38. The compound of claim 29, wherein R3 is
Figure imgf000121_0001
Figure imgf000121_0002
39. The compound of claim 29, wherein R4 is alkyl, aryl or heteroaryl.
40. The compound of claim 29, wherein R4 is 1
Figure imgf000121_0003
^00 -^ , ,
Figure imgf000121_0004
41. The compound of claim 29, wherein R5 is hydrogen.
42. The compound of claim 29, wherein R7 is alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
43. A compound, or a pharmaceutically acceptable salt thereof, of formula IV:
Figure imgf000121_0005
IV wherein, independently for each occurrence, Xi is absent or -0-;
R3 is alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R4 is aryl, amino, (amino)alkyl, amido, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and
R7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl;
provided that when Xi is absent; R3 is not xr R3A or /- v~---/ ~"R3A; wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
provided that when X2 is absent; R4 is
Figure imgf000122_0001
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that X is ZA ; or X2 is ZΛ ; R3 is amino,
Figure imgf000122_0002
Figure imgf000122_0003
44. The compound of claim 43, wherein X] is absent.
45. The compound of claim 43, wherein R3 is amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
46. The compound of claim 43, wherein R3 is
Figure imgf000123_0001
Figure imgf000123_0002
47. The compound of claim 43, wherein R4 is aryl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl.
48. The compound of claim 43, wherein R4 is ^
Figure imgf000123_0003
00 ^, ,
Figure imgf000123_0004
49. The compound of claim 43, wherein R7 is alkyl, cycloalkyl or (cycloalkyl)alkyl. 50. The compound of claim 43, wherein Xj is absent; and R3 is amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
51. The compound of claim 43, wherein R3 is
Figure imgf000123_0005
,
Figure imgf000124_0001
52. The compound of claim 43, wherein R4 is
Figure imgf000124_0002
Figure imgf000124_0003
53. The compound of claim 43, wherein R7 is
Figure imgf000125_0001
54. T
Figure imgf000125_0002
he compound of claim 43, wherein R7
55. A compound, or pharmaceutically acceptable salt thereof, selected from the group
consisting of
Figure imgf000125_0003
Figure imgf000125_0004
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
56. A compound, or a pharmaceutically acceptable salt thereof, of formula V:
Figure imgf000128_0002
V wherein, independently for each occurrence,
Xi is absent, -0-, -S-, -NR- or /A ;
X2 is absent, -0-, -S-, -NR- or ZA ;
Ri is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
Figure imgf000129_0001
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
provided that when X2 is absent; R4
Figure imgf000129_0002
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that Xi is LΛ ; or X2 is Ll - ; or R3 is amino.
57. The compound of claim 56, wherein Xi is absent.
58. The compound of claim 56, wherein Xi is -O-.
59. The compound of claim 56, wherein X2 is absent.
60. The compound of claim 56, wherein X] is absent or -O-; and X2 is absent.
61. The compound of claim 56, wherein Ri is OH.
62. The compound of claim 56, wherein R2 is aralkyl or heteroaralkyl.
63. The compound of claim 56, wherein R2 is aralkyl.
64. The compound of claim 56, wherein R3 is heterocyclyl.
65. The compound of claim 56, wherein R4 is (heterocyclyl)alkyl.
66. The compound of claim 56, wherein R5 is alkyl.
67. The compound of claim 56, wherein Xi is absent or -O-; X2 is absent; Ri is OH; R2 is aralkyl; R3 is heterocyclyl; R4 is alkyl, aryl or heteroaryl; and R5 is alkyl.
8. A compound, or a pharmaceutically acceptable salt thereof, of formula VII:
Figure imgf000130_0001
VII wherein, independently for each occurrence,
Xi is absent, -O-, -S-, -NR- or IΛ ;
X2 is absent, -O-, -S-, -NR- or lΛ ;
Ri is -OH, -SH or -NHR;
R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
R2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R3 is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R5 is hydrogen, alkyl, (cycloalkyl)alkyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
provided that when Xi is absent; R3
Figure imgf000130_0002
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; provided that when X2 is absent; R4 is
Figure imgf000131_0001
not R4A
Figure imgf000131_0002
wherein
R3A is hydrogen, alkyl, alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and
provided that Xi is ZΛ ; or X2 is ^-A ; or R3 is amino.
69. The compound of claim 68, wherein Xi is absent.
70. The compound of claim 68, wherein X2 is absent.
71. The compound of claim 68, wherein Xi is absent; and X2 is absent.
72. The compound of claim 68, wherein Ri is -OH or -NH2.
73. The compound of claim 68, wherein R2 is aralkyl or heteroaralkyl.
74. The compound of claim 68, wherein R2 is aralkyl.
75. The compound of claim 68, wherein R3 is alkenyl, amino, (amino)alkyl, amido, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
76. The compound of claim 68,wherein R3 is (amido)alkyl or heterocyclyl.
77. The compound of claim 68, wherein R4 is (amido)alkyl or heterocyclyl.
78. The compound of claim 68, wherein R5 is alkyl or aryl.
79. A compound, or a pharmaceutically acceptable salt thereof, of formula XII:
Figure imgf000131_0003
XII wherein, independently for each occurrence,
Figure imgf000131_0004
Figure imgf000132_0001
Figure imgf000133_0001
wherein, independently for each occurrence, W is selected, from the group consisting of -NHR7 or -NHR(CH2)PN(R7)2; R7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and p is 1-10 inclusive; and
.CH3 CH3
R6 is ^-CH3 or ^CH3.
80. The compound of claim 79, wherein R3 is
Figure imgf000133_0002
Figure imgf000133_0003
81. The compound of claim 79, wherein R4 is
Figure imgf000133_0004
Figure imgf000133_0005
Figure imgf000134_0001
82. The compound of claim 79, wherein R6 : is„ N — - rCH3 .
CH3
83. The compound of claim 79, wherein R6 is CH3. 84. A compound, or pharmaceutically acceptable salt thereof, selected from the group
consisting of:
Figure imgf000134_0002
Figure imgf000134_0003
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
85. A compound, or a pharmaceutically acceptable salt thereof, of formula XII:
Figure imgf000149_0002
XII wherein, independently for each occurrence,
Figure imgf000149_0003
Figure imgf000150_0001
Figure imgf000150_0002
wherein, independently for each occurrence, W is selected, from the group consisting of -NHR7 or -NHR(CH2)PN(R7)2; R7 is selected from the group consisting of hydrogen, alkyl, aralkyl, heteroaralkyl and acyl; and p is 1-10 inclusive; and 86.
Figure imgf000151_0001
87. The compound of claim 85, wherein R3
Figure imgf000151_0002
Figure imgf000151_0003
The compound of claim 85, wherein R3 is
Figure imgf000151_0004
Figure imgf000151_0005
89. The compound of claim 85, wherein R4 is
Figure imgf000151_0007
1 /hOCH3
Figure imgf000151_0006
Figure imgf000151_0008
Figure imgf000152_0001
90. The compound of claim 85, wherein R6 is CH3.
91. A compound, or pharmaceutically acceptable salt thereof, selected from the group
consisting of:
Figure imgf000152_0002
Figure imgf000152_0003
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
92. A compound, or a pharmaceutically acceptable salt thereof, of formula iso-XII:
Figure imgf000158_0002
iso-XII wherein, independently for each occurrence,
R3 is alkyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
R4 is aryl, heteroaryl, aralkyl or heteroaralkyl; and
R6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl.
93. A pharmaceutical composition, comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of any one of claims 1-92.
94. A method for treating an HIV infection, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-92, or a therapeutically effective amount of a pharmaceutical composition of claim 93.
95. The method of claim 94, wherein the compound is administered as part of a highly active antiretroviral therapy (HAART) regimen.
96. The method of claim 94, wherein the pharmaceutical composition is administered as part of a highly active antiretroviral therapy (HAART) regimen.
97. The method of any one of claims 94-96, further comprising administering a second therapeutic agent.
98 The method of claim 97, wherein the second therapeutic agent is a non-nucleoside reverse transcriptase inhibitor (NNRTI), a nucleoside reverse transcriptase inhibitor (NRTI), a nucleotide reverse transcriptase inhibitor, an entry inhibitor, an integrase inhibitor, a fusion inhibitor, a protease inhibitor, or an inhibitor of a metabolic enzyme.
99. The method of claim 97, wherein the second therapeutic agent is selected from the group consisting of efavirenz (Sustiva™), nevirapine (Viramune™), delavirdine (Rescriptor™), AZT (zidovudine, Retrovir™)/3TC (lamivudine, Epivir™), d4T (stavudine, Zerit™)/3TC, ddl (didanosine, Videx™/VidexEC™), ddC (zalcitabine, Hivid™), d4T, tenofovir (Viread™), and enfuvirtide (Fuzeon™).
100. The method of claim 97, wherein the second therapeutic agent is selected from the group consisting of amprenavir (Agenerase®; APV), tipranavir (Aptivus®; TPV), indinavir (Crixivan®; IDV), saquinavir (Invirase®; SQV), lopinavir and ritonavir (Kaletra®; LPV), fosamprenavir (Lexiva®; FPV), ritonavir (Norvir®; RTV), atazanavir (Reyataz®; ATZ), nelfinavir (Viracept®; NFV), brecanavir, and darunavir.
101. The method of claim 97, wherein the second therapeutic agent is ritonavir (Kaletra®; LPV).
102. The method of claim 97, 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) .
103. The method of claim 97, 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®).
104. The method of claim 97, wherein the second therapeutic agent is T-20 (Fuzeon®; Enfuvirtide; DP-178; Pentafuside; GP41 127-162 AA).
105. The method of claim 97, wherein the second therapeutic agent is TMCCl 14.
106. The method of claim 97, further comprising administering a reverse transcriptase inhibitor.
107. The method of claim 97, wherein the second therapeutic agent is lupinavir.
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WO2008118849A3 (en) 2008-12-18
EP2139883A2 (en) 2010-01-06

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